Conditions: Triple-negative Breast Cancer
Keywords: advanced triple-negative breast cancer triple-negative breast cancer checkpoint inhibition LAG525 spartalizumab PDR001 carboplatin
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 88
Healthy volunteers: no

Brief summary:
The main purpose of this study was to assess the antitumor activity of three combinations: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in participants with advanced triple-negative breast cancer (TNBC) in first or second line therapy.

Detailed description:
This was an open-label, Phase II, randomized, multicenter study to assess the efficacy, safety, and pharmacokinetic characteristics of the following three combinations: LAG525 + spartalizumab (PDR001) (Arm 1), LAG525 + spartalizumab (PDR001) + carboplatin (Arm 2), and LAG525 + carboplatin (Arm 3) in participants with advanced triple-negative breast cancer (TNBC) which progressed after adjuvant or one prior line of systemic therapy for metastatic disease.

Participants were assigned to one of the three treatment arms in a ratio of 1:1:1. In protocol amendment 3 (released on 28-Mar-2019), enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed due to a higher discontinuation rate due to progressive disease and all subsequent enrolled patients were randomized to Arms 2 and 3 only, in a ratio of 1:1.

Study treatment continued until disease progression, unacceptable toxicity, pregnancy, investigator/participant decision, start of a new anti-neoplastic therapy, withdrawal of consent, lost to follow-up, death, or study was terminated by the sponsor. The investigator might decide to stop carboplatin after 6 cycles, even if the above criteria were not met. Participants who continued to derive clinical benefit from the treatment based on the investigator's evaluation following their completion of this trial might receive post-trial access (PTA) i.e. rollover protocol or a post-study drug supply (PSDS).

The end of study was defined as the earliest occurrence of one of the following: (1) all participants had died or (2) discontinued from the study, or (3) another clinical study became available that could continue to provide study treatment in this participant population and all ongoing participants were eligible to be transferred to that clinical study.

Arms:
arm 1: Participants received LAG525 and PDR001 administered as infusion once every 3 weeks arm 2: Participants received LAG525, PDR001 and carboplatin administered as infusion once every 3 weeks. arm 3: Participants received LAG525 and carboplatin administered as infusion once every 3 weeks

Interventions: intervention 1: LAG525 intervention 2: PDR001 intervention 3: Carboplatin
Intervention descriptions: intervention 1: LAG525 was a concentrate for solution for intravenous infusion, came in 100mg vials as a liquid formulation for infusion and was dosed at 400mg every 21 days. For all arms, LAG525 was infused first intervention 2: Spartalizumab was a concentrate for solution for intravenous infusion, came in 100mg vials as a liquid formulation for infusion and was dosed at 300mg every 21 days. Spartalizumab was infused after LAG525 intervention 3: Carboplatin was a concentrate for solution for intravenous infusion, came in 100mg/mL and was dosed per area under the curve (AUC) 6 every 21 days. Carboplatin was infused once LAG525 and spartalizumab infusions were completed

Protocol document:
Prot_000.pdf: 
Novartis Research and Development 
LAG525 
Clinical Trial Protocol CLAG525B2101 / NCT03499899
A phase II open-label, randomized, three-arm, multicenter 
study of LAG525 given in combination with spartalizumab 
(PDR001), or with spartalizumab and carboplatin, or with 
carboplatin, as first or second line therapy in patients with 
advanced triple-negative breast cancer 
Document type: 
Amended Protocol Version 
EUDRACT number: 
2017-004865-28 
Version number: 
04 (Clean) 
Clinical trial phase: 
II 
Release date: 
15-Feb-2021
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Clinical Trial Protocol Template Version 3.0 (31-Jan-2020) 


Novartis 
Confidential 
Page 2 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table of contents 
Table of contents ................................................................................................................. 2 
List of tables ........................................................................................................................ 6 
List of figures ...................................................................................................................... 7 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 12 
Amendment 4 (15-Feb-2021) ............................................................................................ 14 
Amendment 3 (28-Mar-2019) ........................................................................................... 17 
Amendment 2 (05-Oct-2018) ............................................................................................ 19 
Amendment 1 (18-Jun-2018) ............................................................................................ 21 
Protocol summary .............................................................................................................. 25 
1 
Introduction ....................................................................................................................... 28 
1.1 
Background ............................................................................................................ 28 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment ................................................................................................ 28 
1.1.2 
Immunotherapy ..................................................................................... 29 
1.1.3 
Introduction to investigational treatment(s) and other study 
treatment(s) ........................................................................................... 30 
1.2 
Purpose .................................................................................................................. 39 
2 
Objectives and endpoints ................................................................................................... 40 
3 
Study design ...................................................................................................................... 41 
4 
Rationale ............................................................................................................................ 42 
4.1 
Rationale for study design ..................................................................................... 42 
4.1.1 
Rationale for Arm 3 (LAG525 + carboplatin) ...................................... 44 
4.1.2 
Rationale for stratification by liver metastasis ...................................... 44 
4.1.3 
Rationale for stratification by line of therapy ....................................... 45 
4.2 
Rationale for dose/regimen and duration of treatment .......................................... 45 
4.3 
Rationale for choice of combination drugs ............................................................ 46 
4.4 
Purpose and timing of interim analyses/design adaptations .................................. 47 
4.5 
Risks and benefits .................................................................................................. 47 
4.5.1 
Potential benefits to clinical trial participants ....................................... 47 
4.5.2 
Potential risks to clinical trial participants ............................................ 48 
4.5.3 
Risks related to study procedures .......................................................... 49 
4.6 
Rationale for Public Health Emergency mitigation procedures ............................ 49 
5 
Study Population ............................................................................................................... 50 
5.1 
Inclusion criteria .................................................................................................... 51 
5.2 
Exclusion criteria ................................................................................................... 52 


Novartis 
Confidential 
Page 3 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
6 
Treatment ........................................................................................................................... 55 
6.1 
Study treatment ...................................................................................................... 55 
6.1.1 
Investigational and control drugs .......................................................... 55 
6.1.2 
Additional study treatments .................................................................. 56 
6.1.3 
Treatment arms/group ........................................................................... 56 
6.1.4 
Guidelines for continuation of treatment .............................................. 57 
6.1.5 
Treatment duration ................................................................................ 57 
6.2 
Other treatment(s) .................................................................................................. 58 
6.2.1 
Concomitant therapy ............................................................................. 58 
6.2.2 
Prohibited medication ........................................................................... 59 
6.2.3 
Treatments for potential infusion reactions with spartalizumab or 
LAG525................................................................................................. 60 
6.3 
Participant numbering, treatment assignment, randomization .............................. 60 
6.3.1 
Participant numbering ........................................................................... 60 
6.3.2 
Treatment assignment, randomization .................................................. 61 
6.4 
Treatment blinding ................................................................................................ 61 
6.5 
Dose escalation and dose modification.................................................................. 61 
6.5.1 
Dose modifications ................................................................................ 61 
6.5.2 
Follow-up for toxicities ......................................................................... 76 
6.6 
Additional treatment guidance ............................................................................... 77 
6.6.1 
Treatment compliance ........................................................................... 77 
6.6.2 
Emergency breaking of assigned treatment code .................................. 77 
6.7 
Preparation and dispensation ................................................................................. 77 
6.7.1 
Handling of study treatment and additional treatment .......................... 77 
6.7.2 
Instruction for prescribing and taking study treatment ......................... 78 
7 
Informed consent procedures ............................................................................................ 79 
8 
Visit schedule and assessments ......................................................................................... 81 
8.1 
Screening ............................................................................................................... 89 
8.1.1 
Eligibility screening .............................................................................. 89 
8.1.2 
Information to be collected on screening failures ................................. 90 
8.2 
Participant demographics/other baseline characteristics ....................................... 90 
8.3 
Efficacy .................................................................................................................. 91 
8.3.1 
Efficacy assessment (imaging) .............................................................. 91 
8.3.2 
Appropriateness of efficacy assessments .............................................. 94 
8.4 
Safety ..................................................................................................................... 95 
8.4.1 
Laboratory evaluations .......................................................................... 95 


Novartis 
Confidential 
Page 4 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
8.4.2 
Electrocardiogram (ECG) ..................................................................... 96 
8.4.3 
Pregnancy and assessments of fertility ................................................. 98 
8.4.4 
Other safety evaluations ........................................................................ 99 
8.5 
Additional assessments .......................................................................................... 99 
8.5.1 
Pharmacokinetics .................................................................................. 99 
 
 103 
 
 106 
9 
Study discontinuation and completion ............................................................................ 106 
9.1 
Discontinuation .................................................................................................... 106 
9.1.1 
Discontinuation of study treatment ..................................................... 106 
9.1.2 
Withdrawal of informed consent ......................................................... 107 
9.1.3 
Lost to follow-up ................................................................................. 108 
9.1.4 
Early study termination by the sponsor ............................................... 108 
9.2 
Study completion and post-study treatment ........................................................ 108 
9.2.1 
Follow up for safety evaluations ......................................................... 109 
9.2.2 
Follow up for efficacy evaluations ...................................................... 109 
9.2.3 
Survival follow up ............................................................................... 110 
10 Safety monitoring and reporting ...................................................................................... 110 
10.1 
Definition of adverse events and reporting requirements .................................... 110 
10.1.1 
Adverse events .................................................................................... 110 
10.1.2 
Serious adverse events ........................................................................ 113 
10.1.3 
SAE reporting...................................................................................... 114 
10.1.4 
Pregnancy reporting ............................................................................ 114 
10.1.5 
Reporting of study treatment errors including misuse/abuse .............. 115 
10.2 
Additional Safety Monitoring .............................................................................. 116 
10.2.1 
Steering Committee ............................................................................. 116 
11 Data Collection and Database management .................................................................... 116 
11.1 
Data collection ..................................................................................................... 116 
11.2 
Database management and quality control .......................................................... 116 
11.3 
Site monitoring .................................................................................................... 117 
12 Data analysis and statistical methods .............................................................................. 118 
12.1 
Analysis sets ........................................................................................................ 118 
12.2 
Participant demographics and other baseline characteristics ............................... 119 
12.3 
Treatments ........................................................................................................... 119 
12.4 
Analysis of the primary endpoint(s) .................................................................... 120 
12.4.1 
Definition of primary endpoint(s) ....................................................... 120 


Novartis 
Confidential 
Page 5 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
12.4.2 
Statistical model, hypothesis, and method of analysis ........................ 120 
12.4.3 
Handling of missing values/censoring/discontinuations ..................... 121 
12.4.4 
Sensitivity and Supportive analyses .................................................... 121 
12.5 
Analysis of secondary endpoints ......................................................................... 121 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) .................................. 122 
12.5.2 
Safety endpoints .................................................................................. 123 
12.5.3 
Pharmacokinetics ................................................................................ 125 
12.5.4 
Immunogenicity .................................................................................. 126 
 
 126 
 
 127 
 
 127 
 
 128 
12.7 
Interim analyses ................................................................................................... 129 
12.8 
Sample size calculation........................................................................................ 129 
12.8.1 
Primary endpoint(s) ............................................................................. 129 
13 Ethical considerations and administrative procedures .................................................... 130 
13.1 
Regulatory and ethical compliance ...................................................................... 130 
13.2 
Responsibilities of the investigator and IRB/IEC ................................................ 130 
13.3 
Publication of study protocol and results............................................................. 130 
13.4 
Quality Control and Quality Assurance ............................................................... 131 
14 Protocol adherence .......................................................................................................... 131 
14.1 
Protocol amendments........................................................................................... 131 
15 References ....................................................................................................................... 132 
16 Appendices ...................................................................................................................... 139 
16.1 
Appendix 1: Safety follow-up diagram ............................................................... 139 
16.2 
Appendix 2: Statistical considerations ................................................................ 140 
16.3 
Appendix 3: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival, and Overall Survival (based on RECIST 1.1) 142 
16.3.1 
Introduction ......................................................................................... 144 
16.3.2 
Efficacy assessments ........................................................................... 144 
16.3.3 
Efficacy definitions ............................................................................. 153 
16.3.4 
Data handling and programming rules ................................................ 163 
16.3.5 
References (available upon request) ................................................... 167 
 
 168 
 
 170 
 
 170 


Novartis 
Confidential 
Page 6 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
 
 177 
 
 181 
 
 181 
 
List of tables 
Table 2-1 
Objectives and related endpoints .......................................................... 40 
Table 6-1 
Investigational and combination drug ................................................... 55 
Table 6-2 
Dosing regimen ..................................................................................... 56 
Table 6-3 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related 
diarrhea/colitis ....................................................................................... 64 
Table 6-4 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related liver 
laboratory alterations ............................................................................. 66 
Table 6-5 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related skin events ...... 67 
Table 6-6 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related nephritis* ........ 68 
Table 6-7 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related pneumonitis .... 69 
Table 6-8 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related endocrine 
events..................................................................................................... 70 
Table 6-9 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for infusion-related reactions ......................... 72 
Table 6-10 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for “other” potential immune-related AEs 
of special interest ................................................................................... 74 
Table 8-1 
Assessment Schedule ............................................................................ 82 
Table 8-2 
Imaging Assessment Collection Plan .................................................... 92 
Table 8-3 
Assessments & Specifications............................................................... 95 
Table 8-4 
ECOG Performance Status .................................................................... 95 
Table 8-5 
Laboratory Assessments (Central and Local) ....................................... 96 
Table 8-6 
Local and Central ECG collection plan ................................................ 97 
Table 8-7 
Schedule of blood collection log for LAG525 and spartalizumab 
pharmacokinetics (PK) and immunogenicity (IG) .............................. 100 
Table 8-8 
Schedule for blood collection for carboplatin pharmacokinetic (PK) 
blood collection log ............................................................................. 101 
 
 103 


Novartis 
Confidential 
Page 7 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse ....................................................................................... 115 
Table 12-1 
Non-compartmental pharmacokinetic parameters for 
spartalizumab, LAG525 and carboplatin ............................................ 126 
Table 12-2 
Operating characteristics with 32 participants in each arm ................ 130 
Table 16-1 
Operating characteristics with 32, 36 or 40 participants in each arm . 141 
Table 16-2 
Response criteria for target lesions ..................................................... 149 
Table 16-3 
Response criteria for non-target lesions .............................................. 151 
Table 16-4 
Overall lesion response at each assessment ........................................ 152 
Table 16-5 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 160 
Table 16-6 
Options for event dates used in PFS, TTP, duration of response ........ 161 
 
 172 
 
 173 
Table 16-9 
Overall lesion response for a time-point based on consideration of 
target lesions, non-target lesions and new lesions .............................. 175 
 
List of figures 
Figure 3-1 
Study Design ......................................................................................... 42 
Figure 16-1 
Safety follow-up diagram .................................................................... 139 
 


Novartis 
Confidential 
Page 8 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
List of abbreviations 
γ-GT 
Gamma-glutamyl transferase 
ABC/BC/LABC/MBC Advanced Breast Cancer/Breast Cancer/Locally Advanced Breast 
Cancer/Metastatic Breast Cancer 
ACTH 
Adrenocorticotropic hormone 
ADA 
anti-drug antibody 
ADC 
Antibody-Drug conjugates 
AE 
adverse event 
AESI 
adverse event of special interest 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
AUC 
Area Under the Curve 
AUClast 
Area under the plasma concentration-time curve from time zero to time of 
last measurable concentration 
AUCtau 
Area under plasma concentration-time curve over dosing interval 
BAL 
Bronchoalveaolar lavage 
BOR 
Best Overall Response 
CBR 
Clinical Benefit Rate 
CHO 
Chinese Hamster Ovary 
Cmax 
Maximum Concentration 
CMV 
Cytomegalovirus 
CNS 
Central Nervous System 
CR/iCR 
Complete Response/Immune-related complete response 
CRF/eCRF 
Case Report/Record Form (paper or electronic) 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DCR  
Disease Control Rate 
DDI 
Drug-Drug Interaction 
DDS 
Dose Determining analysis Set 
DILI 
Drug Induced Liver Injury 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic acid 
DOR/iDOR 
Duration of Response/ Immune related Duration of Response 
DRESS 
Drug Reaction with Eosinophilia and Systemic Symptoms 
EBV 
Epstein-Barr Virus 
EC 
Ethics committee 
ECG 
Electrocardiogram 
ECHO 
Echocardiography 
ECOG 
Eastern Cooperative Oncology Group 


Novartis 
Confidential 
Page 9 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
EDC 
Electronic Data Capture 
EEA 
European Economic Area 
EMA 
European Medicines Agency 
EOI 
End of Infusion 
EOT 
End of Treatment 
EPR 
Early progression rate  
ER 
Estrogen Receptor 
eSAE 
Electronic Serious Adverse Event 
EU 
European Union 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FPFV 
First Patient First Visit 
FSH 
Follicle Stimulating Hormone 
GABA 
Gamma-aminobutyric acid 
GCP 
Good Clinical Practice 
GDPR 
General Data Protection Requirements 
GGT 
Gamma-Glutamyl-Transferase 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice 
hr/hrs 
Hour(s) 
HA 
Health Authority 
HBcAb 
Hepatitis B core Antibody 
HBsAb 
Hepatitis B surface Antibody 
HBsAg 
Hepatitis B surface Antigen 
HBV 
Hepatitis B Virus 
hCG 
Human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HIV 
human immunodeficiency virus 
HNSTD 
Highest Non-Severely Toxic Dose 
HSV 
Herpes Simplex Virus 
i.v. 
Intravenous 
IB 
Investigator’s Brochure 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Council for Harmonization of Technical Requirements for 
Pharmaceuticals for Human Use 
 
 
IEC 
Independent Ethics Committee 
IFN 
Interferon 
Ig 
Immunoglobulin 
IG 
Immunogenicity 
IL-2 
Interleukin 2 


Novartis 
Confidential 
Page 10 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
irAE 
Immune Related Adverse Event 
IRB 
Institutional Review Board 
 
 
IRT 
Interactive Response Technology 
ITT 
Intent To Treat principle 
IUD 
Intra-uterine device 
iUPD 
Immune related-Unconfirmed Progressive Disease 
LAG-3 
Lymphocyte-Activation Gene 3 
LFT 
Liver function test 
LH 
Luteinizing hormone 
LLQ 
lower limit of quantification 
LPLV 
Last Patient Last Visit 
mAb 
Monoclonal Antibody 
MedDRA 
Medical dictionary for regulatory activities 
MHC 
Major Histocompatibility Complex 
MRCP 
Magnetic resonance cholangiopancreatography 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
NCI 
National Cancer Institute 
NSCLC 
Non-Small Cell Lung Cancer 
ORR/iORR 
Overall Response Rate/immune related overall response rate 
OS 
Overall Survival 
PA 
Posteroanterior 
PARP 
Poly(ADP-ribose) polymerase 
PAS 
Pharmacokinetic Analysis Set 
PBMC 
Peripheral Blood Mononuclear Cells 
PD 
pharmacodynamic(s) 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death-Ligand 1 
PD-L2 
Programmed Death-Ligand 2 
PFS/iPFS 
Progression Free Survival/immune related progression free survival 
Pgp 
P-glycoprotein  
PK 
pharmacokinetic(s) 
PR 
Progesterone Receptor 
PR/iPR 
Partial Response/immune related partial response 
PSDS 
Post Study Drug Supply 
PTA 
Post-Trial Access 
Q2W/Q3W/Q4W 
Every 2/3/4 weeks 
R Value 
ALT/ALP x ULN 
RBC 
red blood cell(s) 
RCC 
Renal Cell Carcinoma 


Novartis 
Confidential 
Page 11 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
RDC 
Remote Data Capture 
RDE 
Recommended Doses for Expansion 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RoW 
Rest of the World 
RP2D 
Recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan  
SEB 
Staphylococcal Enterotoxin B  
SOD 
Sum of Diameter 
SUSAR 
Suspected Unexpected Serious Adverse Reaction 
TBL 
total bilirubin 
TIL 
Tumor-Infiltrating Lymphocytes 
TNBC 
Triple Negative Breast Cancer 
TnI/cTnI 
Troponin I / cardiac Troponin I 
TnT/cTnT 
Troponin T / cardiac Troponin T 
TSH 
Thyroid Stimulation Hormone 
TTF 
Time to Treatment Failure 
TTP 
Time to progression 
TTR/iTTR 
Time To Response/immune related time to response 
ULN 
Upper limit of normal 
UNK 
Unknown 
US 
United States 
USPI 
United States Prescribing Information 
WHO 
World Health Organization 
WoC 
Withdrawal of Consent 


Novartis 
Confidential 
Page 12 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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 participant  
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g., q28 days) 
Dosage 
Dose of the study treatment given to the participant in a time unit (e.g. 100 
mg once a day, 75 mg twice a day) 
Electronic Data 
Capture (EDC) 
Electronic data capture (EDC) is the electronic acquisition of clinical study 
data using data collection systems, such as Web-based applications, 
interactive voice response systems and clinical laboratory interfaces. EDC 
includes the use of Electronic Case Report Forms (eCRFs) which are used 
to capture data transcribed from paper source forms used at the point of 
care 
End of the clinical 
trial 
The end of the clinical trial is defined as the last visit of the last participant or 
at a later point in time as defined by the protocol.  
Enrollment 
Point/time of participant entry into the study at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the 
protocol) 
eSource (DDE) 
eSource Direct Data Entry (DDE) refers to the capture of clinical study data 
electronically, at the point of care. eSource Platform/Applications combines 
source documents and case report forms (eCRFs) into one application, 
allowing for the real time collection of clinical trial information to sponsors 
and other oversight authorities, as appropriate 
Investigational 
drug/treatment 
The drug whose properties are being tested in the study 
Medication number 
A unique identifier on the label of medication kits 
Medication pack 
number 
A unique identifier on the label of each drug package in studies that 
dispense study treatment using an IRT system 
Non-investigational 
medicinal Product 
(NIMP) 
Products which are not the object of investigation (e.g. any background 
therapy administered to each of the clinical trial participants, regardless of 
randomization group, rescue medication, active drug run-ins etc.) 
Part 
A sub-division of a study used to evaluate specific objectives or contain 
different populations. For example, one study could contain a single dose 
part and a multiple dose part, or a part in participants with established 
disease and in those with newly-diagnosed disease 
Participant 
A trial participant (can be a healthy volunteer or a patient) 
Participant number 
A unique number assigned to each participant upon signing the informed 
consent. This number is the definitive, unique identifier for the participant and 
should be used to identify the participant throughout the study for all data 
collected, sample labels, etc. 
Period 
The subdivisions of the trial design (e.g. Screening, Treatment, Follow-up) 
which are described in the Protocol. Periods define the study phases and will 
be used in clinical trial database setup and eventually in analysis 
Personal Data 
Participant information collected by the Investigator that is coded and 
transferred to Novartis for the purpose of the clinical trial. This data includes 
participant identifier information, study information and biological samples 


Novartis 
Confidential 
Page 13 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Premature 
participant 
withdrawal 
Point/time when the participant exits from the study prior to the planned 
completion of all study drug administration and assessments; at this time all 
study drug administration is discontinued and no further assessments are 
planned 
Randomization 
number 
A unique identifier assigned to each randomized participant.  
Screen Failure 
A participant who did not meet one or more criteria that were required for 
participation in the study  
Source 
Data/Document 
Source data refers to the initial record, document, or primary location from 
where data comes. The data source can be a database, a dataset, a 
spreadsheet or even hard-coded data, such as paper or eSource 
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 
Stage 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Study completion 
Point/time at which the participant came in for a final evaluation visit or when 
study drug was discontinued whichever is later. 
Study treatment 
Any drug or combination of drugs administered to the study participants as 
part of the required study procedures; includes investigational drug (s), 
control(s) or background therapy(ies) 
Study treatment 
discontinuation 
When the participant permanently stops taking study treatment prior to the 
defined study treatment completion date 
Treatment 
arm/group  
A treatment arm/group defines the dose and regimen or the combination, 
and may consist of 1 or more cohorts 
Variable (or 
endpoint) 
The variable (or endpoint) to be obtained for each participant that is required 
to address the clinical question. The specification of the variable might include 
whether the participant experiences an intercurrent event. 
Withdrawal of study 
Consent (WoC) 
Withdrawal of consent from the study occurs only when a participant does 
not want to participate in the study any longer, and does not allow any 
further collection of personal data 
 
 
 


Novartis 
Confidential 
Page 14 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Amendment 4 (15-Feb-2021) 
At the time of amendment 4, 20 participants have been randomized to treatment Arm 1, 34 
participants have been randomized to treatment Arm 2, and 34 participants have been 
randomized to treatment Arm 3. Of the 88 randomized participants, 85 participants have 
discontinued the study treatment. Three participants are still receiving treatment in Arm 2 
(LAG525 + spartalizumab + carboplatin), 3 participants are in safety follow-up (of which one 
is still in efficacy follow-up) and 12 are in survival follow-up.  
Amendment rationale  
The primary efficacy analysis was performed with a data cut-off date of 27-Feb-2020. None of 
the three treatment arms met the proof of preliminary efficacy (PPE) criteria of a mean of the 
posterior distribution of ORR ≥ 35% and a posterior probability of (ORR ≥ 25%) > 90%. No 
new safety signals were identified for any of the treatment arms.  
Based on these results and together with an increasingly crowded treatment landscape in 
metastatic TNBC, Novartis decided to not further develop LAG525 in TNBC. This decision is 
not due to safety concerns.  
The main purpose of this amendment is to: 1) define the duration of the follow-up period and 
2) clarify the trial discontinuation rules for participants who are still ongoing in the trial as to 
whether they are eligible for a Post Trial Access (PTA) program i.e. rollover protocol or a post 
study drug supply (PSDS).  
The following modifications were incorporated: 
• The survival follow-up period will be removed and participants who are currently in 
survival follow-up can discontinue from the study with approval of amendment 4.  
• The post treatment follow-up period will be limited to the safety follow-up period of 
150 days after the last dose of LAG525 and/or spartalizumab (whichever was stopped 
last). If carboplatin was stopped more than 150 days after LAG525 and/or 
spartalizumab, the participant can be discontinued 30 days after the last dose of 
carboplatin.  
• The end of study definition was revised to clarify that participants who have 
discontinued their study treatment for at least 150 days will be discontinued from the 
study.  
• Tumor and blood samples at the time of disease progression were removed. 
• The clinical information for LAG525 and spartalizumab (PDR001) were updated 
based on the spartalizumab IB v 9.0 released on 11-May-2020 and LAG525 IB v 6.0 
released on 18-Feb-2020. 
• Language was updated to align with the latest protocol template (OneCTP version 3.0) 
and provide mitigation action plan in case of public health emergencies such as Covid-
19 pandemic.  
The benefit/risk assessment indentified no additional risks related to the COVID-19 pandemic; 
hence, no changes were made.  


Novartis 
Confidential 
Page 15 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through font for deletions and underline for insertions. The following 
sections have been changed in the amended protocol: 
• List of abbreviations, glossary of terms, protocol summary and the whole protocol 
were revised to comply with the latest protocol template (OneCTP version 3.0). 
• Protocol summary: efficacy assessment section was updated to specify that tumor 
assessments during the post-treatment efficacy follow-up period are now optional. 
• Section 1.1.3.1.2: updated based on the IB LAG525 edition 6.0 released on the 
18-Feb-2020.  
• Section 1.1.3.2.2: updated based on the IB PDR001 edition 9.0 released on the 
11-May-2020.  
• Section 1.1.3.3.2: updated based on the IB LAG525 edition 6.0 released on the 
18-Feb-2020 and on the IB PDR001 edition 9.0 released on the 11-May-2020. 
• Figure 3.1: revised to clarify that participants still receiving study treatment will be 
moved into a Post-Trial Access program (PTA), that participants who have stopped 
study treatment for more than 150 days will be discontinued from the study, and that 
efficacy assessments in the post-treatment efficacy follow-up period are now optional. 
• Section 4.6: new section added to describe disruption procedures in case of a Public 
Health emergency. 
• Section 6.1.5: paragraphs added to include PTA information and procedures. 
• Section 7: was updated as per the latest protocol template to provide a list of all ICFs 
used in the study and to include the possibility to conduct an informed consent 
discussion and signature remotely in case of public emergencies (if allowed by local 
health authorities). 
• Table 8-1: was updated to indicate that efficacy assessments are optional during the 
post treatment follow-up period, to clarify that EOT visit is the last visit for 
participants who will transition into the PTA, to define the length of follow-up to 150 
days after last study treatment dose, 
 
 and to clarify that survival follow-up period is removed. 
• Section 8.3.1 and Table 8.2: were updated to clarify that during the efficacy follow-up 
post-treatment tumor assessments are now optional. 
 
 
• Section 9.1.1: was amended to add a new rule for study discontinuation; participants 
will be discontinued if it has been at least 150 days since their last dose of study 
treatment and to specify that efficacy assessments during the follow-up period are 
optional. 
• Section 9.1.2: was updated to add the latest protocol template language on withdrawal 
of consent.  
• Section 9.1.3: was updated to clarify that due diligence should be performed until the 
end of the study before confirmation that a participant is lost to follow-up. 


Novartis 
Confidential 
Page 16 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Section 9.2: was revised to clarify the definition of end of study.  
• Section 9.2.2: was revised to notify that efficacy assessment in the post-treatment 
efficacy follow-up will be optional and participants in efficacy follow-up for at least 
150 days after the last study treatment dose will be discontinued from the study. 
• Section 9.2.3: was amended to indicate that the survival follow-up period will be 
removed upon approval of protocol amendment 4. 
• Section 10.1.4: was updated to add the latest language on pregnancy reporting. 
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 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. 


Novartis 
Confidential 
Page 17 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Amendment 3 (28-Mar-2019) 
As of release of amendment 3, 19 subjects have been randomized to treatment Arm 1, 
21subjects have been randomized to treatment Arm 2, and 21 subjects have been randomized 
to treatment Arm 3 and 2 patients were in screening. 
Amendment rationale 
The main purpose of this amendment is to stop enrollment to treatment Arm 1 (LAG525 + 
spartalizumab combination). Novartis and the study steering committee decided to prematurely 
stop enrollment of subjects to Arm 1 after data review showed an increased treatment 
discontinuation rate due to progressive disease in Arm 1 as compared to Arms 2 and 3 (both 
containing Carboplatin).  
Additionally, the following modifications were incorporated: 
• The total number of subjects to be enrolled was changed from approximately 96 to 
approximately 84 as enrollment to arm 1 was closed prematurely. 
• To clarify in inclusion criterion 9 that the most recently analyzed biopsy should be from 
locally recurrent or metastatic site. 
• To clarify language in exclusion criterion 1 to specify that no prior “immune checkpoint 
inhibitors” are allowed as anticancer treatment, such as anti-LAG-3, anti-PD-1, anti-PD-
L1, or anti-PD-L2 antibody (any line of therapy). The prior expression “immunotherapy” 
was less precise. 
• To correct exclusion criterion 19 by removing pneumococcal vaccine from the list of live 
vaccines as it was incorrectly added. 
• In Section 6.2.2 it was specified that the restriction of less than 10 mg/day prednisone or 
equivalent is only related to the replacement-dose steroids in the setting of adrenal 
insufficiency. 
• To clarify in Table 8-1 that a Central Laboratory Pregnancy test 72 hours prior to 
screening is only required for premenopausal woman. 
• To add in Section 8.3.1 “Efficacy assessment (imaging)” that tumor assessment per 
RECIST 1.1 should also continue after start of subsequent anti-cancer therapy
 
, in order to obtain additional information for supportive analyses. 
• To modify postmenopausal definition in Section 8.4.3 to align with exclusion criterion 23. 
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. The 
following sections have been changed in the amended protocol: 
• In applicable sections, a statement was added that enrollment to treatment arm 1 was 
closed prematurely and figure 3-1 was also updated accordingly. The total number of 
subjects was also revised accordingly (from ~96 to ~84). 
• In exclusion criterion 1 “immunotherapy” was replaced by “immune checkpoint 
inhibitors”. 


Novartis 
Confidential 
Page 18 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Clarification was made to inclusion criterion 9 and Section 8-2 that the most recently 
analyzed biopsy should be from locally recurrent or metastatic site. 
• Exclusion criterion 19 was corrected by removing pneumococcal vaccine from the list of 
live vaccines. 
• Table 6-3 in Section 6.5.1.2.1 was corrected by separating the drug management for 
diarrhea/colitis Grade 1 versus Grade 2. 
• Section 6.1.3 and Section 6.3.2 were amended that subjects will be randomized to 
treatment arms 2 and 3 in a ratio 1:1. 
• Section 6.2.2 was revised to specify that the restriction of less than 10 mg/day prednisone 
or equivalent is only related to the replacement-dose steroids in the setting of adrenal 
insufficiency. 
• To clarify in Table 8-1 that the screening Central Laboratory Pregnancy test is only 
required for premenopausal woman. 
• Section 8.3.1, Figure 3-1, Table 8-1, Section 9.1.1 and Section 9.2.2 were updated to 
highlight that tumor assessment per RECIST 1.1 should also continue after start of 
subsequent antineoplastic therapy
. 
• Postmenopausal definition in Section 8.4.3 was modified to be in alignment with 
exclusion criterion 23 
• Tables 8-7 and 8-8 were revised with the correct dose reference identifications and sample 
numbers when applicable. 
IRB Section 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  
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. 


Novartis 
Confidential 
Page 19 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Amendment 2 (05-Oct-2018) 
As of the release of this amendment, 4 subjects have received study treatment in the trial. 
Amendment rationale 
The purpose of this amendment is to implement Health Authority feedback as well as updates 
to the Novartis standard protocol language for PDR001-related protocols. An increased risk of 
potentially fatal autoimmune myocarditis was observed in non-Novartis clinical trials with the 
combination of anti-LAG-3 and PD-1 inhibitors. Therefore, measures to optimize detection of 
possible autoimmune myocarditis have been included. 
• To add two exclusion criteria to exclude patients with medical history or current diagnosis 
of myocarditis (exclusion criterion 10.ii) or with elevated cardiac Troponin T (cTnT) or 
Troponin I (cTnI) above 2 x ULN at screening (exclusion criterion 10.iii).  
• To add Section 8.4.2.2 on cardiac Troponin monitoring during the first 2 months of the 
study to monitor the risk of potentially fatal autoimmune myocarditis. 
• To clarify the diagnosis and management of immune-mediated myocarditis in Table 6-10 
as part of the risk minimization approach. 
• To clarify in exclusion criterion 18 that additionally to obtaining known HIV history at 
screening, HIV testing may be mandated per local requirements/regulations (e.g. Health 
Authority (HA), EC/IRB). 
• To remove standard chest X-ray (posteroanterior view) to screen for pneumonitis, as chest 
CT is already required during screening and is more sensitive to diagnose pneumonitis. 
• To clarify in Section 6.2.2 that the use of live vaccines is not allowed through the whole 
duration of the study and that there are no prohibited therapies during the post-treatment 
follow-up period. 
• To add Section 6.2.3 related to treatments for potential infusion reactions in order to 
provide guidelines for management of such events. 
• To add flexibility for subjects to be re-screened once for criteria other than laboratory 
abnormalities and to clarify the rules for re-testing and re-screening. 
• To clarify that “Progression of malignancy” should be reported as an AE/SAE in this 
study if the investigator suspects that the study treatment accelerates disease progression.    
• To implement version 5.0 of the NCI-CTCAE grading system throughout the protocol. 
• To use consistently the word “advanced” to describe the study indication as it includes 
both loco-regional recurrent and metastatic TNBC.     
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. The 
following sections have been changed in the amended protocol: 
• List of abbreviations was updated 
• Section 5-2 was updated to revise exclusion criteria 10 and 18 as described in the 
amendment rationale 


Novartis 
Confidential 
Page 20 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Sections 6.2.2 and 6.5.1.2.3 were revised to avoid redundancies 
• Section 6.2.3 was added to provide guidelines for management of potential infusion 
reactions 
• Section 6.5.1.2: Tables 6-3 to 6-10 were updated according to the new version of the 
CTCAE grading system v5.0. Table 6-10 was also revised to clarify the dose interruption 
and re-initiation of LAG525 and spartalizumab in case of myocarditis  
• Section 8: Table 8-1 was modified to replace MUGA scans with cardiac MRI scans 
throughout the study and remove chest X-ray at screening. HIV testing at screening if 
required by local requirements/regulations was added and table was modified to indicate 
at which visits cardiac Troponin is to be measured for the subjects 
• Section 8.1 was updated to add flexibility for subjects to be re-screened once for criteria 
other than laboratory abnormalities and to clarify the rules for re-testing and re-screening. 
• Section 8.4.1: Table 8-5 was updated to add testing of cTnT/TnI and possibility to perform 
local HIV testing when required per local regulations 
• Section 8.4.2.1 was revised to replace MUGA scans with cardiac MRI scans  
• Section 8.4.2.2 was added to described the troponin monitoring guideline 
• Section 8.4.4 was revised to remove chest X-ray at screening  
• Section 8.5.1: Table 8-7 and Table 8-8 were revised to be consistent with the footnotes 
and the dose ID numbers were modified in Table 8-7 
• Section 9.1.4 was updated to clarify reasons for early termination to be consistent with the 
latest version of the Novartis Standard Language for Protocols 
• Section 10.1.1 was updated to clarify that disease progression should be reported as an 
SAE if the investigator considers that progression of malignancy is accelerated by study 
treatment  
• Section 15 was updated to include the references related to immune-mediated myocarditis 
and its management with glucocorticoids 
• All the protocol including sections 1.1.3.2, 4.5.2, 6.1, 6.2 and 6.5 including Tables 6-3 to 
6-10 was modified to be consistent with the latest version of the Novartis PDR001 
compound Standard Language for Protocols  
• In addition, revisions to the protocol were made to be consistent with the latest version of 
the Novartis Standard Language for Protocols and to correct typos including in section 
releated to protocol amendment 1 changes.  
IRB Section 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  
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. 


Novartis 
Confidential 
Page 21 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Amendment 1 (18-Jun-2018) 
Amendment rationale 
At the time of this amendment, no subjects have received study treatment in the trial and the 
original protocol has not been initiated at any study center globally. 
The purpose of this amendment is to incorporate the following modifications: 
 
 
 
 
 
 
 
• To align withdrawal of consent (WoC) language with the European Economic Area (EEA) 
General Data Protection Regulation (GDPR). 
• To specify in exclusion criterion 1 that any type of prior anticancer immunotherapy is not 
allowed. Change in wording for this exclusion criteria improves clarity. 
• To revise inclusion criterion 9 clarifying that the biopsy is needed from the advanced 
setting. 
• To clarify in exclusion criterion 2 that patients who received platinum or mitomycin in the 
advanced setting are not eligible. 
• To specify inclusion criterion 4: Adequate bone marrow and organ function will be 
assessed by central laboratory to standardize eligibility across all sites. 
• To clarify in an additional exclusion criterion that pregnant or nursing (lactating) women 
are excluded from the study. 
• To clarify that blood samples for PK analysis can be taken from any vein except from the 
site (e.g. port) or same arm that is used for drug infusion. The PK samples must not be 
taken from the same arm or site used for drug infusion because this would confound the 
PK data. 
• To specify that assessment of pregnancy status for study eligibility must be ascertained by 
central laboratory because pregnant woman are excluded from this study. 
 
 
• To clarify the time window for collection of end of infusion (EOI) samples for carboplatin 
(Table 8-8) from “2 min prior to EOI” to “EOI (±5 minutes)”. This change makes 
sampling more practical for the sites, still ensuring collection of valid samples for 
analysis. 
• To clarify that central pre-dose ECG at C1D1 and C3D1 can be used for local 
interpretation 
The following amendments were requested by Health Authorities: 


Novartis 
Confidential 
Page 22 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• To describe that subjects who have radiographically progressed per RECIST 1.1 but are 
judged to derive clinical benefit from continued study treatment will be re-consented in a 
separate ICF before they continue receiving the investigational drugs. This will ensure 
subjects and investigators carefully consider the benefits of continued study treatment over 
seeking alternative treatment, potentially forgoing approved therapies if available, or 
choosing no further treatment. 
• To extend the period until when efficacy assessments are performed every 6 weeks from 6 
months to 9 months to increase the chance of capturing progression early. 
• To revise exclusion criterion 15 and include patients with stable CNS metastasis into the 
study. 
• To specify an early safety review after the first 8 subjects are enrolled on each the 
carboplatin, spartalizumab and LAG525 and the carboplatin and LAG525 arm and have 
completed their first 3-week treatment cycle to ensure there is no safety issue with the 
combination of these agents. 
• To provide guidance on dose management of carboplatin in case of nephrotoxicity. 
LAG525 and spartalizumab carry the risk for immune mediated nephritis, a rare immune-
related adverse event associated with immune checkpoint blockade. Carboplatin is also 
associated with nephrotoxicity. In patients with impaired renal function, dosage of 
carboplatin should be reduced as per local labeling for carboplatin and hematologic nadirs 
and renal function monitored. 
• To include body temperature for vital sign monitoring. 
• Specify in exclusion criterion 5, that patients with CTCAE grade 2 toxicity or higher due 
to prior cancer therapy will be excluded (except alopecia). 
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. The 
following sections have been changed in the amended protocol: 
• List of abbreviations was updated 
• Glossary of terms: personal data was added and withdrawal of consent was modified 
• Protocol summary: key inclusion and exclusion criteria were updated to reflect changes 
made in the protocol amendment 
• Section 3, figure 3-1, Section 8.3.1, Table 8-1, Table 8-2 and Section 9.1.1: the period 
until when efficacy assessments are performed every 6 weeks was extended from 6 
months to 9 months 
• Section 5.1:  
• inclusion criterion 4 was modified to clarify that it is assessed by central laboratory 
• inclusion criterion 9 was revised to clarify that the biopsy is needed from the 
advanced setting 
• Section 5.2:  
• exclusion criterion 1 was modified to specify that any type of prior anticancer 
immunotherapy is not allowed 


Novartis 
Confidential 
Page 23 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• exclusion criterion 2 was edited to clarify the exclusion surrounding the previous use 
of platinum and mitomycin 
• exclusion criterion 5 was updated to exclude patients with CTCAE grade 2 toxicity or 
higher due to prior cancer therapy (except alopecia) 
• exclusion criteria 10 was edited to use the word “randomization” consistently in the 
exclusion criteria 
• exclusion criterion 15 was modified to include patients with stable CNS metastasis 
• exclusion criterion 25 was added to exclude pregnant or nursing (lactating) women 
from entering the study 
• Section 6.1.5.1, Section 7 and Table 8-1 were modified to add re-consenting language as a 
condition for subject to receive treatment beyond progression 
• Section 6.5.1.2, Table 6-6: guidance on dose management of carboplatin in case of 
nephrotoxicity was added 
• Section 8.1, Section 8.2, Table 8-1 and Table 8-5 were updated to indicated that serum 
pregnancy test is to be performed by central laboratory 
• Section 8.2 and Table 8-3: body temperature was added in vital signs assessment 
• Section 8.3.1, clarification was provided on imaging assessments for subjects who 
continue study treatment beyond initial disease progression as per RECIST 1.1 
• Table 8-6, Section 8.4.2 and Section 12.5.2. clarified that central pre-dose ECG C1D1 and 
C3D1 can be used for local interpretation  
• Section 8.5.1.1.1, Table 8-7 and Table 8-8 clarification on site to use for withdrawal of 
blood PK/IG sampling was provided 
• Table 8-8: window of +/- 5 minutes was added to PK blood sampling at the end of the 
infusion 
 
 
 
 
 
• Section 9.1.2, language for withdrawal of consent was modified 
• Section 10.2, an early safety review after the first 8 subjects have completed their first 
study treatment cycle on each the carboplatin, spartalizumab and LAG525 and the 
carboplatin and LAG525 arm was added 
• Section 12.4.2, clarification was added regarding ORR descriptive statistics 
• Section 12.5.1 clarification was added regarding treatment groups 
• Section 12.6.1 reference to Appendix 4 was added and confidence intervals used for ORR 
and DOR by line of therapy were clarified 
 
 
IRB Section 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.  


Novartis 
Confidential 
Page 24 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 


Novartis 
Confidential 
Page 25 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Protocol summary 
Protocol number 
LAG525B2101 
Full Title 
A phase II open-label, randomized, three-arm, multicenter study of LAG525 
given in combination with spartalizumab (PDR001), or with spartalizumab and 
carboplatin, or with carboplatin, as first or second line therapy in patients with 
advanced triple-negative breast cancer 
Brief title 
A study of efficacy and safety of LAG525 in combination with spartalizumab, or 
with spartalizumab and carboplatin, or with carboplatin, in patients with 
advanced triple-negative breast cancer. 
Sponsor and 
Clinical Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study is to assess the efficacy, safety, and PK 
characteristics of the following three combinations: i) LAG525 + spartalizumab; 
ii) LAG525 + spartalizumab + carboplatin, and iii) LAG525 + carboplatin in 
participants with advanced TNBC and up to one prior line of systemic 
treatment for metastatic disease. A thorough biomarker strategy to address 
key aspects of tumor immunogenicity will be implemented in the study. 
LAG525 and spartalizumab are two immuno-agents targeting different immune 
checkpoints, and have been tested as single agents and in combination. To 
further enhance the efficacy of checkpoint inhibition, carboplatin will be given 
with LAG525 or with LAG525 and spartalizumab, based on the observation 
that the addition of chemotherapy can change the tumor microenvironment to 
be more favorable to immune response. 
Primary 
Objective(s) 
To assess the antitumor activity of the three treatment arms LAG525 + 
spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + 
carboplatin, in participants with advanced TNBC in first or second line of 
therapy, as measured by the overall response rate (ORR) per investigator’s 
assessment according to Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1. 
Secondary 
Objectives 
• 
To assess the efficacy of the three treatment arms with respect to Duration 
of response (DOR), Time to response (TTR), Progression Free Survival 
(PFS) and Clinical benefit rate (CBR) per investigator’s assessment 
according to RECIST v1.1 
• 
To assess Overall Survival for each treatment arm 
• 
To characterize the safety profile of each treatment arm 
• 
To characterize the pharmacokinetics (PK) of LAG525, spartalizumab, and 
carboplatin in the three investigated combinations 
To assess immunogenicity of LAG525 and spartalizumab in the three 
investigated combinations 
Study design 
This is a phase 2, randomized, open-label, 3-arm, multicenter global study. 
With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + 
spartalizumab) was prematurely closed and subsequent enrolled participants 
will be randomized to Arms 2 and 3 only.  
Study population 
The study will include approximately 84 adult participants (after amendment 3) 
with advanced (loco-regionally recurrent not amenable to curative therapy or 
metastatic) TNBC which progressed after adjuvant or one prior line of 
systemic therapy for metastatic disease and never received prior treatment 
with an immune checkpoint inhibitor. 


