Conditions: Melanoma
Keywords: Unresectable melanoma metastatic melanoma advanced melanoma spartalizumab PDR001 LAG525 capmatinib INC280 canakinumab ACZ885 ribociclib LEE011 immunotherapy platform study LAG-3
Allocation: RANDOMIZED | Intervention model: PARALLEL
Enrollment: 196
Healthy volunteers: no

Brief summary:
The primary purpose of this study is to evaluate the efficacy of novel spartalizumab (PDR001) combinations in previously treated unresectable or metastatic melanoma

Detailed description:
This study was a randomized, open-label, two-part, multi-center, open platform phase II study designed to evaluate the efficacy and safety of the anti-PD-1 antibody PDR001 in combination with novel agents for previously treated unresectable or metastatic melanoma. Additionally, a non-randomized single-arm was added based on interim analysis findings to assess the efficacy and safety of PDR001 in combination with LAG525 in subjects with previously treated unresectable or metastatic LAG-3 positive melanoma.

The study consisted of two parts: the selection part and the expansion part, which were applicable to both the randomized and non-randomized sections. In the randomized section, participants were randomized to one of four combination arms available for enrollment:

* Arm 1: LAG525 600 mg intravenously (i.v.) every 4 weeks (Q4W) and PDR001 400 mg i.v. Q4W.
* Arm 2: INC280 400 mg orally (p.o.) twice daily (BID) and PDR001 400 mg i.v. Q4W.
* Arm 3: ACZ885 300 mg subcutaneously (s.c.) every 4 weeks (Q4W) and PDR001 400 mg i.v. Q4W.
* Arm 4: LEE011 600 mg p.o. once daily (QD) on Days 1-21 of a 28-day cycle and PDR001 400 mg i.v. Q4W.

At each interim analysis, the following determinations were made: (1) which arm met the pre-specified efficacy criteria and expanded to the expansion part, (2) which arms continued enrollment in selection part (up to 45 subjects), and (3) which arms were discontinued due to futility, considering efficacy, safety, and biomarker data. The expansion phase included enrollment of subjects only in the combination arms that met the pre-specified criteria in selection part.

In the non-randomized section, a single combination arm was opened for enrollment in selection part:

• Arm 1A: LAG525 600 mg i.v. Q4W and PDR001 400 mg i.v. Q4W, assessed in a population selected based on the LAG-3 status of their tumor.

Arm 1A would be eligible for enrollment in expansion part only if it met the pre-specified criterion for this arm.

Participants received the study treatment corresponding to their assigned arm on a 28-day cycle basis until disease progression, as determined by local assessment using RECIST v1.1 criteria, or until certain events occurred, such as unacceptable toxicity, initiation of subsequent anti-cancer therapy, withdrawal of consent, investigator's decision, loss to follow-up, death, or termination of the study by the sponsor. Following discontinuation of the study treatment, all subjects were monitored for safety evaluations for up to 150 days after their last dose of the study treatment.

Arms:
arm 1: Participnats randomized to receive LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks arm 2: Participants randomized to receive INC280 orally at a dosage of 400 mg twice daily, in combination with PDR001 intravenously at a dosage of 400 mg every 4 weeks arm 3: Participants randomized to receive to receive ACZ885 at a dosage of 300 mg administered subcutaneously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks arm 4: Participants randomized to receive LEE011 orally at a dosage of 600 mg once daily on Days 1-21 of a 28-day cycle, in combination with PDR001 intravenously at a dosage of 400 mg every 4 weeks arm 5: LAG-3 positive participants received LAG525 at a dosage of 600 mg administered intravenously every 4 weeks, in combination with PDR001 at a dosage of 400 mg administered intravenously every 4 weeks

Interventions: intervention 1: PDR001 intervention 2: LAG525 intervention 3: INC280 intervention 4: ACZ885 intervention 5: LEE011
Intervention descriptions: intervention 1: 400 mg of PDR001 administered every 4 weeks intravenously intervention 2: 600 mg of LAG525 administered every 4 weeks intravenously intervention 3: 400 mg of INC280 administered twice daily orally intervention 4: 200 mg of ACZ885 administered every 4 weeks subcutaneosuly intervention 5: 600 mg of LEE011 orally taken once daily on Days 1-21 of a 28-day cycle