Novartis 
Confidential 
Page 26 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Key Inclusion 
criteria 
• 
Patient is an adult ≥ 18 years old at the time of informed consent 
• 
Patient has advanced (loco-regionally recurrent not amenable to curative 
therapy or metastatic) breast cancer.  
• 
Patient must have measurable disease, i.e., at least one measurable 
lesion as per RECIST 1.1 criteria (Tumor lesions previously irradiated or 
subjected to other loco-regional therapy will only be considered 
measurable if disease progression at the treated site after completion of 
therapy is clearly documented) 
• 
Patient progressed after adjuvant or 1 prior systemic treatment in the 
metastatic setting. Patients with de novo metastatic disease are eligible if 
they received 1 prior line of therapy 
• 
Patient must have received prior systemic treatment that included taxane-
based chemotherapy for adjuvant or metastatic disease 
• 
Patient must have a site of disease amenable to biopsy, and must be 
willing to undergo a new tumor biopsy at screening and during therapy on 
this study, the latter if medically feasible. Patients with an available 
archival tumor tissue do not need to perform a tumor biopsy at screening if 
patient has not received anti-cancer therapy since the biopsy was taken. 
• 
Patient has histologically and/or cytologically confirmed diagnosis of 
advanced TNBC (based on most recently analyzed biopsy from locally 
recurrent or metastatic site, local lab) meeting the following criteria: HER2 
negative in situ hybridization test or an IHC status of 0 or 1+, and ER and 
PR expression is <1 percent as determined by immunohistochemistry 
(IHC) 
For the full inclusion criteria, please refer to Section 5.1. 
Key Exclusion 
criteria 
• 
Patient has received prior immune checkpoint inhibitors as 
anticancer treatment such as anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-
PD-L2 antibody (any line of therapy). 
• 
Patient received prior neoadjuvant or adjuvant therapy with a platinum 
agent or mitomycin and experienced recurrence within 12 months after the 
end of the platinum-based or mitomycin containing therapy, or received 
platinum or mitomycin for metastatic disease. 
• 
Patient has had major surgery within 14 days prior to starting study 
treatment or has not recovered to grade 1 or less from major side effects. 
• 
Patient with presence of CTCAE grade 2 toxicity or higher due to prior 
cancer therapy.  
Exception to this criterion: patients with any grade of alopecia are allowed 
to enter the study. 
• 
Patient has received radiotherapy ≤ 4 weeks prior to randomization (≤ 2 
weeks for limited field radiation for palliation), and has not recovered to 
grade 1 or better from related side effects of such therapy (with the 
exception of alopecia). 
• 
Patient has a known hypersensitivity to other monoclonal antibodies 
(mAbs), platinum-containing compounds, or to any of the excipients of 
LAG525, spartalizumab, or carboplatin. 
• 
Patient has 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 2 weeks prior to first dose of study treatment. Patients with 
treated brain metastases should be neurologically stable and without CNS 
progression for at least 12 weeks prior to randomization and have 


Novartis 
Confidential 
Page 27 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
discontinued corticosteroid treatment (with the exception of < 10 mg/day of 
prednisone or equivalent for an indication other than CNS metastases) for 
at least 4 weeks before first dose of any study treatment. 
For the full exclusion criteria, please refer to  Section 5.2  
Study treatment 
Investigational drugs: LAG525, spartalizumab (PDR001) 
Combination drug: carboplatin 
Efficacy 
assessments 
Tumor assessments by investigator's assessment per RECIST 1.1 
 every 6 weeks 
during the first 9 months and every 12 weeks thereafter. 
• 
Upon the approval of amendment 4, the tumor assessments during the post 
treatment efficacy follow-up period will now be optional and will be left at the 
discretion of the investigator. 
• 
Survival status every 12 weeks. Upon the approval of amendment 4, 
survival follow up is no longer required. 
Pharmacokinetic 
assessments 
• 
Calculation of PK parameters for LAG525, spartalizumab and carboplatin 
Key safety 
assessments 
• 
Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory values, vital signs and ECGs. 
• 
Tolerability: Dose interruptions 
Other 
assessments 
Pharmacokinetics, Immunogenicity 
 
Data analysis 
The primary analysis will be done when all participants have been followed for 
efficacy (tumor assessments) for at least 24 weeks or discontinued tumor 
assessments for any reason prior to 24 weeks. 
The primary efficacy endpoint, ORR, will be determined based on local tumor 
assessment following RECIST 1.1 guidelines. The primary efficacy analysis will 
assess the antitumor activity of each treatment arm based on their respective 
posterior mean and posterior distribution of ORR. Analysis will be done in the 
Full Analysis Set according to the randomized treatment group. 
The safety of each combination will be assessed mainly from the frequency of 
adverse events and the number of laboratory values that fall outside of pre-
determined ranges. 
Key words 
checkpoint inhibition, LAG525, spartalizumab (PDR001), carboplatin, triple-
negative breast cancer, phase 2 


Novartis 
Confidential 
Page 28 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
1 
Introduction 
1.1 
Background 
1.1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Triple-negative breast cancer (TNBC) is an aggressive clinical subset of breast cancer (BC) 
defined by the lack of estrogen receptors (ERs) and progesterone receptors (PRs) and by human 
epidermal growth factor receptor 2 (HER2)-negative status. TNBC accounts for 15% to 20% of 
newly diagnosed breast cancer (BC) cases Kohler et al 2015. Given deficiency in molecular 
targets and lack of approved targeted therapies, chemotherapy remains the treatment of choice 
for subjects with TNBC. Despite a high initial sensitivity to chemotherapy, subjects with TNBC 
suffer high relapse rates after adjuvant therapy, rapid progression and short survival in the 
metastatic setting with a median overall survival (OS) of 9-12 months Liedtke et al 2008. 
Treatment of TNBC remains challenging and new therapeutic options are needed. 
Standard systemic treatment for early stage breast cancer consists of anthracycline- and taxane-
based combination chemotherapy. For the treatment of recurrent TNBC; however, no specific 
recommendations or treatment standards exist NCCN 2017; Cardoso et al 2017. Recently, 
several studies have demonstrated the efficacy of carboplatin and cisplatin particularly in 
mTNBC Isakoff et al 2015; Tutt et al 2014. Platinum agents have particular utility in TNBC 
tumor cells because they have a decreased DNA repair capacity Quinn et al 2003. 
Genomic profiling studies revealed that TNBC is a heterogeneous disease with distinct 
molecular subtypes that each have a distinct prognosis Burstein et al 2015. Genomic features 
of those TNBC subtypes include activation of molecular pathways that may be actionable by 
molecularly targeted or immune-based approaches Burstein et al 2015; Denkert et al 2017. 
Some molecular features of TNBC such as homologous recombination deficiency and high 
genomic instability may predict sensitivity to DNA repair inhibitors, including poly (ADP-
ribose) polymerase-1 (PARP) inhibitors. PARP inhibitors (talazoparib, veliparib, olaparib) are 
in development for the treatment of BRCA-mutant and TNBC, which share similar molecular 
characteristics, and have shown promising results. In a randomized phase 3 trial, the PARP 
inhibitor olaparib monotherapy was compared with single-agent chemotherapy of the 
physician’s choice (capecitabine, eribulin, or vinorelbine) in subjects with a germline BRCA 
mutation and HER2–negative metastatic breast cancer. Median progression-free survival (PFS) 
was significantly longer in the olaparib group than in the standard therapy group (7.0 months 
vs. 4.2 months) Robson et al 2017. Most recently, this study Robson et al 2017 led to FDA 
approval of the PARP inhibitor olaparib for the treatment of subjects with BRCA-mutated mBC 
(Lynparza® USPI 2018). 
Several antibody-drug conjugates (ADC) are in clinical development for TNBC. For instance, 
a tumor-associated calcium signal transducer 2 known as TROP-2 or epithelial glycoprotein-1 
antigen expressed in most TNBCs, may be a potential target. Sacituzumab govitecan, an 
antibody-drug conjugate targeting Trop-2 has shown promising activity in heavily pre-treated 
TNBC Bardia et al 2017. Encouraging results were also seen in the study of another ADC, 
glembatumumab vedotin in advanced glycoprotein NMB (gpNMB)–expressing breast cancer 


Novartis 
Confidential 
Page 29 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
which included a subset of TNBC. Glembatumumab vedotin is an ADC that combines a 
monoclonal antibody against the tumor-associated antigen gpNMB and a potent microtubule 
inhibitor monomethyl auristatin E (MMAE) Yardley et al 2015. 
1.1.2 
Immunotherapy 
Since it has been recognized that immune escape is a hallmark of cancer 
Hanahan and Weinberg 2011, recent research has been focused on treatments to reengage the 
host immune system to attack and eradicate established tumors. The goal of immunotherapy in 
cancer is to sustain or rescue an existing tumor antigen-specific immune response capable of 
eradicating the disease. Tumors have complex mechanisms by which they alter antigen 
processing and presentation within their microenvironments, as well as the activation process 
of an immune response that shields the tumor from immune surveillance and suppresses 
surrounding leukocytes. Consequently, 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. A critical feature of immune activation is that the 
ultimate response is tightly regulated by a balance between immunostimulatory and 
immunosuppressive mechanisms. Antigen specific T cells have an intrinsic mechanism to 
regulate their activation through the balance in expression of a series of membrane receptors 
categorized into co-stimulatory (e.g., 41BB, GITR) and co-inhibitory-“immune checkpoint” 
(e.g., CTLA-4, PD1, LAG-3) receptors Leen et al 2007. The overexpression of immune 
checkpoint receptors on various cells within the tumor microenvironment comprises a 
multifactorial suppressive signal to prevent a strong T-cell–mediated response. 
A clinical blockade of immunosuppressive checkpoint receptors is therefore a promising 
approach to overcome immune suppression and induce tumor regression. Checkpoint inhibitors 
have been successfully introduced to clinical practice with the approvals of the antagonists to 
the CTLA-4 checkpoint (ipilimumab, BMS), PD-1 (e.g., nivolumab [BMS] and pembrolizumab 
[Merck]) and PD-L1 (atezolizumab [Genentech]). 
Importantly, TNBC has been shown to be more immunogenic than other Advanced Breast 
Cancer (ABC) subtypes. Tumor infiltrating lymphocytes (TILs) are seen at higher level in 
TNBCs compared with HR-positive breast cancers Loi et al 2014; Ono et al 2012; 
Denkert 2014; Loi et al 2015 suggesting an immune response to tumor-associated antigens. 
Furthermore, TNBC is characterized by high rates of genetic mutations (due to genomic 
instability), which implicates production of more neoantigens and increased immunogenicity 
Banerji et al 2012. Additionally, given that the binding of inhibitory molecule PD-L1 in tumor 
microenvironment to PD-1 on T cells is a major mechanism of tumor immune evasion, it is 
notable that TNBC is characterized by higher expression of PD-L1 compared to HR-positive 
breast cancers Mittendorf et al 2014. 
An improved understanding of the immunogenicity of TNBC has led to clinical studies of 
several immunotherapeutic agents. Several studies of single-agent immunotherapy in subjects 
with TNBC demonstrated notable responses. Specifically, in a Phase 1 study of a PD-1 inhibitor 
(pembrolizumab), the Overall Response Rate (ORR) among 27 evaluable subjects (any line of 
therapy) was 18.5% Nanda et al 2016. In a Phase 1 study of a programmed cell death ligand 
(PD-L1) antibody (atezolizumab), the ORR was 26% in first-line subjects but less than 10% in 
second and later lines of treatment Schmid et al 2017. In a Phase 2 study of a PD-1 inhibitor 


Novartis 
Confidential 
Page 30 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
(pembrolizumab) as monotherapy in third or later lines of 170 subjects with mTNBC, the ORR 
was 5% and subjects had a durable response with a DOR of 6.3 months Adams et al 2017. 
Although the immune checkpoint blockade generally results in similar enhanced anti-tumor T-
cell activation, those effects are mediated by distinct pathways and they demonstrate enhanced 
activity in combination. Combinations of immunotherapy approaches suggest that synergistic 
blockade of co-inhibitory receptors demonstrates greater antitumor activity than the single-
agent. This has been demonstrated with the combination of a CTLA-4 inhibitor (ipilimumab) 
and a PD-1 inhibitor (nivolumab) that was more active than either single agent in advanced 
melanoma Wolchok et al 2013. Also, there is increasing evidence that cytotoxic agents 
influence the tumor-host environment and consequently the combination of immunotherapy 
with cytotoxic agents may synergize to increase the therapeutic efficacy Zitvogel et al 2013. At 
present, combinations of immune checkpoint inhibitors with and without chemotherapy are 
being investigated in different settings to further improve the clinical outcome for subjects with 
mTNBC. 
1.1.3 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.1.3.1 
Overview of LAG525 
LAG525 is a high-affinity, ligand-blocking, humanized anti-LAG-3 immunoglobulin G4 
(IgG4) antibody (stabilized hinge, S228P) directed against the Lymphocyte-Activation Gene 3 
(LAG-3) immune checkpoint receptor on T-cells. LAG525 blocks LAG-3 from binding to its 
known ligand Major Histocompatibility Complex (MHC) Class II. LAG525 is cross-reactive to 
cynomolgus monkey LAG-3, equipotent to human LAG-3 and it shows functional activity in 
vitro and in vivo. 
1.1.3.1.1 Non-clinical experience with LAG525 
LAG525 binds specifically and with high affinity to human LAG-3. In BIACore assays binding 
to mouse or rat LAG-3 proteins were undetectable demonstrating that LAG525 is not mouse or 
rat cross-reactive. The equilibrium dissociation constant (KD) value for LAG525 binding to 
human LAG-3 was 0.109±0.008 nM. In cell binding assays with human LAG-3 expressing 
Chinese Hamster Ovary (CHO) cells and cynomolgus monkey LAG-3 expressing human 
embryonic kidney (HEK 293) cells, LAG525 binds to human LAG-3 and cyno LAG-3 
expressing cells with a comparable affinity of 1.9 nM and 2.3 nM, respectively. Given that 
LAG525 does not cross-react with rat or mouse LAG-3 but cross-reacts with cynomolgus 
monkey LAG-3, it cannot be evaluated in murine tumor models, making cynomolgus monkey 
a relevant species and the only species for toxicology studies. There was no tissue cross 
reactivity observed in good laboratory practice (GLP) studies with both human and cynomolgus 
monkey tissues specifically to assess the potential for off target binding. 
Inhibition of LAG-3 binding to ligand MHC class II by LAG525 was demonstrated in cell 
binding assay with MHC class II expressing Daudi cells. LAG525 inhibited the binding of 
human LAG-3 to MHC class II with an IC50 of 5.5 nM. Additional support for LAG525 
blockade of MHC class II was provided by hydrogen/deuterium exchange mass spectrometry 


Novartis 
Confidential 
Page 31 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
epitope mapping studies and crystallography. For more details, please consult the most recent 
edition of the [LAG525 Investigator’s Brochure]. 
No specific non-clinical absorption or bioavailability studies were conducted for LAG525. No 
specific studies were conducted to study LAG525 metabolism as classical drug metabolic 
elimination does not represent an important clearance mechanism for monoclonal antibodies 
(mAbs). The majority of monoclonal antibody elimination occurs via intracellular catabolism.  
No specific drug–drug interactions studies were conducted for LAG525. LAG525 is a mAb, 
and is not metabolized by Cytochrome P450 (CYP450) enzymes, or transported by P-
glycoprotein (Pgp) or related ATP-binding cassette membrane transporters. 
The non-clinical toxicology of LAG525 was evaluated in a five-week GLP toxicology study in 
cynomolgus monkeys with safety pharmacology endpoints and an 8 week recovery. There were 
no severely toxic events in any animals. The functional effects on the major physiological 
systems (e.g., cardiovascular, respiratory, and central nervous systems) were evaluated within 
the context of the 5-week GLP general toxicology study, there were no LAG525-related effects 
on any of these parameters. There were no effects of LAG525 on electrocardiogram (ECG) 
results, blood pressure, or respiration rate. 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 with the exception of a hypersensitivity reaction after the third dose in a single 
female animal treated with 6 mg/kg. It was confirmed that this animal was positive for the 
presence of anti-drug antibodies (ADA). Mild increases in fibrinogen (100 mg/kg) and minimal 
increases in globulin (25 and 100 mg/kg) were noted in males but these changes were not 
adverse. 
ADA-dependent hypersensitivity was also observed in the 14-week study with LAG525 in three 
of six animals treated with LAG525 at the dose of 25 mg/kg/week. Hypersensitivity-related 
clinical reactions (ataxia, hypoactive behavior, excessive salivation, and vomitus) were seen in 
two animals, which resulted in mortality in one animal and a significant reduction in exposure 
to LAG525 in the other, due to anti-LAG525 antibodies. Anti-LAG525 antibodies generally 
correlated with reduced exposure on Days 43 and/or 92 in animals that developed anti-LAG525 
antibodies.  
The effect of LAG525 on lymphocytes was tested on blood samples taken from treated and 
control animals. A minimal but statistically significant increase in proliferating CD4+ T cells 
(staining for both CD4 and Ki67 proliferation marker) was observed in animals given LAG525 
at 100 mg/kg/week compared to control animals, similar to observed pharmacology results with 
LAG-3 
blockade 
in 
previously 
reported 
pre-clinical 
studies 
Huard et al 1994; 
Workman et al 2004. 
In accordance with International Conference on Harmonization (ICH) S6 (R1), no genotoxicity 
or mutagenicity studies are planned with LAG525. No carcinogenicity, reproductive toxicity 
and juvenile toxicity studies have been performed to date with LAG525. 
1.1.3.1.2 Clinical experience with LAG525 
Data is available from study [CLAG525X2101C]: An open-label, multicenter Phase I/II study 
to determine the safety and efficacy of LAG525 as a single agent and in combination with 
spartalizumab (PDR001) in participants with advanced solid tumor malignancies. The study 


Novartis 
Confidential 
Page 32 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
consists of dose-escalation parts for LAG525 as single agent, and LAG525 in combination with 
spartalizumab. During dose-escalation, 134 participants were treated with LAG525 single 
agent, and 356 participants were treated with the combination of LAG525 and spartalizumab 
(data cut-off date of 05-Mar-2019). 
The preliminary pharmacokinetics of LAG525 have been characterized from 134 participants 
in single-agent and 356 participants in combination in the clinical study [CLAG525X2101C] 
(data cut-off date of 14-Feb-2019). 
Following a 30-minute intravenous infusion of LAG525 in single-agent cohorts and in 
combination cohorts with spartalizumab, approximately dose-proportional increases in 
LAG525 exposure (Cycle 1 AUClast) were observed from 1 mg/kg to 15 mg/kg as suggested by 
an approximate 20-fold increase in exposure with a 15-fold increase in dose. Based on 
preliminary data, exposure (e.g., Cmax or AUClast) on cycle 3 was relatively higher than that 
on cycle 1 indicating moderate accumulation of LAG525. Between participant PK variability 
was low to moderate. Based on a preliminary population pharmacokinetic model, doses at 240 
mg and above were well described by a linear, two compartment model. The population 
estimated median terminal half-life for a typical patient was 17 days. Compared to a typical 
mAb half-life, a relatively short half-life was observed at low dose levels of LAG525 potentially 
due to soluble target (sLAG-3) mediated drug disposition in the blood circulation. 
No specific assessment of absorption has been performed as LAG525 is administered 
intravenously. The distribution of LAG525 is typical of a monoclonal antibody, mainly into the 
central compartment. The expected metabolic pathway of LAG525 is degradation to small 
peptides and individual amino acids. PK drug-drug interactions (DDIs) are not anticipated for 
LAG525 because it is not expected to interact with drug metabolizing enzymes or transporters. 
Preliminary analysis of immunogenicity in participants on the [CLAG525X2101C] study 
suggests the presence of anti-drug antibodies in some participants. This finding is expected 
following treatment with a therapeutic antibody. No formal immunogenicity assessment has 
been completed as yet with LAG525. 
Preliminary exposure response relationships were explored on the heterogeneous patient 
population in study [CLAG525X2101C]. Exposure-safety analysis did not reveal a relationship 
between LAG525 exposure (observed or model-predicted) and the occurrence of grade 2+ AEs 
(regardless of relationship to drug or related to drug). Exposure-efficacy analysis also showed 
no relationship between LAG525 exposure and efficacy, whether in monotherapy or in 
combination with spartalizumab, though the reason may be due to the heterogeneous patient 
population. 
The preliminary safety information was summarized from the ongoing single-agent dose 
escalation part of the study (N=134; data cut-off date: 05-Mar-2019). Four dose limiting 
toxicities (DLTs) were reported and included Grade 3 events of localized intra-abdominal fluid 
collection (1mg/kg at every two weeks; Q2W), vomiting (5mg/kg Q2W), elevated lipase 
(5mg/kg Q2W) and grade 4 acute kidney injury (10mg/kg Q4W). A Maximum Tolerated Dose 
(MTD) was not identified for LAG525. Furthermore, safety events occurred without a clear 
dose relationship. There was no clear pattern between dose and anti-tumoral activity, and 
selection of a recommended phase 2 dose (RP2D) was not informed by anti-tumor activity. The 
recommended phase II dose selection was therefore supported by a modeling approach to 


Novartis 
Confidential 
Page 33 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
estimate target engagement based on LAG525 PK and soluble LAG-3 (sLAG-3) from patient 
blood samples. sLAG-3 is shed from membrane-bound LAG-3, and circulating sLAG-3 
detected in blood samples was utilized as a pharmacodynamic (PD) marker for target 
engagement. Based on the trial simulation of the PKPD model, the dose of 400 mg LAG525 
Q3W was considered to be appropriate for RDE (Recommended Doses for Expansion)/RP2Ds 
for single-agent LAG525 in a 3-weekly regimen (Q3W), and 800 mg LAG 525 Q4W for single-
agent LAG525 in a 4-weekly regimen (data on file). 
Simulation of the population PK model for LAG525 showed comparable inter-participant 
variability for both fixed/flat and body weight scaled dosing for all dosing regimens (Q2W, 
Q3W, and Q4W). In such cases, it is suggested in the literature that a fixed dosing approach is 
preferable Bai et al 2012; Wang et al 2009, and therefore only fixed dosing schedules were 
considered in the PKPD analysis described above for selecting the LAG525 RP2D. 
Adverse events (AEs) of all grades and regardless of relationship to study treatment were 
reported in 132/134 participants (98.5%) overall, with the most frequently reported (in >20% 
of participants) AEs being fatigue (26.9%) and nausea (26.1%), constipation, anemia and 
decreased appetite (24.6% each), abdominal pain and dyspnea (22.4% each) and vomiting 
(20.9%), which are consistent with AEs commonly reported for participants with advanced 
solid malignancies. 
The safety profile appeared similar across different dose levels and schedules. 
Of the 134 participants treated, 75 (56.0%) experienced grade 3/4 AEs regardless of relationship 
to study treatment. The most frequently reported grade 3/4 AEs occurring in 5% or more of 
participants were anemia (15 participants, 11.2%) and dyspnea (7 participants, 5.2%). 
Seventy-five of the 134 treated (56.0%) experienced AEs (all grades) suspected to be related to 
study treatment. In this participant group, the following Gr 3 or 4 AEs were reported (9 
participants, 6.7%): vomiting (3 participants), fatigue, nausea, amylase increased, lipase 
increased (2 participants each), decreased appetite, abdominal pain, anemia, blood creatinine 
increased, and hyperuricemia (1 participant each). 
Serious adverse events (SAEs), all grades, and regardless of relationship to study treatment, 
were reported in 52 participants (38.8%). The majority of SAEs (47 out of 52 participants who 
experienced SAEs) were Grade 3 or 4 in severity. Among the 52 participants who experienced 
SAEs, 7 participants were suspected to be related to study treatment including intra-abdominal 
fluid collection (1 patient, 1mg/kg Q2W, DLT), abdominal pain and melena (1 participant, 
3mg/kg Q2W), infection and vomiting, (1 patient, 5mg/kg Q2W, DLT), increased lipase, 
increased amylase and diarrhea (1 participant 5mg/kg Q2W, DLT), diarrhea (1 patient, 5mg/kg 
Q2W), and nausea, vomiting, anorexia, and fatigue, (1 patient, 240mg Q2W). One patient 
experienced multiple SAEs suspected to be related to study treatment which included acute 
kidney injury (DLT), tumor lysis syndrome, vomiting (worsening), multiple organ failure, and 
metabolic acidosis. This patient was treated with LAG525 at a dose of 10mg/kg Q4W and 
presented with acute kidney injury 26 days after the first and only dose of LAG525. The patient 
rapidly deteriorated in hospital and died 3 days after admission. An autopsy showed widespread 
metastatic disease consistent with the underlying diagnosis of cancer. The events (acute kidney 
injury, vomiting, metabolic acidosis and tumor lysis syndrome) were considered possibly 
related to LAG525. 


Novartis 
Confidential 
Page 34 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
For further details please refer to the latest [LAG525 Investigator's Brochure]. 
Single-agent LAG525 demonstrated only minimal activity in solid tumors. No RECIST 
responses were seen at any dose level but some participants (RCC, NSCLC, ovarian granulosa 
tumor, thymoma) experienced prolonged stable disease. 
1.1.3.2 
Overview of spartalizumab (PDR001) 
Spartalizumab (PDR001) is a monoclonal antibody (mAb) directed against human Programmed 
Death-1 (PD-1), a critical immune checkpoint receptor that is expressed on CD4 and CD8 T 
cells upon activation (Freeman 2008). Engagement of PD-1 by its ligands, PD-L1 and PD-L2, 
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/PD-L1, to avoid detection by the adaptive immune 
system (Murphy 2011). Inhibitors of immunological checkpoints, including PD-1 and PD-L1 
mAb’s, have demonstrated significant antitumor activity in patients with various solid tumors. 
For further details please refer to the latest PDR001 [Investigator’s Brochure]. 
1.1.3.2.1 Non-clinical experience with spartalizumab 
Spartalizumab (PDR001) is a high-affinity, ligand-blocking, humanized immunoglobulin G4 
(IgG4) antibody directed against PD-1 that blocks the binding of PD-L1 and PD-L2, and 
enhances Interleukin 2 (IL-2) production in ex-vivo lymphocyte stimulation assays.   
It does not cross-react with rodent PD-1; therefore, toxicology studies were performed only in 
cynomolgus monkeys where there was acceptable cross-reactivity with monkey PD-1. Repeat 
administration of spartalizumab to monkeys was tolerated at all doses tested up to 100 
mg/kg/week for 5 weeks in the GLP toxicology single-agent study. No test article-related in-
life, mortality, organ weight changes, or macroscopic findings were noted. There were no 
spartalizumab-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 spartalizumab-related microscopic changes were fully 
reversible after an eight week recovery. Additionally, mostly low grade mononuclear infiltrates 
in the vascular and perivascular space in several tissues of main and recovery treated animals 
and in recovery controls were observed but with a slightly higher incidence in treated animals. 
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. 
Dose-proportional exposure to spartalizumab in each dose group was confirmed. Anti-drug 
antibodies (ADA) to spartalizumab were observed in some spartalizumab treated cynomolgus 
monkeys. A trend of reduced drug exposure was observed in these ADA-positive animals. 
Based on the toxicology studies with spartalizumab as a single-agent, the Highest Non-Severely 
Toxic Dose (HNSTD) dose is 100 mg/kg. 
For further details, please refer to the latest PDR001 [Investigator’s Brochure]. 


Novartis 
Confidential 
Page 35 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
1.1.3.2.2 Clinical experience with spartalizumab 
Spartalizumab is currently being studied alone or in combination with other agents in ongoing 
phase I/Ib/II/III 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 of the safety cut-off of 26-Mar-2020, approximately 1702 participants have been treated 
with spartalizumab across 17 Novartis sponsored clinical studies as described in spartalizumab 
IB. Of these, a total of 562 participants were exposed to spartalizumab single agent. 
The available safety data from these clinical studies indicate that spartalizumab is generally 
well tolerated. In the dose escalation phase of the first-in-man study [CPDR001X2101] in 
participants with advanced solid tumors, no Dose Limiting Toxicities were reported. The 
preliminarily identified safety risks associated with spartalizumab are consistent with and 
characteristic of agents that inhibit the PD-1 receptor, and an advanced cancer population 
investigated in the respective trials. Severe immune-related adverse events (irAEs) were 
infrequent and typically manageable with dose interruption and use of immunosuppressive 
treatment or other supportive therapy as clinically indicated; discontinuations due to irAEs were 
rare. 
Based on pooled safety data from four studies comprising 562 participants treated with single 
agent spartalizumab across different regimen (400 mg Q4W [n=427], 300 mg Q3W [n=59] and 
1-10 mg/kg Q2W or Q4W [n=76]) and various advanced solid tumors types (i.e. mainly non-
small cell lung cancer (NSCLC), melanoma, triple negative breast cancer (TNBC), anaplastic 
thyroid carcinoma, neuroendocrine tumors and nasopharyngeal carcinoma), the most common 
AEs (>10%), all grades, regardless of relationship with study treatment included: fatigue 
(26.7%), decreased appetite (23.7%), anemia (23.5%), dyspnea (22.4%), nausea (21.2%), 
pyrexia (20.6%), cough (20.3%), diarrhea (18%), constipation (18%), vomiting (15.8%), 
asthenia (14.8%) and abdominal pain (12.3%), pruritus (11.4%), weight decrease (11.2%), AST 
increase (10.7%), peripheral oedema and rash (10% each). Most common AEs (>3%), all 
grades, suspected to be study drug related included fatigue (13.3%), decreased appetitive 
(7.1%), pruritus (7.1%), diarrhea (6.6%), nausea (6.0%), rash (6.0%), asthenia (5.5%), pyrexia 
(5.2%), anemia (4.8%) and AST increase (4.6%). 
Most common SAEs (>1%), all grades, regardless of relationship with study treatment were 
dyspnea (4.8%), pneumonia (3.6%), abdominal pain (2.8%), pleural effusion (2.7%), pyrexia 
(2.7%), sepsis (2.1%), pneumonitis (2.1%), hypercalcemia (2.0%), anemia (1.6%), back pain 
(1.4%), respiratory failure (1.4%), cellulitis (1.2%) vomiting (1.2%), hyponatremia (1,2%), and 
fatigue, diarrhea, cardiac arrest, pneumonia aspiration, spinal cord compression (1.1% each). 
Pneumonitis (1.8%) is the only SAE suspected to be study drug related that occurred in more 
than 1% of participants. 
AEs of special interest (AESI) for spartalizumab include endocrinopathies, colitis, skin 
reactions, hepatitis, nephritis, pneumonitis and other immune-related AEs (irAEs), and infusion 
reactions. 


Novartis 
Confidential 
Page 36 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
For further details, please refer to the latest version of the PDR001 [Investigator’s Brochure], 
as well as Section 4.5 (Risks and Benefits) and Section 6.5 (Dose escalation and dose 
modification) of the protocol. 
1.1.3.3 
Overview of the combination of LAG525 and spartalizumab  
1.1.3.3.1 Non-clinical experience with the combination of LAG525 and spartalizumab 
In preclinical studies, in syngeneic tumor murine models (MC38 colorectal cancer, Sa1N 
fibrosarcoma and B16 melanoma) inhibition of either LAG-3 or PD-1 resulted in reduced tumor 
growth with only occasional tumor responses Woo et al 2012. In striking contrast, 70% and 
80% of the Sa1N- and MC38-inoculated mice, respectively, were tumor-free after 50 days 
following combinatorial anti-LAG-3/anti-PD-1 immunotherapy indicating that simultaneous 
blockade of both checkpoints may have synergistic antitumor activity. 
Combination activity of spartalizumab and LAG525 was tested in vitro in Staphylococcal 
Enterotoxin B (SEB)-stimulated peripheral blood mononuclear cells (PBMCs) assay and 
measured by enhanced IL-2 response. Combined blockade of the PD-1 and LAG-3 pathways 
with spartalizumab and LAG525, respectively, enhances the activated T cell response as 
measured by IL-2 secretion over either agent alone, and supports the rationale to block both 
PD-1 and LAG-3 in cancer, where enhanced anti-tumor activity is the desired outcome. 
LAG525 and spartalizumab in combination were tested in 5 week GLP toxicology study. For 
more details, please consult the most recent edition of the [LAG525 Investigator’s Brochure]. 
Neither spartalizumab nor LAG525 behaved differently in this combination study compared to 
their toxicokinetic (TK) characteristics after first dose in their single-agent GLP toxicity studies. 
For animals without notable ADA, the TK for spartalizumab and LAG525 was as expected for 
a typical IgG in this species. The low-dose combination (18/6 mg/kg spartalizumab and 
LAG525 respectively) was well tolerated. At the high-dose combination (18 mg/kg of both 
agents), hypersensitivity reactions were observed in one animal out of four after the fourth dose 
(recovered) and two animals after the fifth dose. 
Pharmacodynamic activity of LAG525 and spartalizumab combination was confirmed in ex-
vivo SEB stimulation assay with whole blood samples in the presence of LAG525 and 
spartalizumab. Blood taken from control animals demonstrated the augmentation of IL-2 
release higher than blood taken from animals treated with LAG525 and spartalizumab 
indicating the target (LAG-3 and PD-1) engagement in vivo. For the assay details, please consult 
the most recent edition of the [LAG525 Investigator’s Brochure]. When the above difference 
was not observed, the presence of ADAs was confirmed. 
In the combination toxicology study there were no additional effects seen attributable to target 
biology of either agent and thus no effect on recommended starting doses in clinic as estimated 
from single agent studies can be expected. 
1.1.3.3.2 Clinical experience with the combination of LAG525 and spartalizumab 
In the combination part of study [CLAG525X2101C], 356 participants have been treated with 
LAG525 in combination with spartalizumab (Data cut-off date of 05-Mar-2019). LAG525 
doses ranged from 0.3 mg/kg to 1000 mg, and spartalizumab doses ranged from 1 mg/kg to 400 


Novartis 
Confidential 
Page 37 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
mg. The combination was tested in a Q3Wand a Q4W schedule. Spartalizumab or LAG525 in 
the combination showed comparable PK to the single agent data at the same dose levels from 
the ongoing [CPDR001X2101] and [CLAG525X2101C] studies. The observed median half-
life for spartalizumab ranged from 7.24 to 23.7 days, which is similar to the results from the 
ongoing [CPDR001X2101] study. There are no human pharmacodynamic data generated to 
date. 
Four participants experienced DLTs which included Gr3 hyperglycemia (80mg LAG525 Q2W 
and 400mg spartalizumab Q4W), Gr4 autoimmune hepatitis and Gr3 fatigue (1000mg LAG525 
Q4W and 400mg spartalizumab, Q4W), Gr3 brain tumor edema (600mg LAG525 Q3W and 
300mg spartalizumab Q3W), and Gr3 pneumonitis (400mg LAG525 and 400mg spartalizumab, 
Q4W). 
The preliminary safety information was summarized from the ongoing combination part of the 
study (data cutoff date: 05-Mar-2019). AEs of all grades and regardless of relationship to study 
treatment were reported in 352 participants (98.9%) overall, with the most frequently reported 
(in >20% of participants) AEs being nausea (28.4%), fatigue (27.0%), decreased appetite 
(22.5%), diarrhea (21.3%) and dyspnea (21.1%). 
Grade 3/4 AEs regardless of relationship to study treatment were reported in 177 participants 
(49.7%). The frequency of each grade 3/4 AE was below 10%. The most frequently reported 
AEs occurring in 2 or more participants included anemia (6.2%), asthenia (4.2%), dyspnea 
(3.3%), fatigue (1.4%), vomiting (1.1%), decreased appetite (1.1%), abdominal pain (1.1%), 
arthralgia (1.1%) and back pain (1.1%). 
Of the 356 participants with the combination, 232 (65.2%) experienced AEs (all grades) 
suspected to be related to study treatment. In this participant group, the following Gr 3 or 4 AEs 
were reported (33 participants, 9.3%): fatigue, hypothyroidism, maculopapular rash, arthralgia, 
anemia, hyponatremia (1 participant each), diarrhea, (2 participants each) aspartate 
aminotransferase increased, alanine aminotransferase increased and hypophosphatemia (3 
participants each), asthenia (4 participants) lipase increased (5 participants). 
Serious adverse events (SAEs), all grades, regardless of relationship to study drug, were 
reported in 150 participants (42.1%). The majority of these participants (124 out of 150) 
experienced SAEs that were Grade 3 or 4 in severity. Among the 150 participants who 
experienced SAEs, 19 participants experienced events that were suspected to be related to study 
treatment. SAE, all grades, regardless of relationship, occurring in more than 2 participants 
were 
dyspnea 
(14 
participants), 
pleural 
effusion 
(9 
participants) 
pyrexia 
(9 
participants),pneumonitis (6 participants), abdominal pain, acute kidney injury, pain in 
extremity, pneumonia (5 participants each), ascites, back pain, colitis, fatigue, nausea, 
hypercalcemia, sepsis (4 participants each). The safety profile appeared similar across different 
dose groups. For more details, please refer to the most recent edition of the [LAG525 
Investigator’s Brochure]. 
Clinical review of the triplicate ECGs collected during the [CLAG525X2101C] study was not 
indicative of QTc prolongation by either LAG525 alone or in combination with spartalizumab. 
Overall, single-agent LAG525 and combination of LAG525 plus spartalizumab were tolerated 
with safety profiles similar to those of other marketed checkpoint inhibitors. 


Novartis 
Confidential 
Page 38 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
The combination part of the ongoing [CLAG525X2101C] study included 5 participants with 
advanced and heavily pre-treated TNBC. Preliminary indicate that two of these participants 
showed durable PRs with treatment for over a year (data on file). 
Anti-tumoral activity was also seen in other solid tumors. Preliminary data indicate that one 
participant with thymoma achieved a CR and 11/100 evaluable participants with a variety of 
solid tumors had a confirmed PR. The majority of participants with confirmed PR had durable 
responses. Several cases of prolonged SD were observed. 
 
 
 
 
 
 
Responses were observed across several dose levels of LAG525 in combination with 
spartalizumab. There was no clear pattern between dose and anti-tumoral activity. Therefore, a 
PKPD modeling approach was used to describe LAG525 PK and sLAG-3 data, and to further 
support determination of the RP2D. As mentioned earlier, the pharmacological criterion chosen 
to guide the selection was the ability to achieve 90% suppression of the target (LAG-3) 
expressed in the tumor in > 90% of participants. Based on the trial simulation of the PKPD 
model, the 400 mg LAG525 Q3W dose was selected as the RP2D for both single-agent LAG525 
and in combination with spartalizumab in a 3-weekly regimen. A total of  23 participants have 
been treated with a Q3W schedule, of which 4 participants received the dose of 400 mg LAG525 
and 300 mg spartalizumab during the escalation. 
1.1.3.4 
Overview of carboplatin 
Carboplatin is a derivative of cisplatin which was the first platinum salt to be used in the 
treatment of malignancies. Carboplatin has a similar mechanism of action to cisplatin, but 
differs in terms of structure and has less toxicity. It reacts with intracellular DNA by forming 
platinum complexes, thereby inhibiting replication and transcription and leading to cell death 
(USPI for Paraplatin®). 
Platinum agents have particular utility in TNBC tumor cells which have a decreased DNA repair 
capacity Quinn et al 2003. Accordingly, high pathologic complete response (pCR) rates have 
been observed among BRCA1 carriers treated with cisplatin in the preoperative setting 
Byrski et al 2010 and high response rates (RRs) were also observed among one small cohort of 
BRCA1 carriers treated with cisplatin in the metastatic setting Byrski et al 2012. 
Preclinical studies demonstrated that sporadic TNBC often has similar features as BRCA1/2-
mutated cancers, including harboring DNA repair defects that might predispose to platinum 
sensitivity Hastak et al 2010. Several clinical trials confirmed the activity of carboplatin in 
TNBC, showing that the addition of neoadjuvant carboplatin to anthracycline/taxane or 
anthracycline-free chemotherapy improved pathologic complete response (pCR) in early-stage 
TNBC, both in sporadic and in BRCA-mutated cancers von Minckwitz et al 2014; 
Sikov et al 2015; Sharma et al 2017; Silver et al 2010; Ryan et al 2009 and Rugo et al 2013. 


Novartis 
Confidential 
Page 39 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Recently, several studies have demonstrated the meaningful activity of platinum-based 
chemotherapy for TNBC Isakoff et al 2015; Tutt et al 2014. In the multicenter phase II clinical 
trial of single agent platinum in metastatic TNBC Isakoff et al 2015, 86 subjects received first- 
or second-line cisplatin (75 mg/m2) or carboplatin (AUC 6) by physician’s choice once every 
3 weeks. The overall response rate (ORR) was 25.6%, including three complete responses and 
19 partial responses. The ORR was 29% in first line, and 12% in second line mTNBC 
Isakoff et al 2015. The larger TNT study Tutt et al 2014, a randomized phase III trial, compared 
carboplatin with docetaxel, both as single agents, in 376 subjects with mTNBC or BRCA1/2 
breast cancer. Using carboplatin in first line TNBC yielded an ORR of 31%; the PFS was 3.1 
months (95% CI: 2.5-4.2 months). The study showed no evidence of superior response to 
carboplatin compared to docetaxel in unselected TNBC subjects, with lower incidence of AE 
with carboplatin Tutt et al 2014. 
Bone marrow suppression is the dose-limiting toxicity of carboplatin. The most frequent AEs 
in a cohort of patients with ovarian cancer receiving single-agent carboplatin as second line 
treatment were myelotoxicity (thrombocytopenia, neutropenia, anemia), and nausea and 
vomiting. Carboplatin has limited nephrotoxic and ototoxic potential; peripheral neurotoxicity 
is infrequent (US label Paraplatin®). In the TBCRC009 trial, single-agent carboplatin had 
generally mild toxicity in mTNBC, with fatigue, nausea, electrolyte abnormalities, and 
hematologic toxicity among the most common adverse events: Thrombocytopenia occurred in 
49% of subjects, anemia in 65%, neutropenia in 35%, hypomagnesemia in 23%, and anorexia 
in 9%. Grade 3 and 4 adverse events were rare. Grade 3 and 4 adverse events occurring in at 
least 5% of all subjects included fatigue, neutropenia, dyspnea, anemia, hyperglycemia, and 
hyponatremia Isakoff et al 2015. 
Carboplatin is administered as infusion therapy. The major route of elimination of carboplatin 
is renal excretion. A mathematical formula incorporating the glomerular filtration rate (GFR) 
and carboplatin target area under the concentration versus time curve (AUC in mg/mL•min) is 
commonly used to determine the initial dose, since it allows compensation for subject variations 
in pretreatment renal function. 
Single agent carboplatin is included in the NCCN and other national guidelines as a reasonable 
option for the treatment of subjects with ABC in all lines of therapy. In particular, ESMO 
guidelines highlighted the benefit of a mild toxicity profile of carboplatin for subjects with 
TNBC Cardoso et al 2017. The NCCN-recommended dose is AUC 6 i.v. on day 1 of each cycle, 
based on the TBCRC009 study Isakoff et al 2015; NCCN 2017. 
For more details, please refer to the local prescribing information for carboplatin. 
1.2 
Purpose 
LAG525 and spartalizumab, two immuno-agents targeting different immune checkpoints, have 
been tested as single agents and in combination. It is expected that the addition of a 
chemotherapy agent, carboplatin, will further enhance the efficacy by making the tumor more 
immuno-reactive or by altering the tumor microenvironment to achieve an optimal anti-tumor 
immune response. 
The goals of this Phase II study are to assess efficacy/safety of the following IO/IO combination 
± carboplatin: i) LAG525 + spartalizumab; ii) LAG525 + spartalizumab + carboplatin, and ii) 


Novartis 
Confidential 
Page 40 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
LAG525 + carboplatin in participants with advanced TNBC and up to one prior line of systemic 
treatment for metastatic disease. With protocol amendment 3, enrollment to Arm 1 (LAG525 + 
spartalizumab) was prematurely closed. 
 
 
 
2 
Objectives and endpoints 
Objectives and related endpoints are described in Table 2-1 below. With protocol amendment 
3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed and all 
subsequent enrolled participants will be randomized to Arms 2 and 3 only. 
Table 2-1 
Objectives and related endpoints 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• 
To assess the antitumor activity of the three 
treatment arms LAG525 + spartalizumab, 
LAG525 + spartalizumab + carboplatin and 
LAG525 + carboplatin, in participants with 
advanced TNBC in first or second line of 
therapy, as measured by the overall 
response rate (ORR) per investigator’s 
assessment according to RECIST v1.1. 
• 
Overall response rate (ORR) per RECIST 
v1.1 per investigators' assessment 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• 
To assess the efficacy of the three treatment 
arms with respect to Duration of response 
(DOR), Time to response (TTR), 
Progression Free Survival (PFS) and 
Clinical benefit rate (CBR) per investigator’s 
assessment according to RECIST v1.1 
• 
Duration of response (DOR), Time to 
response (TTR), PFS and Clinical benefit 
rate (CBR) per investigators' assessment. 
• 
To assess Overall Survival for each 
treatment arm 
• 
Overall Survival (OS) 
• 
To characterize the safety profile of each 
treatment arm 
• 
Adverse events (AEs), serious AEs (SAEs), 
changes in hematology and chemistry 
values, vital signs, weight, ECOG 
performance status, electrocardiograms 
(ECGs), dose interruptions, reductions and 
dose intensity. 
• 
To characterize the pharmacokinetics (PK) 
of LAG525, spartalizumab, and carboplatin 
in the three investigated combinations 
• 
Pharmacokinetic parameters (e.g., Ctrough, 
Cmax, AUC) 
• 
To assess immunogenicity of LAG525 and 
spartalizumab in the three investigated 
combinations 
• 
Antidrug antibodies (ADA) prevalence at 
baseline and ADA incidence on treatment 


Novartis 
Confidential 
Page 41 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Objective(s) 
Endpoint(s) 
3 
Study design 
This is a phase II, open-label, randomized, three-arm, multicenter global study in participants 
with advanced (loco-regionally recurrent not amenable to curative therapy or metastatic) TNBC 
which progressed after adjuvant or one prior line of systemic therapy for metastatic disease.  
With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was 
prematurely closed and subsequent enrolled participants will be randomized to Arms 2 and 3 
only.  
The study objective is to assess efficacy and safety of the following IO/IO ± carboplatin 
combinations (Figure 3-1): 
• Arm 1: LAG525 + spartalizumab (enrollment of this arm is closed with protocol 
amendment 3) 
• Arm 2: LAG525 + spartalizumab + carboplatin 
• Arm 3: LAG525 + carboplatin 


Novartis 
Confidential 
Page 42 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Figure 3-1 
Study Design 
 
 
*
  
**With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed  
Δ Upon the approval of protocol amendment #4, only End of Treatment (EOT) visit but no safety, efficacy and 
survival follow-up will be performed for ongoing patients who will transfer into PTA program (roll over study or 
PSDS) 
+ Participants who had stopped study treatment for more than 150 days will be discontinued from the study – see 
Section 9.1.1 for details. Survival follow-up period is removed after protocol amendment #4 is approved  
† with implementation of protocol amendment #4 for the remaining participants in the study all tumor assessments 
in the post-treatment follow-up period will be optional and will be left at the discretion of the investigator 
4 
Rationale 
4.1 
Rationale for study design 
There is a high unmet medical need for new therapeutic approaches to manage advanced TNBC. 
Immunotherapy has gained much interest as an option due to the promising results seen in 
clinical studies of the PD-1 inhibitor pembrolizumab Nanda et al 2016; Adams et al 2017 and 
the PD-L1 inhibitor atezolizumab Schmid et al 2017 in patients with TNBC. Yet, the main 
limitation of single agent immune checkpoint blockade is that only a subset of participants 
respond, due to the complexity of anti-cancer immune surveillance and therefore inadequacy of 
engaging only one component of the immune system to overcome immune suppression in the 
tumor microenvironment and mount an effective immune response. Combining different 


Novartis 
Confidential 
Page 43 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
checkpoint receptor blockades achieves distinct effects on the immune response 
Anderson et al 2016. Beyond combinations of PD-1 and CTLA-1 inhibitors that have 
demonstrated superior activity compared to monotherapy Wolchok et al 2013, new co-
inhibitory receptors are investigated as potential targets to broaden the therapeutic repertoire 
Anderson et al 2016. 
LAG-3 is a co-inhibitory receptor that may cooperate with PD-1 to inhibit immune responses 
Anderson et al 2016. In preclinical studies, the combined inhibition of PD-1 and LAG-3 
checkpoints synergistically enhances antitumor responses over inhibition of either checkpoint 
alone Woo et al 2012. CD8+LAG-3+PD-1+ T cells from participants with ovarian cancer had 
impaired function in ex vivo assays compared with LAG-3+PD-1− or LAG-3−PD-1− subsets, 
but they restored their functions after the dual blockade of PD1 and LAG-3 
Matsuzaki et al 2010. These data suggest that combined inhibition of LAG-3 and PD-1 in the 
clinic may have significant anti-tumor activity. 
Combining immunotherapy agents with chemotherapeutic agents may provide an additional 
benefit 
to 
achieve 
additive 
or 
synergistic 
clinical 
activity 
Zitvogel et al 2013, 
Emens and Middleton 2015. Chemotherapy can change the tumor microenvironment to be 
more favorable to immune response. Importantly, it can induce immunogenic cell death, which 
facilitates the efficient antigen presentation Kroemer et al 2013. This has been shown to trigger 
potent T cell responses in preclinical models Pfirschke et al 2016; Lu et al 2017. Checkpoint 
inhibitors (anti-PD-1, anti-PD-L1, anti-CTLA4) have been also tested in combination with 
chemotherapy in NSCLC and melanoma in clinical settings and the results appeared to be 
promising Robert et al 2011; Lynch et al 2012; Reck et al 2013; Antonia et al 2014. A number 
of combinations of immune checkpoint inhibitors (anti-PD-1/pembrolizumab, anti-PD-
L1/atezolizumab) with chemotherapy are in Phase III clinical trials in patients with newly 
diagnosed or advanced TNBC. 
This is an open-label, phase II study of the three combinations, LAG525 + spartalizumab (Arm 
1), LAG525 + spartalizumab + carboplatin (Arm 2), and LAG525 + carboplatin (Arm 3) in 
participants with advanced TNBC in first or second line therapy. Enrollment to treatment Arm 
1 (LAG525 + spartalizumab) was prematurely closed with protocol amendment 3. Subsequent 
enrolled participants will be randomized 1:1 to either Arm 2 or Arm 3. The randomization will 
be stratified by the presence or absence of liver metastasis and by line of therapy, i.e. first line 
(following disease progression after adjuvant or neoadjuvant therapy) or second line (following 
one disease progression in advanced or metastatic setting). 
The study will be conducted in patients with TNBC which is more immunogenic than other BC 
subtypes, has higher expression of PD-L1 and increased infiltration by TILs Loi et al 2014; 
Mittendorf et al 2014. These characteristics are considered among prerequisites for immune 
therapy, i.e., immune checkpoint inhibition to be effective in rescuing the existing anti-tumor 
immune response Dammeijer et al 2017. It was therefore plausible to assume that TNBC will 
be responsive to combination therapy with LAG525 + spartalizumab. With protocol amendment 
3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed. The 
reason for this closure was a higher treatment discontinuation rate due to progressive disease in 
Arm 1 as compared to the treatment arms containing carboplatin (Arms 2 and 3). At study entry, 
TNBC status will be confirmed in the most recent biopsy because in up to 15% of participants 
initially diagnosed with TNBC, the hormone receptor status in the metastasis may shift to 


Novartis 
Confidential 
Page 44 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
positive, making those participants eligible for other treatment options Aurilio et al 2014. The 
threshold of ER and PR expression is <1 percent as determined by immunohistochemistry 
(IHC), following the recommendation of the American Society of Clinical Oncology 
(ASCO)/College of American Pathologists (CAP) Hammond et al 2010. 
4.1.1 
Rationale for Arm 3 (LAG525 + carboplatin) 
In Arm 3, LAG525 will be combined with chemotherapy, without the co-inhibitory effect of a 
PD-1 inhibitor. LAG-3 is associated with T cell regulation and represents a potential target for 
modulating T cell responses cancer on its own Anderson et al 2016. In the clinical study 
[CLAG525X2101C], LAG525 has demonstrated only minimal efficacy as single-agent but 
when co-inhibited with spartalizumab clinical responses were observed. LAG-3 blockade has 
also been shown to synergize with anti-tumor vaccination to improve tumor-specific immune 
response, supporting a direct role for LAG-3 in regulating CD8+ T cells Grosso et al 2007. 
While LAG-3 plays a critical role in attenuating the effector function of PD-1+CD8+ infiltrating 
T cells, as has been demonstrated in tumor models, its blockade is effective during early events 
of T cell activation, probably via its binding to MHC class II Demeure et al 2001 After antigen 
encounter within tolerizing environments such as tumor, self-antigen or chronic infection, 
antigen-specific CD8 T cells differentiate into different subpopulations defined by LAG-3 and 
PD-1 expression, with each group having a distinct function and phenotype Grosso et al 2009. 
Signaling through the PD-1 and LAG-3 pathways have distinct functional consequences to CD8 
T cells and manipulation of both antigen and cytokine signaling can influence CD8 tolerance 
through LAG-3 and PD-1 Grosso et al 2009. 
As chemotherapy sensitizes the tumor to immune check point blockade therapy 
Pfirschke et al 2016, we hypothesize that it will create an environment early during T cell 
activation (e.g., increased antigen concentration, antigen availability) that will favor the arising 
of LAG-3+CD8+ T cells which will require only LAG-3 inhibition to differentiate into tumor 
antigen specific effector cells. In this environment, LAG-3 inhibition may be sufficient to obtain 
a clinical response, without the need of additional PD-1 checkpoint blockade. 
4.1.2 
Rationale for stratification by liver metastasis 
The randomization will be stratified by the presence or absence of liver metastasis to account 
for the differential prognosis. Breast cancer patients, including those with TNBC, who have 
visceral metastasis generally have a worse outcome than patients with non-visceral metastasis, 
and the presence of liver metastasis in particular was an independent poor prognostic factor 
Pierga et al 2004; Kim et al 2013; Kassam et al 2009. Additionally, recent trials suggested 
organ-specific tumor responses in patients treated with immune checkpoint inhibitors in various 
diseases and demonstrated a poorer response rate in patients with liver metastasis compared to 
patients with other visceral metastasis.  
For instance, in the study of pembrolizumab as monotherapy in participants with advanced 
TNBC Adams et al 2017, the response rate was lower in participants with visceral metastasis 
(ORR 2% vs 11% in participants with no visceral metastases); no participants with liver 
metastases had a response. Similarly, in lung cancer patients treated with PD-1 and PD-L1 
inhibitors, no responses were seen in patients with liver metastases while all clinical responders 
had primarily intrathoracic disease or CNS involvement Pallai et al 2016. Nishino et al 


Novartis 
Confidential 
Page 45 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
evaluated irRECIST1.1 and standard RECIST1.1 responses in patients with advanced NSCLC 
patients treated with nivolumab and observed less responses in liver lesions Nishino et al 2016. 
In patients with advanced or metastatic melanoma treated with pembrolizumab or nivolumab, 
patients with liver metastases were less likely to respond to treatment Ribas et al 2016; 
Goldinger et al 2016. It was hypothesized that the liver has an intrinsic immune suppressive 
microenvironment Tagliamonte et al 2016; Buonaguro et al 2013, which may help tumors to 
escape from anti-tumor immune attacks during therapy with immune checkpoint inhibitors. 
4.1.3 
Rationale for stratification by line of therapy 
The randomization will be stratified by line of therapy, i.e., first or second line, to account for 
the differential efficacy of first and second line therapy. 
The data from published studies suggest that, for participants with mTNBC, the benefits from 
chemotherapy as well as from immunotherapy are higher in first line compared to second or 
later lines of therapy. In the TBCRC009 study, platinum (carboplatin or cisplatin) alone 
achieved an ORR of 29.0% in first line, and 11.8% in second line Isakoff et al 2015. Similarly, 
in a study of cetuximab with cisplatin versus cisplatin alone in participants with mTNBC, the 
response rate in the cisplatin alone arm as higher in first line (12%) versus second line (6%) of 
therapy Baselga et al 2013. In a phase 1 expansion cohort of single-agent atezolizumab in 
participants with mTNBC, the ORR was 26% for participant in first line and below 10% for 
participants in second or later lines Schmid et al 2017. 
4.2 
Rationale for dose/regimen and duration of treatment 
The combination of LAG525 and spartalizumab has shown promising results in pre-clinical 
assays and responses were observed in clinical studies of spartalizumab alone 
([CPDR001X2101]) 
and 
the 
combination 
of 
LAG525 
and 
spartalizumab 
([CLAG525X2101C]), particularly in participants with TNBC. For the combination, RDEs 
were established for use in three-weekly (q3w) and 4-weekly (q4w) regimens. The RDEs are 
400 mg LAG525 + 300 mg spartalizumab (q3w) and 800 mg LAG525 + 400 mg spartalizumab 
q4w. In this study, a cycle is defined as 3 weeks (21 days) to match the approved schedule of 
carboplatin which is administered in cycles of three weeks (q3w), and doses will be 400 mg 
LAG525 and 300 mg spartalizumab. 
Carboplatin will be dosed per AUC 6 i.v. on day 1 of each cycle, as recommended for single-
agent and combination regimens for the treatment of participants with breast cancer 
NCCN 2017. Single-agent carboplatin at the AUC 6 dose has a well-known and manageable 
safety profile as demonstrated in clinical studies (see Section 1.1.3.4). 
The present study will not include a dose escalation part because recently, carboplatin (dosed 
per AUC5 and AUC6) has been tested as combination partner with checkpoint inhibitors 
pembrolizumab or atezolizuamb in NSCLC studies and the combinations were found to have 
an acceptable safety profile Langer et al 2016; Herbst et al 2016. Of note, the incidence of 
myelotoxicity was not different between platinum-containing chemotherapy with or without 
pembrolizumab Keytruda® US prescribing information 2017. 
Based on available safety data from these combination studies of carboplatin with checkpoint 
inhibitors, it is expected that there will be no significant overlap in the safety profile of 


Novartis 
Confidential 
Page 46 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
carboplatin and LAG525/spartalizumab. The protocol provides guidelines for dose 
modifications for each drug if toxicities occur in individual participants. 
4.3 
Rationale for choice of combination drugs 
Carboplatin has been chosen as combination drug given its proven efficacy in TNBC and its 
generally mild safety profile (see also Section 1.1.3.4). 
In the randomized phase III TNT trial the activity of single-agent carboplatin was tested against 
a standard chemotherapy with single-agent docetaxel in 376 TNBC participants including 
BRCA1/2 mutation carriers Tutt et al 2014. In unselected TNBC participants, there was no 
significant difference in ORR, PFS, or OS between carboplatin and docetaxel. However, 
participants with BRCA1/2 mutation who received carboplatin (n=48) had a significantly higher 
ORR (68% vs 33%) and better PFS (6.8 months vs 3.1 months) compared to participants with 
wild type BRCA1/2 Tutt et al 2014. 
Many participants with TNBC have germ line mutations in the BRCA1/2 genes, which result in 
decreased DNA repair capacity Peshkin et al 2010. The functional link between the BRCA1/2 
pathway and platinum response in TNBC was demonstrated in the TBCRC009 phase II trial of 
platinum monotherapy Isakoff et al 2015. Furthermore, in this trial, responses among those who 
did not carry mutations were associated with the presence of tumor genomic instability patterns 
characteristic of BRCA1/2-mutant tumors. Similarly, Watkins J, et al. Watkins et al 2015 
analyzed a cohort of 126 TNBC participants and demonstrated the positive association between 
allelic imbalance, a form of genomic instability, in BRCA mutant and non-mutant tumors and 
specific sensitivity to carboplatin response. 
Homologous recombination deficiency (HRD) status has been proposed to subclassify TNBC 
tumors, including BRCA1/2 nonmutated tumors more likely to respond to platinum-containing 
therapy Telli et al 2016. However, HRD measure had no predictive performance for carboplatin 
benefit in the TNT trial with only modest increase in efficacy in HRD high participants vs low 
(38.2% vs 29.2, P=NS) Tutt et al 2014; Tutt et al 2016. 
Sporadic BRCA wild-type TNBCs may display molecular features of homologous DNA 
recombination deficiency (BRCA-like phenotype) and harbor alterations in a diverse set of 
DNA repair genes (eg, ATM, RAD51). This suggested that the DNA-damaging platinum 
chemotherapy drugs would have broad activity in TNBC, in the germline BRCA-mutant subset 
and beyond. 
While the main mechanism of action of platinum agents is believed to be the induction of cancer 
cell apoptosis as a response to their covalent binding to DNA, recent studies indicated that 
cellular molecules other than DNA may potentially act as targets, and that part of the antitumor 
effects of platinum drugs occurs through modulation of the immune system Hato et al 2014. 
These immunogenic effects include modulation of STAT signaling Lesterhuis et al 2011; 
induction of an immunogenic type of cancer cell death through exposure of calreticulin and 
release of ATP and high-mobility group protein box-1 (HMGB-1) Kroemer et al 2013; 
Tesniere et al 2010; and enhancement of the effector immune response through modulation of 
programmed death receptor 1-ligand and mannose-6-phosphate receptor expression 
Liu et al 2010. 


Novartis 
Confidential 
Page 47 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
The described above immunogenic momentum of platinum chemotherapy is being explored 
recently in the combination with immune checkpoint blockade. There is a good rationale to 
combine platinum compounds with checkpoint-blocking antibodies: Platinum can provide 
immunogenic cell death (ICD) (in case of oxaliplatin or cisplatin based chemoradiation), tumor 
cell sensitization to CTL lysis, and downregulation of PD-Ls. In several studies conducted in 
patients with advanced NSCLC, the combination of a checkpoint inhibitor, atezolizumab or 
pembrolizumab, with platinum-based chemotherapy demonstrated increased efficacy over the 
chemotherapy alone Lynch et al 2012; Reck et al 2017. 
Specific studies to investigate drug-drug interactions (DDI) between LAG525 and/or 
spartalizumab with carboplatin have not been conducted. Monoclonal antibodies such as 
spartalizumab and LAG525 are eliminated through protein catabolism and target-mediated 
disposition, whereas carboplatin is mainly eliminated via the renal route of elimination. 
Therefore, the potential for drug-drug interaction between the two antibodies and carboplatin is 
considered low. 
Nevertheless, PK of carboplatin, LAG525 and spartalizumab will be characterized in this study, 
so that DDI, if any, between the combination partners, can be explored (Section 12.5.3). As 
spartalizumab and LAG525 are intended to be used in combination with chemotherapy, this 
evaluation is particularly important since chemotherapeutic agents have narrow therapeutic 
range FDA DDI guidance 2012. 
The safety of carboplatin is well established. Combination studies of carboplatin with 
checkpoint inhibitors have not led to new safety signals compared to the known toxicities of 
each agent alone (see Section 4.2). 
4.4 
Purpose and timing of interim analyses/design adaptations 
Not applicable. 
4.5 
Risks and benefits 
4.5.1 
Potential benefits to clinical trial participants 
To date, immune checkpoint inhibitors suppressing the programmed cell death protein 1 (PD-
1), programmed cell death ligand 1 (PD-L1), and cytotoxic T lymphocyte associated protein 4 
(CTLA-4) pathways have demonstrated significant clinical efficacy in multiple tumor types, 
combined with a tolerable and manageable safety profile, supporting recent regulatory 
approvals of mAbs against PD-1/PD-L1 and CTLA-1 in various indications including 
melanoma, non-small cell lung cancer, head and neck cancer, bladder cancer, renal cancer, 
Merkel Cell Carcinoma, and classical Hodgkin’s lymphoma Opdivo® USPI 2018, 
Keytruda® USPI 2017, 
Yervoy®  USPI 2018, 
Tecentriq® USPI 2017. 
LAG525 
and 
spartalizumab are humanized IgG4 monoclonal antibodies which due to their respective 
mechanisms of action, are considered as immune checkpoint inhibitors. 
TNBC has been shown to be more immunogenic than other BC subtypes and clinical studies of 
several immunotherapeutic agents demonstrated notable responses, albeit limited to few 
participants Nanda et al 2016; Schmid et al 2017; Adams et al 2017. 


Novartis 
Confidential 
Page 48 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Combining immune checkpoint inhibitors targeting distinct inhibitory pathways like CTLA-4, 
PD-1 and LAG-3 demonstrated greater antitumor activity than each of the single-agents alone, 
e.g., in preclinical models dual anti-LAG-3/anti-PD-1 antibody treatment eradicated established 
melanoma and colon adenocarcinoma tumors that were largely resistant to single antibody 
treatment Woo et al 2012. Similarly, concurrent blocking of CTLA-4 and PD-1 pathways 
achieved clinical activity in advanced melanoma patients that was distinct from published 
monotherapy data, with rapid and deep tumor regressions in a substantial number of patients 
Wolchok et al 2013. 
In study [CLAG525X2101C], the combination of LAG525 and spartalizumab has shown an 
efficacy signal with durable responses in 2 out of 5 heavily pretreated TNBC participants. The 
combination was well tolerated. 
The addition of a chemotherapeutic agent has a dual effect of rendering tumor cells more 
antigenic to the immune system and at the same time stimulating the immune response, and will 
further enhance the therapeutic effect Zitvogel et al 2013. 
In summary, it is expected that due to the synergistic effects, each of the tested combination 
regimens, LAG525 + spartalizumab, LAG + spartalizumab + carboplatin, and LAG525 + 
carboplatin, will increase the clinical benefit to participants with TNBC who have limited 
options in the advanced disease setting. 
4.5.2 
Potential risks to clinical trial participants 
Immune checkpoint inhibitors may be associated with the occurrence of immune-mediated 
adverse events (irAEs). In general, irAEs can potentially involve every organ system but 
gastrointestinal (GI) (e.g. diarrhea, colitis), dermatologic (e.g. rash, pruritus), hepatic (e.g. 
hepatitis), pulmonary (e.g. pneumonitis), renal (e.g. nephritis) and endocrine toxicities (e.g. 
hypothyroidism, hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism and 
adrenal insufficiency) are being typically the most frequent side effects. Other immune-
mediated AEs may rarely include the nervous system (e.g., encephalitis, Guillain-Barre 
syndrome, myasthenia gravis), eye (e.g., uveitis, vision changes), musculo-skeletal system (e.g., 
myositis, arthritis), pancreas (e.g. pancreatitis), cardiovascular system (e.g., vasculitis, 
myocarditis) or blood system (e.g., anemia, cytopenias), and severe skin reactions such as toxic 
epidermonecrolysis or Steven Johnson syndrome. Furthermore, complications in participants 
with bone marrow or solid organ transplant have been reported (e.g. organ rejection, severe 
graft-versus-host disease). These side effects are generally manageable and reversible with dose 
interruption and administration of corticosteroids and/or other immuno-suppressants. However, 
fatal events have been reported in some cases with checkpoint inhibitor compounds; some 
events like endocrinopathies may further require life-long hormonal replacement. While most 
events are expected to occur during treatment, onset may be delayed and irAEs may also occur 
after 
discontinuation 
of 
study 
treatment 
(Spain et al 2016; 
Hofmann et al 2016; 
Champiat et al 2016; Brahmer et al 2018 and Haanen et al 2017). In addition, mAb’s can be 
associated with infusion-related reactions some of which can be severe; these are often 
immediate and usually occur within minutes of the exposure to the study drug. Therefore, 
infusions should take place in a facility with appropriate resuscitation equipment available at 
the bedside and a physician readily available, and participants monitored for respective signs 


Novartis 
Confidential 
Page 49 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
and symptoms. Participants who experience severe or life-threatening irAEs or infusion 
reactions may need to permanently discontinue spartalizumab and/or LAG525.  
In studies of spartalizumab [CPDR001X2101] and of LAG525 alone and in combination with 
spartalizumab [CLAG525X2101C], the drugs were well tolerated with safety profiles similar 
to those of other marketed checkpoint inhibitors. A MTD was not identified for either LAG525 
or spartalizumab. 
The available data suggests that LAG525 and spartalizumab have a safety profile comparable 
to other immune checkpoint inhibitors. It is therefore important to be vigilant and carefully 
identify AEs that may be suggestive of potential immune-mediated AEs, as their appearance 
may be sub-clinical (for example an asymptomatic laboratory abnormality), and early diagnosis 
is critical for appropriate management and to possibly prevent complications. Serological, 
immunological and histological assessments (such as biopsy of the affected tissue) should be 
performed as deemed appropriate by the investigator to verify the potential immune-mediated 
nature of the AE and to exclude alternative diagnoses or disease progression. Response to 
corticosteroids, if indicated, may contribute to the identification of an AE as irAE.  
Recommended guidelines for prophylactic or supportive treatment for expected toxicities, 
including identification and management of study-drug induced adverse events, are provided in 
Section 6.5.1.1 and Section 6.5.1.2. The risks to participants in this trial may be minimized by 
compliance with the eligibility criteria and study procedures as well as close clinical monitoring.  
Appropriate eligibility criteria and specific dose modification and stopping rules, along with 
adverse event management guidelines (provided in Section 6.5), are included in this protocol. 
Recommended guidelines for prophylactic or supportive management of study-drug induced 
adverse events are provided in same section. There may be unforeseen risks with LAG525 and 
spartalizumab in combination with carboplatin, which could be serious. Refer also to preclinical 
toxicity and/or clinical data found in the latest [LAG525 and PDR001 Investigator’s 
Brochures]. 
Novartis considers the potential risks of the combination regimens with LAG525, 
spartalizumab, and carboplatin are justified by the anticipated benefits that may be afforded to 
participants. 
In addition, prior to enrollment, this protocol will undergo appropriate review by local and 
regional governance bodies including ethic committees and drug regulatory bodies. 
4.5.3 
Risks related to study procedures 
Study related risks include, but are not limited to collection of fresh tumor samples, blood 
collections, and the different imaging methods included. Please refer to the study consent form 
for more information. 
4.6 
Rationale for Public Health Emergency mitigation procedures 
During a Public Health emergency as declared by Local or Regional authorities (i.e. pandemic, 
epidemic or natural disaster), mitigation procedures to ensure participant safety and trial 
integrity are listed in relevant sections. Notification of the Public health emergency should be 
discussed with Novartis prior to implementation of mitigation procedures, and 


Novartis 
Confidential 
Page 50 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
permitted/approved by Local or Regional Health Authorities and Ethics Committees as 
appropriate.  
5 
Study Population 
The study will include patients with advanced (loco-regionally recurrent not amenable to 
curative therapy or metastatic) TNBC which progressed after adjuvant or one prior line of 
systemic therapy for metastatic disease and never received prior treatment with an immune-
checkpoint inhibitor. 
Participants enrolled in this study are not permitted to participate in additional parallel 
investigational clinical studies. 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. 


Novartis 
Confidential 
Page 51 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
5.1 
Inclusion criteria 
Participants eligible for inclusion in this study must meet all of the following criteria: 
1. Patient is an adult ≥ 18 years old at the time of informed consent, and has signed informed 
consent before any trial related activities and according to local guidelines 
2. Patient has advanced (loco-regionally recurrent not amenable to curative therapy or 
metastatic) breast cancer.  
3. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status of 0 or 1. 
4. Patient has adequate bone marrow and organ function as defined by the following 
laboratory values (as assessed by central laboratory for eligibility): 
• Absolute neutrophil count ≥ 1.5× 109/L 
• Platelets ≥ 100 × 109/L 
• Hemoglobin ≥ 9.0 g/dL 
• Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) ≥ 40 
mL/min 
• Alanine aminotransferase (ALT) < 3 x ULN, except for patients that have tumor 
involvement of the liver, who may only be included if ALT ≤5.0 x ULN who are 
excluded if ALT > 5 x ULN 
• Aspartate aminotransferase (AST) < 3 x ULN, except for patients that have tumor 
involvement of the liver, who may only be included if AST ≤5.0 x ULN who are 
excluded if AST > 5 x ULN 
• Total serum bilirubin < 1.5 ULN; or total bilirubin ≤ 3.0 × ULN with direct bilirubin 
within normal range of the central laboratory in patients with well documented 
Gilbert’s Syndrome 
5. Patient must have measurable disease, i.e., at least one measurable lesion as per RECIST 
1.1 criteria (Tumor lesions previously irradiated or subjected to other loco-regional 
therapy will only be considered measurable if disease progression at the treated site after 
completion of therapy is clearly documented). 
6. Patient progressed after adjuvant or 1 prior systemic treatment in the advanced setting. 
Patients with de novo metastatic disease are eligible if they received 1 prior line of 
therapy. 
7. Patient must have received prior systemic treatment that included taxane-based 
chemotherapy for adjuvant or metastatic disease. 
8. Patient must have a site of disease amenable to biopsy, and must be willing to undergo a 
new tumor biopsy at screening and during therapy on this study, the latter if medically 
feasible. Patients with an available archival tumor tissue do not need to perform a tumor 
biopsy at screening if patient has not received anti-cancer therapy since the biopsy was 
taken. 
9. Patient has histologically and/or cytologically confirmed diagnosis of advanced TNBC 
(based on most recently analyzed biopsy from locally recurrent or metastatic site, local 
lab) meeting the following criteria: HER2 negative in situ hybridization test or an IHC 
status of 0 or 1+, and ER and PR expression is <1 percent as determined by 
immunohistochemistry (IHC) Hammond et al 2010. 


Novartis 
Confidential 
Page 52 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
5.2 
Exclusion criteria 
Participants meeting any of the following criteria are not eligible for inclusion in this study. 
1. Patient has received prior immune checkpoint inhibitors as anticancer treatment, such as 
anti-LAG-3, anti-PD-1, anti-PD-L1, or anti-PD-L2 antibody (any line of therapy). 
2. Patient received prior neoadjuvant or adjuvant therapy with a platinum agent or 
mitomycin and experienced recurrence within 12 months after the end of the platinum-
based or mitomycin containing therapy, or received platinum or mitomycin for advanced 
disease. 
3. Patient is concurrently using other anti-cancer therapy. 
4. Patient has had major surgery within 14 days prior to starting study treatment or has not 
recovered to grade 1 or less from major side effects. 
5. Patient with presence of CTCAE grade 2 toxicity or higher due to prior cancer therapy. 
Exception: Patients with any grade of alopecia are allowed to enter the study. 
6. Patient has received radiotherapy ≤ 4 weeks prior to randomization (≤ 2 weeks for limited 
field radiation for palliation), and has not recovered to grade 1 or better from related side 
effects of such therapy (with the exception of alopecia). 
7. Patient has a known hypersensitivity to other monoclonal antibodies, platinum-containing 
compounds, or to any of the excipients of LAG525, spartalizumab, or carboplatin. 
8. Patient with history of Stevens-Johnson Syndrome or Toxic Epidermal Necrolysis, or a 
history of severe hypersensitivity reactions, which in the opinion of the investigator may 
pose an increased risk of serious infusion reaction. 
9. History of acute pancreatitis within 1 year of screening or past medical history of chronic 
pancreatitis. 
10. Clinically significant cardiac disease or impaired cardiac function, including any of the 
following: Cardiac or cardiac repolarization abnormality, including any of the following: 
i. 
History of myocardial infarction (MI), angina pectoris, coronary artery bypass graft 
(CABG) within 6 months prior to randomization 
ii. 
History or current diagnosis of myocarditis 
iii. 
Cardiac troponin T (TnT) or I (TnI) elevated > 2 x ULN at screening. Repeat 
Troponin test if values are between >1 and 2 x ULN  
• Patients with a screening or repeat levels ≤ 1 x ULN may be included.  
• If repeat Troponin levels are > 1 and < 2 x ULN, patient can be included at the 
investigator’s discretion after cardiac assessment 
• Repeat assessment should be performed the following day if possible but may be 
later.  
iv. 
Clinically significant cardiac arrhythmias (e.g., ventricular tachycardia), complete left 
bundle branch block, high-grade AV block (e.g., bifascicular block, Mobitz type II 
and third degree AV block) or uncontrolled hypertension 
v. 
QTcF > 470 msec on screening central ECG or long QT syndrome, family history of 
idiopathic sudden death or congenital long QT syndrome, or any of the following: 


Novartis 
Confidential 
Page 53 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Risk factors for Torsades de Pointe (TdP) including uncorrected hypokalemia or 
hypomagnesemia, history of cardiac failure, or history of clinically 
significant/symptomatic bradycardia 
• Concomitant medication(s) known to cause Torsades de Pointe” per 
www.qtdrugs.org that cannot be discontinued or replaced by safe alternative 
medication. (within 5 half-lives or 7 days prior to starting study drug) 
• Inability to determine the QTcF interval 
11. Patient has active, known or suspected autoimmune disease or immune deficiency. 
Patients with vitiligo, type I diabetes on stable insulin, residual hypothyroidism only 
requiring hormone replacement, psoriasis not requiring systemic treatment or conditions 
not expected to recur in the absence of an external trigger should not be excluded. 
12. History of allogenic bone marrow or solid organ transplant. 
13. History of or current interstitial lung disease or pneumonitis, including clinically 
significant radiation pneumonitis (i.e., affecting activities of daily living or requiring 
therapeutic intervention). 
14. Patient has a concurrent malignancy or malignancy within 3 years of randomization, with 
the exception of adequately treated basal or squamous cell carcinoma, non-melanomatous 
skin cancer or curatively resected carcinoma in situ of any type. 
15. Patient has 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 2 weeks prior to first dose of study 
treatment. Patients with treated brain metastases should be neurologically stable and 
without CNS progression for at least 12 weeks prior to randomization and have 
discontinued corticosteroid treatment (with the exception of < 10 mg/day of prednisone or 
equivalent for an indication other than CNS metastases) for at least 4 weeks before first 
dose of any study treatment. 
16. Patient has carcinomatous meningitis 
17. Patient has clinically significant active bleeding or history thereof within four weeks prior 
to randomization. 
18. Patient has active infection requiring systemic antibiotic therapy. Patients requiring 
systemic antibiotics for infection must have completed therapy before screening is 
initiated. 
• Patient has a known history of HIV infection (testing not mandatory). 
 
Note: As per local regulations or requirements (e.g. HA, EC/IRB), HIV testing during 
screening may be mandated.  
• Patients with active Hepatitis B infection (HBsAg positive) or hepatitis C infection. 
Note: Patients with antecedent of Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA 
negative) are eligible. 
• Patients with positive test for hepatitis C ribonucleic acid (HCV RNA). 
Note: Patients in whom HCV infection resolved spontaneously (positive HCV antibodies 
without detectable HCV-RNA) or those that achieved a sustained virological response 
after antiviral treatment and show absence of detectable HCV RNA ≥ 6 months (with the 


Novartis 
Confidential 
Page 54 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
use of IFN-free regimes) or ≥ 12 months (with the use of IFN-based regimes) after 
cessation of antiviral treatment are eligible. 
19. Patient received any live vaccine against infectious disease (e.g., varicella, yellow fever 
vaccine) within 4 weeks of initiation of study treatment 
20. Patient is currently receiving or has received systemic corticosteroids or any 
immunosuppressive therapy (≥ 10mg/day prednisone or equivalent) within 7 days prior to 
starting study drug (other than replacement-dose steroids in the setting of adrenal 
insufficiency), or who have not fully recovered from side effects of such treatment. 
Topical, inhaled, nasal and ophthalmic steroids are allowed. 
21. Patient has 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  
22. Participation in an interventional, investigational study within 2 weeks prior to the first 
dose of study treatment 
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 study treatment and for 6 months after the last dose of any study treatment. 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 6 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 
• Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
Women are considered postmenopausal and not of child bearing potential if they have had 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e., 
age appropriate, history of vasomotor symptoms) 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 unwilling to use a condom during intercourse while taking study 
treatment, and up for 6 months after stopping study treatment. A condom is required for 
all sexually active male participants to prevent them from fathering a child AND to 
prevent delivery of study treatment via seminal fluid to their partner. In addition, male 
participants must not donate sperm for the time period specified above. 
25. Pregnant or nursing (lactating) women confirmed by a positive hCG central laboratory test 
within 72 hours prior to initiating study treatment.  


Novartis 
Confidential 
Page 55 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
6 
Treatment 
6.1 
Study treatment 
For this study, the investigational drugs are LAG525 and spartalizumab (PDR001). The study 
treatment was defined as LAG525 and spartalizumab or LAG525 with or without spartalizumab 
in combination with carboplatin. With protocol amendment 3, enrollment to Arm 1 (LAG525 
+ spartalizumab) was prematurely closed. Subsequent enrolled participants will be randomized 
to either Arm 2 (LAG525 + spartalizumab + carboplatin) or Arm 3 (LAG525 + carboplatin). 
All drugs will be administered as infusion. 
Infusion must take place in a facility with appropriate resuscitation equipment available at the 
bedside and a physician readily available during the period of drug administration. The 
participant should be closely observed for potential infusion-related reactions including rigors, 
chills, wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever and the vital signs 
should be monitored more frequently if clinically indicated, during infusions and for at least 2 
hours after the last infusion for the first 2 cycles. The same close observation may be applied 
for the subsequent cycles if medically indicated. 
All dosages prescribed and administered to participants and all dose interruptions and changes 
during the study must be recorded on the appropriate electronic Case Report Form (eCRF) page. 
6.1.1 
Investigational and control drugs 
LAG525 and spartalizumab will be supplied by Novartis Drug Supply Management or its 
designee in vials as a liquid formulation for infusion. 
Carboplatin packaging and labeling will be performed according to locally available supplies 
of carboplatin. 
Table 6-1 
Investigational and combination drug 
Investigational/ 
Combination Drug 
(Name and Strength) 
Pharmaceutical 
Dosage Form 
Route of 
Administration 
Supply 
Type 
Sponsor 
(global or 
local) 
LAG525 100mg 
Concentrate for 
solution for infusion 
Intravenous use 
Open-label 
patient 
specific; 
vials 
Sponsor 
global 
spartalizumab 100mg 
Concentrate for 
solution for infusion 
Intravenous use 
Open-label 
patient 
specific; 
vials 
Sponsor 
global 
carboplatin 10mg/mL 
Concentrate for 
solution for infusion 
Intravenous use 
Open-label 
bulk supply; 
vials 
Local 
6.1.1.1 
Treatment regimen 
The recommended dose for the combination of LAG525 + spartalizumab and single agent dose 
of LAG525 have already been established ([CLAG525X2101C], Section 4.2) and will remain 


Novartis 
Confidential 
Page 56 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
constant at the established RDE (LAG525 400mg and spartalizumab 300mg both i.v. every 21 
days). 
Carboplatin will be dosed per AUC 6 given intravenously on day 1 of every 3-week cycle. 
All drugs should be given on the same day. 
Table 6-2 
Dosing regimen 
Dose Level 
LAG525 (i.v.) mg  
spartalizumab  (i.v.) mg  
carboplatin 
(i.v.)  
Starting Dose 
400mg Q3W 
300mg Q3W 
AUC 6 Q3W 
6.1.1.2 
LAG525 and LAG525 + spartalizumab administration 
LAG525 and spartalizumab will be administered via i.v. infusion over 30 minutes once every 3 
weeks. Infusions of each antibody can be extended to up to 2 hours if clinically indicated. 
For participants who receive both drugs, they will be administered separately in the same 
fashion with at least a 30-min break between the two antibody infusions. 
Both study drugs may be infused using the same i.v. access site. LAG525 will be given first 
followed by spartalizumab. 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 spartalizumab infusion must be delayed until it is safe for the 
participant to receive spartalizumab based on the clinical judgement of the investigator. The 
delay between LAG525 and spartalizumab infusions can be up to 4 hours if clinically indicated. 
If spartalizumab cannot be administered safely within 4 hours after LAG525 administration, the 
dose must be omitted. 
6.1.1.3 
Carboplatin administration 
Carboplatin will be administered every three weeks via i.v. infusion over 15 to 60 minutes once 
LAG525 and spartalizumab infusions are completed. A break of 30 minutes must be observed 
between any infusions. Any pre-medications should be administered as per local standard 
practice. 
The dose of carboplatin will be adjusted in order to not exceed 900 mg corresponding to a GFR 
(based on the Calvert formula) capped at 125 mL/min FDA guidance 2010. 
Doses subsequent to the initial dose administered at Cycle 1 Day 1 should be adjusted according 
to the local prescribing information for carboplatin. 
6.1.2 
Additional study treatments 
No additional treatment beyond the investigational drugs LAG525 and spartalizumab and the 
combination drug carboplatin is included in this trial. 
6.1.3 
Treatment arms/group 
Participants were assigned at Cycle 1 Day 1 visit to one of the following 3 treatment arms in a 
ratio of 1:1:1: 


Novartis 
Confidential 
Page 57 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• LAG525+spartalizumab (Arm 1) 
• LAG525+spartalizumab+carboplatin (Arm 2) 
• LAG525+carboplatin (Arm 3) 
Starting with protocol amendment 3, participants will be assigned at Cycle 1 Day 1 visit to Arm 
2 or Arm 3 in a ratio of 1:1. 
Treatment crossover from one arm to another arm will not be permitted in this study. 
6.1.4 
Guidelines for continuation of treatment 
Please refer also to Sections 6.5.1 and 6.5.2. 
6.1.5 
Treatment duration 
Study treatment will continue until the participant experiences one of the following: disease 
progression per investigator’s assessment by RECIST 1.1 (if not meeting the criteria for 
treatment continuation beyond disease progression as stipulated in Section 6.1.5.1) 
 
, unacceptable toxicity, pregnancy, 
treatment is discontinued at the discretion of the investigator or the participant, start of a new 
anti-neoplastic therapy, withdrawal of consent, lost to follow-up, death, or study is terminated 
by the sponsor. 
The investigator may decide to stop carboplatin after 6 cycles, even if the above criteria are not 
met. 
Participants who continue to derive clinical benefit from the treatment based on the 
investigator’s evaluation may receive post-trial access (PTA). PTA means the provision of 
treatment to trial participants following their completion of this trial (EOT visit will be required 
prior to PTA). PTA will be provided until one of the following is met: participant no longer 
derives clinical benefit, investigator discontinues treatment, launch or reimbursement (where 
applicable), treatment fails to achieve registration in the trial participant’s country, or the 
clinical program is discontinued for any other reason 
Mechanisms for provision of PTA may include an extension phase to this study, a separate 
extension protocol, a rollover protocol, provision of the Novartis investigational product in a 
non-trial setting (known as post-study drug supply [PSDS]) when no further safety or efficacy 
data are required, or any other mechanism appropriate for the country. 
The PTA mechanism must comply with local laws and regulations in the participating trial 
countries. If Novartis discontinues the PTA for this trial, Novartis will work with investigators 
to transition participants onto locally available alternative treatment, or standard of care. 
6.1.5.1 
Treatment beyond disease progression 
Emerging clinical data indicate that participants may derive benefit from continuing treatment 
with immunotherapy despite initial evidence of disease progression. 
Participants who received at least one dose of IO compound LAG525 and/or spartalizumab will 
be permitted to continue study treatment beyond initial disease progression per RECIST 1.1 
, unacceptable toxicity, pregnancy, treatment is discontinued at the 


Novartis 
Confidential 
Page 58 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
discretion of the investigator or the participant, start of a new anti-neoplastic therapy, 
withdrawal of consent, lost to follow-up, death, or study is terminated by the sponsor, provided 
they meet all of the following criteria: 
1. Additional informed consent for treatment beyond disease progression per RECIST 1.1 is 
provided by the participant 
2. 
 
3. the continuation of treatment beyond progression will not delay an imminent intervention 
to prevent serious complications of disease progression (e.g. CNS metastases) 
4. participant exhibits adequate tolerance to study treatment 
5. participant performance status is stable 
Participants who meet the above criteria should continue study treatment beyond initial disease 
progression per RECIST 1.1 and continue all study procedures as outlined in Section 8.The 
reasons for the participant continuing treatment will be documented in the eCRF. 
In case of clinical deterioration or suspicion of disease progression, a follow-up imaging 
assessment should be performed promptly rather than waiting for the next scheduled 
assessment. Participants that are no longer deriving clinical benefit 
 
 must be discontinued. 
6.2 
Other treatment(s) 
6.2.1 
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 participant are allowed as follows:  
• Medications to prevent or treat nausea or vomiting. 
• Anti-diarrheal medications (e.g., loperamide) for participants who develop diarrhea. 
• Pain medication to allow the participant to be as comfortable as possible. 
• Treatment with bisphosphonates or denosumab and/or limited-field palliative radiotherapy 
or surgery for pre-existing painful bone metastases is permitted. Participants requiring 
initiation of such treatment during the course of the study must be evaluated for disease 
progression. Radiotherapy like any concomitant medication must be listed on the CRF. 
LAG525/spartalizumab should be held for ≥1 week prior to radiotherapy or surgery, and 
may be resumed ≥2 weeks after radiation or surgery, provided the participant has recovered 
from radiation or surgery related toxicity. Caution is advised for radiation to fields that 
include lung tissue because of the potential increased risk of pneumonitis when lung 
radiotherapy is used during therapy with checkpoint inhibitors. 
• Immunosuppressive agents to treat suspected irAEs. 
• Hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents as per local or published 
guidelines; in case of anemia, thrombocytopenia or neutropenia, potential immune-
mediated etiology should be ruled out. 
• Nutritional support or appetite stimulants. 
• Oxygen therapy and blood products or transfusions. 


Novartis 
Confidential 
Page 59 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Inactivated vaccines. 
The participant must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications, procedures and significant non-drug 
therapies (including physical therapy, herbal/natural medications, and blood transfusions) 
administered after the participant was enrolled into the study must be recorded in the 
concomitant medications / significant non-drug therapies or procedures pages. 
Each concomitant drug must be individually assessed against all exclusion criteria/prohibited 
medication. If in doubt the investigator should contact the Novartis/sponsor medical monitor 
before randomizing a participant or allowing a new medication to be started. If the participant 
is already enrolled, contact Novartis/sponsor to determine if the participant should continue 
participation in the study. 
Please refer to Section 6.2.2 for prohibited medication. 
6.2.1.1 
Permitted concomitant therapy requiring caution and/or action 
Anticoagulation and anti-aggregation agents are permitted if the participants are already at 
stable doses for > 2 weeks at time of first dose and International Normalized Ratio (INR) should 
be monitored as clinically indicated per investigator’s discretion. However, ongoing 
anticoagulant therapy should be temporarily discontinued to allow tumor sample according to 
the institutional guidelines. 
In cases of isolated brain progression or other local progression, participants may receive 
palliative radiotherapy or surgery. In addition, localized, palliative radiotherapy for preexisting 
bone/liver metastases is permitted. LAG525/spartalizumab should be held for ≥1 week prior to 
radiotherapy or surgery. LAG525/spartalizumab may be resumed ≥2 weeks after radiation or 
surgery, provided the participant has recovered from radiation or surgery related toxicity. 
Chemotherapy should be held based on institutional guidelines. If palliative radiotherapy or 
surgery is initiated after start of study treatment, the reason for its use must be clearly 
documented and progression as per RECIST 1.1 must be assessed and documented. In case of 
continuation of study treatment beyond disease progression by RECIST 1.1, the participant will 
continue assessments as defined in Section 8. 
6.2.2 
Prohibited medication 
During the course of the study, participants must not receive other antineoplastic therapies (e.g. 
investigational drugs, devices, chemotherapy, immunotherapies) except those specified in the 
protocol or any other therapies that may be active against cancer or modulate the immune 
responses. However, limited-field palliative radiotherapy may be allowed as concomitant 
therapy (see above). 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, and for prophylaxis against imaging contrast dye 
allergy, standard pre-medication for chemotherapy or replacement-dose steroids in the setting 
of adrenal insufficiency (provided the replacement dose for adrenal insufficiency is < 10 mg/day 
prednisone or equivalent), or transient exacerbations of other underlying diseases such as COPD 
requiring treatment.  


Novartis 
Confidential 
Page 60 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
The use of live vaccines is not allowed through the whole duration of the study. Inactivated 
vaccines are allowed. 
There are no prohibited therapies during the post-treatment follow-up period. 
6.2.3 
Treatments for potential infusion reactions with spartalizumab or 
LAG525 
If a participant experiences an infusion reaction, he/she may receive pre-medication in 
subsequent cycles where the infusion of LAG525 and/or spartalizumab is administered. The 
pre-medication should be chosen per institutional standard of care, at the discretion of the 
treating physician.  
Acute allergic reactions should be treated per institutional standard of care. This includes any 
therapy 
necessary 
to 
restore normal 
cardiopulmonary 
status in 
the 
event of 
anaphylactic/anaphylactoid reactions. 
If a participant experiences a Grade 3 or higher infusion reaction or anaphylactic/anaphylactoid 
reaction, the participant will permanently discontinue LAG525/spartalizumab treatment. 
Further guidelines on management of LAG525/spartalizumab infusion reactions are provided 
in Table 6-9. 
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction”, “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation. 
6.3 
Participant numbering, treatment assignment, randomization 
6.3.1 
Participant numbering 
Each participant is identified in the study by a Participant Number (Participant No.), that is 
assigned when the participant is first enrolled for screening and is retained as the primary 
identifier for the participant throughout his/her entire participation in the trial. The Participant 
No. consists of the Center Number (Center No.) (as assigned by Novartis to the investigative 
site) with a sequential participant number suffixed to it, so that each participant is numbered 
uniquely across the entire database. Upon signing the informed consent form, the participant is 
assigned to the next sequential Participant No. available. 
The investigator or designated staff will contact the IRT and provide the requested identifying 
information for the participant to register them into the IRT. Once assigned, the Participant No. 
must not be reused for any other participant and the Participant No. for that individual must not 
be changed, even if the participant is re-screened. If the participant fails to be randomized or 
start treatment for any reason, the reason will be entered into the Disposition page.  
IRT must be notified within 2 days that the participant was not randomized. 


Novartis 
Confidential 
Page 61 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
6.3.2 
Treatment assignment, randomization 
Participants were assigned to one of the three treatment arms in a ratio of 1:1:1. Starting with 
protocol amendment 3, participants will be assigned to Arm 2 and Arm 3 only in a ratio of 1:1 
(Section 3 and Section 6.1). 
Randomization will be stratified by the presence of liver metastasis and line of therapy (first 
line or second line). 
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased. A participant randomization list will be produced by the 
Interactive Response Technology (IRT) provider using a validated system that automates the 
random assignment of participant numbers to randomization numbers. Random permuted 
blocks scheme will be used for this study. The randomization numbers are linked to the different 
treatment arms, which in turn are linked to medication numbers. A separate medication 
randomization list will be produced by or under the responsibility of Novartis Drug Supply 
Management using a validated system that automates the random assignment of medication 
numbers to medication packs containing each of the study treatments. 
Prior to dosing, all participants who fulfill all inclusion/exclusion criteria will be randomized 
via IRT to one of the treatment arms. The investigator or his/her delegate will call or log on to 
the IRT and confirm that the participant fulfills all the inclusion/exclusion criteria. The IRT will 
assign a randomization number to the participant, which will be used to link the participant to 
a treatment arm and will specify a unique medication number for the first package of study 
treatment to be dispensed to the participant. The randomization number will not be 
communicated to the caller. 
6.4 
Treatment blinding 
Treatment will be open to participants, investigator staff, persons performing the assessments, 
and the Novartis representatives from the Clinical Trial Team. 
6.5 
Dose escalation and dose modification 
Study treatment dose escalation is not permitted. 
6.5.1 
Dose modifications 
For participants who do not tolerate the protocol-specified dosing schedule, dose interruptions 
(LAG525 and spartalizumab and carboplatin) and/or reductions (carboplatin) are either 
recommended or mandated in order to allow participants to continue the study treatment. 
Dose modification recommendations are made for each of the study drugs (for compound 
specific toxicities). Participants who discontinue a drug of the combination regimens (or two 
drugs of the triplet) for toxicity and continue on the other drug(s) may remain on study. 
The following sections address the specific instructions for mandatory dose modifications and 
recommended management for adverse events considered suspected to be related to LAG525 
and/or spartalizumab and/or carboplatin. These modifications/interruptions must be recorded 
on the Study Treatment form in EDC system. 


Novartis 
Confidential 
Page 62 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
The investigators should try to exclude any other etiology and try to identify the most likely 
drug of the combination to cause the AE. 
If the causality of the suspected AE is difficult to determine, the investigator should assume that 
there is contribution from all drugs (LAG525, spartalizumab, carboplatin). 
6.5.1.1 
LAG525 and spartalizumab dose interruptions 
Dose interruption for LAG525 and spartalizumab includes delaying or withholding the 
treatment for any reason (e.g., AE) as well as an interruption of treatments during an infusion. 
The dose may be interrupted for up to 12 weeks (counted from the time the irAE reaches a grade 
that leads to LAG525/spartalizumab interruption). If a participant requires a dose interruption 
of spartalizumab and/or LAG525 of more than 12 weeks, then the participant must discontinue 
the study drug which was interrupted. 
If an AE occurs that requires interruption of LAG525/spartalizumab or carboplatin, then 
treatment for all drugs should be delayed up to a maximum of 2 weeks. If after a maximum of 
a 2 week delay, the AE has resolved to allow administration of LAG525/spartalizumab or 
carboplatin, but not both, the permitted study medication should be resumed. Treatment with 
just the permitted study medication can continue until the AE has resolved to allow resumption 
of treatment with all prescribed study drugs. However, carboplatin can be interrupted for a 
maximum of 42 days, and LAG525/spartalizumab can be interrupted for a maximum of 12 
weeks. If the participant progresses during the dose interruption, or there is no rationale/clinical 
benefit of continuing therapy, the participant should be discontinued any time earlier. 
Dose management for specific potentially immune-related AEs is summarized in Table 6-3, 
Table 6-4, Table 6-5, Table 6-6, Table 6-7, Table 6-8, Table 6-9 and Table 6-10. In case of any 
other AE that is not listed in the guidance tables and thought to be related to study drugs, and 
whether or not the AE is deemed to be immune related, treatment should be interrupted and 
restarted only after the toxicity has been resolved to grade 1 or lower. Deviations to mandatory 
dose interruptions are not allowed. Permanent treatment discontinuation is mandatory for 
specific events indicated as such in below tables or listed in Section 9.1.1. 
6.5.1.2 
Dose interruption requirements for potential immune-mediated 
adverse events 
6.5.1.2.1 Identification of and management requirements for AEs of potential 
immune-mediated etiology (irAE) 
Adverse events of special interest (AESIs) include AEs of a potential immune-mediated 
etiology (irAE) that are associated with spartalizumab/LAG525 treatment. Investigators must 
be vigilant and carefully identify AEs that may be suggestive of potential irAEs as their 
appearance may be sub-clinical and early diagnosis is critical for its adequate management and 
resolution. Collaboration with disease-specific subspecialties is encouraged; corticosteroids are 
the mainstay of treatment for most irAEs. 
An irAE may be of low grade and self-limited, frequently involving the GI tract (i.e., 
diarrhea/colitis), skin (i.e., rashes, pruritus), liver (i.e., hepatitis), lung (i.e., pneumonitis), 
kidneys (i.e., nephritis) and endocrine systems (i.e. hypothyroidism, hyperthyroidism, type I 


Novartis 
Confidential 
Page 63 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
diabetes, hypophysitis including hypopituitarism and adrenal insufficiency). Other immune-
mediated AEs may rarely include the nervous system (e.g. encephalitis, Guillain-Barre 
syndrome, myasthenia gravis), eye (e.g. uveitis, vision changes), musculo-skeletal system (e.g. 
myositis, arthritis), pancreas (e.g. pancreatitis), cardio-vascular system (e.g. vasculitis, 
myocarditis) or blood system (e.g. anemia, cytopenias), and severe skin reactions such as toxic 
epidermal necrolysis or Stevens Johnson syndrome. Furthermore, complications in participants 
with bone marrow or solid organ transplant have been reported (e.g. organ rejection, severe 
graft-versus-host disease). However, nearly all organs can be affected by immune-mediated 
toxicities. IrAEs often occur relatively early (mostly within weeks to 3 months after treatment 
initiation), however, may develop at any time during treatment (even after several months), and 
may also occur after the treatment discontinuation. Serological, immunological and histological 
assessments should be performed as deemed appropriate by the investigator, to verify the 
potential immune-related nature of the AE, and exclude a neoplastic, infectious or metabolic 
origin of the AE. 
Severe grade or persistent lower grade irAEs typically require interrupting or permanently 
discontinuing treatment and administration of systemic steroids, and sometimes other 
immunosuppressive medications (e.g., tumor necrosis factor alpha (TNFa) antagonists, 
mycophenolate or tacrolimus). Early recognition and work-up of irAEs and initiation of 
treatment are critical to reduce the risk of complications, since the majority of irAEs are 
reversible with the use of steroids and other immune suppressants. Some events like 
endocrinopathies may require life-long hormonal replacement. Tapering of steroids should not 
be too rapid (i.e. > 4 weeks) to avoid recurrence or worsening of irAEs. The management of 
irAEs may further include initiation of antibiotics for prophylaxis against opportunistic 
infections. 
Participants should be instructed to return to the study site as soon as possible (instead of waiting 
for their next scheduled visit) if they experience symptoms consistent with an irAE. Participants 
who experience a new or worsening irAE should be contacted and/or evaluated by the study 
site more frequently. 
Based on experience and published guidelines on the management of irAEs in patients treated 
with immune checkpoint inhibitors (Brahmer et al 2018; Haanen et al 2017; NCCN 2018) 
instructions have been developed how to manage irAEs that may occur in participants receiving 
checkpoint inhibitors, such as spartalizumab and/or LAG525. Dose modification requirements 
and AE management guidelines for the potential irAEs are provided in the following tables: 
diarrhea/colitis (Table 6-3), hepatitis (liver laboratory alterations) (Table 6-4), skin (rash) 
(Table 6-5), nephritis (Table 6-6), pneumonitis (Table 6-7), endocrinopathies (Table 6-8), 
encephalitis and other potential immune-related AEs (Table 6-10). In addition, guidance for 
management of spartalizumab/LAG525 infusion-related reaction is provided in (Table 6-9). 
Under the category of OTHERS (Table 6-10) are included several irAE of interest that must be 
managed specifically and for which no specific guidance are provided in the table below. 
OTHERS include (but is not restricted to) the following events : Autoimmune neuropathy, 
demyelinating polyneuropathy, Guillain-Barre syndrome, myasthenia gravis-like syndrome, 
non-infectious myocarditis, non-infectious pericarditis, pancreatitis and, rapid onset of Grade 3 
fatigue in the absence of disease progression. 