Protocol document:
Prot_000.pdf: 
Clinical Development
Spartalizumab (PDR001), LAG525, capmatinib (INC280), 
canakinumab (ACZ885), ribociclib (LEE011)
Oncology Clinical Protocol CPDR001J22011&7
A randomized, open-label, phase II open platform study 
evaluating the efficacy and safety of novel spartalizumab 
(PDR001) combinations in previously treated 
unresectable or metastatic melanoma
Document type
Amended Protocol Version
EUDRACT number
2018-000610-38
Version number
05 (Clean)
Development phase
Phase II
Document status
Final
Release date
26-Jun-2020 (content final)
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 6-Apr-2017
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Table of contents
Table of contents ....................................................................................................2
List of figures .........................................................................................................6
List of tables ........................................................................................................... 6
List of abbreviations............................................................................................. 11
Glossary of terms..................................................................................................15
Protocol summary.................................................................................................17
Amendment 5 (26-Jun-2020) ...............................................................................23
Amendment 4 (24-Jan-2020)................................................................................31
Amendment 3 (29-Apr-2019)...............................................................................34
Amendment 2 (06-Feb-2019)............................................................................... 39
Amendment 1 (24-Jul-2018) ................................................................................41
1
Background........................................................................................................... 46
1.1
Overview of disease pathogenesis, epidemiology and current treatment.46
1.2
Introduction to investigational treatments ................................................46
1.2.1
Overview of spartalizumab ......................................................46
1.2.2
Overview of LAG525 ..............................................................48
1.2.3
Overview of capmatinib........................................................... 52
1.2.4
Overview of canakinumab ....................................................... 54
1.2.5
Overview of ribociclib ............................................................. 56
2
Rationale............................................................................................................... 59
2.1
Study rationale and purpose......................................................................59
2.2
Rationale for the study design .................................................................. 60
2.3
Rationale for dose and regimen selection.................................................62
2.3.1
LAG525 in combination with spartalizumab........................... 62
2.3.2
Capmatinib in combination with spartalizumab ......................62
2.3.3
Canakinumab in combination with spartalizumab...................63
2.3.4
Ribociclib in combination with spartalizumab ........................63
2.4
Rationale for choice of combination drugs............................................... 63
2.4.1
Rationale for LAG525 in combination with spartalizumab.....63
2.4.2
Rationale for capmatinib in combination with spartalizumab .65
2.4.3
Rationale for canakinumab in combination with 
spartalizumab ........................................................................... 66
2.4.4
Rationale for ribociclib in combination with spartalizumab....66
2.5
Rationale for choice of comparators drugs............................................... 67
2.6
Risks and benefits.....................................................................................67
2.6.1
LAG525 and spartalizumab ..................................................... 67
2.6.2
Capmatinib and spartalizumab................................................. 68
2.6.3
Canakinumab and spartalizumab .............................................68
2.6.4
Ribociclib and spartalizumab................................................... 69
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Objectives and endpoints...................................................................................... 69
4
Study design .........................................................................................................72
4.1
Description of study design ...................................................................... 72
4.1.1
Randomized section of the study ............................................. 72
4.1.2
Non-randomized section of the study ......................................75
4.1.3
Subject-level study design (common to randomized and 
non-randomized sections of the study) ....................................76
4.2
Timing of interim analyses and design adaptations..................................78
4.2.1
Randomized section of the study ............................................. 78
4.2.2
Non-randomized section of the study ......................................79
4.3
Definition of end of study......................................................................... 80
4.4
Early study termination.............................................................................81
5
Population.............................................................................................................81
5.1
Patient population.....................................................................................81
5.2
Inclusion criteria.......................................................................................81
5.2.1
Inclusion criteria for arms 1, 2, 3, 4......................................... 81
5.2.2
Inclusion criteria for arm 1A (LAG525/spartalizumab) ..........82
5.3
Exclusion criteria...................................................................................... 83
5.3.1
Exclusion criteria for all arms.................................................. 83
5.3.2
Exclusion criteria specific for arm 2 
(capmatinib/spartalizumab)......................................................85
5.3.3
Exclusion criteria specific for arm 4 
(ribociclib/spartalizumab) ........................................................ 86
6
Treatment.............................................................................................................. 87
6.1
Study treatment.........................................................................................87
6.1.1
Dosing regimen........................................................................ 88
6.1.2
Ancillary treatments for potential infusion reactions with 
spartalizumab or LAG525........................................................ 91
6.1.3
Rescue medication ...................................................................92
6.1.4
Guidelines for continuation of treatment ................................. 92
6.1.5
Treatment duration...................................................................92
6.2
Dose escalation guidelines........................................................................93
6.3
Dose modifications...................................................................................93
6.3.1
Mandatory dose modification and dose delay..........................93
6.3.2
Dose adjustments for QTcF prolongation suspected to be 
related to capmatinib.............................................................. 110
6.3.3
Follow-up for toxicities..........................................................111
6.4
Concomitant medications ....................................................................... 113
6.4.1
Permitted concomitant therapy ..............................................113
6.4.2
Permitted concomitant therapy requiring caution and/or 
action......................................................................................113