Novartis 
Confidential 
Page 64 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Participants receiving spartalizumab and/or LAG525, may experience other irAEs than those 
listed in this document, therefore all AEs of unknown etiology associated with drug exposure 
should be evaluated to determine if it is possibly immune-related. In cases where the specific 
irAE is not listed in the tables below, the investigator should follow the guidance in 
Section 6.5.1.1. Investigators are encouraged to contact the Sponsor as needed to discuss cases 
that warrant separate discussion outside of the scope of the current instructions. 
The dosing modification requirements are mandatory; however, the AE management guidelines 
are recommendations and can be modified according to the local practices. 
General dose modification instructions: 
No changes in dose of spartalizumab and/or LAG525 are allowed. 
Overall AEs are to be graded according to NCI-CTCAE v5.0 (https://ctep.cancer.gov). All dose 
interruptions and the reason for the dose interruption must be documented in the eCRF. 
Overall, participants with AEs suspected to be related to spartalizumab or LAG525 including 
those of potential immune-mediated etiology (irAE) may need to interrupt or permanently 
discontinue study treatment as outlined in Section 6.5. 
Permanently discontinue spartalizumab/LAG525 for any of the following: 
1. Any life-threatening adverse reaction (excluding endocrinopathies controlled with 
hormone replacement therapy). 
2. Inability to reduce corticosteroid dose to 10 mg or less of prednisone or equivalent per day 
within 12 weeks. The 12 weeks’ timeframe will begin from the time the irAE reaches a 
grade that leads to spartalizumab and or LAG525 interruption. 
3. Persistent Grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to Grade 0-1 within 12 weeks after last 
dose of spartalizumab/LAG525. 
4. Any severe or Grade 3 treatment-related adverse reaction that recurs. 
Table 6-3 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related diarrhea/colitis 
Diarrhea/Colitis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose 
Modification requirements 
Grade 1 (Increase of <4 
stools per day over 
baseline; mild increase 
in ostomy output 
compared to baseline) 
• 
Symptomatic treatment 
(loperamide, hydration, diet) 
• 
Monitor closely 
 
• 
May continue 
spartalizumab/LAG525 
treatment 
 
Grade 2 (Increase of 4 - 
6 stools per day over 
baseline; moderate 
increase in ostomy 
output compared to 
baseline; limiting 
instrumental ADL) 
• 
Consult with GI specialist 
• 
Stool evaluation, imaging and 
endoscopy as clinically indicated 
• 
Symptomatic treatment 
(loperamide, hydration, diet) 
• 
Commence steroids  (0.5-1mg/kg 
per day of prednisone or i.v. 
equivalent) until symptoms improve 
• 
Interrupt 
spartalizumab/LAG525 
until diarrhea recovers to 
Grade ≤1 or baseline 


Novartis 
Confidential 
Page 65 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Diarrhea/Colitis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose 
Modification requirements 
and/or abdominal pain/ 
mucus or blood in stool. 
to Grade 1, particularly in case of 
persisting/worsening symptoms, 
ulcerations or bleeding seen on 
endoscopy, or blood in stool. If no 
improvement occurs within days, 
manage as per Grade 3. 
• 
Slowly taper steroids once 
symptoms improve to Grade 1 (ie. 
Over 4-6 weeks) 
Grade 3 Diarrhea: 
Increase of ≥7 stools per 
day over baseline;; 
hospitalization indicated; 
severe increase in 
ostomy output compared 
to baseline; limiting self-
care ADL; 
 
Grade 3 Colitis: Severe 
abdominal pain; 
peritoneal signs 
• 
Consider hospitalization; rule out 
bowel perforation and initiate i.v. 
hydration as needed. 
• 
Consultation with 
gastroenterologist and consider 
endoscopy and biopsy. 
• 
In addition to symptomatic 
treatment initiate treatment with i.v. 
steroids (1 to 2 mg/kg/d of 
methylprednisolone or equivalent) 
• 
Consider antibiotics as appropriate 
• 
If no improvement in 2-3 days: 
consider initiating infliximab 5mg/kg 
and continue steroids. (Infliximab is 
contraindicated in participants with 
sepsis/ perforation).  
• 
Slowly taper steroids once 
symptoms improve to Grade 1 (4 to 
6 weeks) 
• 
If symptoms worsen during steroid 
reduction, initiate a re-tapering of 
steroids starting at a higher dose of 
80 or 100 mg followed by a more 
prolonged taper and administer 
infliximab. 
• 
Interrupt 
spartalizumab/LAG525 
until diarrhea/colitis 
recovers to Grade ≤1 or 
baseline  
Grade 4: Life-
threatening 
consequences; urgent 
intervention indicated 
• Same as Grade 3 
• Permanently discontinue 
spartalizumab/LAG525 


Novartis 
Confidential 
Page 66 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 6-4 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related liver laboratory 
alterations 
Abnormal liver function tests 
Severity 
Recommended 
Adverse Event 
management 
guidelines 
Mandatory Dose Modification 
requirements 
Grade 2: AST or ALT >3.0 - 
5.0 x ULN if baseline was 
normal; >3.0 - 5.0 x 
baseline if baseline was 
abnormal or bilirubin >1.5 - 
3.0 x ULN if baseline was 
normal; >1.5 - 3.0 x 
baseline if baseline was 
abnormal  
(if participant meets criteria 
for potential drug-induced 
liver injury (DILI) cases 
refer to Section 6.5.2.1) 
• Monitor hepatic 
laboratory tests more 
frequently (every 2-3 
days) until returned 
to baseline values 
• Rule-out alternative 
causes (e.g. 
concomitant 
medications, 
infection, disease 
progression) 
• Consider prednisone 
(0.5-1 mg/kg/d) if 
liver tests worsen 
and/or significant 
symptoms 
• 
Interrupt spartalizumab/LAG525 
treatment until recovery to Grade ≤1 
or baseline  
• 
Once recovered restart 
spartalizumab/LAG525 
treatment at the same dose and 
schedule 
• 
Participants with baseline grade 2 
AST/ALT value (>3.0-5.0 ULN) may 
continue spartalizumab/LAG525 
treatment 
Grade 3 or 4: AST or 
ALT >5.0xULN and/or 
bilirubin > 3.0x ULN 
• 
Monitor hepatic 
laboratory tests more 
frequently (every 2-3 
days) until returned 
to baseline values. 
• 
Consult with 
hepatologist; 
consider 
hospitalization and 
liver biopsy to 
establish etiology 
• 
Initiate treatment with 
steroids (prednisone 
1-2 mg/kg/d or i.v. 
equivalent) 
• 
Add prophylactic 
antibiotics for 
opportunistic 
infections as 
appropriate 
• 
Once symptoms/liver 
tests improve to 
Grade ≤1, taper 
steroids over at least 
4 weeks 
• 
If no improvement or 
steroid refractory 
• 
Permanently discontinue 
spartalizumab/LAG525 
• 
Participants with baseline grade 2 
AST/ALT value (>3.0-5.0 ULN) will 
discontinue spartalizumab/LAG525 
treatment if value increased to grade 
3 with increase >=2x baseline, or to 
grade 4 


Novartis 
Confidential 
Page 67 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Abnormal liver function tests 
Severity 
Recommended 
Adverse Event 
management 
guidelines 
Mandatory Dose Modification 
requirements 
after 3 days, 
consider oral 
mycophenolate as 
per local treatment 
guidance 
• 
Infliximab is not 
recommended due to 
its hepatotoxicity 
potential 
* Send viral serology looking for hepatitis A, B, C & CMV and rule out any potential cause of liver injury 
(i.e., alcohol, other medications, etc.) Note: For additional information on follow-up of potential drug 
induced liver injury cases, refer to Section 6.5.2.1. 
Table 6-5 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related skin events 
Skin Events (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse 
Event management 
guidelines 
Mandatory Dose Modification requirements 
Grade 1 (e.g. 
Rash, pruritus) 
covering < 10% 
Body Surface 
Area (BSA) 
• 
Initiate prophylactic and 
symptomatic treatment 
measures. 
• 
Consider mild/moderate 
potency topical steroids 
or urea containing 
creams in combination 
with oral antipruritics 
• 
Reassess after 2 weeks 
• Continue spartalizumab/LAG525 treatment 
Grade 2 (e.g. 
Rash, pruritus): 
10-30% of BSA 
• 
Consider initiating 
systemic steroids (e.g., 
oral prednisolone 0.5-
1mg/kg daily) and 
consider dose 
interruption 
• 
In addition, treat with 
topical emollients, oral 
antihistamines, and 
medium/high-potency 
topical steroids 
• 
If symptoms persist or 
recur consider skin 
biopsy 
• 
Consider dose interruption 
• 
In case of bullous dermatitis, acute 
generalized exanthematous pustulosis or 
Drug Reaction with Eosinophilia and 
Systemic Symptoms (DRESS), interrupt 
spartalizumab/LAG525 until recovery to 
Grade ≤1 or baseline 
 
 
Grade 3 (e.g. 
Rash, pruritus): 
More than 30% 
of BSA,  
• 
Consult with 
dermatologist and 
consider skin biopsy 
 
• 
Interrupt spartalizumab/LAG525 until 
recovery to Grade ≤1 or baseline  


Novartis 
Confidential 
Page 68 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Skin Events (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse 
Event management 
guidelines 
Mandatory Dose Modification requirements 
Other severe 
cutaneous 
adverse 
reactions 
Bullous 
dermatitis 
• Initiate systemic steroids 
(1mg/kg/d  prednisolone 
or i.v. equivalent); 
consider increasing if no 
improvement 
• High-potency topical 
steroids  
• Topical emollients, oral 
antihistamines as 
indicated 
• 
Consider gamma-
aminobutyric acid 
(GABA) agonists or 
aprepitant in case of 
severe pruritus 
 
• 
For participants with severe cutaneous 
adverse reaction or bullous dermatitis, 
risk/benefit before resuming treatment 
should be carefully considered. 
 
Grade 4: Life-
threatening 
• Urgent dermatologic 
consultation and 
additional measures as 
per local guidelines. 
• Permanently discontinue 
spartalizumab/LAG525 
Stevens-Johnson 
syndrome, toxic 
epidermal 
necrolysis  
• 
Hospitalization and 
urgent dermatology 
consultation 
• 
institute supportive care 
immediately as per 
institutional guidelines 
• Permanently discontinue 
spartalizumab/LAG525 
Table 6-6 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related nephritis* 
Nephritis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse 
Event management 
guidelines 
Mandatory Dose Modification 
requirements 
Grade 1: 
Creatinine >ULN to 
≤1.5x ULN 
• 
Monitor creatinine weekly 
• 
Rule-out other causes 
(e.g. fluids, medications, 
i.v. contrast) 
• 
Promote hydration and 
cessation of nephrotoxic 
drugs 
• Continue spartalizumab/LAG525 
treatment 
Grade 2: Creatinine >1.5 
- 3.0 x baseline; >1.5 to 
≤ 3.0 x ULN 
• 
Monitor creatinine every 2 
to 3 days and consult with 
nephrologist 
• 
Rule-out other causes 
(e.g. fluids, medications, 
i.v.contrast) 
• 
Interrupt spartalizumab/LAG525 
until serum creatinine recovers to ≤ 
Grade 1 or baseline  
 


Novartis 
Confidential 
Page 69 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Nephritis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse 
Event management 
guidelines 
Mandatory Dose Modification 
requirements 
• 
Initiate 0.5 to 1 mg/kg/day 
prednisone or equivalents 
if other causes are ruled 
out 
• 
If worsening or no 
improvement: 1 to 2 
mg/kg/day prednisone 
equivalents 
• 
Promote hydration and 
cessation of nephrotoxic 
drugs 
• 
Consider renal biopsy 
Grade 3: Creatinine >3.0 
x baseline; >3.0 to <6 x 
ULN 
• 
Monitor creatinine every 1 
to 2 days and consider 
hospitalization 
• 
Consult with nephrologist 
and consider renal biopsy 
• 
Start 1 to 2 mg/kg/day 
prednisone equivalents 
• 
Once event improves to 
Grade ≤1, slowly taper 
steroids over at least 4-6 
weeks 
• Permanently discontinue 
spartalizumab/LAG525 
Grade 4: Creatinine > 
6.0 x ULN 
• 
Same as Grade 3 
• 
hospital for close 
monitoring and 
management as per 
institutional guidelines 
• Permanently discontinue 
spartalizumab/LAG525 
*In participants with impaired renal function, dosage of carboplatin should be reduced as per local 
labeling for carboplatin and hematologic nadirs and renal function monitored. 
Table 6-7 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related pneumonitis 
Pneumonitis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Grade 1: 
Asymptomatic; clinical 
or diagnostic 
observations only; 
intervention not 
indicated 
• 
Chest imaging/CT scan; repeat 
imaging in 3-4 weeks or as 
clinically indicated  
• 
Monitor symptoms every 2-3 
days, clinical evaluation and 
laboratory work-up for infection; 
pulse oximetry 
• 
Consultation with pulmonologist 
recommended 
• Consider interruption of  
spartalizumab/LAG525 


Novartis 
Confidential 
Page 70 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Pneumonitis (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Grade 2: Symptomatic-
medical intervention 
indicated; limits 
instrumental ADLs 
• 
Chest imaging/CT scan; repeat 
imaging in 3-4 weeks or as 
clinically indicated 
• 
Monitor symptoms daily, 
consider hospitalization 
• 
Clinical evaluation and 
laboratory work up for infection, 
pulse oximetry 
• 
Consult pulmonologist 
• 
Pulmonary function tests 
• 
Bronchoscopy with biopsy 
and/or BAL recommended to 
rule out infection and/or 
disease progression/lung 
• 
Initiate steroids (1 to 2 
mg/kg/day prednisone or 
equivalent). 
• 
Consider empirical antibiotics 
• 
If no improvement within 2-3 
days, or worsening, treat as 
grade 3 
 
• 
Interrupt 
spartalizumab/LAG525 until 
recovery to Grade ≤1 or 
baseline 
 
• 
Permanently discontinue 
spartalizumab/LAG525 
treatment in case of recurring 
grade 2 pneumonitis 
Grade 3: Severe 
symptoms; limits self-
care ADLs; oxygen 
indicated 
Grade 4: Life- 
threatening respiratory 
compromise, urgent 
intervention indicated  
• 
Hospitalization and pulmonary 
and infectious disease 
consultation 
• 
Methylprednisolone (1-2 
mg/kg/d or equivalent) until 
symptoms improve to Grade 
≤1, then slow taper over ≥4-6 
weeks  
• 
If no improvement within 48 
hours, consider infliximab 
and/or other immune-
suppressive therapy, or i.v. Ig 
as per local guidelines 
• 
Empiric antibiotics 
• Permanently discontinue 
spartalizumab/LAG525 
Table 6-8 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for potential immune-related endocrine 
events 
Endocrine events (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Asymptomatic (grade 
1), intervention not 
indicated (e.g., 
 
• Continue spartalizumab/LAG525 
treatment 


Novartis 
Confidential 
Page 71 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Endocrine events (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
hyperthyroidism or 
hypothyroidism) 
Symptomatic 
endocrinopathy (e.g., 
hypophysitis, adrenal 
insufficiency, 
hypothyroidism, 
hyperthyroidism) 
• Endocrinology consultation 
• Rule out infection/sepsis and 
other alternative causes with 
appropriate cultures and 
imaging 
• Evaluate hormone levels (e.g. 
ACTH, cortisol, FSH/LH, TSH, 
free T4, testosterone/estrogen), 
metabolic panel (e.g. Na, K, 
CO2, glucose), and imaging 
(e.g. brain MRI) as clinically 
indicated 
• Initiate hormone replacement 
therapy as appropriate 
• Consider steroids 
(methylprednisolone 1 to 2 
mg/kg/d or equivalent) in case 
of sever hypophysitis or 
thyrotoxicosis 
• Replacement of appropriate 
hormones may be required as 
the steroid dose is tapered 
• Hypophysitis with clinically 
significant adrenal insufficiency 
and hypotension, dehydration, 
and electrolyte abnormalities 
(such as hyponatremia and 
hyperkalemia) constitutes 
adrenal crisis 
• Consider a beta-blocker in case 
of severe hyper-thyroidism. 
• Consider hospitalization (e.g. in 
case of severe adrenal 
insufficiency/crisis), fluid 
replacement, and other 
supportive measures as 
clinically be initiated 
• Interrupt spartalizumab/LAG525 
until symptomatic recovery to 
mild (i.e., grade 1) or no 
symptoms, and controlled with 
hormone replacement therapy 
 
• Hypothyroidism may be managed 
with replacement therapy without 
treatment interruption (unless 
life-threatening) 
 
• Permanently discontinue for life-
threatening (Grade 4) 
endocrinopathies (i.e., 
hyperthyroidism, adrenal 
insufficiency, hypophysitis) or 
recurring severe/life-threatening 
events not controlled by hormone 
replacement therapy 


Novartis 
Confidential 
Page 72 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Endocrine events (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Autoimmune 
diabetes 
(Grade 3 or 
symptomatic 
hyperglycemia) 
 
Autoimmune 
diabetes 
(Grade 4 
hyperglycemia or 
life-threatening 
complications) 
• Initiate anti-glycemic therapy 
(i.e., insulin) as medically 
indicated and monitor glucose 
levels regularly until metabolic 
control is achieved 
• Evaluate for ketoacidosis as 
medically indicated 
• Consultation with 
endocrinologist 
• Consider hospitalization (e.g. in 
case of ketoacidosis) 
• Interrupt spartalizumab/LAG525 
until recovery to grade 1 or 
baseline 
• Permanently discontinue 
spartalizumab/LAG525 in case of 
recurring severe/life-threatening 
events not controlled by anti-
glycemic therapy  
 
Table 6-9 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for infusion-related reactions 
Infusion reaction (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Grade 1 
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated 
• 
Increase monitoring of vital 
signs/pulse oximetry as 
medically indicated until the 
participant is deemed 
medically stable in the 
opinion of the investigator 
• 
Consider slowing infusion 
rate until recovery of 
symptoms 
• Continue 
spartalizumab/LAG525 
Grade 2 
Requires infusion 
interruption but responds 
promptly to symptomatic 
treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, i.v. fluids); 
prophylactic medications 
indicated for < =24 hrs 
• 
Stop Infusion and keep line 
open 
• 
Additional medical therapy as 
per local institutional 
guidelines that may include:  
• 
i.v. fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen and 
corticosteroids as 
indicated 
• 
Increase monitoring of vital 
signs/pulse oximetry as 
medically indicated until the 
• Permanently discontinue 
spartalizumab/LAG525 in 
case of recurring infusion 
reaction despite adequate 
premedication and prolonged 
infusion/slow infusion rate 


Novartis 
Confidential 
Page 73 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Infusion reaction (NCI-CTCAE v5.0) 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
participant is deemed 
medically stable. 
• 
If symptoms resolve, the 
infusion may be restarted at 
50% of the original infusion 
rate  
• 
Premedicate participants 
approximately 1.5 hrs  prior 
to next infusion of 
spartalizumab/LAG525 with:  
• 
Diphenhydramine (50 
mg po or equivalent) 
• 
Acetaminophen (500-
1000 mg po or 
equivalent )  
• 
Or as per local 
institutional guidelines 
Grade 3: 
Prolonged (i.e., not rapidly 
responsive to symptomatic 
medication and/or brief 
interruption of infusion); 
recurrence of symptoms 
following initial 
improvement; 
hospitalization indicated for 
other clinical sequelae 
(e.g., renal impairment, 
pulmonary infiltrates) 
 
Grade 4: 
Life-threatening; pressor or 
ventilatory support 
indicated 
• 
Stop Infusion 
• 
Additional  medical therapy 
as per local institutional 
guidelines that may include:  
• 
i.v. fluids 
• 
Antihistamines 
• 
NSAIDS 
• 
Acetaminophen 
• 
Narcotics 
• 
Oxygen 
• 
Corticosteroids 
• 
Epinephrine 
• 
Close monitoring of vital 
signs, pulse oximetry and 
ECG as medically indicated 
until the participant is 
deemed medically stable. 
• 
Hospitalization as indicated 
• Permanently discontinue 
spartalizumab/LAG525 


Novartis 
Confidential 
Page 74 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 6-10 
Criteria for dose interruption and re-initiation of LAG525 and 
spartalizumab treatment for “other” potential immune-related AEs of 
special interest 
Other immune mediated events- including but not limited to Autoimmune neuropathy, 
Demyelinating polyneuropathy, Guillain-Barre syndrome, Myasthenia gravis- like syndrome, 
Non-infectious myocarditis, pericarditis, pancreatitis, and Grade 3 Fatigue with rapid onset 
in absence of disease progression, encephalitis, vasculitis, myositis, hemolytic anemia, 
uveitis 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
Mild (Grade 1) 
• Provide symptomatic treatment 
evaluate/monitor adequately 
• Continue 
spartalizumab/LAG525 
Moderate (Grade 2) 
• Ensure adequate evaluation to 
confirm etiology or exclude other 
causes 
• Provide symptomatic treatment 
• Systemic corticosteroids may be 
indicated 
• Consider biopsy for confirmation 
of diagnosis.  
• A specialist should be consulted 
• Consider interruption of 
spartalizumab/LAG525 until 
recovery to ≤ Grade 1 or 
baseline 
Severe (Grade 3) 
• Initiate systemic corticosteroids 
(prednisone or equivalent) at a 
dose of 1-2 mg/kg/d or 
equivalent) and other therapies 
as appropriate 
• 
Monitor closely and consult with 
a specialist 
 
 
• 
Interrupt 
spartalizumab/LAG525 until 
recovery to ≤ Grade 1 or 
baseline 
• 
May restart 
spartalizumab/LAG525 
treatment at the same dose 
and schedule 
 
2nd occurrence: 
• 
Permanently discontinue 
spartalizumab/LAG525 
Grade 4 
• Hospitalization and consult with 
specialist 
• Permanently discontinue 
spartalizumab/LAG525 
Guillain-Barre 
Severe peripheral or 
autonomic neuropathy, 
or transverse myelitis 
• Hospitalization and consult with 
specialist 
• Permanently discontinue 
spartalizumab/LAG525 
Encephalitis or aseptic 
meningitis 
• Rule out infectious or other 
causes of moderate to severe 
neurologic deterioration, and 
consult with specialist 
• If other etiologies are ruled out, 
administer corticosteroids at a 
dose of 1 to 2 mg/kg/day 
prednisone equivalents 
• Permanently discontinue 
spartalizumab/LAG525 
Myasthenia gravis 
• 
Consult with specialist 
Grade 2 


Novartis 
Confidential 
Page 75 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Other immune mediated events- including but not limited to Autoimmune neuropathy, 
Demyelinating polyneuropathy, Guillain-Barre syndrome, Myasthenia gravis- like syndrome, 
Non-infectious myocarditis, pericarditis, pancreatitis, and Grade 3 Fatigue with rapid onset 
in absence of disease progression, encephalitis, vasculitis, myositis, hemolytic anemia, 
uveitis 
Grade 
Recommended Adverse Event 
management guidelines 
Mandatory Dose Modification 
requirements 
• 
Consider pyridostigmine and 
systemic corticosteroids 
(prednisone or equivalent) at 
a dose of 1-2 mg/kg/d; other 
therapies as appropriate 
(e.g. i.v. Ig) 
• Hospitalization in case of severe 
cases 
• Interrupt PDR001 until 
recovery to ≤ Grade 1 or 
baseline  
 
Grade ≥3 
• Permanently discontinue 
spartalizumab/LAG525 
Myocarditis any grade, 
or cardiac event 
grade>=3 
Urgent cardiology consult is essential 
to initiate high dose systemic 
corticosteroids (prednisone or 
equivalent) (Mahmood et al 2018, 
Brahmer et al 2018) 
• Permanently discontinue 
spartalizumab/LAG525 
Pancreatitis 
Amylase/lipase 
elevation 
• Evaluate for pancreatitis (clinical 
assessment, abdominal imaging 
and/or MRCP as appropriate) 
• PDR001 may be continued in 
case of asymptomatic, isolated 
enzyme elevations without evidence 
for pancreatitis 
• Initiate steroids in case of ≥ grade 
2 acute pancreatitis 
Grade 2 acute pancreatitis: 
• Interrupt PDR001 until 
recovery to ≤ Grade 1 or 
baseline  
 
Grade ≥3 acute pancreatitis: 
• Permanently discontinue 
spartalizumab/LAG525 
Autoimmune hemolytic 
anemia, hemolytic 
uremic syndrome, or 
acquired hemophilia 
grade ≥3 
• 
Consult with specialist 
Consider systemic corticosteroids 
and other therapies as appropriate 
(e.g. transfusion) per local 
institutional guidelines 
• Permanently discontinue 
spartalizumab/LAG525 
Ocular events 
Consult with ophthalmologist 
Grade 2 
• Interrupt PDR001 until 
recovery to  
≤ Grade 1 or baseline 
 
Grade 3 and 4 
• Permanently discontinue 
spartalizumab/LAG525 
6.5.1.2.2 Guidance for corticosteroids tapering for management of immune-related 
AEs 
Consultation with disease-specific experts is recommended. Steroids must be tapered slowly 
and based on response/recovery of clinical symptoms. 


Novartis 
Confidential 
Page 76 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Consider complete tapering over a period of at least 4 weeks (sometime 6-8 weeks or longer) 
to prevent recurrent irAEs. Slower tapering or re-escalation of corticosteroids therapy may be 
needed if the adverse event is not showing improvement. Once corticosteroid tapering is 
achieved at a level of 10 mg of prednisone/day (or equivalent) or less, spartalizumab/LAG525 
can be restarted as indicated in the dose modification tables. If the dose of prednisone or 
equivalent cannot be reduced to less than 10 mg/day before the administration of next dose of 
study treatment, then LAG 525/spartalizumab must be held (note: next dose can be delayed up 
to 12 weeks). 
6.5.1.3 
Dose modifications for carboplatin 
The local prescribing information should be used for carboplatin dose modifications for the 
management of myelotoxicity and in participants with impaired kidney function. 
6.5.2 
Follow-up for toxicities 
6.5.2.1 
Follow up on potential drug-induced liver injury (DILI) cases 
Participants with transaminase increase combined with total bilirubin (TBL) increase may be 
indicative of potential DILI, and should be considered as clinically important events. 
The threshold for potential DILI may depend on the participant’s baseline AST/ALT and TBL 
value; participants meeting any of the following criteria will require further follow-up as 
outlined below: 
• For participants with normal ALT and AST and TBL value at baseline: AST or ALT > 3.0 
x ULN combined with TBL > 2.0 x ULN 
• For participants with elevated AST or ALT or TBL value at baseline: [AST or ALT > 2 x 
baseline AND > 3.0 x ULN] OR [AST or ALT > 8.0 x ULN], combined with [TBL > 2 x 
baseline AND > 2.0 x ULN] 
Medical review needs to ensure that liver test elevations are not caused by cholestasis, defined 
as ALP elevation > 2.0 x ULN with R value < 2 in participants without bone metastasis, or 
elevation of ALP liver fraction in participants with bone metastasis. 
Note: (The R value is calculated by dividing the ALT by the ALP, using multiples of the ULN 
for both values. It denotes whether the relative pattern of ALT and/or ALP elevation is due to 
cholestatic (R ≤ 2), hepatocellular (R ≥ 5), or mixed (R >2 and < 5) liver injury. 
In the absence of cholestasis, these participants should be immediately discontinued from study 
treatment, and repeat LFT testing as soon as possible, preferably within 48 hours from the 
awareness of the abnormal results. The evaluation should include laboratory tests, detailed 
history, physical assessment and the possibility of liver metastasis or new liver lesions, 
obstructions/compressions, etc. 
1. Laboratory tests should include ALT, AST, albumin, creatine kinase, total bilirubin, direct 
and indirect bilirubin, GGT, prothrombin time (PT)/INR, and alkaline phosphatase. 
2. A detailed history, including relevant information, such as review of ethanol, concomitant 
medications, herbal remedies, supplement consumption, and history of any pre-existing liver 
conditions or risk factors, should be collected. 


Novartis 
Confidential 
Page 77 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
3. Further testing for acute hepatitis A, B, C or E infection and liver imaging (e.g. biliary tract) 
may be warranted. 
4. Obtain PK sample, as close as possible to last dose of, if PK analysis is performed in the 
study. 
5. Additional testing for other hepatotropic viral infection (CMV, EBV or HSV), autoimmune 
hepatitis or liver biopsy may be considered as clinically indicated or after consultation with 
specialist/hepatologist. 
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for LFT abnormalities identified should be considered as “medically 
significant”, and thus, meet the definition of SAE and should be reported as SAE using the term 
“potential drug-induced liver injury”. All events should be followed up with the outcome clearly 
documented. 
6.6 
Additional treatment guidance 
6.6.1 
Treatment compliance 
Study treatment will be dispensed at the site/clinic under the supervision of the investigator 
and/or study personnel. Records of study medication used, dosages administered, intervals 
between visits and the completion of the study will be captured in the Drug Accountability Form 
as well as in IRT. Pharmacokinetic parameters (measures of treatment exposure) will be 
determined in all participants as detailed in pharmacokinetics section. 
6.6.2 
Emergency breaking of assigned treatment code 
Not applicable. 
6.7 
Preparation and dispensation 
Each study site will be supplied with study drug in packaging as described under investigational 
and control drugs section. Only qualified and trained personnel to the preparation procedure 
will handle, prepare and dispense the study drug as described in Pharmacy Manual. 
A unique medication number is printed on the study medication label. 
Investigator staff will identify the study medication kits to dispense to the participant by 
contacting the IRT and obtaining the medication number(s). The study medication has a 2-part 
label (base plus tear-off label), immediately before dispensing the medication kit to the 
participant, site personnel will detach the outer part of the label from the packaging and affix it 
to the source document. 
6.7.1 
Handling of study treatment and additional treatment 
6.7.1.1 
Handling of study treatment 
Study treatment must be received by a designated person 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, all study treatment must be stored according to the 


Novartis 
Confidential 
Page 78 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
instructions specified on the labels and in the [Investigator’s Brochure]. Clinical supplies are to 
be dispensed only in accordance with the protocol. Technical complaints are to be reported to 
the respective Novartis/sponsor CO Quality Assurance. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the study treatment but no information about 
the participant except for the medication number. 
The investigator must maintain an accurate record of the shipment and dispensing of study 
treatment in a drug accountability log. Monitoring of drug accountability will be performed by 
monitors during site visits or remotely and at the completion of the trial. 
At the conclusion of the study, and as appropriate during the course of the study, the investigator 
will return all unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis/sponsor monitor or to the Novartis/sponsor address provided 
in the investigator folder at each site. 
6.7.1.2 
Handling of additional treatment 
Not applicable. 
6.7.2 
Instruction for prescribing and taking study treatment 
Dosing and treatment schedule will be performed according to Section 6.1. 
All kits of study treatment assigned by the IRT will be recorded in the IRT system. 
Additional dosing guidelines for fasting glucose sampling: 
On Day 1 of Cycles 1 and 3, a pre-dose fasting (overnight) glucose sample will be collected. 
The participant must be fasting overnight for at least 10 hours prior to the blood collection for 
fasting glucose but can freely drink water. A pre-dose pharmacokinetic sample will also be 
drawn at the same time. After these blood samples, the participant should have a light breakfast 
prior being administered the study treatment infusions. 
Additional dosing guidelines for pharmacokinetic sampling: 
On days with pharmacokinetic sampling (Cycle 1 Day 1, Day 8 and Day 15, Cycle 2 Day 1 and 
Day 8, Cycle 3 Day 1, Day 8 and Day 15, Day 1 of Cycles 4 to 7, End of Treatment visit), the 
participant does not have to fast overnight unless they are also having a fasting plasma glucose 
sample taken. The pre-dose sample should be drawn just before study treatment dosing. The 
sampling time of the pre-dose PK sample and the dosing time of study treatment infusions must 
be precisely recorded in the eCRF. 


Novartis 
Confidential 
Page 79 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
7 
Informed consent procedures 
Eligible participants may only be included in the study after providing (witnessed, where 
required by law or regulation), IRB/IEC-approved informed consent. 
If applicable, in cases where the participant's representative(s) gives consent (if allowed 
according to local requirements), the participant must be informed about the study to the extent 
possible given his/her understanding. If the participant is capable of doing so, he/she must 
indicate agreement by personally signing and dating the written informed consent document. 
Informed consent must be obtained before conducting any study-specific procedures (e.g. all of 
the procedures described in the protocol). The process of obtaining informed consent must be 
documented in the participant source documents. 
Novartis will provide to investigators in a separate document a proposed informed consent form 
that complies with the ICH GCP guidelines and regulatory requirements and is considered 
appropriate for this study. Any changes to the proposed consent form suggested by the 
investigator must be agreed by Novartis before submission to the IRB/IEC. 
Information about common side effects already known about the investigational drug can be 
found in the Investigator's Brochure (IB). This information will be included in the participant 
informed consent and should be discussed with the participant during the study as needed. Any 
new information regarding the safety profile of the investigational drug that is identified 
between IB updates will be communicated as appropriate, for example, via an investigator 
notification or an aggregate safety finding. New information might require an update to the 
informed consent and then must be discussed with the participant. 
The following informed consent forms are included in this study: 
• Main study consent, which also includes: 
• A subsection that requires a separate signature for the ‘Optional Consent for 
Additional Research’ to allow future research on data/samples collected during this 
study 
• Pregnancy Outcomes Reporting Consents for female subjects or the female partners of any 
male subjects who took study treatment 
• Patient participation beyond disease progression 
Women of child bearing potential must be informed that taking the study treatment 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 requirements. 
Male participants must be informed that if a female partner becomes pregnant while he is 
enrolled in the study, contact with the female partner will be attempted to request her consent 
to collect pregnancy outcome information. 
Participants who will continue study treatment beyond initial disease progression as per 
RECIST 1.1 criteria have to be re-consented. These participants must sign a new, witnessed 
IRB/IEC-approved informed consent form which will detail alternative available therapies.  
As per section 4.6, during a Public Health emergency as declared by Local or Regional 
authorities (i.e. pandemic, epidemic or natural disaster), that may challenge the ability to obtain 


Novartis 
Confidential 
Page 80 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
a standard written informed consent due to limits that prevent an on-site visit, Investigator may 
conduct the informed consent discussion remotely (e.g. telephone, videoconference), if 
allowable by a local Heath Authority. Guidance issued by local regulatory bodies on this aspect 
prevail and must be implemented and appropriately documented (e.g. the presence of an 
impartial witness, sign/dating separate ICFs by trial participant and person obtaining informed 
consent, etc.). 
A copy of the approved version of all consent forms must be provided to Novartis after IRB/IEC 
approval. 


Novartis 
Confidential 
Page 81 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
8 
Visit schedule and assessments 
The Assessment Schedule (Table 8-1) lists all of the assessments and indicates with an “X”, the 
visits when they are to be performed. All data obtained from these assessments must be 
supported in the participant’s source documentation. 
Participants should be seen for all visits/assessments as outlined in Table 8-1 or as close to the 
designated day/time as possible. Missed or rescheduled visits should not lead to automatic 
discontinuation. Participants who prematurely discontinue the study for any reason should be 
scheduled for a visit as soon as possible, at which time all of the assessments listed for the final 
visit will be performed. At this final visit, all dispensed investigational product should be 
reconciled, and the adverse event and concomitant medications recorded on the CRF. 


Novartis 
 
Confidential 
 
 
 
          Page 82 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Table 8-1 
Assessment Schedule 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
Informed consent X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
IRT registration 
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
  
  
IRT 
randomization 
  
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Treatment 
beyond 
progression ICF 
 
for participants who meet the criteria outlined in Section 6.1.5.1  
 
 
 
 
 
 
 
 
Demography 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Inclusion / 
Exclusion criteria X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Medical 
history/current 
medical 
conditions 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
BRCA status if 
known 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Locally confirmed 
TNBC status in 
advanced setting 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  


Novartis 
 
Confidential 
 
 
 
          Page 83 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
Diagnosis and 
extent of cancer 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Prior/concomitant 
medications 
From 30d prior to starting study treatment until 150d safety follow-up or start of new antineoplastic medication, whichever is 
sooner. If new antineoplastic medication is started, only medications relative to the suspected AEs/SAEs should be collected. 
  
  
Antineoplastic 
therapies 
(prior/since 
discontinuation of 
study treatment)  
X 
  
  
  
  
  
  
  
  
  
X 
X 
X 
X 
X 
X 
X 
  
Physical 
Examination 
S 
S 
  
  
S 
  
S 
  
  
S 
S 
  
  
  
  
  
  
  
Performance 
status 
X 
X 
  
  
X 
  
X 
  
  
X 
X 
X 
  
  
  
  
  
  
Body Height 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
Body Weight 
X 
X 
  
  
X 
  
X 
  
  
X 
X 
  
  
  
  
  
  
  
Vital Signs 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
  
  
  
  
  
  
Hematology 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
  
  
  
  
  
  
Chemistry 
X 
X 
X 
X 
X 
X 
X 
  
  
X 
X 
X 
  
  
  
  
  
  
Thyroid Panel- 
TSH 
X 
  
  
  
X 
  
X 
  
  
X 
X 
X 
  
  
  
  
  
  
Thyroid Panel- 
Free T3; Free T4 X 
Only if TSH is abnormal 
  
  
  
  
  
  


Novartis 
 
Confidential 
 
 
 
          Page 84 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
Hepatitis testing 
X 
If clinically indicated perform testing as needed 
  
  
  
  
  
  
Local HIV 
testing, if 
required per local 
requirements/reg
ulations 
S 
 
 
 
 
 
 
 
Cytokines for 
safety 
X 
Anytime when a suspected cytokine release syndrome occurs, immediately after the AE, and one week after occurrence of the 
AE 
  
Coagulation 
X 
X 
  
  
X 
  
X 
  
  
X 
X 
X 
  
  
  
  
  
  
Cardiac Troponin  X 
 
 
X 
 
X 
X 
 
X 
         
 
 
 
 
 
 
 
 
Urinalysis 
(macroscopic) 
S 
  
  
  
S 
  
S 
  
  
S 
S 
  
  
  
  
  
  
  
Urinalysis 
(microscopic) 
Any time dipstick urinalysis is abnormal 
  
  
  
  
  
  
  
Pregnancy Test 
(serum)1 
≤72 hours 
before first 
dose of 
study 
treatment 
  
  
  
  
  
  
  
  
  
X 
X 
  
  
  
X 
  
  
Pregnancy test 
(urine) 
  
  
  
  
S 
  
S 
  
  
S 
  
  
S 
S 
S 
  
  
  


Novartis 
 
Confidential 
 
 
 
          Page 85 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
Tumor evaluation 
(CT 
scan/MRI/Bone 
scan) 
-28 to -1 
Every 6 weeks (+/- 1 week) for the first 9 months and every 12 weeks (+/- 1 week) thereafter, 
. See Table 
8-2 for imaging collection plan and Section 8.3.1. Upon the approval of amendment 4, the tumor assessments during the post-treatment efficacy 
follow-up period will be now optional and will be left at the discretion of the investigator.  
  
Chest X-ray 
 
If clinically indicated 
  
  
  
  
  
  
ECG (Central) 
At least 72 
hours prior 
randomizati
on 
X 
  
  
  
  
X 
  
  
  
X 
  
  
  
  
  
  
  
ECG (Local) 
  
S 
  
  
S 
  
S 
  
  
On Day 1 of 
every 2 cycles 
after cycle 3 
  
  
  
  
  
  
  
  
Cardiac imaging 
(MRI/ECHO) 
X 
If clinically indicated 
X 
  
  
  
  
  
  
  
Adverse Events 
Suspected AE up to Day 150; non-suspected AE up to Day 150 or start of new post treatment anti-neoplastic medication, 
whichever is sooner. See Appendix 1 (Safety follow-up diagram) 
  
  
Serious Adverse 
Events 
Suspected SAE up to Day 150 and beyond; non-suspected SAE up to Day 150 or start of new post treatment anti-neoplastic medication, whichever is 
sooner. See Appendix 1 (Safety follow-up diagram) 


Novartis 
 
Confidential 
 
 
 
          Page 86 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
Newly obtained 
tumor sample2 
X 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
LAG525 infusion    
Day 1 of each cycle (21 days) until EOT 
  
  
  
  
  
  
  
  


Novartis 
 
Confidential 
 
 
 
          Page 87 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
Period 
Screening Treatment 
End of 
Treatment 
(EOT) 
Follow-up3 
Visit Name 
Screening 
Cycl
e 1 
Day 
1 
Cycl
e 1 
Day 
8 
Cycl
e 1 
Day 
15 
Cycl
e 2 
Day 
1 
Cycl
e 2 
Day 
8 
Cycl
e 3 
Day 
1 
Cycl
e 3 
Day 
8 
Cycl
e 3 
Day 
15 
Subseq. cycles 
Day 1 
End of 
Treatment 
(EOT) 
30 
day 
Safet
y F-
up 
60 
day 
Safet
y F-
up 
90 
day 
Safet
y F-
up 
120 
day 
Safet
y F-
up 
150 
day 
Safet
y F-
up 
End 
Post 
Treatme
nt 
Follow-
up 
Surviv
al F-
up4 
Days 
-21 to -1 
1 
8 
±1 
15 
±1 
22 
±1 
29 
±1 
43 
±1 
50 
±1 
57 
±1 
- 
±3 
- 
- 
-0 +7 
- 
±7 
- 
±7 
- 
±7 
- 
-0 
+14 
- 
- 
spartalizumab 
infusion  
  
Day 1 of each cycle (21 days) until EOT 
  
  
  
  
  
  
  
  
carboplatin 
infusion 
  
Day 1 of each cycle (21 days) until EOT 
  
  
  
  
  
  
  
  
PK sampling 
  
At C1D1, C1D8, C1D15, C2D1, C2D8, C3D1, C3D8, C3D15, Day 1 
of Cycles 4 to 7, EOT -See Table 8-7 and Table 8-8 for PK 
collection log 
  
  
  
  
  
  
  
  
Immunogenicity 
(IG) sampling 
  
On Day 1 of Cycles 1 to 7, EOT - See Table 8-7 for immunogenicity 
sampling plan      
  
  
  
  
  
  
  
  
Participant's 
disposition  
X 
  
  
  
  
  
  
  
  
  
X 
  
  
  
  
  
X 
  
Efficacy 
followup3   
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
X 
  
Safety followup 
visit3 
  
  
  
  
  
  
  
  
  
  
  
X 
  
  
  
X 
  
  
Safety follow-up 
Call3 
  
  
  
  
  
  
  
  
  
  
  
  
S 
S 
S 
  
  
  
Survival 
followup3,4 
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
  
 
S =Assessment to be recorded in the source documentation only 
X = assessment to be recorded in the clinical database or received electronically from a vendor 
1 by Central Laboratory, unless participant is postmenopausal (see Exclusion Criterion 23 for definition of postmenopausal status) 


Novartis 
 
Confidential 
 
 
 
          Page 88 of 185 
Amended Protocol Version 04 (Clean) 
 
 
 
 
Protocol No. CLAG525B2101 
 
2 If new tumor sample cannot be obtained, archival tumor sample obtained maximum 6 months prior to start of study treatment is acceptable providing 
the participant has not received antineoplastic therapy since then. 
3 For ongoing participants who will transfer into PTA program (roll over study or PSDS) only EOT visit will be performed but no safety, efficacy and 
survival follow-up. 
4 Follow-up duration is limited to 150 days after the last dose of LAG525 and/or spartalizumab (whichever was stopped last). If carboplatin was stopped 
more than 150 days after LAG525 and/or spartalizumab, the participant can be discontinued 30 days after the last dose of carboplatin. Survival follow-up 
period is removed after Protocol Amendment #4 is approved.


Novartis 
Confidential 
Page 89 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
8.1 
Screening 
All study participants must be thoroughly informed about all aspects of the study, including the 
study treatment, visit schedule, required evaluations, and all regulatory requirements for 
informed consent. Written informed consent must be obtained before any study specific 
assessments are performed, including screening. If the participant is unable to read, an impartial 
witness should be present during the entire informed consent discussion. 
For details of screening assessments, refer to Table 8-1. 
The screening assessments must be performed within 21 days of first dose of study treatment 
to confirm participant’s eligibility with the exception of the central serum pregnancy test which 
must be conducted within 72 hours prior to start of study treatment. 
For participants who may have had procedures previously performed as part of the participant’s 
routine disease care (prior to signing study informed consent), the following procedures can be 
used providing a proper documentation in participant’s file is available: 
 
 
 
Participants will also be asked to participate in an optional tumor tissue collection at disease 
progression. If so, the participant will have to sign an additional consent within the main 
informed consent form. 
A participant who has a laboratory test result(s) that does not satisfy the entrance criteria may 
have the test(s) repeated. These test(s) may be repeated as soon as the investigator believes the 
re-test result(s) is/are likely to be within the acceptable range to satisfy the entrance criteria, but 
should be completed within 21 days of screening period. In this case, the participant will not be 
required to sign another ICF, and the original participant ID number assigned by the investigator 
will be used. In the event that the laboratory test(s) cannot be performed within 21 days of 
screening period or the re-test(s) do not meet the entrance criteria, or other eligibility criteria 
have changed and are not met anymore, the participant is considered a screen failure. 
A new ICF will need to be signed if the investigator chooses to re-screen the participant after a 
participant has screen failed, however, the participant ID number will remain the same. All 
required screening activities must be performed when the participant is re-screened for 
participation in the study to satisfy the requirements defined in Table 8-1. An individual 
participant may only be re-screened once for the study. Once the number of participants 
screened and enrolled is likely to ensure target enrollment, the Sponsor may close the study to 
further screening. In this case, the participants who screen failed will not be permitted to re-
screen. 
8.1.1 
Eligibility screening 
Following registering in the IRT for screening, participant eligibility will be checked according 
to study inclusion and exclusion criteria as described in Section 5 once all screening procedures 


Novartis 
Confidential 
Page 90 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
are completed. A list of procedures to be performed during the 21-day screening period is 
summarized in Table 8-1. 
Results of all screening/baseline evaluations must be reviewed by the investigator or his/her 
designee prior to start study treatment of each participant to ensure that all inclusion and 
exclusion criteria have been satisfied. 
The eligibility check will be embedded in the IRT system. Please refer and comply with detailed 
guidelines in the IRT manual. 
8.1.2 
Information to be collected on screening failures 
Participants who sign an informed consent form and subsequently found to be ineligible prior 
to randomization will be considered a screen failure. The reason for screen failure should be 
recorded on the appropriate Case Report Form. The demographic information, informed 
consent, and Inclusion/Exclusion pages must also be completed for screen failure participants. 
No other data will be entered into the clinical database for participants who are screen failures, 
unless the participant experienced a serious adverse event during the screening phase (see SAE 
section for reporting details). If a screen failure participant experiences an AE which does not 
meet SAE criteria, details about the AE will be recorded only in the investigator’s source 
documents. If the participant fails to be randomized, the IRT must be notified within 2 days of 
the screen fail that the participant was not randomized. 
Participants who are randomized and fail to start treatment, e.g., participants randomized in 
error, will be considered an early terminator. The reason for early termination should be 
recorded on the appropriate Case Report Form.  
8.2 
Participant demographics/other baseline characteristics 
The following participant demographics and baseline characteristics are to be collected on all 
participants on the eCRF: 
• Demography including age, sex, race and ethnicity (as per local regulations) 
• Height, weight 
• Medical history/current medical condition (including BRCA mutation status, if available) 
present before signing the informed consent. Investigators will have the discretion to 
record abnormal test findings on the appropriate CRF whenever in their judgment, the test 
abnormality occurred prior to the informed consent signature. 
• Confirmed TNBC status in advanced setting 
• Diagnosis and extent of cancer 
• Prior and concomitant medication: all medications and significant non-drug therapies 
taken within 4 weeks prior to first dose of study treatment as well as during study 
treatment. 
• Prior antineoplastic therapy 
 
 
 
 


Novartis 
Confidential 
Page 91 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Furthermore, the following assessments will be performed to assess the eligibility of the 
participant: 
• Vital signs including body temperature, blood pressure and pulse 
• ECOG performance status 
• ECG 
• Cardiac imaging 
• Tumor evaluation 
• Laboratory evaluations (e.g., hematology, coagulation, biochemistry, thyroid function, 
urinalysis) 
In addition a serum pregnancy test will be performed for women with childbearing potential by 
central laboratory and the result will automatically be transferred to Novartis. 
Participants will be stratified at randomization according to: Absence or presence of liver 
metastasis and line of therapy (first or second line) in the advanced setting. 
Country-specific regulations should be considered for the collection of demographic and 
baseline characteristics in alignment with CRF. 
8.3 
Efficacy 
8.3.1 
Efficacy assessment (imaging) 
Tumor response will be assessed locally according to the Novartis guideline version 3.1 
(Section 16.3 Appendix 3) based on RECIST 1.1 Eisenhauer et al 2009 
 
 
. The imaging assessment collection plan is presented 
in Table 8-2. 
The local investigator’s assessment will be used for the primary endpoint analysis (RECIST 
1.1) and for treatment decision making based on secondary 
 efficacy endpoints 
(RECIST 1.1 
). 
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. Central review of the imaging data may 
be performed if deemed necessary. Please refer to the site imaging operations manual for 
additional information on image acquisition and data collection by the imaging CRO. 


Novartis 
Confidential 
Page 92 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 8-2 
Imaging Assessment Collection Plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Chest, abdomen and 
pelvis CT or MRI (with 
intravenous contrast 
enhancement) 
Mandated 
Mandated during treatment period, every 6 weeks 
(+/- 1 week) for the first 9 months and every 12 
weeks (+/- 1 week) thereafter. With amendment 
#4 the imaging assements during the efficacy 
follow-up period will be optional and will be left at 
the investigator’s discretion. 
Brain CT or MRI 
Mandated 
If clinically indicated 
Whole body bone 
scan 
Mandated 
If clinically indicated 
Localized bone CT, 
MRI or x-ray 
For any lesions identified on the 
whole body 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 
Color photography 
(with scale/ruler) 
For any skin lesions present 
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis 


Novartis 
Confidential 
Page 93 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
CT or MRI of other 
metastatic sites (e.g., 
neck) 
If clinically indicated 
If lesions were documented at baseline, follow 
same schedule as CT/MRI of chest, abdomen, 
and pelvis 
Baseline imaging assessments 
Imaging assessments will be performed at screening/baseline within 28 days of start of 
treatment (Day -28 to Day -1 prior to Cycle 1 Day 1). 
Any imaging assessments already completed during the regular work-up of the participant 
within 28 days prior to start of treatment, including before signing the main study ICF (Informed 
Consent Form), can be considered as the baseline images for this study. Any imaging 
assessments obtained after randomization cannot be considered baseline images. The following 
assessments are required at screening/baseline: 
• Chest, abdomen and pelvis CT or MRI 
• Brain CT or MRI 
• Whole body bone scan 
• Localized bone CT, MRI or x-ray, for any lesions identified on the whole body bone scan 
that are not visible on the chest, abdomen and pelvis CT or MRI 
• CT or MRI of other metastatic sites (e.g., neck), if clinically indicated 
If a participant is known to have a contraindication to CT intravenous (IV) contrast media or 
develops a contraindication during the trial, a non-contrast CT of the chest (MRI is not 
recommended due to respiratory artifacts, however if CT is not feasible per local regulations, 
MRI can be performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and 
pelvis should be performed. 
A whole body bone scan should be performed per institutional standard of care (e.g., Tc-99 
bone scan, whole body bone MRI, Fluorodeoxyglucose positron emission tomography (FDG-
PET) or sodium fluoride (NaF) PET). Localized CT, MRI or X-rays should be acquired for all 
skeletal lesions identified on the screening whole body bone scan, which are not visible on the 
chest, abdomen and pelvis CT/MRI. 
If clinically indicated, CT or MRI of other areas (e.g., neck) of disease as appropriate should be 
performed. 
Any potentially measurable lesion that has been previously treated with radiotherapy should be 
considered as a non-measurable lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a measurable 
lesion. 
Chest x-rays and ultrasound should not be used to measure tumor lesions. 
Post-baseline imaging assessments 
Imaging assessments as described in Table 8-2 should be performed using the same imaging 
modality used at baseline, irrespective of study treatment interruption or actual dosing 
(see Table 8-1). Imaging assessments for response evaluation will be performed every 6 weeks 
(+/- 7 days) during the first 9 months, and every 12 weeks (+/- 7 days) thereafter as outlined 
below. Imaging assessments should be scheduled using the randomization date as the reference 


Novartis 
Confidential 
Page 94 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
date (not the date of the previous tumor assessment), and should be respected regardless of 
whether treatment with study treatment is temporarily withheld or unscheduled assessments 
performed. 
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a participant, as necessary. 
Clinical suspicion of disease progression at any time requires a physical examination and 
imaging assessments to be performed promptly rather than waiting for the next scheduled 
imaging assessment. 
Each lesion that is measured at baseline must be measured by the same method and when 
possible, the same local radiologist/physician throughout the study so that the comparison is 
consistent. If an unscheduled imaging assessment is performed because progression is 
suspected, subsequent imaging assessments should be performed in accordance with the 
original imaging schedule. If the suspicion is confirmed, a complete imaging assessment as 
per Table 8-2 needs to be done as soon as possible. If the progression is not confirmed, an 
individual imaging procedure will not need to be repeated at the next scheduled imaging if it 
has been done within 4 weeks. 
Combined PET/CT may be used only if the CT is of similar diagnostic quality as a CT 
performed without PET, including the utilization of i.v. contrast media. At the discretion of the 
Investigators, FDG-PET scans may be performed to document progressive disease per RECIST 
1.1 (Section 16.3 Appendix 3). 
An additional tumor assessment must be performed to confirm response (CR or PR) no less 
than 4 weeks after the criteria for response are first met. 
For participants who discontinue study treatment for reasons other than documented disease 
progression per RECIST 1.1, death, lost to follow-up, or withdrawal of consent, tumor 
assessments must continue to be performed every 6 weeks in the first 9 months and every 12 
weeks thereafter, until documented disease progression per RECIST 1.1 per investigator, death, 
lost to follow-up, or withdrawal of consent. Even after the start of subsequent anti-cancer 
therapy, every effort will be made to continue tumor assessments until disease progression, 
death, withdrawal of consent or loss to follow-up. 
For participants who continue study treatment beyond initial RECIST 1.1. PD, 
 
 or discontinuation of 
study treatment (whichever occurs first) as outlined in Table 8-2.  
For participants who discontinue study treatment 
, continuation of tumor 
assessments 
. 
Upon the approval of amendment 4 by Institutional review board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities, the tumor assessments during the post-treatment 
efficacy follow-up period will be optional and will be left at the discretion of the investigator. 
8.3.2 
Appropriateness of efficacy assessments 
Tumor response will be assessed locally according to the Novartis guideline version 3.1 
(Section 16.3 Appendix 3) based on RECIST 1.1 Eisenhauer et al 2009 
 
 


Novartis 
Confidential 
Page 95 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
8.4 
Safety 
Safety assessments are specified below with the assessment schedule detailing when each 
assessment is to be performed. 
For details on AE collection and reporting, refer to AE section. 
Table 8-3 
Assessments & Specifications  
Assessment 
Specification 
Physical 
examination 
At screening, a complete physical examination will be performed including the examination of 
general appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, 
abdomen, back, lymph nodes, extremities, vascular, and neurological. Additionally include 
examination of breasts and loco-regional lymph nodes. If indicated based on medical history 
and/or symptoms, rectal, external genitalia and pelvic exams will be performed. 
A short physical exam will be performed at all visits as indicated above (see Table 8-1) during 
treatment except where a complete physical examination is required (see above). It will 
include at least the examination of general appearance and vital signs (body temperature, 
blood pressure [SBP and DBP] and pulse). If indicated based on symptoms, additional exams 
will be performed. 
Information for all physical examinations must be included in the source documentation at the 
study site and additionally reported in appropriate CRF page for blood pressure (SBP and 
DBP), vital signs, height and weight. Clinically relevant findings that are present prior to 
signing informed consent must be recorded on the appropriate CRF that captures medical 
history. Significant findings made after signing informed consent which meet the definition of 
an Adverse Event must be recorded as an adverse event. 
Vital sign 
Vital signs include blood pressure (supine position preferred when ECG is collected), pulse 
measurement, and body temperature. 
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 specified in Table 8-1. 
Performance status: 
ECOG Performance status scale will be used as described in Table 8-4. 
Table 8-4 
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 
8.4.1 
Laboratory evaluations 
Clinically significant abnormalities must be recorded as either medical history/current medical 
conditions or adverse events as appropriate. 


Novartis 
Confidential 
Page 96 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 8-5 
Laboratory Assessments (Central and Local) 
Test 
Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands (absolute values preferred , %s are acceptable) 
Chemistry 
Albumin, Alkaline phosphatase, ALT, AST, Gamma-glutamyl-transferase (GGT), Lactate 
dehydrogenase (LDH), Calcium, Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatinine clearance, Creatine kinase, Direct Bilirubin, Indirect Bilirubin if Total 
Bilirubin > grade 1, Total Bilirubin, Total Cholesterol, Blood Urea Nitrogen (BUN) or Urea, Uric 
Acid, Amylase, Lipase, Glucose (fasting)1, Cardiac Troponin T (cTnT) recommended or 
Troponin I (cTnI) if unable to assay TnT2 
Urinalysis 
(local) 
Local Laboratory: Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, 
Leukocytes esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen) 
Local laboratory Microscopic Panel (Red Blood Cells, White Blood Cells, Casts, Crystals, 
Bacteria, Epithelial cells) 
Coagulation 
International normalized ratio [INR]), Activated partial thromboplastin time (APTT) 
Thyroid 
At baseline: TSH (Thyroid Stimulation Hormone), Free T3 and Free T4 
At the subsequent visits as indicated in Table 8-1: TSH only. 
If TSH is abnormal, central lab will test Free T3 and Free T4 
Hepatitis 
markers 
HBV-DNA, HBsAg, HBsAb, HBcAb, HCV RNA-PCR (baseline) 
HIV serology 
(local) 
If required per local regulations: local HIV testing at screening 
Cytokines 
IFN-γ, IL-6, IL-1,TNF-α 
Pregnancy 
Test 
A central laboratory serum pregnancy hCG test must be performed at screening within 72 
hours before first dose of study treatment, at EOT, at 30-day and 150-Day safety follow-up. 
A local laboratory urine pregnancy test must be performed at day 1 of every cycle beginning 
with cycle 2, and at home every 30-days after 30-day safety follow-up visit until120-day follow-
up. 
1 Glucose (fasting) will be evaluated on Cycle 1 Day 1 and Cycle 3 Day 1, other visits do not require 
fasting state 
2 Troponin will be tested locally as outlined in Section 8.4.2.2. 
Lab parameters will be evaluated by a central laboratory except for urinalysis, HIV testing (to 
be performed only if required per local regulations), urine pregnancy tests and troponin levels, 
which will be performed locally. Please refer to [Central Laboratory Manual] for details. 
Local laboratory assessments may be performed if medically indicated or when the treating 
physician cannot wait for central laboratory results for decision making. In this particular 
situation, the blood sample obtained at the same time point should be submitted to the central 
laboratory for analysis in parallel with local analysis. 
Samples for safety cytokine panel at screening will be stored below -70°C by central laboratory 
and analyzed only if post-screening samples are received. 
8.4.2 
Electrocardiogram (ECG) 
In this study local and central ECG will be used, depending on the time point and purpose. 
The preferred sequence of cardiovascular data collection during study visits is ECG collection 
first, followed by vital signs, and blood sampling. The Fridericia QT correction formula (QTcF) 
should be used for clinical decisions. 


Novartis 
Confidential 
Page 97 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
At screening, eligibility will be based on the average of triplicate ECGs (central read). In order 
to ensure ECG evaluation is received from the central laboratory for eligibility assessment, it is 
advisable to perform the ECG at least 72 hours prior to the scheduled randomization date. 
A standard 12 lead ECG will be conducted prior to dosing on day 1 of cycles as indicated in 
Table 8-1. The ECG will be assessed locally to confirm participant safety. Any abnormality 
will be documented in the AE pages of the eCRF. 
Standard triplicate 12 lead ECG will be performed on C1D1 and C3D1, pre-dose and post-dose, 
and submitted for central read. Any unscheduled ECG and the EoT ECG will be submitted for 
central read to ensure that any ECG-related AEs are assessed and confirmed centrally. Standard 
triplicate 12 lead ECG will be performed after the participant has been resting for 5-10 min 
prior to each time point. Triplicate ECGs should be taken approximately 2 minutes apart. 
Table 8-6 
Local and Central ECG collection plan 
Cycle 
Day 
Time 
ECG Type 
Screening 
  
at least 72 hrs prior to 
randomization 
12 Lead, triplicate, central 
1 
1 
Pre-dose 
After completion of 
infusions (±10 min) 
12 Lead, local (pre-dose)* 
and 
12 Lead, triplicate, central (pre- 
and post- dose) 
2 
1 
Pre-dose 
12 Lead, local 
3 
1 
Pre-dose 
After completion of 
infusions (±10 min) 
12 Lead, local (pre-dose)* 
and 
12 Lead, triplicate, central (pre- 
and post- dose) 
Every 2 cycles after the third cycle 
(odd numbered cycles) 
1 
Pre-dose 
12 Lead, local 
EOT 
  
Anytime 
12 Lead, triplicate, central 
Unscheduled or Unplanned sample (as 
clinically indicated) 
Anytime 
12 Lead, triplicate, central 
For any study arm, pre-dose is before start of infusion of the first drug, post-dose is after infusion of 
the last drug *if central 12 Lead ECG was performed it can be used for local interpretation (read and 
signed by investigator) 
Triplicate 12 Lead ECGs are to be collected with ECG machines supplied by the ECG central 
laboratory. 
Single 12 Lead ECGs are collected at the study site using an ECG machine for safety assessment 
in real time by a qualified physician to ensure participant safety. The original ECGs 
appropriately signed must be collected and archived at the study site. Only clinically significant 
abnormalities must be reported as adverse events. 
In the event that a QTcF value of > 470 ms is observed, or if an unscheduled ECG is performed 
for safety reasons, it is recommended to collect a time-matched PK sample and record the time 
and date of the last study drug intake to determine the drug exposure. 
Additional, unscheduled, safety ECGs may be repeated at the discretion of the investigator at 
any time during the study as clinically indicated. Unscheduled ECGs with clinically significant 


Novartis 
Confidential 
Page 98 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
findings should be collected in triplicate. Local cardiologist ECG assessment may also be 
performed at any time during the study at the discretion of the investigator. 
All ECGs, including unscheduled triplicate safety ECGs with clinically relevant findings, 
collected during the study should be transmitted to the central core ECG laboratory for review. 
The results of the centrally assessed ECGs are automatically transferred into the clinical 
database. 
8.4.2.1 
Cardiac imaging - MRI or echocardiography (ECHO) 
Cardiac imaging will be done at screening, during the study treatment period if clinically 
indicated and at the end of treatment visit. 
8.4.2.2 
Troponin monitoring guidance 
Cardiac enzyme troponin-T or I will be performed at screening. Troponin T assessment is 
recommended (Troponin I to be used if unable to assay TnT).  
Additional safety assessments must be done during the first 2 months as outlined in Table 8-1. 
If Troponin level is above ULN during the first 2 months, or if level is above the screening 
value (if value was 1-2 fold ULN), echocardiogram and ECG must be performed. If ECG and 
ECHO are normal, Troponin must be repeated the following day. However if either ECG or 
ECHO are abnormal and suggestive of myocarditis, a cardiologist must be consulted. 
8.4.3 
Pregnancy and assessments of fertility 
A condom is required for all sexually active male participants treated with carboplatin (Arm 2 
and Arm 3) to prevent them from fathering a child AND to prevent delivery of study treatment 
via seminal fluid to their partner. In addition, male participants should not donate sperm for the 
time period as defined per exclusion criteria 24 (Section 5). 
All premenopausal women who are not surgically sterile will have pregnancy testing as follows. 
Additional pregnancy testing might be performed if requested by local requirements. 
• At screening, a serum pregnancy testing will be performed within 72 hours of first dose of 
study treatment on all female participants of childbearing potential as defined per 
exclusion criteria 25. 
• During study treatment, urine pregnancy tests will be performed on Day 1 of each cycle at 
the clinic/investigator’s site. Any positive urine test needs to be confirmed with a serum 
test. If positive, the participant must be discontinued from the study treatment. 
• At end of treatment visit, 30day and 150day safety follow-up visits, a serum pregnancy 
test will be performed. 
Assessments of Fertility 
Medical documentation of oophorectomy, hysterectomy, or tubal ligation must be retained as 
source documents. Subsequent hormone level assessment to confirm the woman is not of child 
bearing potential must also be available as source documentation in the following case: 
1. Surgical bilateral oophorectomy without a hysterectomy 


Novartis 
Confidential 
Page 99 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
In the absence of the above medical documentation, follicle stimulating hormone (FSH) testing 
is required of any female participant, regardless of reported reproductive/menopausal status at 
screening/baseline. 
8.4.4 
Other safety evaluations 
Chest X-ray 
Standard chest X-ray (posteroanterior (PA) view) will be performed as per Table 8-1 if 
clinically indicated. 
8.5 
Additional assessments 
8.5.1 
Pharmacokinetics 
8.5.1.1 
Pharmacokinetics (PK) and Immunogenicity (IG) 
PK and IG samples will be collected at the visits defined in the assessment schedule. Follow 
instructions outlined in the laboratory manual regarding sample collection, numbering, 
processing and shipment. Blood samples for LAG525 and spartalizumab PK and IG evaluation 
will be collected from all participants who receive at least one dose of LAG525 and 
spartalizumab. Blood samples for carboplatin PK evaluation will be collected from all 
participants who receive at least one dose of carboplatin. Time points of blood sample collection 
for LAG525 and spartalizumab PK and IG and for carboplatin PK will be collected from C1D1 
to C7D1 as outlined in Table 8-7 and Table 8-8 (Section 8.5.1.1), respectively. 
The exact date and clock times of drug administration PK and IG blood draw will be recorded 
on the appropriate eCRF. If participants experience a SAE or an AE leading to the 
discontinuation of the study treatment, an unscheduled PK blood sample should be obtained as 
close as possible to the event occurrence. If participants experience suspected immunologically 
related AE such as infusion-related reaction, hypersensitivity, cytokine release syndrome and 
anaphylaxis, an unscheduled IG blood sample should be obtained as close as possible to the 
event occurrence. The date and time of the last dose and the time of PK blood draw should be 
recorded.
 
 
8.5.1.1.1 Pharmacokinetic and Immunogenicity blood collection and handling 
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
any vein except from the site of infusion (e.g. port) or from the same arm that is used for drug 
infusion. A total of 3.5 mL of blood will be collected for PK analysis in serum and a total of 5 
mL for IG analysis in serum for LAG525 at each designated sampling timepoint. For time points 
when sampling of LAG525 (mAb) PK and IG coincide, 8.5 mL of blood will be collected in 
total for both IG and LAG525 PK. A total of 2.5 mL of blood will be collected for PK analysis 
in serum, and a total of 3.5 mL for IG analysis in serum for spartalizumab at each designated 
sampling timepoint. For time points when sampling of spartalizumab (mAb) PK and IG 
coincide, 6 mL of blood will be collected in total for both IG and spartalizumab PK. After 
clotting, the resulting serum will be separated in aliquots and will be stored frozen until analysis. 


Novartis 
Confidential 
Page 100 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Another 4 mL of blood at each designed timepoint will be collected for the PK analysis of 
carboplatin. 
Refer to the [CLAG525B2101 Laboratory Manual] for detailed instructions for the collection, 
handling, and shipment of PK samples. 
Table 8-7 
Schedule of blood collection log for LAG525 and spartalizumab 
pharmacokinetics (PK) and immunogenicity (IG) 
Scheduled timepoints for PK 
and immunogenicity 
sampling (hours) 
Dose Reference 
Identification (ID) 
For LAG525 
Sample 
number for 
LAG525 
Dose Reference 
Identification (ID) for 
spartalizumab 
Sample 
number for 
spartalizu
mab 
Cycle 
Day 
Scheduled 
time 
(hours)a 
 
 Dose ID 
following 
sampling 
Dose 
ID prior 
to 
sampli
ng* 
PK 
IGb 
Dose ID 
following 
sampling 
Dose ID 
prior to 
sampling* 
PK 
IG 
1 
1 
pre-
infusiong 
101 
  
101 
401 
201 
  
201 
501 
1 
1 
1 hr (± 5 
min) post - 
EOI 
101 
  
102 
  
201 
  
202 
  
1 
8 
168 hr 
(±24h) 
101 
  
103 
  
201 
  
203 
  
1 
15 
336 hr 
(±24h) 
101 
  
104 
  
201 
  
204 
  
2 
1 
pre-
infusiong 
(i.e., 504 hr 
(±24h) 
post-C1D1 
dose) 
102 
101 
105 
402 
202 
201 
205 
502 
2 
8 
168 hr 
(±24h) 
102 
  
106 
  
202 
  
206 
  
3 
1 
pre-
infusiong 
(i.e., 504 hr 
(±24h) post 
C2D1 
dose) 
103 
102 
107 
403 
203 
202 
207 
503 
3 
1 
1 hr (± 5 
min) post - 
EOI 
103 
  
108 
  
203 
  
208 
  
3 
8 
168 hr 
(±24h) 
103 
  
109 
  
203 
  
209 
  
3 
15 
336 hr 
(±24h) 
103 
  
110 
  
203 
  
210 
  
4 
1 
pre-
infusiong 
(i.e., 504 hr 
(±24h) 
post-C3D1 
dose) 
104 
103 
111 
404 
204 
203 
211 
504 


Novartis 
Confidential 
Page 101 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Scheduled timepoints for PK 
and immunogenicity 
sampling (hours) 
Dose Reference 
Identification (ID) 
For LAG525 
Sample 
number for 
LAG525 
Dose Reference 
Identification (ID) for 
spartalizumab 
Sample 
number for 
spartalizu
mab 
Cycle 
Day 
Scheduled 
time 
(hours)a 
 
 Dose ID 
following 
sampling 
Dose 
ID prior 
to 
sampli
ng* 
PK 
IGb 
Dose ID 
following 
sampling 
Dose ID 
prior to 
sampling* 
PK 
IG 
5 
1 
pre-
infusiong 
(i.e., 504 hr 
(±24h) 
post-C4D1 
dose) 
105 
104 
112 
405 
205 
204 
212 
505 
6 
1 
pre-
infusiong 
(i.e., 504 hr 
(±24h) 
post-C5D1 
dose) 
106 
105 
113 
406 
206 
205 
213 
506 
7 
1 
pre-
infusiong 
(i.e., 504 
hrs (±24h) 
post-C6D1 
dose) 
107 
106 
114 
407 
207 
206 
214 
507 
EOT 
  
  
 
 
1000 
5000 
 
 
3000 
600
0 
Unsched
uled 
  
  
  
1001+
c 
5001
+d 
  
3001
+e 
600
1+f 
EOI = End of infusion for each compound * These dose reference IDs refer to the dose administered and dosing 
time of the last dose prior to collection of the corresponding PK samples a Time is relative to the beginning of the 
infusion for each compound unless otherwise indicated b IG samples are being collected together with PK samples 
at the same time. c PK sample numbers for any unscheduled PK collection will start with 1001 for LAG525. d IG 
sample numbers for any unscheduled IG collection will start with 5001 for LAG525. e PK sample numbers for any 
unscheduled PK collection will start with 3001 for spartalizumab. f IG sample numbers for any unscheduled IG 
collection will start with 6001 for spartalizumab. g Take PK samples within 30 min before the each compound 
infusion begins. 
Note:PK/IG blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
any vein except from the site of infusion (e.g. port) or from the same arm that is used for drug infusion. 
Table 8-8 
Schedule for blood collection for carboplatin pharmacokinetic (PK) 
blood collection log 
Scheduled timepoints for PK and (hours) 
Dose Reference Identification 
(ID) 
PK (plasma) 
sample 
number 
PK (plasma 
ultra filtrate) 
sample 
number 
Cycle 
Day 
Scheduled time 
(hours) 
Dose ID 
following 
sampling 
Dose ID prior 
to sampling* 
1 
1 
Pre-infusiona 
301 
  
301 
601 
1 
1 
EOI (±5 minutes) 
301 
  
302 
602 
1 
1 
1 hr (±10 
minutes) post-
EOI 
301 
  
303 
603 


Novartis 
Confidential 
Page 102 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Scheduled timepoints for PK and (hours) 
Dose Reference Identification 
(ID) 
PK (plasma) 
sample 
number 
PK (plasma 
ultra filtrate) 
sample 
number 
Cycle 
Day 
Scheduled time 
(hours) 
Dose ID 
following 
sampling 
Dose ID prior 
to sampling* 
1 
1 
2 hr (±10 
minutes) post-
EOI 
301 
  
304 
604 
1 
1 
3 hr (±10 
minutes) post-
EOI 
301 
  
305 
605 
3 
1 
Pre-infusiona 
302 
31 
306 
606 
3 
1 
EOI (±5 minutes) 
302 
  
307 
607 
3 
1 
1 hr (±10 
minutes) post-
EOI 
302 
  
308 
608 
3 
1 
2 hr (±10 
minutes) post-
EOI 
302 
  
309 
609 
3 
1 
3 hr (±10 
minutes) post-
EOI 
302 
  
310 
610 
4 
1 
Pre-infusiona 
303 
32 
311 
611 
Unscheduled 
  
  
  
7001+b 
8001+c 
EOI = end of infusion * These dose reference IDs refer to the dose administered and dosing time of the last dose 
prior to collection of the corresponding PK sample a Take PK samples within 30 min before the carboplatin infusion 
begins b Sample numbers for any unscheduled plasma collection will start with 7001. C Sample numbers for any 
unscheduled plasma ultra filtrate collection will start with 8001. Note: PK blood samples will be taken by either 
direct venipuncture or an indwelling cannula inserted in any vein except from the site of infusion (e.g. port) or from 
the same arm that is used for drug infusion. Plasma ultrafiltration involves separation of free from protein-bound 
microsolute in small volumes (0.15 – 1.0 mL) of serum, plasma, and other biological samples. 
8.5.1.1.2 Analytical method 
The validated analytical method for the quantification of LAG525 in human serum consists of 
trypsin digestion and solid phase extraction as sample clean-up. Prior to mass spectrometric 
detection, a reverse phase liquid chromatography step is incorporated to reduce sample 
complexity. The triple quadrupole mass spectrometer is set-up in tandem mode. LAG525 is 
quantified via detection on of a surrogate peptide. Using a sample volume of 50 µL of human 
serum, the validated LC-MS/MS LAG525 assay has an estimated LLOQ of 0.25 µg/mL. 
Spartalizumab (PDR001) is quantified in human serum using a sample preparation method 
consisting of protein precipitation and tryptic digestion. The assay consists of a reduced phase 
liquid chromatography step prior to triple quadrupole mass spectrometry detection. 
Spartalizumab is quantified via detection on of a surrogate peptide. The validated method has 
an estimated LLOQ of 0.25 µg/mL, using 25 µL of human serum. 
Carboplatin is measured via an Inductively Coupled Plasma Mass Spectrometer using the ratio 
response of platinium (Pt) to its internal standard. Carboplatin is measured both in ultrafiltrate 
(estimated LLOQ 1 ng/mL) and plasma (estimated LLOQ 100 ng/mL). 


Novartis 
Confidential 
Page 103 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 104 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 105 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 106 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
9 
Study discontinuation and completion 
9.1 
Discontinuation 
9.1.1 
Discontinuation of study treatment 
Participants may voluntarily discontinue from the study treatment for any reason at any time. 
The investigator must discontinue study treatment for a given participant if, he/she believes that 
continuation would negatively impact the participant's well-being. 
Study treatment must be discontinued under the following circumstances: 
• Adverse event requiring permanent discontinuation of study treatment as per Section 6.5. 
• Progressive disease per RECIST 1.1 
 (see criteria in Section 6.1.5.1 
for continuation of treatment beyond disease progression by RECIST 1.1) 
• Protocol deviation that results in significant risk to participant’s safety 
• Use of prohibited treatment as per Section 6.2.2. 
• Pregnancy (Pregnancy will be followed for outcome) 
If discontinuation of study treatment occurs, the investigator should make a reasonable effort 
to understand the primary reason for the participant’s premature discontinuation of study 
treatment and record this information. 
The investigator must also contact the IRT to register the participant’s discontinuation from 
study treatment. 
Participants who discontinue study treatment or who decide they do not wish to participate in 
the study further should NOT be considered withdrawn from the study UNLESS they withdraw 
their consent (see withdrawal of informed consent Section 9.1.2). Where possible, they should 
return for the assessments indicated in the Assessment Schedule. If they fail to return for 
these assessments for unknown reasons, every effort (e.g. telephone, e-mail, letter) should be 
made to contact the participant/pre-designated contact as specified in the lost to follow-up 
section. This contact should preferably be done according to the study visit schedule. 
If the participant cannot or is unwilling to attend any visit(s), the site staff should maintain 
regular telephone contact with the participant, or with a person pre-designated by the 
participant. This telephone contact should preferably be done according to the study visit 
schedule. 


Novartis 
Confidential 
Page 107 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
After study treatment discontinuation for reasons 
, 
death, lost to follow-up, or withdrawal of consent, at a minimum, the following data should be 
collected at clinic visits or via telephone/email contact: 
• new antineoplastic therapy 
• new / concomitant treatments 
• adverse events/Serious Adverse Events 
• tumor assessments must continue to be performed every 6 weeks (+/- 7 days) if 
discontinuation occurs within the first 9 months, and every 12 weeks (+/- 7 days) 
thereafter 
, death, 
lost to follow-up or withdrawal of consent. 
• with implementation of protocol amendment #4, all tumor assessments during the post-
treatment efficacy follow-up period will be optional for the remaining participants in the 
study and will be left at the discretion of the investigator. Moreover, participants who had 
stopped LAG525 and/or spartalizumab 150 days ago (whichever was stopped last) or who 
had stopped carboplatin more than 150 days after LAG525 and/or spartalizumab will be 
discontinued from the study (either immediately or for those who had received carboplatin 
30 days after the last dose of carboplatin). 
In some circumstances participants may be allowed to continue to receive study treatment 
beyond disease progression as per RECIST criteria. These participants will continue 
assessments as outlined in the assessments section, and will complete the EOT visit only after 
permanent discontinuation of study treatment. End of treatment is not considered as the end of 
the study. 
9.1.2 
Withdrawal of informed consent 
Participants may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a participant: 
• Does not want to participate in the study anymore 
and 
• Does not want any further visits or assessments 
and 
• Does not want any further study related contacts 
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the participant’s decision to withdraw his/her consent and 
record this information. 
Where consent to the use of personal and coded data is not required, participant therefore cannot 
withdraw consent. They still retain the right to object to the further use of personal data. 
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing. 
Further attempts to contact the participant are not allowed unless safety findings require 
communicating or follow-up. 


Novartis 
Confidential 
Page 108 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
All efforts should be made to complete the assessments prior to study discontinuation. A final 
evaluation at the time of the participant’s study discontinuation should be made as detailed in 
the assessment table. 
Novartis will continue to retain and use all research results (data) that have already been 
collected for the study evaluation. 
For US (United States) 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 of the informed consent form.  
For EU (European Union) and RoW (Rest of the 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. 
9.1.3 
Lost to follow-up 
For participants whose status is unclear because they fail to appear for study visits without 
stating an intention to discontinue or withdraw, the investigator must show "due diligence" by 
documenting in the source documents steps taken to contact the participant, e.g. dates of 
telephone calls, registered letters, etc. A participant should not be considered as lost to follow-
up until due diligence has been completed or until the end of the study. 
9.1.4 
Early study termination by the sponsor 
The study can be terminated by Novartis at any time.  
Reasons for early termination: 
• Unexpected, significant, or unacceptable safety risk to participants enrolled in the study 
• Decision based on recommendations from applicable board(s) after review of safety and 
efficacy data 
• Discontinuation of study drug development 
In taking the decision to terminate, Novartis will always consider the participant welfare and 
safety. Should early termination be necessary, participants must be seen as soon as possible 
(instructions will be provided to the investigator for contacting the participant, when the 
participant should stop taking drug and when the participant should come for a final visit) and 
treated as a prematurely withdrawn participant. 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 participant’s interests. The investigator or sponsor depending on the local 
regulation will be responsible for informing IRBs/IECs of the early termination of the trial. 
9.2 
Study completion and post-study treatment 
Study completion is defined as when the last participant finishes their Study Completion visit, 
and any repeat assessments associated with this visit have been documented and followed-up 
appropriately by the Investigator, or in the event of an early study termination decision, the date 
of that decision. 


Novartis 
Confidential 
Page 109 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
The primary analysis will be conducted when all participants have been followed for efficacy 
(tumor assessments) for at least 24 weeks or discontinued tumor assessments for any reason 
prior to 24 weeks. The primary analysis data will be summarized in the primary clinical study 
report (CSR). Following the cut-off date for the analysis reported in the primary CSR, the study 
will remain open. Ongoing participants will continue to receive study treatment and be followed 
as per the schedule of assessments, as long as participants derive benefit from study treatment. 
The end of study is defined as the earliest occurrence of one of the following: (1) all participants 
have died or (2) discontinued from the study, or (3) another clinical study becomes available 
that can continue to provide study treatment in this participant population and all ongoing 
participants are eligible to be transferred to that clinical study. All participants who have 
stopped their study treatment for at least 150 days after the last dose of LAG525 and/or 
spartalizumab (whichever was stopped last) will be discontinued from the study. If carboplatin 
was stopped more than 150 days after LAG525 and/or spartalizumab, the participant can be 
discontinued 30 days after the last dose of carboplatin. 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative setting to participants who in the opinion of the 
Investigator are still deriving clinical benefit. The final analysis will occur at the end of the 
study. Any additional data for participants continuing to receive study treatment past the data 
cutoff date for the primary CSR, as allowed by the protocol, will be reported in the final CSR 
on completion of the study. 
9.2.1 
Follow up for safety evaluations 
All participants must be followed for safety up to 150 days after the last dose of LAG525 and/or 
spartalizumab whichever was stopped last. After the 30-day onsite safety follow-up visit, 
participants will be followed (via telephone call or onsite visit if participant happens to be 
visiting the site) at 60 (+/- 7), 90 (+/-7), 120 (+/-7) and 150 (+14) days after the last dose of 
LAG525 and/or spartalizumab (whichever was stopped last). If carboplatin is stopped more 
than 150 days after LAG525 and/or spartalizumab, only the 30-day safety follow-up visit needs 
to be performed. 
All safety assessments should be completed as per Table 8-1. However, if the participant begins 
post treatment antineoplastic medication before the 150-Day safety follow-up visit the 
collection of new SAEs and AEs unrelated to study medication will stop and thereafter only 
suspected AEs and suspected SAEs will continue to be collected up to Day 150. Suspected 
SAEs will continue to be collected beyond the 150-Day safety visit (see Section 16.1 Appendix 
1). Data collected should be added to the appropriate eCRF pages. For female participants of 
child bearing potential, a pregnancy test will be performed at the time points listed in Table 8-
1. 
9.2.2 
Follow up for efficacy evaluations 
Participants who discontinue study treatment for reasons 
, 
death, lost to follow-up or withdrawal of consent, should continue tumor assessment 
 
, death, lost to follow-up or withdrawal of consent at the same intervals as per 
Table 8-2. 


Novartis 
Confidential 
Page 110 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Upon the approval of amendment 4 by Institutional review board (IRBs)/Independent Ethics 
Committee (IECs) and Health Authorities, the tumor assessments will be optional and will be 
left at the discretion of the investigator. Participants who are in efficacy follow-up for at least 
150 days after the last dose of study treatment can be discontinued from the study.  
9.2.3 
Survival follow up 
Participants will enter the survival follow-up period once they complete the safety follow-up 
period and efficacy follow-up period after treatment discontinuation (whichever is longer). 
Participants will then be contacted by telephone every 12 weeks to follow-up on their survival 
status. Any new antineoplastic therapies that have been started since the last contact date will 
also be collected during these phone calls.  
The survival follow-up period will be removed and participant that are currently in survival 
follow-up can discontinue from the study at the time of the approval of amendment 4 by 
Institutional review board (IRBs)/Independent Ethics Committee (IECs) and Health 
Authorities. 
10 
Safety monitoring and reporting 
10.1 
Definition of adverse events and reporting requirements 
10.1.1 
Adverse events 
An adverse event (AE) is any untoward medical occurrence (e.g., any unfavorable and 
unintended sign [including abnormal laboratory findings], symptom or disease) in a participant 
or clinical investigation participant after providing written informed consent for participation 
in the study. Therefore, an AE may or may not be temporally or causally associated with the 
use of a medicinal (investigational) product. 
The investigator has the responsibility for managing the safety of individual participant and 
identifying adverse events. 
Novartis qualified medical personnel will be readily available to advise on trial related medical 
questions or problems. 
The occurrence of adverse events must be sought by non-directive questioning of the participant 
at each visit during the study. Adverse events also may be detected when they are volunteered 
by the participant during or between visits or through physical examination findings, laboratory 
test findings, or other assessments. 
Adverse events must be recorded in the Adverse Events CRF under the signs, symptoms or 
diagnosis associated with them, accompanied by the following information (as far as possible) 
(if the event is serious refer to  Section 10.1.2 ): 
1. The Common Toxicity Criteria (CTC) AE grade (version 5.0). 
Adverse events will be assessed and graded according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 5.0. 
2. its relationship to the study treatment. If the event is due to lack of efficacy or progression 
of underlying illness (i.e. progression of the study indication) the assessment of causality 


Novartis 
Confidential 
Page 111 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
will usually be ‘Not suspected’. The rationale for this guidance is that the symptoms of a 
lack of efficacy or progression of underlying illness are not caused by the trial drug, they 
happen in spite of its administration and/or both lack of efficacy and progression of 
underlying disease can only be evaluated meaningfully by an analysis of cohorts, not on a 
single participant 
3. its duration (start and end dates) or if the event is ongoing, an outcome of not 
recovered/not resolved must be reported. 
4. whether it constitutes an SAE (see  Section 10.1.2  for definition of SAE) and which 
seriousness criteria have been met 
5. action taken with study treatment. 
All adverse events must be treated appropriately. Action taken with study treatment may include 
one or more of the following: 
• Dose not changed 
• Dose Reduced (only for carboplatin) 
• Drug interrupted/withdrawn 
6. its outcome  
a. not recovered/not resolved; 
b. recovered/resolved; 
c. recovered/resolved with sequelae; 
d. fatal; or unknown 
If the event worsens the event should be reported a second time in the CRF noting the start date 
when the event worsens in toxicity. For grade 3 and 4 adverse events only, if improvement to a 
lower grade is determined a new entry for this event should be reported in the CRF noting the 
start date when the event improved from having been Grade 3 or Grade 4. 
Conditions that were already present at the time of informed consent should be recorded in 
medical history of the participant. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. 
Adverse event monitoring should be continued for at least: 
• 150 days following the last dose of LAG525 and/or spartalizumab 
• until the start of a new post treatment antineoplastic medication if sooner than the 150 
days mentioned above. If a participant starts a post treatment antineoplastic therapy, then 
only adverse events suspected to be related to study treatment should be collected out to 
150 days after discontinuation of LAG525 and/or spartalizumab 
• 30 days after discontinuation of carboplatin if the participant continued carboplatin more 
than 150 days after the last dose of LAG525 and/or spartalizumab. 
Once an adverse event is detected, it must be followed until its resolution or until it is judged to 
be permanent (e.g. Continuing at the end of the study), and assessment must be made at each 
visit (or more frequently, if necessary) of any changes in severity, the suspected relationship to 
treatment, the interventions required to treat it, and the outcome. 


Novartis 
Confidential 
Page 112 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (RECIST 1.1 
 guidelines), should not be reported as a serious adverse event, 
except if the investigator considers that progression of malignancy is related to acceleration of 
tumour growth due to study treatment. Newly emerging clinical evidence indicates that a very 
small number of participants treated with immune checkpoint inhibitors may develop tumor 
growth acceleration. This is termed hyperprogression or hyperprogressive disease (Champiat et 
al 2017) and is distinct from pseudoprogression. If the investigator suspects that treatment with 
spartalizumab or LAG525 accelerates tumor growth it should be reported as an SAE. Note: 
Progressive disease which occurs as the result of treatment failure/resistance to the treatment is 
not an AE or SAE and should not be recorded as such. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression) will be reported as per usual guidelines used for such events with 
proper attribution regarding relatedness to the drug. 
Information about adverse drug reactions for LAG525 and spartalizumab can be found in the 
Investigator’s Brochures. For carboplatin adverse drug reactions, please refer to the local label. 
Abnormal laboratory values or test results constitute adverse events only if they fulfill at least 
one of the following criteria: 
• they induce clinical signs or symptoms 
• they are considered clinically significant 
• they require therapy 
10.1.1.1 Adverse Events of Special Interest 
Adverse events of special interest (AESI) are defined as events (serious or non-serious) which 
are ones of scientific and medical concern specific to the sponsor’s product or program, for 
which ongoing monitoring and rapid communication by the investigator to the sponsor may be 
appropriate. Such events may require further investigation in order to characterize and 
understand them.  
Adverse events of special interest are defined on the basis of an ongoing review of the safety 
data. AESIs are discussed in detail in the latest [Investigator Brochure].  
• Endocrinopathies (Hypothyroidism, hyperthyroidism, diabetes, hypophysitis and 
hypopituitarism, adrenal insufficiency) 
• Pneumonitis 
• Colitis  
• Hepatitis 
• Nephritis 
• Encephalitis 
• Rash 
• Other immune-mediated events 
• Infusion reactions 
For Adverse events related to carboplatin refer to the local product label. 


Novartis 
Confidential 
Page 113 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
10.1.2 
Serious adverse events 
An SAE is defined as any adverse event [appearance of (or worsening of any pre-existing)] 
undesirable sign(s), symptom(s) or medical conditions(s)) which meets any one of the following 
criteria: 
• fatal 
• life-threatening 
Life-threatening in the context of an SAE refers to a reaction in which the participant was at 
risk of death at the time of the reaction; it does not refer to a reaction that hypothetically might 
have caused death if it were more severe (please refer to the ICH-E2D Guidelines). 
• results in persistent or significant disability/incapacity 
• constitutes a congenital anomaly/birth defect 
• requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for:  
• routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition.  
• 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 participant’s 
general condition 
• treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• is medically significant, e.g. defined as an event that jeopardizes the participant or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
Medical and scientific judgment should be exercised in deciding whether other situations should 
be considered serious reactions, such as important medical events that might not be immediately 
life threatening or result in death or hospitalization but might jeopardize the participant or might 
require intervention to prevent one of the other outcomes listed above. Such events should be 
considered as “medically significant”. Examples of such events are intensive treatment in an 
emergency room or at home for allergic bronchospasm, blood dyscrasias or convulsions that do 
not result in hospitalization or development of dependency or abuse. 
All malignant neoplasms will be assessed as serious under “medically significant” if other 
seriousness criteria are not met and the malignant neoplasm is not a disease progression of the 
study indication. 
Any suspected transmission via a medicinal product of an infectious agent is also considered a 
serious adverse reaction. 
All reports of intentional misuse and abuse of the product are also considered serious adverse 
event irrespective if a clinical event has occurred. 


Novartis 
Confidential 
Page 114 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
10.1.3 
SAE reporting 
To ensure participant safety, every SAE, regardless of causality, occurring after the participant 
has provided informed consent must be reported to Novartis safety within 24 hours of learning 
of its occurrence and until: 
• at least 150 days following the last dose of LAG525 and/or spartalizumab 
• the start of a new post treatment antineoplastic medication if sooner than the 150 days 
mentioned above 
• 30 days after discontinuation of carboplatin if the participant continued carboplatin more 
than 150 days after the last dose of LAG525 and/or spartalizumab. 
If a participant starts a post treatment antineoplastic therapy, then only SAEs suspected to be 
related to study treatment should be collected out to 150 days after discontinuation of LAG525 
and/or spartalizumab. SAEs suspected to be related to LAG525 and/or spartalizumab will 
continue to be collected beyond the 150-Day safety visit. 
Detailed instructions regarding the submission process and requirements are to be found in the 
investigator folder provided to each site. 
SAEs will be collected on all participants having signed an ICF and until reporting period is 
completed as described above. For participants who fail the screening, SAEs will be collected 
until the time the participant is deemed a Screen Failure. 
All follow-up information for the SAE including information on 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 must be reported separately as a new event. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study treatment, an oncology Chief Medical 
Office and Participant 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 
study treatment 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 accordance with EU Guidance 
2011/C 172/01 or as per national regulatory requirements in participating countries. 
Any SAEs experienced after the reporting period described above should only be reported to 
Novartis Safety if the investigator suspects a causal relationship to study treatment. 
10.1.4 
Pregnancy reporting 
Pregnancies 
If a female trial participant becomes pregnant, the study treatment should be stopped, and the 
trial participant must be asked to read and sign the pregnancy consent form to allow the Study 
Doctor to ask about her pregnancy. To ensure participant safety, each pregnancy occurring after 


Novartis 
Confidential 
Page 115 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
signing the informed consent 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. 
Pregnancy should be recorded and reported by the investigator to the Novartis Chief Medical 
Office and Patient Safety (CMO&PS). Pregnancy follow-up should be recorded on the same 
form and should include an assessment of the possible relationship to the study treatment and 
pregnancy outcome. Any SAE experienced during pregnancy must be reported. 
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. 
The collection of this information could last for up to delivery or several months after delivery 
if applicable following the birth.  
10.1.5 
Reporting of study treatment errors including misuse/abuse 
Medication errors are unintentional errors in the prescribing, dispensing, administration or 
monitoring of a medicine while under the control of a healthcare professional, participant or 
consumer (EMA definition). 
Misuse refers to situations where the medicinal product is intentionally and inappropriately used 
not in accordance with the protocol. 
Abuse corresponds to the persistent or sporadic, intentional excessive use of a medicinal 
product, which is accompanied by harmful physical or psychological effects. 
Study treatment errors and uses outside of what is foreseen in the protocol will be collected in 
the DAR (dose administration record) eCRF irrespective of whether or not associated with an 
AE/SAE and reported to Safety only if associated with an SAE. Misuse or abuse will be 
collected and reported in the safety database irrespective of it being associated with an AE/SAE 
within 24 hours of Investigator’s awareness. 
Table 10-1 
Guidance for capturing the study treatment errors including 
misuse/abuse  
Treatment error 
type 
Document in Dose 
Administration (DAR) eCRF 
(Yes/No) 
Document in AE 
eCRF 
Complete SAE 
form 
Unintentional study 
treatment error 
Yes 
Only if 
associated with 
an AE 
Only if associated 
with an SAE 
Misuse/Abuse 
Yes 
Yes 
Yes, even if not 
associated with a 
SAE 
For more information on AE and SAE definition and reporting requirements, please see the, 
respective sections. 


Novartis 
Confidential 
Page 116 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
10.2 
Additional Safety Monitoring 
In addition to the ongoing safety monitoring throughout the study, a safety review will occur 
after the first 8 participants on each the carboplatin, spartalizumab and LAG525 and the 
carboplatin and LAG525 arm have completed their first 3-week treatment cycle. This safety 
review will be performed by a Novartis review team including at least a clinician and a safety 
representative. 
10.2.1 
Steering Committee 
The steering committee (SC) will be established comprising investigators participating in the 
trial, and Novartis representatives from the Clinical Trial Team. 
The SC will ensure transparent management of the study according to the protocol through 
recommending modifications as circumstances require. The SC will review protocol 
amendments as appropriate. Together with the clinical trial team, the SC will also develop 
recommendations for publications of study results. The details of the role of the Steering 
Committee will be defined in a Steering Committee charter. 
11 
Data Collection and Database management 
11.1 
Data collection 
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, allow modification and/or verification of the entered 
data by the investigator staff. 
The investigator/designee is responsible for assuring that the data (recorded on CRFs) (entered 
into eCRF) is complete, accurate, and that entry and updates are performed in a timely manner. 
The Investigator must certify that the data entered are complete and accurate 
After final database lock, the investigator will receive copies of the participant data for 
archiving at the investigational site. 
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification. 
11.2 
Database management and quality control 
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 are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
World Health Organization (WHO) Drug Reference List, which employs the Anatomical 


Novartis 
Confidential 
Page 117 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Therapeutic Chemical classification system. Medical history/current medical conditions and 
adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Dates of screenings, randomizations and screen failures, as well as randomization codes and 
data about all study treatment (s) dispensed to the participant and all dosage changes will be 
tracked using an Interactive Response Technology (IRT). The system will be supplied by a 
vendor, who will also manage the database. The data will be sent electronically to Novartis at 
specific timelines. 
Once all the necessary actions have been completed and the database has been declared to be 
complete and accurate, it will be locked. Any changes to the database after that time can only 
be made after written agreement by Novartis development management. 
11.3 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, a Novartis or 
delegated CRO representative will review the protocol and data capture requirements (i.e. 
eSource DDE or eCRFs) with the investigators and their staff. During the study, Novartis 
employs several methods of ensuring protocol and GCP compliance and the quality/integrity of 
the sites’ data. The field monitor will visit the site to check the completeness of participant 
records, the accuracy of data capture / data entry, the adherence to the protocol and 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. Continuous remote monitoring of each site’s data 
may be performed by a centralized Novartis or delegated CRO/CRA organization. Additionally, 
a central analytics organization may analyze data & identify risks & trends for site operational 
parameters, and provide reports to Novartis clinical teams to assist with trial oversight. 
The investigator must maintain source documents for each participant 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 on CRFs must be traceable to these source documents in the 
participant’s file. The investigator must also keep the original informed consent form signed by 
the participant (a signed copy is given to the participant). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the data capture and/or data entry. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion criteria, 
documentation of SAEs, and of data that will be used for all primary variables. Additional 
checks of the consistency of the source data with the CRFs are performed according to the 
study-specific monitoring plan. No information in source documents about the identity of the 
participants will be disclosed. 


Novartis 
Confidential 
Page 118 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
12 
Data analysis and statistical methods 
With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was 
prematurely closed. Participant data from Arm 1 will still contribute to the efficacy and safety 
objectives of the trial as per the analysis defined in this section. 
The primary analysis of the study data will be reported in the primary CSR based on all 
participants’ data up to the time when all participants have been followed for efficacy (tumor 
assessments) for at least 24 weeks or discontinued tumor assessments for any reason prior to 24 
weeks. Any additional data (e.g., DoR, OS, safety) for participants continuing to receive study 
treatment past the data cut-off date for the primary CSR, as allowed by the protocol, will be 
reported in the Final analysis on completion of the study. 
Any data analysis carried out independently by the investigator should be submitted to Novartis 
before publication or presentation. 
12.1 
Analysis sets 
The Full Analysis Set (FAS) comprises all participants to whom study treatment has been 
assigned by randomization. According to the intent to treat principle, participants will be 
analyzed according to the treatment and strata they have been assigned to during the 
randomization procedure. 
The Safety Set includes all participants who received at least one dose of study treatment (i.e., 
at least one dose of any component of the study treatment, including incomplete infusion of 
spartalizumab, LAG525 or carboplatin). Participants will be analyzed according to the study 
treatment received, where treatment received is defined as the randomized treatment if the 
participant took at least one dose of that treatment or the first treatment received if the 
randomized treatment was never received. 
The LAG525 pharmacokinetic analysis set (PAS-LAG525) includes all participants who 
provide at least one evaluable LAG525 PK concentration. For a concentration to be evaluable, 
participants are required to: 
• receive a planned dose of LAG525 prior to sampling 
• for pre-dose samples, have the sample collected before the next dose administration 
• for end-of-infusion samples, have the sample collected 1 hour (± 5 min) post end of 
infusion 
The spartalizumab pharmacokinetic analysis set (PAS-Spartalizumab) includes all 
participants who provide at least one evaluable spartalizumab PK concentration. For a 
concentration to be evaluable, participants are required to: 
• receive a planned dose of spartalizumab prior to sampling 
• for pre-dose samples, have the sample collected before the next dose administration 
• for end-of-infusion samples, have the sample collected 1 hour (± 5 min) post end of 
infusion 
The carboplatin pharmacokinetic analysis set (PAS-carboplatin) includes all participants who 
provide at least one evaluable carboplatin PK concentration. For a concentration to be 
evaluable, participants are required to: 


Novartis 
Confidential 
Page 119 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• receive a planned dose of carboplatin prior to sampling, 
• for pre-dose samples, have the sample collected before the next dose administration 
• for samples scheduled to be taken prior to End of Infusion (EOI), have the samples 
collected prior to EOI 
• for post-EOI samples, have the samples collected post EOI. The PAS will be used for all 
PK analyses. 
 
 
 
 
Additional details, including definition of determinant, will be provided in the SAP. 
12.2 
Participant demographics and other baseline characteristics 
Demographic and other baseline data including disease characteristics will be listed and 
summarized descriptively by treatment group for the FAS. In addition, number of participants 
treated will be summarized by age/gender combination and by race for each treatment arm in 
the Safety Set for DSUR reporting purposes. 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
Relevant medical histories and current medical conditions at baseline will be summarized 
separately by system organ class, preferred term, and treatment group. 
12.3 
Treatments 
The Safety set will be used for the analyses below. Categorical data will be summarized as 
frequencies and percentages. For continuous data, mean, standard deviation, median, 25th and 
75th percentiles, minimum, and maximum will be presented. 
The duration of exposure in weeks to LAG525, spartalizumab and carboplatin (as applicable) 
as well as the dose intensity (computed as the ratio of actual cumulative dose received and 
actual duration of exposure) and the relative dose intensity (computed as the ratio of dose 
intensity and planned dose intensity) will be summarized by means of descriptive statistics 
using the safety set. 
The number of participants with dose adjustments (reductions in the case of carboplatin, 
interruption, or permanent discontinuation) and the reasons will be summarized by treatment 
group, and all dosing data will be listed. 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed and summarized according to the Anatomical Therapeutic 
Chemical (ATC) classification system, by treatment group. 