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6.4.3
Prohibited concomitant therapy while receiving study 
drug(s) .................................................................................... 117
6.4.4
Radiotherapy.......................................................................... 120
6.5
Subject numbering, treatment assignment or randomization .................120
6.5.1
Subject numbering .................................................................120
6.5.2
Treatment assignment or randomization................................120
6.5.3
Treatment blinding.................................................................121
6.6
Study drug preparation and dispensation................................................121
6.6.1
Study treatment packaging and labeling ................................121
6.6.2
Drug supply and storage......................................................... 122
6.6.3
Study drug compliance and accountability............................122
6.6.4
Disposal and destruction ........................................................ 122
7
Visit schedule and assessments .......................................................................... 122
7.1
Study flow and visit schedule................................................................. 122
7.1.1
Molecular pre-screening.........................................................139
7.1.2
Screening................................................................................ 139
7.1.3
Run-in period .........................................................................140
7.1.4
Treatment period....................................................................140
7.1.5
Discontinuation of study treatment ........................................141
7.1.6
Withdrawal of consent ...........................................................142
7.1.7
Follow up for safety evaluations (Safety follow up)..............142
7.1.8
Follow-up for efficacy evaluations (Efficacy follow up).......143
7.1.9
Survival follow-up .................................................................143
7.1.10
Lost to follow-up.................................................................... 143
7.2
Assessment types....................................................................................144
7.2.1
Efficacy assessments.............................................................. 144
7.2.2
Safety and tolerability assessments........................................147
7.2.3
Biomarkers............................................................................. 157
8
Safety monitoring and reporting.........................................................................162
8.1
Definition of adverse events and reporting requirements.......................162
8.1.1
Adverse events ....................................................................... 162
8.1.2
Serious adverse events ........................................................... 164
8.2
Emergency unblinding of treatment assignment .................................... 166
8.3
Pregnancies.............................................................................................166
8.4
Warnings and precautions.......................................................................166
8.5
Reporting of study treatment errors including misuse/abuse .................166
8.6
Data Monitoring Committee...................................................................167
8.7
Steering Committee ................................................................................167
9
Data collection and management........................................................................ 168
9.1
Data confidentiality ................................................................................168
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9.2
Site monitoring .......................................................................................168
9.3
Data collection........................................................................................ 169
9.4
Database management and quality control.............................................169
10 Statistical methods and data analysis .................................................................170
10.1
Analysis sets ...........................................................................................170
10.1.1
Full Analysis Set .................................................................... 170
10.1.2
Safety set................................................................................ 170
10.1.3
Per-Protocol set...................................................................... 171
10.1.4
Dose-determining analysis set ...............................................171
171
10.1.6
Other analysis sets..................................................................172
10.2
Subject demographics/other baseline characteristics..............................172
10.3
Treatments (study treatment, concomitant therapies, compliance) ........172
10.4
Primary objective....................................................................................172
10.4.1
Variable.................................................................................. 172
10.4.2
Statistical hypothesis, model, and method of analysis...........173
10.4.3
Handling of missing values/censoring/discontinuations........178
10.4.4
Supportive and Sensitivity analyses....................................... 178
10.5
Secondary objectives ..............................................................................178
10.5.1
Key secondary objective ........................................................178
10.5.2
Other secondary efficacy objectives ......................................178
10.5.3
Safety objectives .................................................................... 180
10.5.4
Immunogenicity .....................................................................182
10.5.5
Biomarkers............................................................................. 182
184
184
185
186
10.7
Interim analysis....................................................................................... 186
10.7.1
Randomized section of the study ........................................... 186
10.7.2
Non-randomized section of the study ....................................187
10.8
Sample size calculation...........................................................................187
10.8.1
Randomized section of the study ........................................... 187
10.8.2
Non-randomized section of the study ....................................192
10.9
Power for analysis of key secondary variables.......................................194
11 Ethical considerations and administrative procedures ....................................... 194
11.1
Regulatory and ethical compliance.........................................................194
11.2
Responsibilities of the investigator and IRB/IEC/REB..........................194
11.3
Informed consent procedures.................................................................. 194
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11.4
Discontinuation of the study...................................................................195
11.5
Publication of study protocol and results ...............................................195
11.6
Study documentation, record keeping and retention of documents........196
11.7
Confidentiality of study documents and subject records........................197
11.8
Audits and inspections............................................................................ 197
11.9
Financial disclosures...............................................................................197
12 Protocol adherence ............................................................................................. 197
12.1
Amendments to the protocol...................................................................197
13 References (available upon request)................................................................... 198
14 Appendices ......................................................................................................... 202
14.1
Appendix 1: AJCC Melanoma Staging System (Edition 8)...................202