Novartis 
Confidential 
Page 120 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
12.4 
Analysis of the primary endpoint(s) 
The primary objective is to assess the antitumor activity of the three combinations LAG525 + 
spartalizumab, LAG525 + spartalizumab + carboplatin, and LAG525 + carboplatin, in 
participants with advanced TNBC in first or second line of therapy. 
12.4.1 
Definition of primary endpoint(s) 
The primary efficacy variable is the overall response rate (ORR) defined as the proportion of 
participants with best overall response (BOR) of complete response (CR) or partial response 
(PR), as per local review and according to RECIST 1.1 (see Section 16.3 Appendix 3 for 
details). 
BOR is defined as the best response recorded from the randomization date until disease 
progression as per RECIST 1.1. If any new antineoplastic therapy is taken while on study, any 
subsequent assessments will be excluded from the best overall response determination. 
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met. 
The BOR for each participant 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 
PR = at least two determinations of PR or better at least 4 weeks apart before progression (and 
not qualifying for a CR) 
SD = at least one SD assessment (or better) > 5 weeks after randomization (and not qualifying 
for CR or PR). 
PD = progression ≤ 13 weeks after randomization (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 5 weeks or early progression within the first 13 weeks) 
12.4.2 
Statistical model, hypothesis, and method of analysis 
The primary objective of the study is to assess the anti-tumor activity of the three treatment 
arms LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + 
carboplatin, in participants with advanced TNBC in first or second line of therapy, as measured 
by ORR per investigator’s assessment according to RECIST v1.1. ORR based on RECIST1.1 
will be calculated based on the FAS and according to the Intent-To-Treat (ITT) principle. 
In a randomized phase III study of carboplatin compared to docetaxel for participants with 
metastatic or recurrent locally advanced triple negative breast cancer or BRCA1/2 breast cancer, 
including 188 participants randomized to carboplatin, the ORR with carboplatin in first line was 
31.4% Tutt et al 2014. In the phase II clinical trial of platinum monotherapy in metastatic 
TNBC, with 86 participants treated by carboplatin or cisplatin in first (69 participants) or second 
line (17 participants) the ORR was 25.6%. Specifically in second line, the ORR with cisplatin 
alone (9 participants) was 22.2% and no participant responded in second line out of the 8 
participants treated by carboplatin Isakoff et al 2015. Based on cisplatin response rate in second 
line and considering that differences in population treated by the two drugs may explain the 


Novartis 
Confidential 
Page 121 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
lower response rate observed with carboplatin, the ORR with carboplatin in second line is 
assumed around 20%. 
Hence, based on those published results and assuming a similar proportion of participants 
enrolled in first line and second line of therapy, the response rate with single agent carboplatin 
in participants with advanced TNBC in 1st and 2nd line overall is expected to be 25% 
Isakoff et al 2015, Tutt et al 2014. A 10% absolute improvement in the response rate to 35% is 
considered a minimum clinically meaningful improvement in this study population. Therefore, 
proof of preliminary efficacy in each treatment group will be declared if both of the following 
conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 
The posterior distribution of ORR will be derived from the prior distribution and all available 
data from the participants included in the FAS. A minimally informative unimodal Beta prior 
Neuenschwander et al 2008 will be used for ORR in each arm (see Section 16.3 Appendix 3 for 
further details). 
Additionally, ORR will be summarized by treatment group along with the two-sided exact 
binomial 95% confidence interval Clopper CJ and Pearson 1934. 
Waterfall graphs, which display the best percentage change from baseline in the sum of 
diameters of all target lesions for each participant with measurable disease at baseline, will be 
used to depict the anti-tumor activity of each treatment group. 
12.4.3 
Handling of missing values/censoring/discontinuations 
Participants with unknown or missing BOR as per RECIST 1.1 will be counted as failures. If 
there is no baseline tumor assessment, all post-baseline overall lesion responses are expected to 
be ‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall 
response must be “Unknown” unless progression is reported. For the computation of ORR, 
these participants will be included in the FAS and will be counted as ‘failures’. 
Only tumor assessments performed on or before the start of a new antineoplastic treatment other 
than study drug(s) will be considered in the assessment of BOR. 
12.4.4 
Sensitivity and Supportive analyses 
Supportive and sensitivity analyses will be conducted to support the primary objective, if 
appropriate, and the details of these analyses will be defined in the SAP. 
12.5 
Analysis of secondary endpoints 
The secondary objectives are: 
• To assess the efficacy of each treatment arm with respect to Duration of response (DOR), 
Time to response (TTR), Progression Free Survival (PFS), and Clinical benefit rate (CBR) 
per investigator’s assessment according to RECIST v1.1 
• To assess Overall Survival for each treatment arm 


Novartis 
Confidential 
Page 122 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• To characterize the safety profile of each treatment arm 
• To characterize the pharmacokinetics (PK) of LAG525, spartalizumab and carboplatin in 
the three investigated combinations 
• To assess immunogenicity of LAG525 and spartalizumab in the three investigated 
combinations 
12.5.1 
Efficacy and/or Pharmacodynamic endpoint(s) 
Clinical benefit rate (CBR) is defined as the proportion of participants with a best overall 
response of complete response (CR) or partial response (PR) or an overall lesion response of 
stable disease (SD), lasting for a duration of at least 24 weeks. CR, PR and SD are defined as 
per local review according to RECIST 1.1 (see Section 16.3 Appendix 3 for details). CBR will 
be evaluated according to RECIST 1.1 (see Section 16.3 Appendix 3 for details). 
CBR based on RECIST 1.1 will be calculated based on the FAS and according to the ITT 
principle. 
CBR 
and 
its 
two-sided 
exact 
binomial 
95% 
confidence 
interval 
Clopper CJ and Pearson 1934 will be presented by treatment group. 
Time to response (TTR) is defined as the time from the date of randomization to the first 
documented response of either complete response (CR) or partial response (PR), which must 
be subsequently confirmed (i.e., the start date of response, not the date when response was 
confirmed). 
TTR will be evaluated according to RECIST 1.1 (see Section 16.3 Appendix 3 for details). 
All participants in the FAS will be included in TTR calculations. Participants without a 
confirmed CR or PR will be censored at the study-maximum follow-up time (i.e., LPLV-FPFV) 
for participants with a PFS event (i.e., disease progression or death due to any cause), or at the 
date of the last adequate tumor assessment for participants without a PFS event. TTR will be 
listed and summarized by treatment group. TTR will be analyzed in the FAS population 
according to the treatment groups assigned at randomization. The TTR distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians will be presented for each treatment group only if a 
sufficient number of responses is observed. 
Duration of response (DOR) only applies to participants whose best overall response is 
complete response (CR) or partial response (PR) based on tumor response data per local review. 
DOR will be evaluated according to RECIST 1.1 (see Section 16.3 Appendix 3 for details). 
The start date is the date of first documented response of CR or PR (i.e., the start date of 
response, not the date when response was confirmed), and the end date is defined as the date of 
the first documented progression or death due to underlying cancer. Participants continuing 
without progression or death due to underlying cancer will be censored at the date of their last 
adequate tumor assessment. DOR based on RECIST 1.1 will be listed and summarized by 
treatment group for all participants in the FAS with confirmed BOR of CR or PR. DoR will be 
analyzed in the FAS population according to the treatment groups assigned at randomization. 
The DoR distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier 
curves, medians and 95% confidence intervals of the medians will be presented for each 
treatment group only if a sufficient number of responses is observed. 


Novartis 
Confidential 
Page 123 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Progression-Free Survival (PFS) is defined as time from date of randomization to the date of 
event defined as the first documented progression or death due to any cause. PFS will be 
assessed via local review according to RECIST 1.1 (see Section 16.3 Appendix 3 for further 
details). PFS will be censored if no PFS event is observed before the earliest of (i) the analysis 
cut-off date, and (ii) the date when a new anti-neoplastic therapy is started. The censoring date 
will be the date of the last adequate tumor assessment prior to cut-off/start of new anti-
neoplastic therapy. 
PFS will be analyzed in the FAS population according to the treatment groups. The PFS 
distribution will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, 
medians and 95% confidence intervals of the medians will be presented for each treatment 
group. 
Overall Survival (OS) is defined as the time from date of randomization to date of death due 
to any cause. If a participant is not known to have died, then OS will be censored at the latest 
date the participant was known to be alive (on or before the cut-off date). OS will be analyzed 
in the FAS population according to the treatment groups. The OS distribution will be estimated 
using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% confidence 
intervals of the medians will be presented for each treatment group. 
12.5.2 
Safety endpoints 
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group. 
Safety summaries (tables, figures) will include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g., change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). 
The on-treatment period lasts from the date of first administration of study treatment to 30 days 
after the date of the last actual administration of any study treatment. 
The overall observation period will be divided into three mutually exclusive segments: 
• Pre-treatment period: from day of participant’s informed consent to the day before first 
dose of study medication 
• On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
• Post-treatment period: starting at day 31 after last dose of study medication. 
If dates are incomplete in a way that clear assignment to pre-, on-, or post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. Additional 
details to address incomplete AE and/or dosing dates will be addressed in the SAP. 
Adverse events 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. 


Novartis 
Confidential 
Page 124 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Additional summaries will be displayed to report all AEs, AEs related to study treatment, all 
SAEs and SAEs related to study treatment collected up to 150 days after last administration of 
LAG525/spartalizumab or up to 30 days after the last dose of carboplatin whichever comes last. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Serious adverse events, non-serious adverse events and adverse events of special interest 
(AESI) during the on-treatment period will be tabulated. 
All deaths (on-treatment, up to 150 days after last administration of LAG525/spartalizumab or 
up to 30 days after the last dose of carboplatin whichever comes last, 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. 
Vital signs 
Data on vital signs will be tabulated based on notable vital sign values. All vital signs data will 
be listed by treatment group, participant and visit/time, notable values will be flagged. 
12-lead ECG 
12-lead ECGs including PR, QRS, QT and QTcF will be obtained for each participant during 
the study. ECG data will be read and interpreted centrally. 
All ECG data will be listed by treatment group, participant and visit/time, abnormalities will be 
flagged. Categorical analysis of QT/QTc interval data based on the number of participants 
meeting or exceeding predefined limits in terms of absolute QT/QTc intervals or changes from 
baseline will be presented. 
Clinical laboratory evaluations 
All laboratory data will be listed by treatment group, participant, and visit/time. 
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. 
CTCAE 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 version 5.0, results will be 
categorized as low/normal/high based on laboratory normal ranges. 
The following listings/summaries will be generated separately for hematology and biochemistry 
tests: 
• Listing of all laboratory data with values flagged to show the corresponding CTCAE 
version 5.0 grades if applicable and the classifications relative to the laboratory normal 
ranges 


Novartis 
Confidential 
Page 125 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
For laboratory tests where grades are defined by CTCAE version 5.0 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each participant 
will be counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE version 5.0 grades to compare baseline to the worst on-
treatment value 
For laboratory tests where grades are not defined by CTCAE version 5.0, 
• Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value. 
 
 
Other safety evaluations 
Other safety data (e.g., cardiac imaging) will be summarized or listed as appropriate. 
12.5.3 
Pharmacokinetics 
The respective PAS for each study drug will be used in the pharmacokinetic data analysis. 
Drug concentration values below the lower limit of quantitation (LLOQ) will be displayed in 
listings as zero with a flag and handled as zero in the calculations for mean, CV for mean, 
standard deviation, minimum, median, maximum, but handled as missing for the calculation of 
the geometric means and their CV. 
Descriptive statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, 
geometric mean, geometric CV%, minimum and maximum) for spartalizumab, LAG525 and 
carboplatin concentrations will be presented at each scheduled timepoint and visit by treatment 
group. 
All spartalizumab, LAG525 and carboplatin concentration data will be displayed graphically 
and by treatment group and visit. 
PK parameters may be calculated using the PK sampling in cycle 1 and cycle 3, as appropriate. 
The descriptive statistics (n, mean, CV%, standard deviation (SD), median, geometric mean, 
geometric CV%, minimum and maximum) will be presented for all PK parameters for 
spartalizumab, LAG525 and carboplatin by treatment group for both cycle 1 and cycle 3 defined 
in Table 12-1 except Tmax, where only n, median, minimum and maximum will be presented. 


Novartis 
Confidential 
Page 126 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 12-1 
Non-compartmental pharmacokinetic parameters for spartalizumab, 
LAG525 and carboplatin 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1) 
AUCtau 
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x 
time x volume-1) 
Cmin or 
Ctrough 
The minimum observed plasma or serum drug concentration (mass 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) 
12.5.3.1 Data handling principles 
Missing values for any PK parameters or concentrations will not be imputed and will be treated 
as missing. 
Below the limit of quantitation (BLQ) values will be set to zero by the Bioanalyst, and will be 
displayed in the listings as zero and flagged. BLQ values will be treated as missing for the 
calculation of the geometric means and geometric CV%. 
12.5.4 
Immunogenicity 
Immunogenicity will be characterized descriptively by tabulating anti-drug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. Additional details will be specified in 
the SAP. 


Novartis 
Confidential 
Page 127 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 128 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 129 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
12.7 
Interim analyses 
No formal interim analysis is planned for this trial. The primary analysis of the study data will 
be reported in the primary CSR based on all participants’ data up to the time when all 
participants have been followed for efficacy (tumor assessments) for at least 24 weeks or 
discontinued tumor assessments for any reason prior to 24 weeks. Any additional data (e.g., 
DoR, OS, safety) for participants continuing to receive study treatment past the data cutoff date 
for the primary CSR, as allowed by the protocol, will be reported in the Final analysis on 
completion of the study.  
12.8 
Sample size calculation 
12.8.1 
Primary endpoint(s) 
The sample size calculation is based on the primary variable ORR considering the statistical 
model, hypothesis and method of analysis detailed in Section 12.4.2. Proof of preliminary 
efficacy (PPE) for each drug combination (study arm) will be declared if both of the following 
conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 


Novartis 
Confidential 
Page 130 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Approximately 32 participants were planned to be enrolled in each arm for a total of 
approximately 96 participants. In a given arm of 32 participants, the type-I error rate is 8% 
while the probability of declaring proof of preliminary efficacy (PPE) is at least 80% for ORR 
≥ 45% (Table 12-2). With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + 
spartalizumab) was prematurely closed. Therefore, approximately 84 participants will be 
enrolled (approximately 20 participants in Arm 1, and 32 participants per arm for Arms 2 and 
3). 
Table 12-2 
Operating characteristics with 32 participants in each arm 
True 
ORR 
Probability of declaring PPE in each arm 
(12 or more responders) 
Probability of missing PPE (11 or less 
responders) in each arm 
25 % 
0.079 
0.921 
30 % 
0.228 
0.772 
35 % 
0.448 
0.552 
40% 
0.675 
0.325 
45 % 
0.847 
0.153 
13 
Ethical considerations and administrative procedures 
13.1 
Regulatory and ethical compliance 
This clinical study was designed and shall be implemented, executed and reported in accordance 
with the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC, US CFR 21), and with the ethical 
principles laid down in the Declaration of Helsinki. 
13.2 
Responsibilities of the investigator and IRB/IEC 
Before initiating a trial, the investigator/institution must obtain approval/favorable opinion from 
the Institutional Review Board/Independent Ethics Committee (IRB/IEC) for the trial protocol, 
written informed consent form, consent form updates, participant recruitment procedures (e.g., 
advertisements) and any other written information to be provided to participants. 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 Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs, and regulatory authorities as required. If an inspection of the clinical site is 
requested by a regulatory authority, the investigator must inform Novartis immediately that this 
request has been made. 
13.3 
Publication of study protocol and results 
The protocol will be registered in a publicly accessible database such as clinicaltrials.gov and 
as required in EudraCT. In addition, after study completion and finalization of the study report 
the results of this trial will be submitted for publication and posted in a publicly accessible 
database of clinical trial results, such as the Novartis clinical trial results website and all required 
Health Authority websites (e.g. Clinicaltrials.gov, EudraCT etc.). 


Novartis 
Confidential 
Page 131 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
For details on the Novartis publication policy including authorship criteria, please refer to the 
Novartis publication policy training materials that were provided to you at the trial investigator 
meetings 
13.4 
Quality Control and Quality Assurance 
Novartis maintains a robust Quality Management System (QMS) that includes all activities 
involved in quality assurance and quality control, to ensure compliance with written Standard 
Operating Procedures as well as applicable global/local GCP regulations and ICH Guidelines. 
Audits of investigator sites, vendors, and Novartis systems are performed by auditors, 
independent from those involved in conducting, monitoring or performing quality control of the 
clinical trial. The clinical audit process uses a knowledge/risk based approach. 
Audits are conducted to assess GCP compliance with global and local regulatory requirements, 
protocols and internal SOPs, and are performed according to written Novartis processes 
14 
Protocol adherence 
This protocol defines the study objectives, the study procedures and the data to be collected on 
study participants. Additional assessments required to ensure safety of participants should be 
administered as deemed necessary on a case by case basis. Under no circumstances including 
incidental collection is an investigator allowed to collect additional data or conduct any 
additional procedures for any purpose involving any investigational drugs under the protocol, 
other than the purpose of the study. If despite this interdiction prohibition, data, information, 
observation would be incidentally collected, the investigator shall immediately disclose it to 
Novartis and not use it for any purpose other than the study, except for the appropriate 
monitoring on study participants. 
Investigators ascertain they will apply due diligence to avoid protocol deviations. If an 
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 and Health Authorities, where required, it cannot be 
implemented. 
14.1 
Protocol amendments 
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 prior to 
implementation. 
Only amendments that are required for participant safety may be implemented immediately 
provided the Health Authorities are subsequently notified by protocol amendment and the 
reviewing IRB/IEC is notified. 
Notwithstanding the need for approval of formal protocol amendments, the investigator is 
expected to take any immediate action required for the safety of any participant 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. 


Novartis 
Confidential 
Page 132 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
15 
References 
References are available upon request 
Adams S, Schmid P, Rugo HS, et al (2017) Phase 2 study of pembrolizumab (pembro) 
monotherapy for previously treated metastatic triple-negative breast cancer (mTNBC): 
KEYNOTE-086 cohort A. J Clin Oncol: 35.15 suppl. Abstract 1008. 
Anderson AC, Joller N, Kuchroo VK (2016) Lag-3, Tim-3, and TIGIT: Co-inhibitory Receptors 
with Specialized Functions in Immune Regulation. Immunity p. 989-1004. 
Antonia SJ, Gettinger SN, Chow LQM, et al (2014) Nivolumab (anti-PD-1; BMS-936558, 
ONO-4538) and ipilimumab in first-line NSCLC: Interim phase I results. Journal of Clinical 
Oncology 32, no. 15_suppl 8023-8023. 
Aurilio G, Disalvatore D, Pruneri G, et al (2014) A meta-analysis of oestrogen receptor, 
progesterone receptor and human epidermal growth factor receptor 2 discordance between 
primary breast cancer and metastases. Eur. J. Cancer p. 277-89. 
Bai S, Jorga K, Xin Y, et al (2012) A guide to rational dosing of monoclonal antibodies. Clin 
Pharmacokinet p. 119-35. 
Banerji S, Cibulskis K, Rangel-Escareno C, et al (2012) Sequence analysis of mutations and 
translocations across breast cancer subtypes. Nature p. 405-9. 
Bardia A, Mayer IA, Diamond JR, et al (2017) Efficacy and Safety of Anti-Trop-2 Antibody 
Drug Conjugate Sacituzumab Govitecan (IMMU-132) in Heavily Pretreated Patients With 
Metastatic Triple-Negative Breast Cancer. J. Clin. Oncol. p. 2141-2148. 
Baselga J, Gómez P, Greil R, et al (2013) Randomized phase II study of the anti-epidermal 
growth factor receptor monoclonal antibody cetuximab with cisplatin versus cisplatin alone in 
patients with metastatic triple-negative breast cancer. J. Clin. Oncol. p. 2586-92. 
Brahmer JR, Lacchetti C, Thompson JA (2018) Management of immune-related adverse 
events in patients treated with immune checkpoint inhibitor therapy: American society of 
clinical oncology clinical practice guideline summary. J Oncol Pract. ASCO 14(4) p. 247-50. 
Buonaguro L, Petrizzo A, Tagliamonte M, et al (2013) Challenges in cancer vaccine 
development for hepatocellular carcinoma. J. Hepatol. p. 897-903. 
 
 
Byrski T, Dent R, Blecharz P, et al (2012) Results of a phase II open-label, non-randomized 
trial of cisplatin chemotherapy in patients with BRCA1-positive metastatic breast cancer. Breast 
Cancer Res. p. R110. 
Byrski T, Gronwald J, Huzarski T, et al (2010) Pathologic complete response rates in young 
women with BRCA1-positive breast cancers after neoadjuvant chemotherapy. J. Clin. Oncol. 
p. 375-9. 
Cardoso F, Costa A, Senkus E, et al (2017) 3rd ESO-ESMO international consensus guidelines 
for Advanced Breast Cancer (ABC 3). Breast p. 244-259. 
Champiat S, Lambotte O, Barreau E, et al (2016) Management of immune checkpoint blockade 
dysimmune toxicities: a collaborative position paper. Ann. Oncol. p. 559-74. 


Novartis 
Confidential 
Page 133 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Champiat S, Dercle L, Ammari S, et al (2017) Hyperprogressive Disease Is a New Pattern of 
Progression in Cancer Patients Treated by Anti-PD-1/PD-L1. Clin Cancer Res. 23(8):1920-8. 
Clopper CJ and Pearson ES (1934) The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika: 26: 404-13.  
Common Terminology Criteria for Adverse Events (CTCAE) Version 5.0 November 27, 2017. 
U.S. Department of Health and human services. NIH.NCI. (https://ctep.cancer.gov) 
Dammeijer F, Lau SP, van Eijck CHJ, et al (2017) Rationally combining immunotherapies to 
improve efficacy of immune checkpoint blockade in solid tumors. Cytokine Growth Factor Rev. 
p. 5-15. 
Demeure CE, Wolfers J, Martin-Garcia N, et al (2001) T Lymphocytes infiltrating various 
tumour types express the MHC class II ligand lymphocyte activation gene-3 (LAG-3): role of 
LAG-3/MHC class II interactions in cell-cell contacts. Eur. J. Cancer p. 1709-18. 
Denkert C (2014) The immunogenicity of breast cancer--molecular subtypes matter. Ann. 
Oncol. p. 1453-5. 
Denkert C, Liedtke C, Tutt A, et al (2017) Molecular alterations in triple-negative breast cancer-
the road to new treatment strategies. Lancet p. 2430-2442. 
Eisenhauer EA, Therasse P, Bogaerts J, et al (2009) New response evaluation criteria in solid 
tumours: revised RECIST guideline (version 1.1). Eur. J. Cancer p. 228-47. 
Emens LA, Middleton G (2015) The interplay of immunotherapy and chemotherapy: 
harnessing potential synergies. Cancer Immunol Res p. 436-43. 
Follow-up for information letter regarding AUC-based dosing of carboplatin. October 22, 2010. 
U.S.Department of Health and human services. NIH.NCI. 
Freeman G (2008) Structures of PD-1 with its ligands: sideways and dancing cheek to cheek. 
Proc Natl Acad Sci p. 10275–6 
Goldinger SM, Tsai KK, Tumeh P, et al (2016) Correlation between metastatic site and response 
to anti-Programmed Death-1 (PD-1) agents in melanoma. J Clin Oncol:34:(suppl; abstr 9549). 
Grosso JF, Goldberg MV, Getnet D, et al (2009) Functionally distinct LAG-3 and PD-1 subsets 
on activated and chronically stimulated CD8 T cells. J. Immunol. p. 6659-69. 
Grosso JF, Kelleher CC, Harris TJ, et al (2007) LAG-3 regulates CD8+ T cell accumulation 
and effector function in murine self- and tumor-tolerance systems. J. Clin. Invest. p. 3383-92. 
Guidance for Industry. Drug interaction studies – study design, data analysis, implications for 
dosing and labeling. Recommendations (2012). US Department of Health and Human Services. 
FDA. CDER. February 2012. Clinical Pharmacology 
Haanen JBAG, CF, Robert C, et al (2017) On behalf of the ESMO Guidelines Committee 
( 2017) Management of toxicities from immunotherapy: ESMO Clinical Practice Guidelines 
for diagnosis, treatment and follow-up. Annals of Oncology: 28 (Suppl 4): iv119–iv142. 
Hammond ME, Hayes DF, Wolff AC (2011) Clinical Notice for American Society of Clinical 
Oncology-College of American Pathologists guideline recommendations on ER/PgR and HER2 
testing in breast cancer. J. Clin. Oncol. p. e458. 
Hammond ME, Hayes DF, Dowsett M, et al (2010) American Society of Clinical 
Oncology/College 
of 
American 
Pathologists 
guideline 
recommendations 
for 


Novartis 
Confidential 
Page 134 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
immunohistochemical testing of estrogen and progesterone receptors in breast cancer. Arch. 
Pathol. Lab. Med. p. 907-22. 
Hanahan D, Weinberg RA (2011) Hallmarks of cancer: the next generation. Cell p. 646-74. 
Hastak K, Alli E, Ford JM (2010) Synergistic chemosensitivity of triple-negative breast cancer 
cell lines to poly(ADP-Ribose) polymerase inhibition, gemcitabine, and cisplatin. Cancer Res. 
p. 7970-80. 
Hato SV, Khong A, de Vries IJ, et al (2014) Molecular pathways: the immunogenic effects of 
platinum-based chemotherapeutics. Clin. Cancer Res. p. 2831-7. 
Herbst RS, Baas P, Kim DW, et al (2016) Pembrolizumab versus docetaxel for previously 
treated, PD-L1-positive, advanced non-small-cell lung cancer (KEYNOTE-010): a randomised 
controlled trial. Lancet p. 1540-50. 
Hofmann L, Forschner A, Loquai C, et al (2016) Cutaneous, gastrointestinal, hepatic, 
endocrine, and renal side-effects of anti-PD-1 therapy. Eur. J. Cancer p. 190-209. 
Huard B, Gaulard P, Faure F, et al (1994) Cellular expression and tissue distribution of the 
human LAG-3-encoded protein, an MHC class II ligand. Immunogenetics p. 213-7. 
Isakoff SJ, Mayer EL, He L, et al (2015) TBCRC009: A Multicenter Phase II Clinical Trial of 
Platinum Monotherapy With Biomarker Assessment in Metastatic Triple-Negative Breast 
Cancer. J. Clin. Oncol. p. 1902-9. 
Kassam F, Enright K, Dent R, et al (2009) Survival outcomes for patients with metastatic triple-
negative breast cancer: implications for clinical practice and trial design. Clin. Breast Cancer p. 
29-33. 
Keytruda® USPI 2017 
Kim H, Choi DH, Park W, et al (2013) Prognostic factors for survivals from first relapse in 
breast cancer patients: analysis of deceased patients. Radiat Oncol J p. 222-7. 
Kohler BA, Sherman RL, Howlader N, et al (2015) Annual Report to the Nation on the Status 
of Cancer, 1975-2011, Featuring Incidence of Breast Cancer Subtypes by Race/Ethnicity, 
Poverty, and State. J. Natl. Cancer Inst. p. djv048. 
Kroemer G, Galluzzi L, Kepp O, et al (2013) Immunogenic cell death in cancer therapy. Annu. 
Rev. Immunol. p. 51-72. 
Langer CJ, Gadgeel SM, Borghaei H, et al (2016) Carboplatin and pemetrexed with or without 
pembrolizumab for advanced, non-squamous non-small-cell lung cancer: a randomised, phase 
2 cohort of the open-label KEYNOTE-021 study. Lancet Oncol. p. 1497-1508. 
Leen AM, Rooney CM, Foster AE (2007) Improving T cell therapy for cancer. Annu. Rev. 
Immunol. p. 243-65. 
Lesterhuis WJ, Punt CJ, Hato SV, et al (2011) Platinum-based drugs disrupt STAT6-mediated 
suppression of immune responses against cancer in humans and mice. J. Clin. Invest. p. 3100-
8. 
Liedtke C, Mazouni C, Hess KR, et al (2008) Response to neoadjuvant therapy and long-term 
survival in patients with triple-negative breast cancer. J. Clin. Oncol. p. 1275-81. 


Novartis 
Confidential 
Page 135 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Liu WM, Fowler DW, Smith P, et al (2010) Pre-treatment with chemotherapy can enhance the 
antigenicity and immunogenicity of tumours by promoting adaptive immune responses. Br. J. 
Cancer p. 115-23. 
Loi S, Drubay D, Adams S, et al (2015) Pooled individual patient data analysis of stromal tumor 
infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-
based chemotherapy. Abstract presented at: 38th Annual San Antonio Breast Cancer 
Symposium; December 8-12, 2015; San Antonio, TX. Abstract S1-03.  
Loi S, Drubay D, Adams S, et al (2015) Pooled individual patient data analysis of stromal tumor 
infiltrating lymphocytes in primary triple negative breast cancer treated with anthracycline-
based chemotherapy. Abstract presented at: 38th Annual San Antonio Breast Cancer 
Symposium; December 8-12, 2015; San Antonio, TX. Abstract S1-03. 
Loi S, Michiels S, Salgado R, et al (2014) Tumor infiltrating lymphocytes are prognostic in 
triple negative breast cancer and predictive for trastuzumab benefit in early breast cancer: 
results from the FinHER trial. Ann. Oncol. p. 1544-50. 
Lu J, Zhu X, Wang J, et al (2017) Immunogenic chemotherapy sensitizes non-small cell lung 
cancer to immune checkpoint blockade therapy in preclinical models. Biomedical Res: 28: 828-
34. 
Lynch TJ, Bondarenko I, Luft A, et al (2012) Ipilimumab in combination with paclitaxel and 
carboplatin as first-line treatment in stage IIIB/IV non-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase II study. J. Clin. Oncol. p. 2046-54. 
Lynparza® USPI 2018 
Mahmood SS, Fradley MG, Cohen JV et al (2018) Myocarditis in patients treated with immune 
checkpoint inhibitors. J Am Coll Cardiol. 71(16):1755-64 
Matsuzaki J, Gnjatic S, Mhawech-Fauceglia P, et al (2010) Tumor-infiltrating NY-ESO-1-
specific CD8+ T cells are negatively regulated by LAG-3 and PD-1 in human ovarian cancer. 
Proc. Natl. Acad. Sci. U.S.A. p. 7875-80. 
Mittendorf EA, Philips AV, Meric-Bernstam F, et al (2014) PD-L1 expression in triple-negative 
breast cancer. Cancer Immunol Res p. 361-70. 
Murphy K (2011) Janeway’s Immunobiology. 8th ed; New York: Garland Science. 
NCCN Clinical Practice Guidelines in Oncology: Breast Cancer. Version 4.2017. 
https://www.nccn.org/professionals/physician_gls/pdf/breast.pdf (accessed on February 09, 
2018)  
Nanda R, Chow LQ, Dees EC, et al (2016) Pembrolizumab in Patients With Advanced Triple-
Negative Breast Cancer: Phase Ib KEYNOTE-012 Study. J. Clin. Oncol. p. 2460-7. 
Neuenschwander B, Branson M, Gsponer T (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med p. 2420-39. 
Nishino M, Ramaiya NH, Chambers ES, et al (2016) Immune-related response assessment 
during PD-1 inhibitor therapy in advanced non-small-cell lung cancer patients. J Immunother 
Cancer p. 84. 


Novartis 
Confidential 
Page 136 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Ono M, Tsuda H, Shimizu C, et al (2012) Tumor-infiltrating lymphocytes are correlated with 
response to neoadjuvant chemotherapy in triple-negative breast cancer. Breast Cancer Res. 
Treat. p. 793-805. 
Opdivo® USPI 2018 
Pallai RN, Kamphorst AO, Owonikoko TK, et al (2016) Liver metastases and sensitivity to 
checkpoint inhibition in patients with non-small cell lung cancer (NSCLC). DOI: 
10.1200/JCO.2016.34.15_suppl.e20665 Journal of Clinical Oncology 34, no. 15_suppl – . 
Paraplatin® USPI. Rev July 2010 
Peshkin BN, Alabek ML, Isaacs C (2010) BRCA1/2 mutations and triple negative breast 
cancers. Breast Dis p. 25-33. 
Pfirschke C, Engblom C, Rickelt S, et al (2016) Immunogenic Chemotherapy Sensitizes 
Tumors to Checkpoint Blockade Therapy. Immunity p. 343-54. 
Pierga JY, Fumoleau P, Brewer Y, et al (2004) Efficacy and safety of single agent capecitabine 
in pretreated metastatic breast cancer patients from the French compassionate use program. 
Breast Cancer Res. Treat. p. 117-29. 
Quinn JE, Kennedy RD, Mullan PB, et al (2003) BRCA1 functions as a differential modulator 
of chemotherapy-induced apoptosis. Cancer Res. p. 6221-8. 
Reck M, Bondarenko I, Luft A, et al (2013) Ipilimumab in combination with paclitaxel and 
carboplatin as first-line therapy in extensive-disease-small-cell lung cancer: results from a 
randomized, double-blind, multicenter phase 2 trial. Ann. Oncol. p. 75-83. 
Reck M, Socinski MA, Cappuzzo F, et al (2017) Primary PFS and safety analyses of a 
randomized phase III study of carboplatin + paclitaxel +/− bevacizumab, with or without 
atezolizumab in 1L non-squamous metastatic NSCLC (IMPOWER150). ESMO Immuno 
Oncology Congress 2017 Abstract LBA1_PR 
Ribas A, Hamid O, Daud A, et al (2016) Association of Pembrolizumab With Tumor Response 
and Survival Among Patients With Advanced Melanoma. JAMA p. 1600-9. 
Riley JL (2009) PD-1 signaling in primary T cells. Immunol Rev. 229(1): 114-25. 
Robert C, Thomas L, Bondarenko I, et al (2011) Ipilimumab plus dacarbazine for previously 
untreated metastatic melanoma. N. Engl. J. Med. p. 2517-26. 
Robson M, Im SA, Senkus E, et al (2017) Olaparib for Metastatic Breast Cancer in Patients 
with a Germline BRCA Mutation. N. Engl. J. Med. p. 523-533. 
Rugo H, Olopade O, DeMichele A, et al (2013) Veliparib/carboplatin plus standard neoadjuvant 
therapy for high-risk breast cancer: First efficacy results from the I-SPY 2 TRIAL. Cancer Res: 
73(24 Suppl): Abstract S5-02. 
Ryan PD, Tung NM, Isakoff SJ, et al (2009) Neoadjuvant cisplatin and bevacizumab in triple 
negative breast cancer (TNBC): Safety and efficacy. J Clin Oncol: 27:abstract 551. 
Schmid P, Cruz C, Braiteh FS, et al (2017) Atezolizumab in metastatic TNBC (mTNBC): Long-
term clinical outcomes and biomarker analyses. Proceedings: AACR Annual Meeting 2017; 
April 1-5, 2017; Washington, DC. AACR; Cancer Res: 77(13 Suppl): Abstract 2986. 
 
 


Novartis 
Confidential 
Page 137 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Sharma P, López-Tarruella S, García-Saenz JA, et al (2017) Efficacy of Neoadjuvant 
Carboplatin plus Docetaxel in Triple-Negative Breast Cancer: Combined Analysis of Two 
Cohorts. Clin. Cancer Res. p. 649-657. 
Sikov WM, Berry DA, Perou CM, et al (2015) Impact of the addition of carboplatin and/or 
bevacizumab to neoadjuvant once-per-week paclitaxel followed by dose-dense doxorubicin and 
cyclophosphamide on pathologic complete response rates in stage II to III triple-negative breast 
cancer: CALGB 40603 (Alliance). J. Clin. Oncol. p. 13-21. 
Silver DP, Richardson AL, Eklund AC, et al (2010) Efficacy of neoadjuvant Cisplatin in triple-
negative breast cancer. J. Clin. Oncol. p. 1145-53. 
Spain L, Diem S, Larkin J (2016) Management of toxicities of immune checkpoint inhibitors. 
Cancer Treat. Rev. p. 51-60. 
Tagliamonte M, Petrizzo A, Tornesello ML, et al (2016) Combinatorial immunotherapy 
strategies for hepatocellular carcinoma. Curr. Opin. Immunol. p. 103-13. 
Tecentriq® USPI 2017 
Telli ML, Timms KM, Reid J, et al (2016) Homologous Recombination Deficiency (HRD) 
Score Predicts Response to Platinum-Containing Neoadjuvant Chemotherapy in Patients with 
Triple-Negative Breast Cancer. Clin. Cancer Res. p. 3764-73. 
Tesniere A, Schlemmer F, Boige V, et al (2010) Immunogenic death of colon cancer cells 
treated with oxaliplatin. Oncogene p. 482-91. 
Tutt A, Cheang MCU, Kilburn L, et al (2016) BRCA1 methylation status, silencing and 
treatment effect in the TNT trial: A randomized phase III trial of carboplatin compared with 
docetaxel for patients with metastatic or recurrent locally advanced triple negative or BRCA1/2 
breast cancer. SABCS 2016, abstract S6-01. 
Tutt A, Ellis P, Kilburn L et al (2014) Abstract S3-01: The TNT trial: A randomized phase III 
trial of carboplatin (C) compared with docetaxel (D) for patients with metastatic or recurrent 
locally advanced triple negative or BRCA1/2 breast cancer (CRUK/07/012). Thirty-Seventh 
Annual CTRC-AACR San Antonio Breast Cancer Symposium; December 9-13, 2014; San 
Antonio, TX. 
USPI for Paraplatin (2010) Paraplatin® USPI. Rev July 2010. 
Von Minckwitz G, Schneeweiss A, Loibl S, et al (2014) Neoadjuvant carboplatin in patients 
with triple-negative and HER2-positive early breast cancer (GeparSixto; GBG 66): a 
randomised phase 2 trial. Lancet Oncol. p. 747-56. 
Wang DD, Zhang S, Zhao H, et al (2009) Fixed dosing versus body size-based dosing of 
monoclonal antibodies in adult clinical trials. J Clin Pharmacol p. 1012-24. 
Watkins J, Weekes D, Shah V, et al (2015) Genomic Complexity Profiling Reveals That 
HORMAD1 Overexpression Contributes to Homologous Recombination Deficiency in Triple-
Negative Breast Cancers. Cancer Discov p. 488-505. 
Wolchok JD, Kluger H, Callahan MK, et al (2013) Nivolumab plus ipilimumab in advanced 
melanoma. N. Engl. J. Med. p. 122-33. 


Novartis 
Confidential 
Page 138 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Woo SR, Turnis ME, Goldberg MV, et al (2012) Immune inhibitory molecules LAG-3 and PD-
1 synergistically regulate T-cell function to promote tumoral immune escape. Cancer Res. p. 
917-27. 
Workman CJ, Cauley LS, Kim IJ, et al (2004) Lymphocyte activation gene-3 (CD223) regulates 
the size of the expanding T cell population following antigen activation in vivo. J. Immunol. p. 
5450-5. 
Yardley DA, Weaver R, Melisko ME, et al (2015) EMERGE: A Randomized Phase II Study of 
the Antibody-Drug Conjugate Glembatumumab Vedotin in Advanced Glycoprotein NMB-
Expressing Breast Cancer. J. Clin. Oncol. p. 1609-19. 
Yervoy® USPI 2018 
Zitvogel L, Galluzzi L, Smyth MJ, et al (2013) Mechanism of action of conventional and 
targeted anticancer therapies: reinstating immunosurveillance. Immunity p. 74-88. 


Novartis 
Confidential 
Page 139 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16 
Appendices 
16.1 
Appendix 1: Safety follow-up diagram 
Figure 16-1 
Safety follow-up diagram 
 


Novartis 
Confidential 
Page 140 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.2 
Appendix 2: Statistical considerations 
The primary endpoint is the overall response rate (ORR). The analysis of the primary endpoint, 
which is Bayesian, uses a binomial sampling and a Beta prior distribution. 
Based on clinical discussions and available literature, the null value for the ORR was set to 
25%. Moreover, a minimum ORR improvement of 10% was considered necessary to justify 
further development (see Section 12.4.2 for information on published data available to help 
elicit the 25% and 35% targets). 
The two criteria to assess the proof of preliminary efficacy (PPE) in each treatment group are 
thus: 
• Clinical relevance: posterior mean ≥ 35% 
• Bayesian statistical significance: pr(ORR ≥ 25% | data) ≥ 0.90 
The first criterion is met if the posterior mean ORR is at least 35% which is the minimum ORR 
of clinical interest. The second criterion provides reasonable evidence that the posterior ORR 
is better than the null value of 25%. Both criteria need to be met by at least one treatment group 
in order to meet the primary objective of the study. 
Each analysis by treatment group is performed separately using a Beta-binomial model as 
follows: 
Let us assume that yi out of ni patients have a response as per ORR in treatment group i (either 
LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin or LAG525 + spartalizumab 
+ carboplatin). 
The likelihood function is yi ~ Bin(ni, pi) where pi denotes the ORR for treatment group i. 
Assume pi follows a beta prior distribution: [pi] ~ Beta(ai, bi), where ai > 0 , bi > 0 
The posterior distribution of pi is therefore: [pi | yi] ∼ Beta(ai + yi, bi + ni - yi) 
A minimally informative prior with unimodal Beta(0.35/(1-0.35),1) distribution is used. The 
prior parameters are chosen so that the prior mean for ORR is equal to 35%. This ensures that 
the clinical relevance criterion is met, if the observed ORR is exactly equal to 35%. 
With the two criteria stated above the minimally required sample size is 32. 
To better understand the design, operating characteristics for various true ORR were assessed 
using simulations as follows: 
• Generate 100,000 trials with ORR results (yes / no) for ni participants per treatment group, 
where the ORR follows a binomial distribution yi ~ Bin(ni, pi). 
• Evaluate for each of these simulated trials whether the PPE criteria are met. 
• The probability of declaring preliminary efficacy is the average number of trials meeting 
PPE over the 100,000 sampled trials. 
The operating characteristics presented in Section 12.8.1 of the protocol consider ni=32, with 
varying pi from 0.25 to 0.45. Operating characteristics for additional sample sizes of 36 and 40 
participants by treatment group were also assessed and full results are presented in the Table 16-
1 hereafter: 


Novartis 
Confidential 
Page 141 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
Table 16-1 
Operating characteristics with 32, 36 or 40 participants in each arm 
Number of 
participants 
True 
ORR 
Probability of declaring PPE 
in each arm 
Probability of missing PPE 
in each arm 
32 
25 % 
0.079 
0.921 
30 % 
0.228 
0.772 
35 % 
0.448 
0.552 
40% 
0.675 
0.325 
45 % 
0.847 
0.153 
36 
25 % 
0.092 
0.908 
30 % 
0.263 
0.737 
35 % 
0.507 
0.493 
40% 
0.738 
0.262 
45 % 
0.893 
0.107 
40 
25 % 
0.102 
0.898 
30 % 
0.296 
0.704 
35 % 
0.559 
0.441 
40% 
0.787 
0.213 
45 % 
0.924 
0.076 
Based on the Operating Characteristics the minimal sample size of 32 participants by treatment 
group was considered as adequate. 


Novartis 
Confidential 
Page 142 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.3 
Appendix 3: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival, and Overall 
Survival (based on RECIST 1.1) 
 
Document type: 
TA Specific Guideline 
Document status: 
Version 3.2: February 11, 2016 
Version 3.1: November 29, 2011 
Version 3: October 19, 2009  
Version 2: January 18, 2007  
Version 1: December 13, 2002 
Release date: 
11-Feb-2016 
 


Novartis 
Confidential 
Page 143 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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 
OS 
Overall survival 
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 


Novartis 
Confidential 
Page 144 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.3.1 
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 16.3.2 and the definition of best response in 
Section 16.3.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 16.3.3.2 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 16.3.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the SAP (Statistical Analysis Plan) to provide further details needed for programming. 
16.3.2 
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. 
16.3.2.1 Definitions 
16.3.2.1.1 
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 16.3.3.2.8. 
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. 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ³15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring ³10 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. 


Novartis 
Confidential 
Page 145 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• 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 ³ 
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. 
16.3.2.1.2 
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 
16.3.3.2.8. 
16.3.2.2 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. 
• 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. 


Novartis 
Confidential 
Page 146 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• 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 major change in technique (e.g. from CT 
to MRI, or vice-versa), or a change in any other imaging modality. A change from 
conventional to spiral CT or vice versa will not constitute a major “change in method” for 
the purposes of response assessment. A change in methodology will result by default in a 
UNK overall lesion response assessment as per Novartis calculated response. 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 new disease is indicated by a positive PET scan but is not confirmed by CT (or some 
other conventional technique such as MRI) at the same assessment, then follow-up 
assessments by CT will be needed to determine if there is truly progression occurring at 
that site. In all cases PD will be the date of confirmation of new disease by CT (or some 
other conventional technique such as MRI) rather than the date of the positive PET scan. 
If there is a positive PET scan without any confirmed progression at that site by CT, then a 
PD cannot be assigned. 
• 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. 
• Physical exams: Evaluation of lesions by physical examination is accepted when lesions 
are superficial, with at least 10mm size, and can be assessed using calipers.  
• Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions, unless pre-specified by the 
protocol. 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.  
• 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. 


Novartis 
Confidential 
Page 147 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• 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. 
16.3.2.3 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 16.3.2.1.1. 
• Nodal target: See Section 16.3.2.1.1. 
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 
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 


Novartis 
Confidential 
Page 148 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
16.3.2.4 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 16-2) and non-target lesions (Table 16-3) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target and 
non-target lesions together (Table 16-4) as well as the presence or absence of new lesions. 
16.3.2.4.1 
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. 
16.3.2.4.1.1 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 participant 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. 
16.3.2.4.1.2 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 


Novartis 
Confidential 
Page 149 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
16.3.2.4.2 
Determination of target lesion response 
Table 16-2 
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 mm 2. 
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 
• 
SOD for CR may not be zero when nodal lesions are part of target lesions 
• 
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 
• 
In exceptional circumstances an UNK response due to change in method could be over-ruled by the 
investigator or central reviewer using expert judgment based on the available information (see Notes on 
target lesion response and methodology change in Section 16.3.2.2). 
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 
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 
on the sum of tumor measurements as presented in Table 16-2 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 


Novartis 
Confidential 
Page 150 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
• 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. 
1. 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. 
2. 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. 
3. 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.  
• A change in method for the evaluation of one or more lesions will usually lead to an UNK 
target lesion response unless there is progression indicated by the remaining lesions which 


Novartis 
Confidential 
Page 151 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
have been evaluated by the same method. In exceptional circumstances an investigator or 
central reviewer might over-rule this assignment to put a non-UNK response using expert 
judgment based on the available information. E.g. a change to a more sensitive method 
might indicate some tumor shrinkage of target lesions and definitely rule out progression 
in which case the investigator might assign an SD target lesion response; however, this 
should be done with caution and conservatively as the response categories have well 
defined criteria. 
16.3.2.4.3 
Determination of non-target lesion response 
Table 16-3 
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 baseline2. 
• 
The assignment of PD solely based on change in non-target lesions in light of target lesion response of 
CR, PR or SD should be exceptional. In such circumstances, the opinion of the investigator or central 
reviewer does prevail. 
• 
It is recommended that the investigator and/or central reviewer should use expert judgment to assign a 
Non-UNK response wherever possible (see notes section for more details) 
Notes on non-target lesion response 
• The investigator and/or central reviewer can use expert judgment to assign a non-UNK 
response wherever possible, even where lesions have not been fully assessed or a different 
method has been used. In many of these situations it may still be possible to identify 
equivocal progression (PD) or definitively rule this out (non-CR/Non-PD) based on the 
available information. In the specific case where a more sensitive method has been used 
indicating the absence of any non-target lesions, a CR response can also be assigned. 
• 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. ³ 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless there is unequivocal progression of the non-target lesions (in which 
case response is PD) or it is not possible to determine whether there is unequivocal 
progression (in which case response is UNK). 
• 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 


Novartis 
Confidential 
Page 152 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 16.3.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied. 
16.3.2.4.4 
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 
1. 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 16.3.2.5). 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ³ 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 16.3.2.2. 
16.3.2.5 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 16-
4. 
Table 16-4 
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 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
Once confirmed PR was achieved, all these assessments are considered PR. 
As defined in Section 16.3.2.4. 


Novartis 
Confidential 
Page 153 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK). 
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. 
16.3.3 
Efficacy definitions 
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 16.3.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts. 
16.3.3.1 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 30 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 


Novartis 
Confidential 
Page 154 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• 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) 
The time durations specified in the SD/PD/UNK definitions above are defaults based on a 6 
week tumor assessment frequency. However these may be modified for specific indications 
which are more or less aggressive. In addition, it is envisaged that the time duration may also 
take into account assessment windows. E.g. if the assessment occurs every 6 weeks with a time 
window of +/- 7 days, a BOR of SD would require a SD or better response longer than 5 weeks 
after randomization/start of treatment. 
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 (³30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not ³20% 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. 


Novartis 
Confidential 
Page 155 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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: 
• 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. The objective of this endpoint is to summarize patients with signs of “activity” 
defined as either shrinkage of tumor (regardless of duration) or slowing down of tumor growth.  
Clinical benefit rate (CBR) is the proportion of patients with a best overall response of CR or 
PR , or an overall lesion response of SD or Non-CR/Non-PD which lasts for a minimum time 
duration (with a default of at least 24 weeks in breast cancer studies). This endpoint measures 
signs of activity taking into account duration of disease stabilization. 
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). 
16.3.3.2 Time to event variables 
The protocol should state which of the following variables is used in that study. 


Novartis 
Confidential 
Page 156 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.3.3.2.1 
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. 
PFS rate at x weeks is an additional measure used to quantify PFS endpoint. It is recommended 
that a Kaplan Meier estimate is used to assess this endpoint.  
16.3.3.2.2 
Overall survival 
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”). 
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive. 
16.3.3.2.3 
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. 
16.3.3.2.4 
PFS2 
A recent EMA guidance (EMA 2012) recommends a substitute end point intermediate to PFS 
and OS called PFS2, a surrogate for OS when OS cannot be measured reliably, which assesses 
the impact of the experimental therapy on next-line treatment. The main purpose of this 
endpoint is to assess long term maintenance strategies, particularly of resensitizing agents and 
where it is necessary to examine the overall “field of influence”. 
PFS2, which could be termed PFS deferred, PFS delayed, tandem PFS, or PFS version 2.0, is 
the time from date of randomization/start of treatment to the date of event defined as the first 
documented progression on next-line treatment or death from any cause. The censoring rules 
for this endpoint will incorporate the same principles as those considered for PFS in this 


Novartis 
Confidential 
Page 157 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
document, and in addition may involve other considerations which will need to be detailed in 
the protocol.  
Please note that data collection for the PFS2 is limited to the date of progression and not specific 
read of the tumor assessments. 
It is strongly recommended that the teams consult regulatory agencies for scientific advice given 
the limited experience with the use of this endpoint in regulatory setting in light of 
methodological issues w.r.t. censoring foreseen. 
16.3.3.2.5 
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. 
16.3.3.2.6 
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). 
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). 


Novartis 
Confidential 
Page 158 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
16.3.3.2.7 
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 16.3.3.2.5. 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. 
• 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. 
16.3.3.2.8 
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 


Novartis 
Confidential 
Page 159 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
In the calculation of the assessment date for time to event variables, any unscheduled 
assessment should be treated similarly to other evaluations. 
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 or the survival follow-up 
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 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 16.3.3.2.8). 
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 available, the last known date patient alive from the survival follow-up page is 
used. 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. 


Novartis 
Confidential 
Page 160 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.3.3.2.9 
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 non-
measurable disease is derived slightly differently according to Table 16-5. 
Table 16-5 
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 16.3.2.4. 
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. 
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. 
16.3.3.2.10 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 


Novartis 
Confidential 
Page 161 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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 16.3.3.2.7, 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 16-6 
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) Ignore clinical progression and follow 
situations above  
(2) Date of discontinuation (visit date at which 
clinical progression was determined) 
As per above 
situations 
Progressed 
F 
New anticancer therapy given 
Ignore the new anticancer therapy and follow 
situations above (ITT approach)  
Date of last adequate assessment prior to new 
anticancer therapy 
(3) Date of secondary anti-cancer therapy 
(4) Date of secondary anti-cancer therapy 
As per above 
situations 
Censored 
Censored 
Event 
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 Section 16.3.3.2.7. 
2 =After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 
16.3.3.2.7. 
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. 