14.2
Appendix 2: Guidelines for Response, Duration of Overall Response, 
TTF, TTP, Progression-Free Survival and Overall Survival (based on 
RECIST 1.1) ...........................................................................................205
14.2.1
Introduction............................................................................205
14.2.2
Efficacy assessments.............................................................. 206
14.2.3
Efficacy definitions................................................................214
14.2.4
Data handling and programming rules...................................223
14.3
Appendix 3: Recommended management of suspected immune-related 
adverse events related to spartalizumab and/or LAG525.......................228
List of figures
Figure 4-1
Overview of study design for randomized section of the 
study.........................................................................................74
Figure 4-2
Overview of study design for non-randomized section of the 
study.........................................................................................76
Figure 4-3
Overview of study design at subject level................................78
Figure 4-4
Pre-specified criteria for decision making at each decision point 
(interim analysis) in part 1 to determine expansion in part 2 or 
drop of a combination arm.......................................................79
List of tables
Table 3-1
Objectives and related endpoints .............................................70
Table 6-1
Dose and schedule of administration for investigational drugs 
used in the study.......................................................................88
Table 6-2
Reference of AE and specific dose management criteria.........95
Table 6-3
Dose reduction steps for capmatinib........................................95
Table 6-4
Dose reduction steps for ribociclib .......................................... 95
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Table 6-5
Colitis/diarrhea suspected to be related to spartalizumab or 
spartalizumab/LAG525............................................................ 97
Table 6-6
Abnormal liver tests suspected to be related to spartalizumab or 
LAG525/spartalizumab............................................................98
Table 6-7
Rash/skin events suspected to be related to spartalizumab or 
spartalizumab/LAG525............................................................ 98
Table 6-8
Creatinine alterations suspected to be related to spartalizumab 
or spartalizumab/LAG525........................................................98
Table 6-9
Pneumonitis suspected to be related to spartalizumab or 
spartalizumab/LAG525............................................................ 99
Table 6-10
Endocrinopathies suspected to be related to spartalizumab or 
spartalizumab/LAG525............................................................ 99
Table 6-11
Infusion reactions and cytokine release syndrome suspected to 
be related to spartalizumab or spartalizumab/LAG525 ...........99
Table 6-12
Other adverse events suspected to be related to spartalizumab or 
spartalizumab/LAG525............................................................ 99
Table 6-13
Hematological adverse events suspected to be related to 
capmatinib..............................................................................100
Table 6-14
Creatinine alterations suspected to be related to capmatinib .100
Table 6-15
Abnormal liver test results suspected to be related to 
capmatinib..............................................................................101
Table 6-16
Pancreatitis, amylase and lipase elevations suspected to be 
related to capmatinib.............................................................. 102
Table 6-17
QTc prolongations suspected to be related to capmatinib 
(Further guidance is provided in Section 6.3.2).....................102
Table 6-18
Diarrhea, vomiting or nausea suspected to be related to 
capmatinib..............................................................................102
Table 6-19
Skin events suspected to be related to capmatinib.................103
Table 6-20
Pneumonitis or interstitial lung disease (ILD) suspected to be 
related to capmatinib.............................................................. 103
Table 6-21
Fatigue/asthenia suspected to be related to capmatinib .........103
Table 6-22
Peripheral edema suspected to be related to capmatinib........103
Table 6-23
Other adverse events suspected to be related to capmatinib..104
Table 6-24
Infections suspected to be related to canakinumab................104
Table 6-25
Hematological adverse events suspected to be related to 
canakinumab ..........................................................................104
Table 6-26
Creatinine alterations suspected to be related to 
canakinumab ..........................................................................104
Table 6-27
Hepatic adverse events suspected to be related to 
canakinumab ..........................................................................104
Table 6-28
Pancreatitis, amylase and/or lipase elevations suspected to be 
related to canakinumab ..........................................................106
Table 6-29
Hypertension suspected to be related to canakinumab ..........106
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Table 6-30
Diarrhea suspected to be related to canakinumab..................106
Table 6-31
Skin related toxicities suspected to be related to 
canakinumab ..........................................................................106
Table 6-32
Fatigue/asthenia suspected to be related to canakinumab......106
Table 6-33
Other adverse events suspected to be related to 
canakinumab ..........................................................................106
Table 6-34
Hematological adverse events suspected to be related to 
ribociclib ................................................................................107
Table 6-35
Abnormal liver tests suspected to be related to ribociclib .....107
Table 6-36
QTcF prolongation suspected to be related to ribociclib .......109
Table 6-37
Other adverse events suspected to be related to ribociclib ....109
Table 6-38
Guidance on specific clinical and diagnostic assessments which 
can be performed to rule out possible alternative causes of 
observed LFT abnormalities ..................................................112
Table 6-39
List of medications to be used with caution while on treatment 
with capmatinib (arm 2)......................................................... 114
Table 6-40
List of medications to be used with caution during ribociclib 
treatment (arm 4)....................................................................116
Table 6-41
List of strong CYP3A4 inducers prohibited while on treatment 
with capmatinib (Arm 2)........................................................ 117
Table 6-42
Drugs with a known risk of QT prolongation and/or ‘Torsades 
de Pointes’ prohibited while on treatment with capmatinib...118
Table 6-43
List of prohibited medications while on treatment with 
ribociclib (arm 4).................................................................... 119
Table 7-1
Allowable visit windows........................................................123
Table 7-2
Visit evaluation schedule (applicable for all subjects, in both 
part 1 and part 2) ....................................................................125
Table 7-3
Imaging Assessment Collection Plan....................................144
Table 7-4
ECOG Performance Status.................................................... 148
Table 7-5
Clinical laboratory parameters collection plan ......................149
Table 7-6
Central ECG collection plan ..................................................151
Table 7-7
Blood (serum) collection schedule for spartalizumab
immunogenicity samples (applicable for 
all subjects).............................................................................153
Table 7-8
Blood (serum) collection schedule for LAG525
 immunogenicity samples (only applicable 
for subjects enrolled in arm 1 and arm 1A)............................154
 
155
Table 7-10
Blood (serum) collection schedule for canakinumab
 immunogenicity samples (only applicable 
for subjects enrolled in arm 3) ...............................................155
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Table 7-12
Biomarker sample collection plan..........................................157
Table 7-13
Guidelines for mandatory biopsy collection (applicable for all 
arms) and tissue quality criteria (recommended for arm 1A, 
mandatory for other arms)......................................................159
Table 8-1
Guidance for capturing the study treatment errors including 
misuse/abuse .......................................................................... 167
Table 10-1
Probabilities thresholds used to declare efficacy or futility for 
an arm..................................................................................... 173
Table 10-2
Exact binomial 95% confidence intervals around potential 
observed ORR for N=74 ........................................................ 174
Table 10-3
Type I error assessment: Probability of a successful result for 
scenario where the true ORR equals 0.10 for each arm and 
sample size of the expansion arm is 50 subjects....................175
Table 10-4
Probabilities thresholds used to declare efficacy or futility for 
arm 1A.................................................................................... 176
Table 10-5
Posterior probability ORR≥20% given observed ORR at time of 
1st interim analysis of selection phase.................................... 176
Table 10-6
Posterior probability ORR≥20% given observed ORR at time of 
2nd interim analysis in expansion phase .................................177
Table 10-7
Parameter definitions for categorization of biomarker outcome 
at subject level........................................................................ 182
 