Novartis 
Confidential 
Page 162 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• (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) (ITT) is the recommended approach; events 
documented after the initiation of new cancer therapy will be considered for the primary 
analysis i.e. progressions and deaths documented after the initiation of new cancer therapy 
would be included as events. This will require continued follow-up for progression after the 
start of the new cancer therapy. In such cases, it is recommended that an additional sensitivity 
analysis be performed by censoring at last adequate assessment prior to initiation of new cancer 
therapy. 
Option (2), i.e. censoring at last adequate assessment may be used as a sensitivity analysis. If a 
high censoring rate due to start of new cancer therapy is expected, a window of approximately 
8 weeks performed after the start of new cancer therapy can be used to calculate the date of the 
event or censoring. This should be clearly specified in the analysis plan.  
In some specific settings, local treatments (e.g. radiation/surgery) may not be considered as 
cancer therapies for assessment of event/censoring in PFS/TTP/DoR analysis. For example, 
palliative radiotherapy given in the trial for analgesic purposes or for lytic lesions at risk of 
fracture will not be considered as cancer therapy for the assessment of BOR and PFS analyses. 
The protocol should clearly state the local treatments which are not considered as antineoplastic 
therapies in the PFS/TTP/DoR analysis. 
The protocol should state that tumor assessments will be performed every x weeks until 
radiological progression irrespective of initiation of new antineoplastic therapy. It is strongly 
recommended that a tumor assessment is performed before the patient is switched to a new 
cancer therapy. 
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 16-6 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition: 
• 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 


Novartis 
Confidential 
Page 163 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
16.3.4 
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). 
16.3.4.1 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). 
16.3.4.2 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 
• Participant/guardian decision 
• Progressive disease 
• Study terminated by the sponsor 
• Non-compliant with study treatment 
• No longer requires treatment 


Novartis 
Confidential 
Page 164 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given) 
Death is a reason which “must” lead to discontinuation of patient from trial.  
16.3.4.3 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 survival follow-up. 
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 
• Participant/guardian decision 
• Death 
• Progressive disease 
• Study terminated by the sponsor 
16.3.4.4 Medical validation of programmed overall lesion response 
In order to be as objective as possible the RECIST programmed calculated response assessment 
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). This contrasts with the slightly 
more flexible guidance given to local investigators (and to the central reviewers) to use expert 
judgment in determining response in these type of situations, and therefore as a consequence 
discrepancies between the different sources of response assessment often arise. To ensure the 
quality of response assessments from the local site and/or the central reviewer, the responses 
may be re-evaluated by clinicians (based on local investigator data recorded in eCRF or based 
on central reviewer data entered in the database) 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. 


Novartis 
Confidential 
Page 165 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
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. 
16.3.4.5 Programming rules 
The following should be used for programming of efficacy results: 
16.3.4.5.1 
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. 
16.3.4.5.2 
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 16.3.3.2.7). 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. 
16.3.4.5.3 
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. 
16.3.4.5.4 
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)’. 
16.3.4.5.5 
Study/project specific programming 
The standard analysis programs need to be adapted for each study/project. 
16.3.4.5.6 
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 and the survival page. 
For survival the following censoring reasons are possible: 


Novartis 
Confidential 
Page 166 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
• Alive 
• Lost to follow-up 
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 16-6) 
• 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 16.3.3.2.7. 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. 


Novartis 
Confidential 
Page 167 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 
 
16.3.5 
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 
EMA Guidance: 2012 Guideline on the evaluation of anticancer medicinal products in man 
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 
 


Novartis 
Confidential 
Page 168 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 169 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 170 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 171 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 172 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 173 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 174 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 175 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 176 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 177 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 178 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 179 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 180 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 181 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 182 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 183 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 184 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 


Novartis 
Confidential 
Page 185 of 185 
Amended Protocol Version 04 (Clean) 
 
Protocol No. CLAG525B2101 

SAP_001.pdf: 
Clinical Development 
LAG525 
CLAG525B2101 / NCT03499899
A phase II open-label, randomized, three-arm, multicenter 
study of LAG525 given in combination with spartalizumab 
(PDR001), or with spartalizumab and carboplatin, or with 
carboplatin, as first or second line therapy in patients with 
advanced triple-negative breast cancer 
Statistical Analysis Plan (SAP) 
Amendment 2 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
 
Release date: 
07-Sep-2021
Number of pages: 
63 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


Novartis 
Confidential 
Page 2 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
 
Document History – Changes compared to previous final version of SAP 
 
Date 
Time 
point 
Reason for 
update 
Outcome for update 
Section and title 
impacted 
(Current) 
7-
Jun-
2018 
Prior 
to 
FSFV 
Creation of 
final version 
N/A - First version 
NA 
13-
May-
2020 
Prior 
to 
DBL 
Change 
of 
CTCAE 
version and 
subgroup 
analysis 
1. added subgroup analysis for early 
relapsed patients 
2. CTCAE version was changed to v5.0 
3. Subgroup will be analyzed even if no 
arm meets the preliminary efficacy 
criteria 
 
7-
Sep-
2020 
Prior 
to 
final 
DBL 
Update 
to 
summarize 
Covid-19 
PD and to 
include 
inconclusive 
samples for 
IG analsysis 
1. Added summary of COVID-19 
related protocol deviations  
2. Added summary of subjects with 
ADA-inconclusive samples in the IG 
analysis 
3. Changed study design figure per 
protocol amendment 4 
Section 2.3.7 
Section 2.11.1 
Section 1.1 
 


Novartis 
Confidential 
Page 3 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Table of contents 
Table of contents ................................................................................................................. 3 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design ............................................................................................................ 8 
1.2 
Study objectives and endpoints ............................................................................. 10 
2 
Statistical methods ............................................................................................................. 11 
2.1 
Data analysis general information ......................................................................... 11 
2.1.1 
General definitions ................................................................................ 12 
2.2 
Analysis sets .......................................................................................................... 16 
2.2.1 
Subgroup of interest .............................................................................. 19 
2.3 
Subject disposition, demographics and other baseline characteristics .................. 20 
2.3.1 
Basic demographic and background data .............................................. 20 
2.3.2 
Baseline stratification factors ................................................................ 20 
2.3.3 
Diagnosis and extent of cancer ............................................................. 20 
2.3.4 
Medical history...................................................................................... 21 
2.3.5 
Other ...................................................................................................... 21 
2.3.6 
Subject disposition ................................................................................ 21 
2.3.7 
Protocol deviations ................................................................................ 22 
2.3.8 
Analysis sets .......................................................................................... 22 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................ 23 
2.4.1 
Study treatment / compliance ................................................................ 23 
2.4.2 
Prior, concomitant and post therapies ................................................... 30 
2.5 
Analysis of the primary objective .......................................................................... 31 
2.5.1 
Primary endpoint ................................................................................... 31 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 32 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 33 
2.5.4 
Supportive analyses ............................................................................... 33 
2.6 
Analysis of the key secondary objective ............................................................... 35 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 35 
2.7.1 
Secondary endpoints ............................................................................. 35 
2.7.2 
Statistical hypothesis, model, and method of analysis .......................... 36 
2.7.3 
Handling of missing values/censoring/discontinuations ....................... 38 
 
 39 
2.9 
Safety analyses....................................................................................................... 41 
2.9.1 
Adverse events (AEs) ............................................................................ 41 


Novartis 
Confidential 
Page 4 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.9.2 
Deaths .................................................................................................... 44 
2.9.3 
Laboratory data ..................................................................................... 44 
2.9.4 
Other safety data ................................................................................... 45 
2.10 
Pharmacokinetic endpoints .................................................................................... 48 
2.11 
PD and PK/PD analyses ........................................................................................ 49 
2.11.1 
Immunogenicity .................................................................................... 49 
 
 52 
2.12 
Patient-reported outcomes ..................................................................................... 52 
 
 52 
 
 52 
 
 52 
 
 52 
 
 53 
 
 53 
 
 54 
2.15 
Interim analysis ...................................................................................................... 54 
3 
Sample size calculation ..................................................................................................... 54 
3.1 
Primary analysis .................................................................................................... 54 
3.2 
Power for analysis of key secondary variables ...................................................... 55 
4 
Change to protocol specified analyses .............................................................................. 55 
5 
Appendix ........................................................................................................................... 55 
5.1 
Imputation rules ..................................................................................................... 55 
5.1.1 
Study drug ............................................................................................. 55 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 56 
5.2 
AEs coding/grading ............................................................................................... 57 
5.3 
Laboratory parameters derivations ........................................................................ 58 
5.4 
Statistical models ................................................................................................... 61 
5.4.1 
Primary analysis .................................................................................... 61 
5.4.2 
Key secondary analysis ......................................................................... 62 
5.5 
Rule of exclusion criteria of analysis sets.............................................................. 62 
 
 62 
6 
Reference ........................................................................................................................... 63 
 
 


Novartis 
Confidential 
Page 5 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
List of abbreviations 
ADA 
Antidrug Antibodies 
AE 
Adverse event 
AESI 
Adverse Event of Specific Interest 
ALP 
Alkaline Phosphatase 
ALT 
Alanine aminotransferase 
AST 
Aspartate aminotransferase 
ATC 
Anatomical Therapeutic Classification 
AUC 
Area Under the Curve 
BMI 
Body Mass Index 
BOR 
Best Overall Response 
BRCA1/2 
Breast Cancer 1/2 genes 
CBR 
Clinical Benefit Rate 
CD8 
Cluster of differentiation 8 
CR 
Complete Response 
CRO 
Contract Research Organization 
CRS 
Case Retrieval Strategy 
CSR 
Clinical Study report 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
 
 
DBL 
Database Lock 
DI 
Dose Intensity 
DOR 
Duration Of Response 
DSUR 
Development Safety Update Report 
ECG 
Electrocardiogram 
eCRF 
Electronic Case Report Form 
ECOG 
Eastern Cooperative Oncology Group 
FAS 
Full Analysis Set 
FSFV 
First Subject First Visit 
IHC 
Immunohistochemistry 
LAG-3 
Lymphocyte-Activation Gene 3 
LSLV 
Last Subject Last Visit 
EOI 
End of Infusion 
EOT 
End Of Treatment 
ER 
Estrogen Receptor 
GFR 
Glomerular Filtration Rate 
HGLTs 
High Level Group Terms 
HLT 
High Level Terms 
i.e. 
id est 
IG 
Immunogenicity 
ITT 
Intent-To-Treat 
iRECIST 
Immune-related RECIST 


Novartis 
Confidential 
Page 6 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
IRT 
Interactive Response Technology 
kg 
killogram 
MedDRA 
Medical Dictionary for Regulatory Activities 
mg 
milligram 
min 
minute 
mL 
milliliter 
NCI 
National Cancer Institute 
NMQ 
Novartis MedDRA Queries 
o.d. 
Once Daily 
ORR 
Overall Response Rate / Objective Response Rate 
OS 
Overall Survival 
PAS 
Pharmacokinetic Analysis Set 
PD 
Progressive Disease 
PD-1 
Programmed Death 1 
PD-L1 
Programmed Death-Ligand 1 
PD-L2 
Programmed Death-Ligand 2 
PDI 
Planned Dose Intensity 
PFS 
Progression-Free Survival 
PgR 
Progesterone receptor 
PK 
Pharmacokinetics 
PR 
Partial Response 
PRO 
Patient-reported Outcomes 
PT 
Preferred Term 
qd 
Qua’que di’e / once a day 
RDI 
Relative Dose Intensity 
RAP 
Report and Analysis Process 
RECIST 
Response Evaluation Criteria in Solid Tumors  
sd 
Standard deviation 
SD 
Stable Disease 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SMQ 
Standardized MedDRA Queries 
SOC 
System Organ Class 
SOD 
Sum Of Diamaters 
TA 
Tumor Assessment 
TBL 
Total Bilirubin 
TFLs 
Tables, Figures, Listings 
 
 
TNBC 
Triple Negative Breast Cancer 
TP 
Time Point 
TTR 
Time To Response 
ULN 
Upper Limit of Normal 
UNK 
Unknown 


Novartis 
Confidential 
Page 7 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
WHO 
World Health Organization 
WHO-DD 
WHO-Drug Dictionnary 
WHO DRL 
WHO Drug Reference Listing 


Novartis 
Confidential 
Page 8 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the clinical study reports 
(CSR, either CSR for the primary analysis or CSR for the final analysis) of study 
CLAG525B2101, a phase II, randomized, open-label, three-arm multicenter study of LAG525 
given in combination with spartalizumab (PDR001), or with spartalizumab and carboplatin, or 
with carboplatin, as first or second line therapy in patients with advanced triple-negative breast 
cancer.  
The content of this SAP is based on protocol CLAG525B2101 v04. All decisions regarding 
final analysis, as defined in the SAP document, have been made prior to database lock of the 
study data. This SAP has been amended before the final close-out CSR for safety and PK 
analysis, for which no inferential analysis is planned.   
1.1 
Study design 
This is a randomized, phase II , open-label, three-arm, multicenter study evaluating the safety 
and efficacy of LAG525 given in combination with spartalizumab, or LAG525 with 
spartalizumab and carboplatin, or LAG525 with carboplatin, as first or second line therapy in 
patients with advanced triple-negative breast cancer. Approximately 96 subjects will be 
randomized to one of the following treatment arms in 1:1:1 ratio: 
• LAG525 + PDR001 
• LAG525 + PDR001 + carboplatin 
• LAG525 + carboplatin 
Randomization will be stratified by the following factors:  
• Presence of liver metastasis (Yes / No) 
• Line of therapy (First line: following disease progression after adjuvant or neoadjuvant 
therapy / Second line: following one disease progression in advanced or metastatic 
setting) 
 
With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + PDR001) was 
prematurely closed. Novartis and the study steering committee decided to prematurely 
stop enrollment of subjects to Arm 1 after data review showed an increased treatment 
discontinuation rate due to progressive disease in Arm 1 as compared to Arms 2 and 3 (both 
containing carboplatin) 
 
Overall response rate (ORR), as assessed by local investigators review of tumor response and 
using RECIST 1.1 criteria, is the primary endpoint in this study.  
 
The primary analysis was conducted when all subjects have been followed for efficacy (tumor 
assessments) for at least 24 weeks or discontinued tumor assessments for any reason prior to 24 
weeks. The primary analysis data will be summarized in the primary clinical study report (CSR).  
Any additional data for subjects continuing to receive study treatment past the data cut-off date 
for the primary CSR, as allowed by the protocol, will be reported in the final CSR on completion 
of the study. 
No formal interim analysis is planned for this trial. 


Novartis 
Confidential 
Page 9 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Figure 1-1 
Study Design 
 
  
**With protocol amendment 3, enrollment to treatment Arm 1 (LAG525 + spartalizumab) was prematurely closed  
Δ Upon the release of protocol amendment #4, ongoing patients who will transfer into PTA program (roll over 
study or PSDS) only EOT visit will be performed but no safety, efficacy and survival follow-up  
+ Patients who had stopped study treatment more than 150 days will be discontinued from the study – see 
Section 9.1.1 for details. Survival follow-up period is removed after protocol amendment #4 is approved  
† with implementation of protocol amendment #4 for the remaining participants in the study all tumor 
assessments in the post-treatment follow-up period will be optional and will be left at the discretion of the 
investigator  
 
Efficacy 
Every 6 weeks during 
the first 9 months 
and  
every 12 weeks 
thereafter 
Safety 
Follow-up+   
21  days  
Patient with advanced triple 
negative BC  N = 84 
Screening Period 
Eligibility check  
 
Randomization Ratio: 1:1:1 
Stratification Factors: +/-  liver metastases, 1L/2L 
Treatment Δ, † 
LAG525 (400 mg i.v. every 
21 days)   + 
spartalizumab (300mg i.v. 
every 21 days) + 
carboplatin (AUC = 6 i.v. 
every 21 days) 
Treatment**, Δ, † 
LAG525 (400 mg i.v. every 
21 days)  
+ 
spartalizumab (300mg i.v. 
every 21 days)  
Treatment Δ, † 
LAG525 (400 mg i.v. 
every 21 days)  
+ 
carboplatin (AUC = 6 
i.v. every 21 days) 
End of Treatment (EOT)   Within 7 days of last dose 
Ongoing tumor 
assessments 
 
 death, lost 
to Follow-up, withdrawal 
of consent 
End of post treatment 
30-day Safety 
90-day Safety 
F ll
120-day Safety 
150-day Safety 
 Study Discontinuation 
 
up to 150 days after 
the last dose of 
spartalizumab/LAG525 
or 
start of new 
antineoplastic therapy 


Novartis 
Confidential 
Page 10 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
1.2 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-1 Objectives and related endpoints 
 
Objective(s) 
Endpoint(s) 
Primary objective(s) 
Endpoint(s) for primary objective(s) 
• To assess the antitumor activity of the three 
treatment arms LAG525 + spartalizumab, 
LAG525 + spartalizumab + carboplatin and 
LAG525 + carboplatin, in subjects with 
advanced TNBC in first or second line of 
therapy, as measured by the objective 
response rate (ORR) per investigator’s 
assessment according to RECIST v1.1. 
• Overall response rate (ORR) per 
RECIST v1.1 per investigators' 
assessment 
Secondary objective(s) 
Endpoint(s) for secondary objective(s) 
• To assess the efficacy of the three treatment 
arms with respect to Duration of response 
(DOR), Time to response (TTR), Progression 
Free Survival (PFS) and Clinical benefit rate 
(CBR) per investigator’s assessment 
according to RECIST v1.1 
• Duration of response (DOR), Time 
to response (TTR), PFS and Clinical 
benefit rate (CBR) per investigators' 
assessment. 
• To assess Overall Survival for each treatment 
arm 
• Overall Survival (OS) 
• To characterize the safety profile of each 
treatment arm 
• Adverse events (AEs), serious AEs 
(SAEs), changes in hematology and 
chemistry values, vital signs, 
weight, ECOG performance status, 
electrocardiograms (ECGs), dose 
interruptions, reductions and dose 
intensity. 
• To characterize the pharmacokinetics (PK) of 
LAG525, spartalizumab, and carboplatin in 
the three investigated combinations 
• Pharmacokinetic parameters (e.g., 
Ctrough, Cmax, AUC) 
• To assess immunogenicity of LAG525 and 
spartalizumab in the three investigated 
combinations 
• Antidrug antibodies (ADA) 
prevalence at baseline and ADA 
incidence on treatment 


Novartis 
Confidential 
Page 11 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The primary analysis and final analysis will be performed by Novartis and/or a designated CRO. 
SAS version 9.3 or later and R version 3.2.3 or later software will be used to perform all data 
analyses and to generate tables, figures and listings. 
Data included in the analysis 
The analysis cut-off date for the primary analysis of study data was established after all 
randomized subjects have been followed for efficacy (tumor assessments) for at least 24 weeks 
or discontinued tumor assessments for any reason prior to 24 weeks. All statistical analyses will 
be performed using all data collected in the database up to the data cut-off date. All data with 
an assessment date or event start date (e.g. vital sign assessment date or start date of an adverse 
event) prior to or on the cut-off date will be included in the analysis. Any data collected beyond 
the cut-off date will not be included in the analysis and will not be used for any derivations. 


Novartis 
Confidential 
Page 12 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings. 
The analysis cut-off date for the final analysis of study data will be established at the end of the 
study, when all subjects have died or discontinued from the study, or another clinical study 
became available that can continue to provide study treatment in this subject population and all 
subjects ongoing are eligible to be transferred to that clinical study. 
General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all study centers will be pooled for 
the analysis. Due to expected small number of subjects enrolled at centers, no center effect will 
be assessed. 
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables 
by treatment arm; a missing category will be included as applicable. Percentages will be 
calculated using the number of subjects in the relevant population or subgroup as the 
denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (i.e. mean, standard deviation, median, minimum, and maximum) by treatment arm. 
2.1.1 
General definitions  
Investigational drug and study treatment 
Investigational drug will refer to LAG525 or spartalizumab (PDR001), combination partner 
will refer to carboplatin only, whereas study treatment will refer to LAG525 + spartalizumab, 
LAG525 + spartalizumab + carboplatin or LAG525 + carboplatin. 
The term investigational treatment may also be referred to as study treatment which is used 
throughout this document. 
Date of first administration of investigational drug / combination partner 
The date of first administration of investigational drug / combination partner is defined as the 
first date when a non-zero dose of investigational drug / combination partner is administered 
and recorded on the ‘Study treatment – LAG525/PDR001/carboplatin’ eCRF pages. The date 
of first administration of study drug / combination partner will also be referred as start of 
investigational drug / combination partner. 
Date of last administration of investigational drug / combination partner 
The date of last administration of investigational drug / combination partner is defined as the 
last date when a nonzero dose of investigational drug / combination partner is administered and 
recorded on the ‘Study treatment – LAG525/PDR001/carboplatin’ eCRF pages. The date of last 
administration of investigational drug / combination partner will also be referred as end of 
investigational drug / combination partner. 


Novartis 
Confidential 
Page 13 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Date of first administration of study treatment  
The date of first administration of study treatment is derived as the first date when a nonzero 
dose 
of 
study 
treatment 
was 
administered 
as 
per 
the 
‘Study 
treatment 
– 
LAG525/PDR001/carboplatin’ eCRF pages. The date of first administration of study treatment 
will also be referred as start of study treatment. 
The date of first administration of study treatment is derived as the first date when a nonzero 
dose of any component of study treatment was administered as per the ‘Study treatment – 
LAG525/PDR001/carboplatin’ eCRF pages. (Example: if 1st dose of spartalizumab is 
administered on 05-Jan-2018, and 1st dose of LAG525 is administered on 03-Jan-2018, then the 
date of first administration of study treatment is on 03-Jan-2018).  
Date of last administration of study treatment  
The date of last administration of study treatment is defined as the last date when a nonzero 
dose 
of 
study 
treatment 
was 
administered 
as 
per 
‘Study 
treatment 
– 
LAG525/PDR001/carboplatin’ eCRF pages.  
The date of last administration of study treatment is derived as the last date when a nonzero 
dose of any component of study treatment was administered as per ‘Study treatment – 
LAG525/PDR001/carboplatin’ eCRF pages. (Example: if the last spartalizumab dose is 
administered on 15-Apr-2018, and the last dose of LAG525 is administered on 17-Apr-2018, 
then the date of last administration of study treatment is on 17-Apr-2018).  
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
The reference start date for safety assessments (e.g. adverse event onset, laboratory 
abnormality occurrence, vital sign measurement, dose interruption, ECOG performance 
status, PK etc.) is the start of study treatment.  
The reference start date for all other, non-safety assessments (i.e., tumor assessment, survival 
time, disease progression, tumor response) is the date of randomization.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 
Note: Some measurements may belong to safety measurement and to efficacy measurement 
(‘death’ is an efficacy endpoint, but it can also be included in the safety analysis). For safety, 
the ‘study day’ will be calculated relative to start of study treatment, while for efficacy overall 
survival will be derived relative to randomization date.  


Novartis 
Confidential 
Page 14 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375. If duration is reported in 
years, duration in days will be divided by 365.25. 
Baseline 
For efficacy evaluations, the last non-missing assessment, including unscheduled assessments 
on or before the date of randomization is taken as “baseline” value or “baseline” assessment.  
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken for ”baseline” assessment.  
In case time of assessment (e.g. pre-dose ECG) and time of treatment start is captured, the last 
available assessment before the treatment start date/time is used for baseline.  
For safety parameters (e.g ECGs), where study requires multiple replicates per time point, the 
average of these measurements would be calculated for baseline (if not already available in the 
database). 
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 value closest to normal should be considered as baseline. 
If subjects have no value as defined above, the baseline result will be missing. 
On-treatment assessment/event and observation periods  
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments:  
1. pre-treatment period: from day of subject’s informed consent to the day before first 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of any study treatment (including start and stop date) 
3. post-treatment period: starting at day 31 after last administration of study treatment. 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. Refer to Section 
5.1.2 for imputation rules concerning AE start and stop dates.  
For other safety data, the on-treatment period will start from the day after the date of first 
administration of study treatment, unless the time of assessment and time of treatment start is 
available on the day of study treatment start. For data where time of assessment (e.g. ECGs) 
and time of treatment start are captured, data collected on the day of first administration of study 


Novartis 
Confidential 
Page 15 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
treatment at a time before (after respectively) the time of first administration of study treatment 
will be considered on the pre-treatment period (on the on-treatment period respectively).  
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs). However, all safety data (including those from the post-treatment 
period) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged. 
Additional summaries will be displayed to report deaths, all AEs, AEs related to study treatment, 
all SAEs and SAEs related to study treatment collected up to 150 days after last administration 
of LAG525/spartalizumab or up to 30 days after the last dose of carboplatin whichever comes 
last.. 
Last contact date  
The last contact date will be derived for subjects not known to have died at the analysis cut-off 
using the last complete date among the following: 
Table 2-1 
Last contact date data sources 
Source data 
Conditions 
Date of Randomization 
No Condition 
Last contact date/last date subject was known to 
be alive from Survival Follow-up page 
Subject status is reported to be alive, lost to 
follow-up or unknown 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 
Start/End dates from study treatment pages 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from disposition page at 
end of treatment 
No condition. 
Tumor (RECIST / iRECIST) assessment date 
Result is not missing 
Verification for treatment beyond RECIST1.1 PD 
At least one non missing parameter value 
Laboratory/PK/IG collection dates 
Was sample taken? = ‘Yes’.  
Vital signs date 
At least one non-missing parameter value 
Performance Status date 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the subject was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring if coming from Survival eCRF.  
The last contact date will be used for censoring of subjects in the analysis of overall survival. 


Novartis 
Confidential 
Page 16 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.2 
Analysis sets 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all subjects to whom study treatment has been assigned 
by randomization. According to the intent to treat principle, subjects will be analyzed according 
to the treatment and strata they have been assigned to during the randomization procedure. 
Safety set 
The Safety Set includes all subjects who received at least one dose of study treatment (i.e., at 
least one dose of any component of the study treatment, including incomplete infusion of 
spartalizumab, LAG525 or carboplatin). Subjects will be analyzed according to the study 
treatment received, where treatment received is defined as the randomized treatment if the 
subject took at least one dose of that treatment or the first treatment received if the randomized 
treatment was never received. 
Pharmacokinetic analysis set (PAS) 
The LAG525 pharmacokinetic analysis set (PAS-LAG525) includes all subjects who provide 
at least one evaluable LAG525 PK concentration. For a concentration to be evaluable, subjects 
are required to: 
• Receive a planned dose of LAG525 prior to sampling. 
• For pre-dose samples: have the sample collected prior to dosing on the assessment day and 
for samples post-C1D1 have the sample collected approximately 504 hr ± 24 hours after the 
previous dose.  
• For end-of-infusion samples: have the sample collected 1 hour post end of infusion within 
± 5 minutes of the scheduled time point;  
• For 168 and 336 hours samples: have the sample collected 168, 336 hours post end of 
infusion within ± 24 hours of the scheduled timepoint. 
The spartalizumab pharmacokinetic analysis set (PAS-Spartalizumab) includes all subjects 
who provide at least one evaluable Spartalizumab PK concentration. For a concentration to be 
evaluable, subjects are required to: 
• Receive a planned dose of spartalizumab prior to sampling. 
• For pre-dose samples: have the sample collected prior to dosing on the assessment day and 
for samples post-C1D1 have the sample collected approximately 504 hr ± 24 hours after the 
previous dose.  
• For end-of-infusion samples: have the sample collected 1 hour post end of infusion within 
± 5 minutes of the scheduled time point; have the sample collected 168, 336 hours post end 
of infusion within ± 24 hours of the scheduled timepoint. 
 
The carboplatin pharmacokinetic analysis set (PAS-carboplatin) includes all subjects who 
provide at least one evaluable carboplatin PK concentration. For a concentration to be evaluable, 
subjects are required to: 
• Receive a planned dose of carboplatin prior to sampling, 


Novartis 
Confidential 
Page 17 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• For pre-dose samples, have the sample collected before the next dose administration within 
30 minutes before the infusion begins 
• For samples scheduled to be taken prior to End of Infusion (EOI), have the samples collected 
prior to EOI 
• For end-of-infusion samples: have the sample collected 1, 2 and 3 hours post end of infusion: 
within ± 10 minutes of the scheduled time point 
The PAS will be used for all PK analyses. 
Immunogenicity (IG) analysis sets 
The LAG525 Immunogenicity prevalence setincludes all subjects in the Full analysis set with 
a determinant baseline LAG525 IG sample or at least one determinant post-baseline LAG525 
IG sample. 
The LAG525 Immunogenicity incidence set includes all subjects in the LAG525 
Immunogenicity prevalence set with a determinant LAG525 baseline IG sample and at least 
one determinant LAG525 post-baseline IG sample. 
The spartalizumab Immunogenicity prevalence set includes all subjects in the Full analysis 
set with a determinant baseline spartalizumab IG sample or at least one determinant post-
baseline spartalizumab IG sample. 
The spartalizumab Immunogenicity incidence set includes all subjects in the spartalizumab 
Immunogenicity prevalence set with a determinant spartalizumab baseline IG sample and at 
least one determinant spartalizumab post-baseline IG sample. 
 
See Section 2.11.1 for the definition of determinant. 
Subject Classification:  
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-4.  
Table 2-2 
Subject classification based on protocol deviations and non-PD 
criteria 
 
Analysis set 
Protocol 
deviations 
leading to exclusion 
Non protocol deviation leading to exclusion 
FAS  
No written inform 
consent 
Not applicable 
Safety set 
No written inform 
consent 
No dose of any component of study 
treatment  
PAS-LAG525 
No written inform 
consent 
No evaluable LAG525 PK concentration 


Novartis 
Confidential 
Page 18 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a subject 
withdraws full consent is recorded in the eCRF.  
Additional data for which there is a separate informed consent, e.g. PK,
 etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion. 
Analysis set 
Protocol 
deviations 
leading to exclusion 
Non protocol deviation leading to exclusion 
PAS-
Spartalizumab 
No written inform 
consent 
No evaluable spartalizumab PK 
concentration 
PAS-carboplatin 
No written inform 
consent 
No evaluable carboplatin PK concentration 
LAG525 
IG 
prevalence set 
No written inform 
consent 
Subject not in the FAS 
No determinant baseline LAG525 IG 
sample and no determinant post-baseline 
LAG525 IG sample 
LAG525 
IG 
incidence set 
No written inform 
consent 
Subject not in the FAS 
No determinant baseline LAG525 IG 
sample 
No determinant post-baseline LAG525 IG 
sample 
Spartalizumab 
IG prevalence set 
No written inform 
consent 
Subject not in the FAS 
No determinant baseline spartalizumab IG 
sample and no determinant post-baseline 
spartalizumab IG sample 
Spartalizumab 
IG incidence set 
No written inform 
consent 
Subject not in the FAS 
No determinant baseline spartalizumab IG 
sample 
No determinant post-baseline spartalizumab 
IG sample 


Novartis 
Confidential 
Page 19 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.2.1 
Subgroup of interest 
Efficacy 
The primary efficacy endpoint ORR and the secondary endpoint DOR based on investigators’ 
review of tumor assessments as per RECIST 1.1 will be summarized by the following subgroups 
to examine the homogeneity of treatment effect, provided that the primary efficacy analysis 
based on the FAS has shown a proof of preliminary efficacy for at least one treatment arm:  
• Stratification factors: presence of liver metastasis (yes/no) and line of therapy (first 
line / second line) (based on randomization data from IRT) 
• Age category (< 65 years, ≥ 65 years) 
• Age category (< 50 years, ≥ 50 years) 
 
  
 
 
 
  
 
 
 
 
 
 
 
 
  
• Relapse free interval for the firstline patients (<12 month, ≥12 months) where 
realapse interval is defined as,  
the last dose date of prior adjuvant/neoadjuvant therapy - the progression date after 
the prior antineoplastic therapy+1 
• Relapse free interval for the firstline patients (<6 months, 7-12 months, and >=12 
months) where realapse interval is defined as,  
the last dose date of prior adjuvant/neoadjuvant therapy - the progression date after 
the prior antineoplastic therapy+1 
For subgroup analysis, only point estimates by treatment arm and 95%-confidence intervals will 
be provided (see Section 2.5.4, Section 2.7.2, Section 2.8 for further analysis details). The 
objective of the efficacy subgroup analysis is to demonstrate homogeneity of treatment effect 
in the above subgroups.  
Safety 
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses (overall summary of AEs and of AESIs, and AEs by PT) will be 
repeated on safety set in the following subgroups: 


Novartis 
Confidential 
Page 20 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Age group (< 65 years, ≥ 65 years)The objective for carrying out these subgroup analyses is 
to identify potential safety issues that may be limited to a subgroup of subjects, or safety 
issues that are more commonly observed in a subgroup of subjects. 
2.3 
Subject disposition, demographics and other baseline 
characteristics 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. Summaries will be reported by treatment arm and for all 
subjects and listings will be reported by treatment arm to assess baseline comparability. No 
inferential statistics will be provided. 
2.3.1 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed by 
treatment arm. Categorical data (e.g. gender, age groups: <65, ≥ 65 - < 85 and ≥ 85 years, race, 
ethnicity and ECOG performance status at baseline) will be summarized by frequency counts 
and percentages; the number and percentage of subjects with missing data will be provided. 
Continuous data (e.g. age, weight, height and body mass index (BMI)) will be summarized by 
descriptive statistics (N, mean, median, standard deviation, minimum and maximum). BMI 
(kg/m2) will be calculated as weight[kg] / (height[m]2) using height at screening and weight at 
baseline.  
In addition, number of subjects treated will be summarized by age/gender combination and by 
race for each treatment arm in the Safety Set for DSUR reporting purposes. 
2.3.2 
Baseline stratification factors 
The number (%) of subjects in each stratum (Presence of liver metastasis and Line of therapy) 
based on data obtained from the IRT system will be summarized overall and by treatment arm 
for the FAS. Discordances between the stratum recorded in IRT at the time of randomization 
and the actual stratum recorded in the clinical database through the data collected on eCRF will 
be cross-tabulated and listed. 
2.3.3 
Diagnosis and extent of cancer  
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: diagnosis of disease (Breast Cancer / Triple Negative Breast Cancer), 
primary site of cancer, predominant histology / cytology, histological grade, stage at initial 
diagnosis, time since initial diagnosis, time from initial diagnosis to first recurrence / 
progression (in months), time since most recent relapse/progression to randomization (in 
months), stage at time of study entry, presence/absence of target and non-target lesions, number 
and type of metastatic sites involved, sum of diameters (SOD) for target lesions (in mm), HER2 
receptor status, estrogen receptor (ER) status and progesterone receptor (PgR) status. 
Note: Presence/absence of target and non-target lesions will be based on the data collected on 
RECIST target/non-target lesion assessment eCRF pages. Metastatic sites will be based on 
diagnosis page. 


Novartis 
Confidential 
Page 21 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.3.4 
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on eCRF will be summarized and listed by treatment arm. The summaries will be 
presented by primary system organ class (SOC), preferred term (PT) and treatment arm. 
Medical history and current medical conditions will be coded using the Medical Dictionary for 
Regulatory Activities (MedDRA) terminology. The MedDRA version used for reporting will 
be specified in the CSR and as a footnote in the applicable tables/listings. 
2.3.5 
Other 
Other categorical data (e.g. BRCA mutation status, PD-L1 status groups and LAG-3 status 
group: positive and negative based on relevant thereshold(s), CD8+ values) will be 
summarized by frequency counts and percentages; the number and percentage of subjects with 
missing data will be provided: see section 2.13 for further details. 
 
2.3.6 
Subject disposition 
Enrollment by country and center will be summarized for all screened subjects and also by 
treatment arm using the FAS. The number (%) of randomized subjects included in the FAS will 
be presented overall and by treatment arm. The number (%) of screened and not-randomized 
subjects and the reasons for screening failure will also be displayed. The number (%) of subjects 
in the FAS who are still on treatment, who discontinued the study phases and the reason for 
discontinuation will be presented overall and by treatment group. 
The following summaries will be provided (with % based on the total number of FAS subjects): 
• Number (%) of subjects who were randomized (based on data from IRT system) 
• Number (%) of subjects who were randomized but not treated (based on ‘Study 
treatment’ eCRF pages not completed for any study treatment component) 
• Primary reason for not being treated (based on the ‘Treatment disposition’ eCRF 
page eCRF page)  
• Number (%) of subjects who were treated (based on ‘Study treatment’ eCRF pages 
of each study treatment component completed with non-zero dose administered) 
• Number (%) of subjects who are still on-treatment (based on the ‘Treatment 
disposition’ eCRF page not completed);  
• Number (%) of subjects who discontinued the study treatment phase (based on the 
‘Treatment disposition’ eCRF page)  
• Primary reason for study treatment phase discontinuation (based on the ‘Disposition’ 
eCRF page for ‘Treatment disposition’) 
• Primary reason for discontinuation of each study drug (based on the ‘Disposition’ 
eCRF page for LAG525/PDR001/carboplatin) 
• Number (%) of subjects who have entered the post-treatment follow-up (based on 
the ‘Subject status at EOT’ eCRF page); 


Novartis 
Confidential 
Page 22 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• Number (%) of subjects who have discontinued from the post-treatment follow-up 
(based on the ‘Post-treatment follow-up disposition’ eCRF page); 
• Reasons for discontinuation from the post-treatment follow-up (based on ‘Post-
treatment follow-up disposition’ eCRF page); 
• Number (%) of subjects who have entered the survival follow-up (based on the 
‘Subject status’ eCRF page at EOT, safety follow-up visits or at the end of Post-
treatment follow-up). 
2.3.7 
Protocol deviations 
The number (%) of subjects in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan) overall and by treatment arm 
for the FAS. Major protocol deviations leading to exclusion from analysis sets will be tabulated 
separately overall and by treatment arm. All protocol deviations will be listed. 
In addition to the pre-defined standard protocol deviation terms, 6 new protocol deviations and 
the corresponding relationship (health status related vs. site lockdown, patient concerns, etc.) 
to the COVID-19 pandemic have been defined  in alignment with “FDA Guidance on Conduct 
of Clinical Trials of Medical Products during COVID-19 Public Health Emergency” (December 
2020) and “Guidance on the management of clinical trials during the COVID-19 (coronavirus) 
pandemic” (April 2020) from EMA as listed below. 
• Missing visits 
• Changes in procedures and assessments 
• Planned visits not done at sites 
• Changes in drug supply method 
• Treatment not given 
• Patient discontinuation due to COVID-19 situation 
The number and percentage of patients with any protocol deviations in the FAS will be 
summarized by COVID-19 relationship (related or not-related) and by treatment arm in the 
post-text table. A cross-tabulation of COVID-19 related protocol deviation vs. corresponding 
detailed relationship will also be produced by treatment arm. The detailed relationship is listed 
as below: 
• COVID-19 health status related 
• COVID-19 situation: Site issue  
• COVID-19 situation: Lockdown / Quarantine of patient  
• COVID-19 situation: Patient concern  
• COVID-19 situation: Drug supply issue  
• COVID-19 situation: Other 
 
2.3.8 
Analysis sets 
The number (%) of subjects in each analysis set (defined in Section 2.2) will be summarized by 
treatment arm and stratum. 


Novartis 
Confidential 
Page 23 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, average cycle dose and actual cumulative dose, dose intensity (DI) and 
relative dose intensity (RDI) will be summarized by treatment arm, separately for each 
component of study treatment. The duration of exposure will also be presented for the study 
treatment (LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin or LAG525 + 
carboplatin). Duration of exposure will be categorized into time intervals; frequency counts and 
percentages will be presented for the number (%) of subjects in each interval. The number (%) 
of subjects who have dose reductions (for carboplatin), interruptions, and the reasons, will be 
summarized by treatment arm.  
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced. 
The safety set will be used for all summaries and listings of study treatment.  
Duration of exposure to study treatment 
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to LAG525, spartalizumab or carboplatin (as applicable depending on the treatment 
arm): 
Duration of exposure to study treatment (weeks) = (last date of exposure to study treatment) – 
(date of first administration of study treatment) + 1.  
The last date of exposure to study treatment is the latest of the last dates of exposure to LAG525, 
spartalizumab or carboplatin (as applicable depending on the treatment arm) (see Table 2-5). 
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries (< 3 weeks, at least 3 weeks, at least 6 weeks, etc.) and continuous 
summaries (i.e. mean, standard deviation etc.) using appropriate units of time. Summary of 
cycles received will include categorical summaries (at least 1 cycle, at least 3 cycles, at least 5 
cycles and etc). 
Duration of exposure to LAG525, spartalizumab and carboplatin 
Duration of exposure to LAG525 (weeks) = (last date of exposure to LAG525) – (date of first 
administration of LAG525) + 1.  
Duration of exposure to spartalizumab (weeks) = (last date of exposure to spartalizumab) – 
(date of first administration of spartalizumab) + 1.  
Duration of exposure to carboplatin (weeks) = (last date of exposure to carboplatin) – (date of 
first administration of carboplatin) + 1.  
Table 2-3 
Definition of last date of exposure of study drug 
Study drug 
Definition of last date of exposure 
of study drug  
Example 


Novartis 
Confidential 
Page 24 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
LAG525 
spartalizumab 
carboplatin 
The planned end date of the last cycle 
in which the last non-zero dose of the 
investigational drug was last 
administered (i.e last date of 
administration + (planned interval 
duration-1day)) 
Note : If the subject died or was lost to 
follow-up before the derived last date, 
the last date of exposure to 
investigational drug is the date of death 
or the date of last contact, respectively.  
If the derived last date of exposure 
goes beyond the data cut-off date, it 
should be truncated to the date of data 
cut-off. 
In a once every 3 weeks 
administration, the last date of 
exposure is the date of 
administration in the last cycle + 
20 days 
Summary of duration of exposure of LAG525, spartalizumab and carboplatin will include 
categorical summaries based on 21-day intervals (< 3 weeks, at least 3 weeks, at least 6 weeks, 
etc.) and using descriptive statistics (mean, standard deviation etc). 
Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.  
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the ‘Study treatment – 
LAG525/PDR001/carboplatin’ eCRF pages.  
For subjects who did not take any drug component the cumulative dose for that component is 
by definition equal to zero. 
For LAG525 and spartalizumab, the planned cumulative dose and actual cumulative dose will 
be expressed in mg.  
For carboplatin, they will be expressed as calculated AUC (mg/mL x min). To that end the 
prescribed / administered dose in mg will be used to calculate the AUC using Calvert’s formula 
based on the derived GFR value. Calvert’s formula is given as: 
• Carboplatin dosage (mg) = AUC (mg/mL x min) x [GFR (mL/min) + 25] 
And the back-calculation for AUC is 
• AUC (mg/mL x min) = Carboplatin dose (mg) / [GFR (mL/min) + 25] 
For the calculation of GFR, creatinine value in the dabatase with a measurement time closest to 
the dosing date and the subject’s age and weight at the creatinine collection time will be used 
with the Cockcroft & Gault formula. If the interval between the measurement time and dosing 
time is the same before and after dose, the measurement corresponding to the time before dose 
will be used. Cockcroft & Gault’s formula (Cockroft and Gault 1976) is given as: 


Novartis 
Confidential 
Page 25 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• Male GFR (mL/min) = [140 – age (years)] x weight (kg) x 1.23 / sCr (μmol/L) 
• Female GFR (mL/min) = [140 – age (years)] x weight (kg) x 1.04 / sCr (μmol/L) 
OR 
• Male GFR (mL/min) = [140 – age (years)] x weight (kg) / [72 x sCr (mg/dL)] 
• Female GFR (mL/min) = [140 – age (years)] x weight (kg) x 0.85 / [72 x sCr (mg/dL)] 
Note: The planned dose of carboplatin is per AUC 6 in general, but could be lower if the 
corresponding dose (mg) was higher than 900 mg (maximum dose in mg allowed as per the 
protocol). Hence if for a subject the first carboplatin dose prescribed was capped at 900 mg, the 
prescribed carboplatin dose (AUC) will be back calculated and will be used as planned dose in 
AUC to compute the planned cumulative dose. 
Dose intensity and relative dose intensity 
Dose intensity (DI) for subjects with non-zero duration of exposure is defined as follows:  
For LAG525 and spartalizumab, DI (mg / cycle) = Actual Cumulative dose (mg) / Duration of 
exposure to study treatment (cycle),  
For carboplatin, DI (AUC / cycle) = Actual Cumulative dose (AUC) / Duration of exposure to 
study treatment (cycle), 
where Duration of exposure to study treatment (cycle) = Duration of exposure to study treatment 
(day) / 21. It will be rounded up to the nearest cycle if the last date of exposure to study treatment 
is replaced by the cut-off date: e.g. 66 days will be rounded to 4 cycles. 
If for example, the duration of exposure to spartalizumab is 6 weeks and the subject receives 
two injections of spartalizumab 300 mg: 
DI (mg/cycle) = Actual Cumulative dose (mg) / Duration of exposure (cycle) 
 
 
= 600 (mg) / (42/21) (cycle) = 300 (mg/cycle) 
For subjects who did not take any drug component the DI for that component is by definition 
equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
For LAG525 and spartalizumab, PDI (mg / cycle) = Planned Cumulative dose (mg) / Duration 
of exposure (cycle). PDI (mg / cycle) is 400 mg/cycle for LAG525 and 300 mg/cycle for 
spartalizumab. 
For carboplatin, PDI (AUC / cycle) = Planned Cumulative dose (AUC) / Duration of exposure 
(cycle).  
Note: PDI (AUC / cycle) is AUC 6/cycle for carboplatin in general, but could be lower if the 
corresponding dose (mg) was higher than 900 mg. Hence if for a subject the first carboplatin 
dose prescribed is 900 mg, the prescribed carboplatin dose (AUC) will be back calculated and 
will be used as PDI per cycle for that subject. 
Relative dose intensity (RDI) is defined as follows: 


Novartis 
Confidential 
Page 26 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
For LAG525 and spartalizumab, RDI = DI (mg / cycle) / PDI (mg / cycle). 
For carboplatin, RDI = DI (AUC / cycle) / PDI (AUC / cycle). 
DI and RDI will be summarized separately for each of the study treatment components, but 
using the duration of exposure of each of the components.  
Some examples are given below on how to compute duration of exposure (cycle), 
planned/actual cumulative dose, PDI, DI and RDI in Table 2-6 and Table 2-7 for LAG525 and 
in Table 2-8 and Table 2-9 for carboplatin. For spartalizumab refer to LAG525 examples. 
Table 2-4 
Example 1 of LAG525 dose administration and exposure 
Record 
number 
Start/End 
Date 
Dose 
Administered 
(mg) 
Dose 
Stopped or 
Paused, Dose 
Interrupted? 
Dose 
Permanently 
Discontinued 
Reason 
1 
13Jun2018 
400 
No 
No 
 
2 
04Jul2018 
400 
No 
No 
 
3 
25Jul2018 
400 
No 
No 
 
4 
15Aug2018 
0 
Yes 
No 
AE 
Duration of exposure (day) = (23Aug2018 = data cut-off date since LAG525 was not 
permanently discontinued) – (13Jun2018) + 1 = 72 days  
Duration of exposure (cycle) for 72 days = 4 cycles (rounded from 3.4 cycles) 
Planned cumulative dose (for 72 days, 4 cycles) = 1600 mg  
Actual cumulative dose (for 72 days, 4 cycles) = 1200 mg  
Dose intensity = (actual cumulative dose / duration of exposure in cycles) = 1200 mg / 4 cycles 
= 300 mg / cycle 
Planned dose intensity = (planned cumulative dose / duration of exposure in cycle) = 1600 mg 
/ 4 cycles = 400 mg / cycle  
Relative dose intensity = (DI / PDI) x 100 = (300 mg/cycle) / (400 mg/cycle) x 100 = 75% 
Table 2-5 
Example 2 of LAG525 dose administration and exposure 
Record 
number 
Start/End 
Date 
Dose 
Administered 
(mg) 
Dose 
Stopped or 
Paused, Dose 
Interrupted? 
Dose 
Permanently 
Discontinued 
Reason 
1 
13Jun2018 
400 
No 
No 
 
2 
04Jul2018 
400 
No 
No 
 
3 
25Jul2018 
400 
No 
No 
 
4 
15Aug2018 
0 
Yes 
Yes 
AE / AE 
Duration of exposure (days) = (25Jul2018 + 20 days since LAG525 was permanently 
discontinued) – (13Jun2018) + 1 = 63 days  
Duration of exposure (cycle) for 63 days = 3 cycles 


Novartis 
Confidential 
Page 27 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Planned cumulative dose (for 63 days, 3 cycles) = 1200 mg  
Actual cumulative dose (for 63 days, 3 cycles) = 1200 mg  
Dose intensity = (actual cumulative dose / duration of exposure in cycle) = 1200 mg / 3 cycles 
= 400 mg / cycle 
Planned dose intensity = (planned cumulative dose / duration of exposure in cycle) = 1200 mg 
/ 3 cycles = 400 mg / cycle  
Relative dose intensity = (DI / PDI) x 100 = (400 mg/cycle) / (400 mg/cycle) x 100 = 100% 
Table 2-6 
Example 1 of carboplatin dose administration and exposure 
Record 
number 
Start/ 
End Date 
Dose 
Prescribed 
(mg) 
Dose 
Administered 
(mg) 
Dose 
Prescribed 
(AUC) 
Dose 
Administered 
(AUC) 
Dose 
Permanently 
Discontinued 
1 
13Jun2018 
800 
800 
6 
6 
No 
2 
04Jul2018 
650 
800 
5 
6 
No 
3 
25Jul2018 
650 
650 
5 
5 
No 
4 
15Aug2018 
0 
0 
0 
0 
Yes 
Duration of exposure (days) = (25Jul2018 + 20 days since carboplatin was permanently 
discontinued) – (13Jun2018) + 1 = 63 days  
Duration of exposure (cycle) for 63 days = 3 cycles 
Planned cumulative dose (for 63 days, 3 cycles) = 18 AUC  
Actual cumulative dose (for 63 days, 3 cycles) = 17 AUC  
Dose intensity = (actual cumulative dose / duration of exposure in cycle) = 17 AUC / 3 cycles 
= 5.7 AUC / cycle 
Planned dose intensity = (planned cumulative dose / duration of exposure in cycle) = 18 AUC 
/ 3 cycles = 6 AUC / cycle  
Relative dose intensity = (DI / PDI) x 100 = (17 AUC/cycle) / (18 AUC/cycle) x 100 = 94.4% 
Table 2-7 
Example 2 of carboplatin dose administration and exposure 
Record 
number 
Start/ 
End Date 
Dose 
Prescribed 
(mg) 
Dose 
Administered 
(mg) 
Dose 
Prescribed 
(AUC) 
Dose 
Administered 
(AUC) 
Dose 
Permanently 
Discontinued 
1 
13Jun2018 
900 
900 
5.9 
5.9 
No 
2 
04Jul2018 
900 
900 
5.9 
5.9 
No 
3 
25Jul2018 
750 
750 
5 
5 
No 
4 
15Aug2018 
0 
0 
0 
0 
Yes 
Duration of exposure (days) = (25Jul2018 + 20 days since carboplatin was permanently 
discontinued) – (13Jun2018) + 1 = 63 days  
Duration of exposure (cycle) for 63 days = 3 cycles 


Novartis 
Confidential 
Page 28 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Planned cumulative dose (for 63 days, 3 cycles) = 5.9 x 3 AUC = 17.7 AUC, as dose prescribed 
is 900 mg, the planned dose is the planned dose prescribed (AUC)  
Actual cumulative dose (for 63 days, 3 cycles) = 15.8 AUC  
Dose intensity = (actual cumulative dose / duration of exposure in cycle) = 15.8 AUC / 3 cycles 
= 5.3 AUC / cycle 
Planned dose intensity = (planned cumulative dose / duration of exposure in cycle) = 17.7 AUC 
/ 3 cycles = 5.9 AUC / cycle  
Relative dose intensity = (DI / PDI) x 100 = (15.8 AUC/cycle) / (17.7 AUC/cycle) x 100 = 89.3% 
Dose reductions or interruptions 
The number of subjects who have dose reductions, administration stopped/paused during 
infusion or interruptions, and the reasons, will be summarized separately for each of the study 
treatment components.  
‘Dose changed’, ‘Dose interrupted’, “Was drug administration stopped or paused” fields from 
the ‘Study treatment’ eCRF pages for each study treatment component will be used to determine 
the dose reductions, dose interruptions and administration stopped /paused, respectively. 
The corresponding fields ‘Reason for change’ and ‘Reason for administration stopped or paused’ 
will be used to summarize the reasons. 
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered is different from the prescribed dose. 
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption are entered on consecutive dose administrations with different reasons, separate 
interruptions will be counted. However, if the reason is the same in this mentioned multiple 
entries on consecutive dose administrations, then it will be counted as one interruption.  
Reduction: A dose change where the prescribed dose level is lower than the previous prescribed 
dose level. Any dose change to correct a dosing error will not be considered a dose reduction. 
Only dose change is collected in the eCRF, number of reductions will be derived 
programmatically based on the change and the direction of the change.  
Note: No dose reductions are permitted for LAG525 or spartalizumab. 
For carboplatin, it is considered as a reduction only if the difference between the previous 
prescribed dose in AUC and the current prescribed dose in AUC is greater than 15% of the 
previous prescribed dose in AUC. 
Notes: 
• A prescribed dose reduction lower than the previous prescribed dose, but where the 
administered dose is 0 mg or higher than the prescribed dose, will not be counted as a 
dose reduction: see records 10 and 11 in Table 2-10. 
• A decrease in dose from the protocol planned starting dose or a decrease from the 
previous non-zero dose will be counted as a dose reduction even if this decrease has 
been directly preceded by an interruption: see record 8 in Table 2-10. 