185
 
185
Table 10-10
Simulation based sample size (N) with percentages for 
declaring ‘futile’ and ‘efficacious’ combination arms in the 
selection phase ....................................................................... 188
Table 10-11
Exact binomial 95% confidence intervals for various sample 
size in expansion phase and observed ORR........................... 192
Table 10-12
Operating characteristics for different sample size in expansion 
and under true underlying ORR............................................. 193
Table 14-1
Definition of Primary Tumor (T)...........................................202
Table 14-2
Definition of Regional Lymph Node (N)...............................202
Table 14-3
Definition of Distant Metastasis (M) ..................................... 203
Table 14-4
AJCC pathological (pTNM) prognosis stage groups............. 203
Table 14-5
Response criteria for target lesions ........................................ 210
Table 14-6
Response criteria for non-target lesions.................................212
Table 14-7
Overall lesion response at each assessment ...........................214
Table 14-8
Overall lesion response at each assessment: subjects with non-
target disease only.................................................................. 220
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Table 14-9
Options for event dates used in PFS, TTP, duration of 
response.................................................................................. 221
Table 14-10
Recommended clinical management for suspected immune-
related diarrhea/colitis............................................................ 228
Table 14-11
Recommended clinical management for suspected immune-
related liver laboratory alterations .........................................229
Table 14-12
Recommended clinical management for suspected immune-
related rash and other skin events .......................................... 230
Table 14-13
Recommended clinical management for suspected immune-
related nephritis...................................................................... 231
Table 14-14
Recommended clinical management for suspected immune-
related pneumonitis................................................................231
Table 14-15
Recommended clinical management for suspected immune-
related endocrinopathies.........................................................232
Table 14-16
Recommended clinical management for suspected infusion 
reaction or cytokine release syndrome...................................233
Table 14-17
Recommended clinical management guidelines for suspected 
other potential immune-related events...................................234
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List of abbreviations
aBC
Advanced breast cancer
ADA
Anti-drug antibodies
AE
Adverse event
AJCC
American Joint Committee on Cancer
ALP
Alkaline phosphatase
ALT
Alanine aminotransferase
ANA
Antinuclear antibody
ANSM
Agence Nationale de Sécurité du Medicament
Anti-HCV
Antibody to Hepatitis C virus
ASMA
Anti-smooth muscle antibody
AST
Aspartate aminotransferase
AUC
Area under the curve
BCRP
Breast Cancer Resistance Protein
BICR
Blinded independent central review
BID
bis in diem/twice a day
BLRM
Bayesian logistic regression model
BOR
Best overall response
C1D1
Cycle 1 Day 1 
CAPS
Cryopyrin-associated periodic syndromes
CBD
Cannabidiol
CD8
Cluster of differentiation 8
CD-transferrin
Carbohydrate-deficient transferrin
CI
Confidence interval
CMO & PS 
Chief Medical Office and Patient Safety
CMV
Cytomegalovirus
CNS
Central nervous system
CPI
Checkpoint Inhibitor
CR
Complete response
CRF
Case report/record form
CRO
Contract research organization
CSR
Clinical study report
CT
Computed tomography
CTC
Common terminology criteria
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
Ctrough
Trough concentration
CV
Coefficient of variation
CxDy
Cycle x day y
CYP
Cytochrome P450 
DCR
Disease control rate
DDI
Drug-drug interaction
DILI
Drug-induced liver injury
DLT
Dose limiting toxicity
DMC
Data Monitoring Committee
DNA
Deoxyribonucleic acid
DoR
Duration of response
EBV
Epstein-Barr virus
EC50
Concentration of a drug that gives half-maximal response
ECG
Electrocardiogram
ECOG PS
Eastern Cooperative Oncology Group performance status
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eCRF
Electronic case report/record form
ERCP
Endoscopic retrograde cholangio-pancreatography
EDC
Electronic data capture
EDTA
Ethylenediaminetetraacetic acid
ELISA
Enzyme-linked immunosorbent assay
EoT
End of treatment
EWOC
Escalation with overdose control
FDA
Food and Drug Administration
FFPE
Formalin fixed paraffin embedded
FSFV
First subject first visit
GCP
Good Clinical Practice
GGT
Gamma-glutamyltransferase
GLP
Good Laboratory Practice
HA
Health Authority
HBcAb
Hepatitis B core antibody
HBsAb
Hepatitis B surface antibody
HbsAg
Hepatitis B surface antigen
HBV
Hepatitis B virus
HBV-DNA
Deoxyribonucleic acid of Hepatitis B virus
HCC
Hepatocellular carcinoma
hCG
Human chorionic gonadotropin
HCV
Hepatitis C virus
HCV RNA
Hepatitis C virus ribonucleic acid
HEV RNA
Hepatitis E virus ribonucleic acid
HGF
Hepatocyte growth factor
HIV
Human immunodeficiency virus
HR
Hormone receptor
HSV
Herpes simplex virus
IA
Interim analysis
IB
Investigator's Brochure
ICF
Informed consent form
ICH
International Council for Harmonization
IEC
Independent ethics committee
IFN
Interferon
IG
Immunogenicity
IgA
Immunoglobulin A
IgG
Immunoglobulin G
IgE
Immunoglobulin E
IgM
Immunoglobulin M
IgM anti-HAV
Immunoglobulin M antibody to hepatitis A virus
IgM & IgG 
anti-CMV
Immunoglobulin M and immunoglobulin G antibodies to cytomegalovirus
IgM & IgG 
anti-EBV
Immunoglobulin M and immunoglobulin G antibodies to Epstein-Barr virus
IgM & IgG 
anti-HEV
Immunoglobulin M and immunoglobulin G antibodies to hepatitis E virus
IgM & IgG 
anti-HBc
Immunoglobulin M and immunoglobulin G antibodies to hepatitis B core
IgM & IgG 
anti-HSV
Immunoglobulin M and immunoglobulin G antibodies to Herpes simplex virus
IHC
Immunohistochemistry
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IL
Interleukin
ILD
Interstitial lung disease
INR
International normalized ratio 
IRB
Institutional review board
IRT
Interactive Response Technology 
ITIM
Immunoreceptor tyrosine-based inhibition motif
i.v.
intravenous
Kd
Equilibrium dissociation constant
LAG-3
Lymphocyte-activation gene 3
LDH
Lactate dehydrogenase
LFTs
Liver function tests
LLN
Lower limit of normal
LSFV
Last subject first visit
MAPK
Mitogen-activated protein kinase
MATE
Multidrug and toxin extrusion protein
MCMC
Markov chain Monte Carlo
MCV
Mean corpuscular volume
MDSC
Myeloid-derived suppressor cells
MEK
Mitogen-activated protein kinase kinase 
mg
milligram
MHC
Major histocompatibility complex
ml
milliliter
MRI
Magnetic resonance imaging
mRNA
Messenger ribonucleic acid
MTD
Maximum Tolerated Dose
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSAI
Non-Steroidal Aromatase Inhibitor
NSCLC
Non-small cell lung cancer
OCT
Organic cation transporter
ORR
Objective response rate
OS
Overall survival
PBMC
Peripheral blood mononuclear cell
PCR
Polymerase chain reaction
PD
Progressive disease
PD-1
Programmed cell death 1
PD-L1
Programmed cell death ligand 1
pFBP
Proportion of subjects with an favorable biomarker profile
PFS
Progression-free survival
PHI
Protected health information
PI3K
Phosphoinositide 3-kinase 
PK
Pharmacokinetics
p.o.
per os/by mouth/orally
PP
Posterior probability
PPI
Proton pump inhibitors
PR
Partial response
PT
Prothrombin time
Q2W
Every two weeks
Q3W
Every three weeks
Q4W
Every four weeks
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Q8W
Every eight weeks
QD
quaque die/every day/once a day
QTcF
Corrected QT interval using Fridericia's formula
RAP
The Report and Analysis Plan is a regulatory document which provides evidence of 
preplanned analyses
RCC
Renal cell carcinoma
REB
Research Ethics Board
RECIST
Response Evaluation Criteria In Solid Tumors
RNA
Ribonucleic acid
RoW
Rest of World
RP2D
Recommended phase two dose
R Value
Division of the ALT value by the ALP value, using multiples of the ULN
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
s.c.
Subcutaneous
SC
Steering Committee
SD
Stable disease
SJS
Stevens-Johnson syndrome 
SOD
Sum of diameter
T1/2
Elimination half-life
T3
Triiodothyronine
T4
Thyroxine
TdP
Torsades de Pointe
TCR
T cell receptor
TEN
Toxic Epidermal Necrolysis
THC
Tetrahydrocannabinol
TIL
Tumor infiltrating lymphocytes
TIGIT
T cell immunoglobulin and ITIM domain
TIM-3
T cell immunoglobulin and mucin-domain containing protein 3
TNF
Tumor necrosis factor
TnI
Troponin I
TnT
Troponin T
Treg
Regulatory T cell
TSH
Thyroid-stimulating hormone
UNK
Unknown
ULN
Upper limit of normal
US/USA
United States of America
USM
Urgent Safety Measure
VISTA
V-domain Ig suppressor of T cell activation
WHO
World Health Organization
WNT
The WNT signaling pathways are a group of signal transduction pathways made of 
proteins that pass signals into a cell through cell surface receptors.
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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, tissue,
urine, stool, etc. taken from a study subject 
Cycles
Number and timing or recommended repetitions of therapy are usually expressed 
as number of days (e.g.: every 28 days)
Dosage
Dose of the study drug given to the subject 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.
Enrollment
Point/time of subject entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
For non-randomized arm 1A, enrollment defines the point/time when consented 
subject is deemed eligible for treatment in this arm.
Investigational 
drug(s)/study 
drug(s)
The drug(s) whose properties are being tested in the study. 
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
Other treatment
Treatment that may be needed/allowed during the conduct of the study 
(concomitant or rescue therapy)
Part 
A sub-division of a study used to evaluate specific objectives or contain different 
populations. 
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
Subject information collected by the Investigator that is transferred to Novartis for the 
purpose of the clinical trial. This data includes subject identifier information, study 
information and biological samples.
Randomization 
number
A unique identifier assigned to each randomized subject
Screen Failure
A subject 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
Start of the clinical 
trial
The start of the clinical trial is defined as the signature of the informed consent by 
the first subject.
Study treatment
For this study, the study treatment is defined as the combination of spartalizumab 
(investigational drug common for all combination arms in this study) with another 
investigational drug (which is different in each combination arm).
Study treatment 
interruption 
Includes any delay or withholding of study treatment for any reason as well as an 
interruption during an infusion of study treatment for any reason
Study treatment 
discontinuation
Point/time when subject permanently stops taking study treatment for any reason
Subject number 
(Subject No.)
A unique identifying number assigned to each subject upon signing the informed 
consent. This number is the definitive, unique identifier for the subject and should 
be used to identify the subject throughout the study for all data collected, sample 
labels, etc.
Supportive 
treatment
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for pemetrexed 
disodium.
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Treatment group / 
combination arm
A combination arm (also called treatment group within this document) defines the 
dose and regimen or the combination, and may consist of 1 or more cohorts. 
Cohorts are not expanded, new cohorts are enrolled.
Variable
A measured value or assessed response that is determined from specific 