Novartis 
Confidential 
Page 29 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• If the dose decrease is followed by an interruption, with the dose resuming at the same 
level prior to the interruption, the second dose decrease or change in dosing frequency 
will not be counted as dose reduction: see record 6 in Table 2-10. 
• If, due to a dosing error, a subject receives higher than protocol planned starting dose 
and moves down to the planned starting dose then this is not a dose reduction: see record 
3 in Table 2-10. However if the change is directly from a higher than planned starting 
dose down to a lower than protocol planned starting dose, then this is a dose reduction. 
• If, due to a dosing error, a subject receives lower than previous non-zero dose and 
resumes later at the protocol specified dose reduction, then lower dose received due to 
dosing error and protocol specified dose reduction are dose reductions. 
• If, due to a dosing error, a subject receives lower than previous non-zero dose and 
resumes later at lower than previous non-zero dose, then 2 dose reductions will be 
counted.  
Table 2-8 
Examples of possible dose changes for carboplatin and dose 
reduction outcome 
Record 
number 
Prescribed 
dose 
(AUC) 
Administered 
dose 
(AUC) 
Counted 
as a dose 
reduction 
(Yes/No) 
Comment 
1 
6 
6 
No 
 
2 
6.5 
6.5 
No 
Dose increased by error 
3 
6 
6 
No 
Correcting dosing error 
4 
5 
5 
Yes 
Prescribed dose reduction (e.g. due to AE) 
5 
0 
0 
No 
Dose interruption 
6 
5 
5 
No 
Resume previous dose 
7 
0 
0 
No 
Dose interruption 
8 
5 
4 
No 
Dosing error (not a prescribed dose 
reduction) 
9 
5 
5 
No 
Correcting dosing error in row 8 
10 
4 
0 
No 
Prescribed dose reduction (e.g. due to AE) 
but not administered due to dosing error 
11 
4 
5 
No 
Prescribed dose reduction (e.g. due to AE) 
but not administered due to dosing error 
12 
4 
4 
Yes 
Prescribed dose reduction (e.g. due to AE) 
and row 11 was not counted as a dose 
reduction (administered dose was 5 by 
error) 


Novartis 
Confidential 
Page 30 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Treatment beyond RECIST progression 
The number of subjects who continue treatment beyond RECIST1.1 progression according to 
local investigators assessment based on protocol specified criteria will be summarized. It 
includes all subjects who received any study treatment (i.e. at least one dose of LAG525, 
spartalizumab or carboplatin (including incomplete infusion)) after RECIST1.1 progression 
assessed by local investigators. Those subjects will be identified using the field “Will the subject 
continue treatment beyond disease progression as per RECIST1.1?” on the Verification for 
Treatment Beyond RECIST1.1 PD eCRF pages.  
2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of subjects who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery (excluding biopsy procedures) 
will be summarized by treatment arm. Prior anti-neoplastic medications will be summarized by 
therapy type (e.g. chemotherapy, hormonal therapy, etc.), setting (e.g. adjuvant, metastatic, etc.) 
and also by lowest ATC class, preferred term and treatment. Summaries will include total 
number of regimens, best response and time from last treatment to progression for the last 
therapy. The medication therapy type of any combination therapy will be classified based on 
the following order: immunotherapy, chemotherapy, biologic therapy (other than 
immunotherapy), targeted therapy, hormonal therapy. For example, a combination therapy of 
chemotherapy and biologic therapy will be classified as ‘chemotherapy’. For radiotherapy, time 
since last radiotherapy, locations and setting of last therapy will be summarized. For prior 
surgery, time since last surgery, procedure and residual disease of last therapy will be 
summarized.  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.  
Anti-neoplastic medications will be coded using the World Health Organization (WHO) Drug 
Dictionary (WHO-DD); Details regarding MedDRA and WHO-DD version will be included 
in the footnote in the tables/listings.  
The above analyses will be performed using the FAS. 
Post treatment anti-cancer therapy 
Anti-neoplastic therapies since discontinuation of study treatment will be listed and medications 
will be summarized by ATC class, preferred term, overall and by treatment group by means of 
frequency counts and percentages using FAS. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a subject coinciding with the study treatment 
period. Concomitant therapy include medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  


Novartis 
Confidential 
Page 31 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Concomitant medications will be coded using the WHO Drug Reference Listing (DRL) 
dictionary that employs the WHO Anatomical Therapeutic Chemical (ATC) classification 
system and summarized by lowest ATC class and preferred term using frequency counts and 
percentages. Concomitant non-drug therapies/procedures will be coded using MedDRA and 
summarized by SOC and preferred term. Concomitant medications with immunosuppressive 
intent (agents to treat suspected irAEs) will be summarized by lowest ATC class and preferred 
term 
using 
frequency 
counts 
and 
percentages. 
Concomitant 
medications 
with 
immunosuppressive intent will be programmatically flagged using a pre-specified list from the 
clinical team. 
All concomitant systemic corticosteroids will be summarized by lowest ATC class and 
preferred term using frequency counts and percentages. Additionally, the cumulative number 
of days while on study treatment that a subject took any systemic corticosteroid will be 
summarized. Systemic corticosteroids) will be programmatically flagged using a pre-specified 
list from the clinical team.  
All summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
Additional summaries will be provided to report medications starting between 31 days after last 
dose of study treatment and up to 150 days after last administration of LAG525/spartalizumab. 
All reported concomitant therapies will be listed. Any concomitant therapies starting more 
than 150 days after the last dose of LAG525 or spartalizumab, or 30 days after last dose of 
study treatment whichever comes last, will be flagged in the listing. The safety set will be 
used for all concomitant medication tables and listings. 
2.5 
Analysis of the primary objective 
The primary objective is to to assess the antitumor activity of the three treatment arms LAG525 
+ spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + carboplatin, in subjects 
with advanced TNBC in first or second line of therapy, as measured by the objective response 
rate (ORR) per investigator’s assessment according to RECIST v1.1. 
2.5.1 
Primary endpoint 
The primary endpoint of the study is ORR defined as the proportion of subjects with best overall 
response (BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1 
(see Appendix 3 of the study protocol). ORR will be calculated based on the FAS using local 
investigators review of tumor assessment data. Tumor assessments performed before the start 
of any further antineoplastic therapy (i.e. any additional secondary antineoplastic therapy or 
surgery) will be considered in the assessment of BOR. Treatment with bisphosphonates or 
denosumab for pre-existing painful bone metastases and limited-field palliative radiotherapy is 
permitted as per protocol, and will not be considered as new antineoplastic therapy. 


Novartis 
Confidential 
Page 32 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
BOR is defined as the best response recorded from the randomization date until disease 
progression as per RECIST 1.1. Complete and partial responses must be confirmed by repeat 
assessments that should be performed not less than 4 weeks after the criteria for response are 
first met. 
The BOR for each subject 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 
PR = at least two determinations of PR or better at least 4 weeks apart before progression (and 
not qualifying for a CR) 
SD = at least one SD assessment (or better) > 5 weeks after randomization (and not qualifying 
for CR or PR). 
PD = progression ≤ 13 weeks after randomization (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 5 weeks or early progression within the first 13 weeks) 
2.5.2 
Statistical hypothesis, model, and method of analysis 
The primary objective of the study is to assess the anti-tumor activity of the three treatment 
arms LAG525 + spartalizumab, LAG525 + spartalizumab + carboplatin and LAG525 + 
carboplatin, in subjects with advanced TNBC in first or second line of therapy, as measured by 
ORR per investigator’s assessment according to RECIST v1.1. ORR based on RECIST1.1 will 
be calculated based on the FAS and according to the treatment group assigned at randomization 
following the Intent-To-Treat (ITT) principle. 
In a randomized phase III study of carboplatin compared to docetaxel for subjects with 
metastatic or recurrent locally advanced triple negative breast cancer or BRCA1/2 breast cancer, 
including 188 subjects randomized to carboplatin, the ORR with carboplatin in first line was 
31.4% [Tutt et al 2014]. In the phase II clinical trial of platinum monotherapy in metastatic 
TNBC, with 86 subjects treated by carboplatin or cisplatin in first (69 subjects) or second line 
(17 subjects) the ORR was 25.6%. Specifically in second line, the ORR with cisplatin alone (9 
subjects) was 22.2% and no subject responded in second line out of the 8 subjects treated by 
carboplatin [Isakoff et al 2015]. Based on cisplatin response rate in second line and considering 
that differences in population treated by the two drugs may explain the lower response rate 
observed with carboplatin, the ORR with carboplatin in second line is assumed around 20%. 
Hence, based on those published results and assuming a similar proportion of subjects enrolled 
in first line and second line of therapy, the response rate with single agent carboplatin in subjects 
with advanced TNBC in 1st and 2nd line overall is expected to be 25%. A 10% absolute 
improvement in the response rate to 35% is considered a minimum clinically meaningful 
improvement in this study population. Therefore, proof of preliminary efficacy in each 
treatment group will be declared if both of the following conditions are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 


Novartis 
Confidential 
Page 33 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
The posterior distribution of ORR will be derived from the prior distribution and all available 
data from the subjects included in the FAS. A minimally informative unimodal Beta prior 
[Neuenschwander et al 2008] will be used for ORR in each arm (see Appendix 2 of study 
protocol for further details). All available data from the subjects included in the FAS will be 
used to derive posterior distribution of ORR by treatment arm. 
The study will be positive if the proof of preliminary efficacy is declared for any treatment 
group. 
ORR will be summarized using descriptive statistics (N, %) by treatment group along with the 
two-sided exact binomial 95% confidence interval [Clopper and Pearson 1934]. 
2.5.3 
Handling of missing values/censoring/discontinuations 
Subjects with unknown or missing BOR as per RECIST 1.1 will be counted as failures. If there 
is no baseline tumor assessment, all post-baseline overall lesion responses are expected to be 
‘Unknown’. If no valid post-baseline tumor assessments are available, the best overall response 
must be “Unknown” unless progression is reported. If a complete response is not confirmed, 
the best overall response must be “Unknown” unless it occurs after the first 5 weeks (stable 
disease), or confirmed partial response or progression is reported. If a partial response is not 
confirmed, the best overall response must be “Unknown” unless it occurs after the first 5 weeks 
(stable disease) or progression is reported. For the computation of ORR, these subjects with 
unknown BOR will be included in the FAS and will be counted as ‘failures’. 
Only tumor assessments performed on or before the start of a new antineoplastic treatment other 
than study drug(s) (not considering palliative radiotherapy) will be considered in the assessment 
of BOR. 
2.5.4 
Supportive analyses 
A sensitivity analysis considering subjects with unconfirmed PR or CR as responders may be 
performed if large delayed treatment effect is observed (i.e. with PR or CR at the last assessment 
prior to the cut-off date and ongoing in efficacy follow-up). 
Timing of all tumor assessments will be depicted graphically for investigators’ review of tumor 
assessments and displayed by treatment arm. 
Subgroup analysis for ORR 
The primary endpoint of ORR will be summarized using descriptive statistics (N, %) for the 
subgroups specified in Section 2.2.1 based on the primary analysis source (i.e., investigator 
assessment) and the same conventions as for the primary analysis.  
 
  
Reasons for “Unknown” BOR 
Subjects with ‘unknown’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used: 
• No valid post-baseline assessment 


Novartis 
Confidential 
Page 34 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• All post-baseline assessments have overall lesion response UNK 
• New anti-neoplastic therapy started before first post-baseline assessment 
• SD too early 
• PD too late  
Note 1: A SD is considered as “SD too early” if the SD is documented within first 5 weeks after 
randomization date (i.e. until Day 35 included).  
Note 2: A PD is considered as “PD too late” if the first documentation of PD is recorded more 
than 13 weeks after randomization date (.i.e. from Day 92 included) with no qualifying CR, PR 
or SD in between. 
Note 3: Special (and rare) cases where BOR is “unknown” due to both too early SD and too 
late PD will be classified as “SD too early”. 
Waterfall plot to depict anti-tumor activity 
Waterfall graphs will be used to depict the anti-tumor activity. These plots will display the 
best percentage change from baseline in the sum of diameters of all target lesions for each 
subject. Only subjects with measurable disease at baseline will be included in the waterfall 
graphs. Special consideration is needed for assessments where the target lesion response is 
CR, PR or SD, but the appearance of a new lesion or a worsening of non-target lesions results 
in an overall lesion response of PD. As a conservative approach, such assessments will not be 
considered for display as bars in the graph, since the percentage change in the sum of diameters 
of target lesions reflects the non-PD target lesion response, but the overall lesion response is 
PD. A subject with only such assessments will be represented by a special symbol (e.g. ) in 
the waterfall graph. Assessments with “unknown” target lesion response and assessments with 
unknown overall response will be excluded from the waterfall plots. Subjects without any valid 
assessments will be completely excluded from the graphs. 
The total number of subjects displayed in the graph will be shown and this number will be 
used as the denominator for calculating the percentages of subjects with tumor shrinkage and 
tumor growth. Footnote will explain the reason for excluding some subjects (due to absence of 
any valid assessment). 
All possible assessment scenarios are described in Table 2-11. 
Table 2-9 
 Inclusion/exclusion of assessments used in waterfall graph 
 
Criteria for inclusion/exclusion 
Possible sources of 
contradictions 
case Target response 
Overall lesion 
response 
Include 
in waterfall? 
Non-target 
response 
New lesion? 
1 
CR/PR/SD 
PD 
Yes but as ‘ 
only 
PD 
any 
2 
CR/PR/SD 
PD 
Yes but as ‘ 
only 
any 
Yes 
3 
UNK 
UNK or PD 
No 
any 
any 
4 
CR/PR/SD 
UNK 
No 
UNK 
No 
5 
CR/PR/SD 
CR/PR/SD 
Yes as a bar 
SD/IR 
No 
6 
PD 
PD 
Yes as a bar 
any 
any 


Novartis 
Confidential 
Page 35 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Percentage change from baseline in the sum of diameters of all target lesions over the time will 
be displayed for individual subjects. 
2.6 
Analysis of the key secondary objective 
Not applicable 
2.7 
Analysis of secondary efficacy objective(s) 
The secondary efficacy objectives are:  
• To assess the efficacy of the three treatment arms with respect to Duration of 
response (DOR), Time to response (TTR), Progression Free Survival (PFS) and 
Clinical benefit rate (CBR) per investigator’s assessment according to RECIST 
v1.1 
• To assess Overall Survival for each treatment arm 
2.7.1 
Secondary endpoints 
Duration of response (DOR) 
Duration of response only applies to subjects whose best overall response is complete response 
(CR) or partial response (PR) according to RECIST 1.1 based on local investigators’ review of 
tumor assessment data. The start date is the date of first documented response of CR or PR (i.e., 
the start date of response, not the date when response was confirmed), and the end date is 
defined as the date of the first documented progression or death due to underlying cancer. 
Subjects continuing without progression or death due to underlying cancer will be censored at 
the date of their last adequate tumor assessment using the censoring rule described for PFS 
analysis (see Section 2.7.3). 
Time to response (TTR) 
Time to response (CR or PR) is the time from date of randomization to first documented 
response of CR or PR (which must be confirmed subsequently using local investigators’ review 
of tumor assessment data and according to RECIST 1.1). The start date is the date of first 
documented response of CR or PR (i.e., the start date of response, not the date when response 
was confirmed). 
All subjects in the FAS will be included in the time to response calculation. Subjects who did 
not achieve a confirmed PR or CR will be censored at: 
• the maximum follow-up time (i.e. FSFV - LSLV used for the analysis) for subjects 
who had a PFS event (i.e. either progressed or died due to any cause); 
• the last adequate tumor assessment date for all other subjects. 
Progression-Free Survival (PFS)  
PFS is defined as time from date of randomization to the date of event defined as the first 
documented progression or death due to any cause. PFS will be assessed via local review of 
tumor assessments according to RECIST 1.1 (see Appendix 3 of study protocol for further 
details). The analysis will be based on FAS and will include all data observed up-to the cut-off 


Novartis 
Confidential 
Page 36 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
date. PFS will be censored at the date of the last adequate tumor assessment if no PFS event is 
observed prior to the analysis cut-off date or before the start of the new anticancer therapy date, 
whichever is earlier (see Section 2.7.3 for additional details regarding censoring rules and 
determination of date of last adequate tumor assessment).  
Discontinuation due to disease progression (collected on the ‘Treatment disposition’ and ‘Post 
treatment follow up disposition’ eCRF pages) without supporting objective evidence 
satisfying progression criteria per RECIST 1.1 will not be considered disease progression for 
PFS derivation. Clinical deterioration will not be considered as a qualifying event for 
progression. 
Clinical benefit rate (CBR) 
CBR is defined as the proportion of subjects with a best overall response (BOR) of confirmed 
CR or PR, or SD lasting 24 weeks or longer, according to RECIST 1.1 criteria. A subject will 
be considered to have SD for 24 weeks or longer if a SD response is recorded at (24-1) weeks 
or later from randomization, allowing for the ±1 week visit window for tumor assessments. 
CBR will be calculated using the FAS based on the investigators’ tumor assessments.  
Overall Survival (OS) 
Overall Survival is defined as the time from date of randomization to date of death due to any 
cause. All deaths occurring on or before the cut-off date in the FAS will be used in the OS 
analysis. If a subject is not known to have died, then OS will be censored at the latest date the 
subject was known to be alive (on or before the cut-off date).  
2.7.2 
Statistical hypothesis, model, and method of analysis 
Duration of response 
DOR based on RECIST 1.1 will be listed and summarized by treatment group for all subjects 
in the FAS with confirmed BOR of CR or PR. DoR will be analyzed in the FAS population 
according to the treatment groups assigned at randomization. The DoR distribution will be 
estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 95% 
confidence intervals of the medians [Brookmeyer and Crowley 1982] will be presented for each 
treatment group only if a sufficient number of responses is observed. DoR will also be 
summarized for the subgroups specified in Section 2.2.1.  
Time to response 
TTR will be listed and summarized by treatment group. TTR will be analyzed in the FAS 
population according to the treatment groups assigned at randomization. The TTR distribution 
will be estimated using the Kaplan-Meier method, and the Kaplan-Meier curves, medians and 
95% confidence intervals of the medians [Brookmeyer and Crowley 1982] will be presented for 
each treatment group only if a sufficient number of responses is observed. A responders-only 
analysis will also be performed in this case. 
Progression-Free Survival 
PFS will be analyzed in the FAS population according to the treatment group assigned at 
randomization and including all data observed up to the cut-off date. The survival distribution 


Novartis 
Confidential 
Page 37 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
of PFS will be estimated using the Kaplan-Meier method. The results will be plotted graphically 
by treatment arm using Kaplan-Meier curves. The medians of PFS and 95% confidence 
intervals of the medians [Brookmeyer and Crowley 1982], along with the proportion of subjects 
event-free at 3, 6, 12 and 18 months and the associated 95% confidence intervals, will be 
presented for each treatment group. 
Censoring pattern of PFS 
Number of subjects with a PFS event and number of subects censored for the PFS analysis will 
be summarized. In addition, a summary of reasons for PFS censoring will be provided by 
treatment arm based on the following reasons: 
1: Ongoing without event 
2: Lost to follow-up 
3: Withdrew consent 
4: Adequate assessment no longer available 
5: Initiation of new cancer therapy prior to progression 
6: Event after >=2 missing tumor assessments 
The PFS censoring reasons are defined in the following way.  
If the time interval between the last adequate tumor assessment (TA) date and the earliest of the 
following dates is smaller or equal to interval of 2 missing tumor assessments: 
1. Analysis cut-off date,  
2. Start date of further anti-neoplastic therapy, 
3. Date of consent withdrawal, 
4. Visit date of study treatment discontinuation or end of post-treatment follow-up 
discontinuation due to lost to follow-up. 
Then the PFS censoring reason will be: 
1. ‘Ongoing’,  
2. ‘New cancer therapy added’,  
3. ‘Withdrew consent’,  
4. ‘Lost to follow-up’, 
If the time interval is larger than the interval of 2 missing tumor assessments with no event 
observed. then the PFS censoring reason will always default to ‘Adequate assessment no longer 
available’. If the time interval between the last adequate tumor assessment date and the PFS 
event date is larger than the interval of 2 missing tumor assessments then the subect will be 
censored and the censoring reason will be 'Event documented after two or more missing tumor 
assessments'. 
These summaries on censoring reasons will be produced for PFS by investigators’ assessment. 
The censoring patterns will be compared between treatment arms.  
As a supportive analysis, the same type of analysis will be done for PFS, without  censoring the 
data of tumor assessments after the start a the new anticancer therapy. 


Novartis 
Confidential 
Page 38 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Clinical benefit rate  
CBR based on RECIST 1.1 will be calculated based on the FAS and according to the ITT 
principle. CBR and its two-sided exact binomial 95% confidence interval [Clopper and Pearson 
1934] will be presented by treatment group. 
Overall Survival  
OS will be analyzed in the FAS population according to the treatment group assigned at 
randomization and including all data observed up to the cut-off date. The survival distribution 
of OS will be estimated using the Kaplan-Meier method. The medians of OS and 95% 
confidence intervals of the medians [Brookmeyer and Crowley 1982], along with the proportion 
of subjects alive at 3, 6, 12 and 18 months and the associated 95% confidence intervals, will be 
presented for each treatment group. 
Censoring pattern of OS 
The pattern of censored data will be examined between the treatment arms: reasons for 
censoring (‘Alive’ or ‘Lost to follow-up’) and death cause will be summarized by treatment 
arm. In addition, survival status, reason for censoring and death cause will be listed. Subjects 
not known to have died will be censored for ‘Lost to follow-up’ if the time between their last 
contact date and the analysis cut-off date is longer than the protocol specified interval between 
the survival follow-up assessments plus 2 weeks, i.e., 15 weeks for this study. 
Duration of follow-up for PFS/OS  
Study follow-up will be summarized using the following methods: summary of duration 
between randomization and cut-off date, and follow-up times for PFS/OS, which are defined 
as follows: 
o Duration between randomization and data cut-off date = (Cut-off date – Date of 
randomization + 1) / 30.4375 (months). This item will be summarized overall. 
o Follow-up time = (Date of event or censoring – Date of randomization + 1) / 
30.4375 (months) regardless of censoring. Date of censoring is defined as the last 
adequate tumor assessment date for PFS or last contact date for OS. This item will 
be summarized by treatment arm. 
All summaries will be reported in months. Date of censoring is the same as defined for the 
PFS and OS analysis. 
In addition, median time to censoring will be computed by reversing censoring variable and 
performing Kaplan-Meier analysis. 
2.7.3 
Handling of missing values/censoring/discontinuations 
PFS and DOR will be censored at the date of the last adequate tumor assessment if no PFS event 
is observed prior to the analysis cut-off date or before the start of the new anticancer therapy 
date, whichever is earlier. 
The date of last adequate tumor assessment is the date of the last tumor assessment with overall 
lesion response of CR, PR or SD before an event or a censoring reason occurred. In this case 
the last tumor evaluation date at that assessment will be used. If no post-baseline assessments 


Novartis 
Confidential 
Page 39 
SAP 
14-Feb-2022 (11:46)
CLAG525B2101 
are available (before an event or a censoring reason occurred) then the date of randomization 
will be used. 
In particular, PFS and DOR will be censored at the last adequate tumor assessment if one of the 
following occurs: absence of event; the event occurred after a new anticancer therapy is 
administered; the event occurred after two or more missing tumor assessments. The term 
“missing adequate tumor assessment” is defined as a TA not performed or tumor assessment 
with overall lesion response of “UNK”. The rule to determine number of missing TAs is based 
on the time interval between the date of last adequate tumor assessment and the date of an event. 
If the interval is greater than twice the protocol-specified interval between the TAs and 2 times 
the protocol-allowed time window around assessments, then the number of missing assessments 
will be 2 or more. 
Refer to Table 2-12 for censoring and event date options and outcomes for PFS and DOR. 
Table 2-10 
Outcome and event/censor dates for PFS/DOR analysis 
Situation 
Date 
Outcome 
No baseline assessment 
Date of randomization 
Censored 
Progression or death at or 
before next scheduled 
assessment 
Date of progression (or death) 
Progressed 
Progression or death after 
exactly one missing assessment 
Date of progression (or death) 
Progressed 
Progression or death after two or 
more missing assessments 
Date of last adequate 
assessment prior to missed 
assessment 
Censored 
No progression (or death) 
Date of last adequate 
assessment 
Censored 
Treatment discontinuation due to 
‘Disease progression’ without 
documented progression, i.e. 
clinical progression based on 
investigator claim 
Date of last adequate 
assessment  
Censored 
New anticancer therapy given 
prior to protocol defined 
progression 
Date of last adequate 
assessment on or prior to 
starting new anti-cancer 
therapy 
Censored 
Death before first PD 
assessment 
Date of death 
Progressed 
For Overall Survival, if a subject is not known to have died at the time of analysis cut-off, then 
OS will be censored at the date of last known date subject was alive, i.e., last contact date (see 
Section 2.1).  
 
 
 


Novartis 
Confidential 
Page 40 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 


Novartis 
Confidential 
Page 41 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
2.9 
Safety analyses 
All safety analyses will be based on the safety set.  
2.9.1 
Adverse events (AEs) 
AE summaries will include all AEs occurring during on treatment period. Additional summaries 
will be displayed to report all AEs, AEs related to study treatment, all SAEs and SAEs related 
to study treatment collected up to 150 days after last administration of LAG525/spartalizumab 
or up to 30 days after the last dose of carboplatin whichever comes last. All AEs collected in 
the AE eCRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings.  
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject 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. 


Novartis 
Confidential 
Page 42 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
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 the LAG525 + PDR001 + carboplatin 
arm, then on their frequency in the LAG525 + PDR001 arm and LAG525 + carboplatin arm.  
The following adverse event summaries will be produced by treatment arm: overview of 
adverse events (number and % of subjects with any AE, treatment-related AE, SAE, treatment-
related SAE, fatal SAE, treatment-related fatal SAE, AE leading to discontinuation, treatment-
related AE leading to discontinuation, AE leading to dose adjustment/interruption, AE requring 
additional therapy), 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 
adjustment/interruption, 
requiring 
additional 
therapy, 
requiring 
immunosuppressive medication, requiring systemic corticosteroid (> 10 mg of prednisone or 
equivalent), and leading to fatal outcome. Concomitant medications with immunosuppressive 
intent and systemic corticosteroids (>10 mg of prednisone or equivalent) will be 
programmatically flagged using a pre-specified list from the clinical team.  
In addition, a summary of serious adverse events with number of occurrences will be produced 
(an occurrence is defined as >1 day between start and prior end date of record of same preferred 
term). For the legal requirements of ClinicalTrials.gov and EudraCT at the time of the CSR for 
the final analysis, two required tables on on-treatment adverse events which are not serious 
adverse events with an incidence greater than 5% and on-treatment serious adverse events and 
SAE suspected to be related to study treatment will be provided by system organ class and 
preferred term on the safety set population. 
If for a same subject, 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 / treatment-related SAE / non SAE has to be 
checked in a block e.g., among AEs 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 treatment-related SAEs and SAEs irrespective of study 
treatment relationship will be provided by SOC and PT. 
2.9.1.1 
Adverse events of special interest / grouping of AEs 
Adverse Events of Special Interest (AESI) consist of one or more well-defined safety events 
which are similar in nature and for which there is a specific clinical or safety interest in 
connection with the study compound. All definitions of AESI for LAG525 and spartalizumab 
will be stored in their respective Case Retrieval Strategy (CRS) sheet with clear versioning and 
reference to the MedDRA version used. If a CRS update is necessary, the final version needs 
to be available in a reasonable time ahead of the DBL. The CRS version will be included as a 
footnote of the AESI tables.  


Novartis 
Confidential 
Page 43 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Data analysis of AESIs 
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound LAG525 or spartalizumab. 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.  
AESI for LAG525 will be based on the most recent version of the dSPP and CRS for LAG525. 
Based on the current version of the dSPP and spartalizumab CRS, AESI for spartalizumab are: 
• Endocrinopathies  
• Pneumonitis 
• Colitis 
• Hepatitis 
• Nephritis 
• Encephalitis 
• Rash 
• Infusion reaction 
• Other immune disorders 
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on treatment period will be summarized.  
Summaries of these AESIs will be provided by treatment arm, (specifying grade, SAE, 
relationship, leading to treatment discontinuation, leading to dose adjustment/interruption, 
hospitalization, death, requiring immunosuppressive medication etc.). If sufficient number of 
events occurred, analysis of time to first occurrence will be applied.  
Additional summaries will be provided to report all AESIs, AESIs related to study treatment, 
all serious AESIs and serious AESIs related to study treatment collected during the on-treatment 
period and up to 150 days after last administration of LAG525/spartalizumab or up to 30 days 
after the last dose of carboplatin whichever comes last. 
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated.  
Time to first occurrence of AESIs 
Time to first occurrence of an AESI is defined as time from start of study treatment to the date 
of first occurrence of first event within an AESI, i.e. time in days is calculated as (start date of 
first occurrence of event ) – (start of study treatment) +1.  
In the absence of an event during the on-treatment period, the censoring date applied will be 
the earliest of the following dates:  


Novartis 
Confidential 
Page 44 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
• death date 
• new anticancer antineoplastic therapy start date (not considering palliative radiotherapy),  
• end date of on-treatment period  
• data cut-off date 
• withdrawal of informed consent date. 
The corresponding censoring reason will be used: death, new anti cancer therapy, treatment 
discontinuation, ongoing at cut-off date or consent withdrawal. 
The following AESIs will be considered for time to first occurence analysis: Endocrinopathies, 
Colitis and Rash.  
Failure curves (ascending Kaplan-Meier curves) will be constructed by treatment arm. Median 
together with 95% confidence interval as well as 25th percentile and 75th percentile will be 
presented for each treatment arm.  
In addition, the median time to occurrence for the subset of subjects who experienced the event 
of interest will be calculated. Simple descriptive statistics, median, min and max as well as 25th 
percentile and 75th percentile, will be presented.  
2.9.2 
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. Additional summary will be 
displayed to report all deaths up to 150 days after last administration of LAG525/spartalizumab 
or up to 30 days after the last dose of carboplatin whichever comes last. 
All deaths will be listed, post treatment deaths will be flagged. A separate listing of deaths prior 
to starting treatment will be provided for all screened subjects. 
2.9.3 
Laboratory data 
Laboratory data from all sources (central and local laboratories) 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 2.1.1). 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 
• Worst post-baseline CTC grade (regardless of the baseline status). Each subject will be 
counted only for the worst grade observed post-baseline. 
• Shift tables using CTC grades to compare baseline to the worst on-treatment value  
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value. 
The following listings will be produced for the laboratory data: 
• Listings of all laboratory data, with CTC grades and classification relative to the laboratory 
normal range. Lab data collected during the post-treatment period will be flagged. 
• Listing of all CTC grade 3 or 4 laboratory toxicities 


Novartis 
Confidential 
Page 45 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Magnesium data from Q2 lab analyzed between 05-Jun-2018 and 09-Jul-2018 and between 
22-Nov-2018 and 02-Jan-2019 were excluded because the vendor (Q2 Solutions) identified an 
issue with serum magnesium (Mg) test results that were analyzed during these two time 
period. A carryover effect from assays run prior to the Mg tests on those days resulted in an 
increase of measured Mg test results. Hence, the Mg test results reported during these times 
may have been inaccurately increased and therefore should be considered as unreliable. 
For the biochemistry data, two versions of the tables will be produced. One version will include 
all data and another version will exlude unreliable magnesium data.  
 
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), ALT, AST and alkaline 
phosphatase (ALP). The number (%) of subjects with worst post-baseline values as per Novartis 
Liver Toxicity guidelines will be summarized: 
The following summaries will be produced: 
• ALT or AST > 3xULN  
• ALT or AST > 5xULN 
• ALT or AST > 8xULN 
• ALT or AST > 10xULN 
• ALT or AST > 20xULN 
• TBL > 2xULN 
• TBL > 3xULN 
• ALT or AST > 3xULN & TBL > 2xULN 
• ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (potential Hy’s law) 
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as, liver metastates, liver function at baseline etc. 
A figure displaying time course of hepatic function tests (ALT, AST, TBL, ALP) in subjects 
with potential Hy’s law will be displayed in the Safety Set. Additonally, evaluation of drug-
induced serious hepatotoxicity (eDISH) plots will be produced to display ALT and AST values 
by TBL values in units of ULN.  
2.9.4 
Other safety data 
2.9.4.1 
ECG and cardiac imaging data 
At scheduled visits, triplicate 12-lead ECG’s will be performed. ECG machines will 
automatically calculate heart rate and measures of PR, QRS, QT, and QTcF intervals. ECG data 
will be read and interpreted centrally. 


Novartis 
Confidential 
Page 46 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Unscheduled safety ECG’s may be performed at the discretion of the investigator at any time 
during the study as clinically indicated. Unscheduled ECG’s with clinically significant findings 
should be collected in triplicate. 
Clinically significant abnormalities observed from single 12-lead ECGs collected at the study 
site are not part of the data analysis described below, but must be reported as adverse events. 
ECHO/MUGAs will be performed to assess cardiac ejection fraction. The same procedure 
(either ECHO or MUGA) should be performed at baseline, follow-up visits if clinically 
indicated, and at EOT. All ECHO/MUGA assessments will be read and interpreted locally. 
Data handling 
In case the study requires ECG replicates at any assessment, the average of the ECG parameters 
at that assessment should be used in the analyses. 
Data analysis 
The number and percentage of subjects with notable ECG values will be presented by treatment 
arm.  
• QT, QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤ 60ms 
- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 
- 
Decrease from baseline >25% and to a value < 50 bpm 
• PR 
- 
Increase from baseline >25% and to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and to a value > 120 ms  
- 
New values of QRS > 120 ms 
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged. 
For left ventricular ejection fraction (LVEF), a shift table using CTC grades for ’Ejection 
fraction - decrease’ as defined per CTCAE version 5.0 to compare baseline to the worst on-
treatment value will be provided:  
CTCAE 
0 
1 
2 
3 
4 


Novartis 
Confidential 
Page 47 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Ejection 
fraction - 
decrease 
- 
- 
Resting ejection fraction 
(EF) 50 - 40%; 10 - 19% 
drop from baseline 
Resting ejection fraction 
(EF) 39 - 20%; ≥20% 
drop from baseline 
Resting ejection 
fraction (EF) <20% 
2.9.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), pulse rate (beats per minute), 
systolic and diastolic blood pressure (mmHg). 
Data handling 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-13 
below. 
Table 2-11 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented by treatment arm. Descriptive statistics will be tabulated for baseline, at each post-
baseline time point and changes from baseline at each post-baseline time point for each vital 
sign measure. Figures of change from baseline in systolic and diastolic blood pressure values 
over time will be displayed via boxplots based on time windows. 
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. In the listing, the assessments collected outside of on-treatment period will be 
flagged.  
2.9.4.3 
ECOG performance status 
The ECOG PS scale (Table 2-14 will be used to assess physical health of subjects, ranging from 
0 (most active) to 5 (least active): 


Novartis 
Confidential 
Page 48 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Table 2-12 
ECOG Performance Scale 
Score 
Description 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature, e.g., light house work, office work 
2 
Ambulatory and capable of all self-care but unable to carry out any work 
activities. Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
5 
Dead 
Frequency counts and percentages of subjects in each score category will be provided by 
treatment arm and time point in subjects of the safety set. 
2.10 
Pharmacokinetic endpoints 
The secondary objective for PK is to to characterize the PK of LAG525, spartalizumab, and 
carboplatin in the three investigated combinations. 
PK parameters 
The PK parameters which may be calculated using the PK sampling in cycle 1 and cycle 3, as 
appropriate, are shown in Table 2-15 The PK parameters are derived based on the non-
compartmental methods using Phoenix WinNonlin® software version 6.4. 
Table 2-13 
Non-compartmental PK parameters for LAG525, spartalizumab and 
carboplatin 
AUClast 
The AUC from time zero to the last measurable concentration sampling time 
(tlast) (mass x time x volume-1) 
AUC0-t 
AUC0-t is the area under the plasma (or serum or blood) concentration-time 
curve to a defined point in time. For LAG525/spartalizumab AUC0-t = AUC0-
504h and for carboplatin AUC0-t = AUC0-3h (amount x time x volume-1) 
Cmin or 
Ctrough 
The minimum observed plasma or serum drug concentration (mass 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) 
Race 
Accumulation ratio calculated as AUC0-t on Cycle 3 / AUC0-t on Cycle 1 
Descriptive statistics (n, arithmetic mean, CV% mean, standard deviation (SD), median, 
geometric mean, CV% geo-mean, minimum and maximum) will be presented by treatment for 
Pharmacokinetic analysis set for all PK parameters defined in Table 2-15 except Tmax, where 
only n, median, minimum and maximum will be presented.  


Novartis 
Confidential 
Page 49 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
All individual PK parameters will be listed by treatment using the Safety set. 
PK concentrations  
Descriptive statistics (n, m (number of non-zero concentrations), arithmetic mean, CV% mean, 
SD, median, geometric mean, CV% geo-mean, minimum and maximum) for LAG525, 
spartalizumab and carboplatin concentration will be presented at each scheduled time point by 
treatment for the Pharmacokinetic analysis set. 
Individual concentration-time profiles for LAG525, spartalizumab and carboplatin 
concentrations with median will be displayed graphically by treatment for Safety set on the 
semi-log view. In addition, the mean (+/- SD) and geometric mean concentration-time profiles 
for LAG525, spartalizumab and carboplatin by treatment over time will be displayed 
graphically for Pharmacokinetic analysis set on the linear and semi-log view. 
All individual plasma concentration data for LAG525, spartalizumab and carboplatin will be 
listed by treatment for the Safety set. 
Handling of PK data below LLOQ or missing 
All concentration values below the lower limit of quantitation (LLOQ) (< 0.25 µg/mL for 
spartalizumab, <5 µg/mL for LAG525, < 1 ng/mL for carboplatin ultrafiltrate and < 100 ng/mL 
for carboplatin plasma) are set to zero by the Bioanalyst, and will be displayed in the listings as 
zero and flagged. LLOQ values will be treated as zero in any calculations of summary statistics, 
and treated as missing for the calculation of the geometric means and their CV%. The number 
of non-zero concentrations will also be reported in the summary statistics. 
Missing values for any PK data will not be imputed and will be treated as missing. 
2.11 
PD and PK/PD analyses 
The secondary PD objective is to assess immunogenicity of LAG525 and spartalizumab in the 
three investigated combinations. 
 
 
 
 
 
 
 
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 


Novartis 
Confidential 
Page 50 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
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 and are further characterized in 
the neutralization assay to indicate the presence of neutralizing antibodies (NAb). 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: 
o ADA-negative sample: Determinant sample where assay is ADA negative and and 
respective drug (i.e. LAG525 or spartalizumab) PK concentration at the time of IG 
sample collection is less than the drug tolerance level.  
o ADA-positive sample: Determinant sample where assay is ADA positive. 
o 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) and ADA-positive NAb samples, both 
overall and by time point (including baseline). For summaries by time point, the 
denominator is the number of subjects at that time point with a determinant sample. 
Listings will be provided of sample ADA status (including titer for positive samples). 


Novartis 
Confidential 
Page 51 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
2.11.1.2 Subject ADA status 
Subect ADA status will be defined for both investiganional drugs LAG525 and spartalizumab, 
based on their respective sample ADA status and respective PK concentrations. Any IG sample 
collected after 150 days of the last dose of the respective drug (i.e. LAG525 or spartalizumab) 
will not be used for summaries or derivations and will only be included in the listing. 
Subject ADA status is defined as follows: 
• 
Treatment-induced ADA-positive subject: subject with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample.  
• 
Treatment-boosted ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample.  
• 
Treatment-unaffected ADA-positive subject: subject 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 subject: subject with ADA-positive sample at baseline 
and at least one post baseline determinant sample, all of which are ADA-negative 
samples.  
• 
ADA-negative subject: subject with ADA-negative sample at baseline and at least one 
post baseline determinant sample, all of which are ADA-negative samples.   
• 
Inconclusive subject: subject 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 subject status (n and %) will be provided using 
Immunogenicity incidence set:  
• 
Treatment-boosted ADA-positive subjects; denominator is the number of subjects with 
ADA-positive sample at baseline.  
• 
Treatment-induced ADA-positive subjects; denominator is the number of subjects with 
ADA-negative or ADA- inconclusive sample at baseline.  
• 
ADA-inconclusive subjects: denominator is the number of subjects in Immunogenicity 
incidence set. 
• 
ADA-negative subjects: denominator is the number of subjects in Immunogenicity 
incidence set. 
• 
ADA-positive subjects (i.e. ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive subjects; denominator is 
the number of subjects in Immunogenicity incidence set.  
Listings will be provided of subject ADA status. 


Novartis 
Confidential 
Page 52 
2.12 
Patient-reported outcomes 
Not applicable. 


Novartis 
Confidential 
Page 53 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 


Novartis 
Confidential 
Page 54 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
2.15 
Interim analysis 
No formal interim analysis is planned for this trial. The primary analysis of the study data will 
be reported in the primary CSR based on all subjects’ data up to the time when all subjects have 
been followed for efficacy (tumor assessments) for at least 24 weeks or discontinued tumor 
assessments for any reason prior to 24 weeks. Any additional data (e.g., DoR, OS, safety) for 
subjects continuing to receive study treatment past the data cut-off date for the primary CSR, 
as allowed by the protocol, will be reported in the final analysis on completion of the study.  
3 
Sample size calculation 
3.1 
Primary analysis 
The sample size calculation is based on the primary variable ORR considering the statistical 
model, hypothesis and method of analysis detailed in Section 2.5. Proof of preliminary efficacy 
(PPE) for each drug combination (study arm) will be declared if both of the following conditions 
are met: 
• the mean of the posterior distribution of ORR is at least 35% 
and 
• the posterior probability that the ORR is ≥ 25% is at least 0.9 
Approximately 32 subjects will be enrolled in each arm for a total of approximately 96 subjects. 
In a given arm of 32 subjects, the type-I error rate is 8% while the probability of declaring proof 
of preliminary efficacy (PPE) is at least 80% for ORR ≥ 45% (Table 3-1). 


Novartis 
Confidential 
Page 55 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Table 3-1 
Operating characteristics with 32 subjects in each arm 
True 
ORR 
Probability of declaring PPE in each arm 
(12 or more responders) 
Probability of missing PPE (11 or less 
responders) in each arm 
25 % 
0.079 
0.921 
30 % 
0.228 
0.772 
35 % 
0.448 
0.552 
40% 
0.675 
0.325 
45 % 
0.847 
0.153 
3.2 
Power for analysis of key secondary variables 
Not applicable. 
4 
Change to protocol specified analyses 
Not applicable. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 
Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the subject is considered as on-going:  
The subject should be treated as on-going and the cut-off date should be used as the dose end 
date.  
Note: Scenario 1 should not be applicable for final CSR. All subjects should have EOT page 
complete before the Database lock for Final CSR  
Scenario 2: If the dose end date is completely or partially missing and the EOT page is available:  
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used. 
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy = the year 
of EOT date and mm < the month of EOT date:  
            Use last day of the Month (mm) 
All other cases should be considered as a data issue and the statistician should contact the data 
manager of the study. 


Novartis 
Confidential 
Page 56 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Subjects with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
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 
Table 5-2 
Imputation of end dates (AE, CM) 
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
After imputation, compare the imputed end date with the start date of that 
specific record: if imputed end date before start date then impute to start 
date 
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period* (if same year as 
partial end date) 


Novartis 
Confidential 
Page 57 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* (if same 
month and year as partial end date) 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
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, 
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) if 
the overall response at that assessment is CR/PR/SD/UNK. 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 
a previous and following assessment is 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. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
Note: The latest available MedDRA version at the time of the analyses should be used. The 
MedDRA version used should be specified in the footnote of relevant tables. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 5.0.  


Novartis 
Confidential 
Page 58 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
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).  
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 5.0. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 5.0 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAEv5.0, 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 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 


 
Novartis 
 
Confidential 
 
Page 59 
SAP  
 
14-Feb-2022 (11:46) 
 
CLAG525B2101 
 
Table 5-3 
CTC grades for laboratory values in Novartis Oncology (based on CTCAE v5.0 – Nov 2017)
 


Novartis 
Confidential 
Page 60 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 


 
Novartis 
Confidential 
Page 61 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
Imputation Rules 
CTC grading for blood differentials is based on absolute values. However,  this data may not 
be reported as absolute counts but rather as percentage of WBC.  
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) 
Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, 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 will be assigned as described above for grading. 
5.4 
Statistical models 
5.4.1 
Primary analysis 
Analysis of Binary Data 
Dual-criterion based Proof of Concept designs 
The two criteria to assess the proof of preliminary efficacy (PPE) in each treatment group are 
thus: 
• Clinical relevance: posterior mean ≥ 35% 
• Bayesian statistical significance: pr(ORR ≥ 25% | data) ≥ 0.90 
Let pi denote the ORR for treatment group i and which follows a beta prior distribution Beta 
[a,b], where a>0, b>0. Let yi out of ni subjects be responders. Therefore, the posterior 
distribution of pi is Beta( a+ yi, b+ ni-yi) [Spiegelhalter et al. 2004]. 
A minimally informative unimodal Beta prior [Neuenschwander et al. 2008] Beta [0.35/(1-
0.35),1] will be used. The parameters were chosen so that the mean of the prior distribution is 
equal to 0.35, which ensures that the clinical relevance criterion is met, if the observed ORR is 
exactly equal to 35%.  


Novartis 
Confidential 
Page 62 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
The efficacy criteria will be assessed based on the actual number of subjects enrolled in the 
study. For example, if the total number of subjects is 32 in a given treatment group, the first 
efficacy criterion requires that at least 12 subjects are responders. In that case, the posterior 
distribution is Beta (0.35/(1-0.35)+12 , 1+32-12) and the posterior probability pr(ORR ≥ 25% | 
data) = 0.939.  
For further details, see Appendix 2 of the study protocol. 
 
Confidence interval for response rate 
Responses will be summarized in terms of percentage rates with 95% confidence intervals 
using exact binomial confidence interval (implemented using SAS procedure FREQ with 
EXACT statement for one-way table [Clopper and Pearson 1934]. 
Analysis of time to events Data 
Kaplan-Meier estimates 
An estimate of the survival function in each treatment group will be constructed using Kaplan-
Meier (product-limit) method as implemented in PROC LIFETEST with METHOD=KM 
option. The PROC LIFETEST statement will use the option CONFTYPE=LOGLOG. 
Median survival for each treatment group will be obtained along with 95% confidence 
intervals calculated from PROC LIFETEST output using the method of [Brookmeyer and 
Crowley 1982]. Kaplan-Meier estimates of the survival function with 95% confidence 
intervals at specific time points will be summarized. The standard error of the Kaplan-
Meier estimate will be calculated using Greenwood’s formula [Collett 1994]. 
 
Treatment of ties 
The STRATA statement in LIFETEST procedure will be used to analyze time to event data 
with ties.  
5.4.2 
Key secondary analysis 
Not applicable 
5.5 
Rule of exclusion criteria of analysis sets  
Not applicable. 
 
  
 
 
 
 
 
 
 


Novartis 
Confidential 
Page 63 
SAP  
14-Feb-2022 (11:46) 
CLAG525B2101 
 
 
 
 
 
 
6 
Reference 
1. Brookmeyer R and Crowley J (1982). A Confidence Interval for the Median Survival Time. 
Biometrics, 38, 29 - 41.  
2. Cockcroft, D. W. & Gault, M. H. Prediction of creatinine clearance from serum creatinine. 
Nephron 16, 31–41 (1976). 
3. Clopper CJ and Pearson ES (1934). The use of confidence or fiducial limits illustrated in 
the case of the binomial. Biometrical, 26, 404-413. 
4. Collet D (1994). Modelling survival data in medical research. London, Chapman & Hall. 
5. Neuenschwander B, Branson M and Gsponer T (2008). Critical aspects of the Bayesian 
approach to Phase I cancer trials. Statistics in Medicine, 27, 2420-2439. 
6. Rup B, et al. (2015). Standardizing terms, definitions and concepts for describing and 
interpreting unwanted immunogenicity of biopharmaceuticals: recommendations of the 
Innovative Medicines Initiative ABIRISK consortium. Clinical and Experimental 
Immunology 181:385-400. 
7. Shankar G, et al. (2014). Assessment and reporting of the clinical immunogenicity of 
therapeutic proteins and peptides – harmonized terminology and tactical recommendations. 
The AAPS Journal 16:658-673. 
8. Spiegelhalter DJ, Abrams KR and Myles JP (2004). Bayesian Approaches to Clinical Trials 
and Health-care Evaluation. Chichester, Wiley.