assessments and used in data analysis to evaluate the drug being tested in the 
study
Withdrawal of 
consent
Withdrawal of consent from the study occurs only when a subject does not want to 
participate in the study any longer, and does not allow any further collection of 
personal data
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Protocol summary
Title
A randomized, open-label, phase II open platform study evaluating the efficacy and 
safety of novel spartalizumab (PDR001) combinations in previously treated 
unresectable or metastatic melanoma
Brief title
Study of efficacy and safety of novel spartalizumab combinations in patients with 
previously treated unresectable or metastatic melanoma
Sponsor and 
phase
Novartis, Phase II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
Subjects who have failed to respond, or progressed while being on standard 
treatment for unresectable or metastatic melanoma which include targeted therapy 
(for patients with V600BRAF-mutant melanoma only) and/or immune checkpoint 
inhibitors (e.g. pembrolizumab, or nivolumab with or without ipilimumab) will be 
enrolled in this study. As of today, patients who have failed these standard therapies
have 
very 
limited 
treatment 
options. 
The mechanisms of primary and acquired resistance to checkpoint inhibitors 
treatment are not well understood and are mainly due to a combination of intrinsic or 
extrinsic resistance mechanisms. The combinations tested in this study aim to alter 
the tumor and/or microenvironment in favorable way to overcome treatment 
resistance and restore T cell function. Considering the high number of potential 
targets and available compounds, an open platform design is applied for this study.
Using the anti-PD-1 antibody spartalizumab as backbone, this study will evaluate 
novel compounds, which may help alter the tumor microenvironment through 
different mechanisms which may
potentially reverse resistance to immune 
checkpoint 
blockade 
and 
restore 
T 
cell 
function.
LAG525 
Although the PD-1/PD-L1 checkpoint axis plays a critical inhibitory role, secondary 
inhibitory immune checkpoints such as LAG-3 may also play a vital role leading to T 
cell dysfunction. Inhibition of LAG-3 with LAG525 may help restore T cell function.
Capmatinib 
Neutrophils recruited to the tumor microenvironment play an immunosuppressive 
role, restraining T cell expansion, effector functions and contribute to resistance to 
immune therapy. In cancer patients, high serum levels of the c-MET ligand HGF 
correlated with increasing neutrophil counts and poor responses to checkpoint 
blockade therapies. Inhibition of c-MET with the capmatinib may help restore T cell 
function.
Canakinumab
Cytokines like IL-1β, derived from the tumor microenvironment and secreted by 
malignant cells, promotes tumor cell proliferation, increases invasiveness and 
dampens anti-tumor immune response, in part by recruiting inhibitory neutrophils. 
Inhibition of IL-1β with the IL-1β antagonist canakinumab may help restore T cell 
function. 
Ribociclib
D-cyclin-CDK4/6-p16-pRb pathway is often up-regulated in melanoma but the 
cytostatic action of CDK4/6 inhibitors have only shown modest clinical benefit when 
used as single agent. The cytotoxic T cell-mediated clearance of tumor cells, along 
with the efficacy of CDK4/6 inhibition on tumor growth, have been shown to be further 
enhanced with immune checkpoint blockade. Given the magnitude of immune 
modulatory effects observed from CDK4/6 inhibitors, the combination of CDK4/6 
inhibitors with check point inhibitors such as anti PD-1/PD-L1 may help to overcome 
resistance to anti PD-1/PD-L1. 
Primary objective
and key secondary 
objective
Primary: To evaluate the efficacy of each combination arm, as measured by 
confirmed objective response rate (ORR)
Key secondary: To evaluate the efficacy of each combination arm in terms of 
duration of response (DoR)
Secondary 
objectives
!
To evaluate the efficacy of each combination arm as measured by
progression-free survival (PFS) and disease control rate (DCR) as per local 
RECIST v1.1 assessment 
!
To evaluate overall survival (OS) of each combination arm
!
To characterize the safety and tolerability of each combination arm through the 
incidence and severity of AEs including changes in laboratory values, vital 
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signs, cardiac assessment and dose interruptions, reductions, and permanent 
discontinuations of study treatment
!
To characterize the prevalence and incidence of immunogenicity of 
spartalizumab, LAG525 and canakinumab in each combination arm, through 
the prevalence of anti-drug antibodies (ADA) at baseline and ADA incidence 
on treatment
!
To evaluate changes from baseline in levels and phenotype of T cell 
populations in the tumor and tumor microenvironment, assessing the 
proportion of subjects with a favorable biomarker profile (pFBP)
Study design
This is a randomized, open-label, two-part, multi-center, open platform phase II 
study to assess the efficacy and safety of the anti-PD-1 antibody spartalizumab in 
combination with novel agents in previously treated unresectable or metastatic 
melanoma. A non-randomized single-arm (Arm 1A) has been added with protocol 
amendment 5 to assess the efficacy and safety of spartalizumab in combination 
with LAG525 in subjects with previously treated unresectable or metastatic LAG-3 
positive melanoma, based on encouraging results from arm 1. 
The study consists of a selection phase (Part 1) and an expansion phase (Part 2).
- Randomized section of the study
Part 1 : Selection phase
The randomized section of this study started with the following three initial 
combination arms:
!
Arm 1: LAG525 600 mg i.v. Q4W and spartalizumab 400 mg i.v. Q4W
o
Declared futile at interim analysis 2
!
Arm 2: Capmatinib 400 mg p.o. BID and spartalizumab 400 mg i.v. Q4W
o
Declared futile at interim analysis 1
!
Arm 3: Canakinumab 300 mg s.c. Q4W. and spartalizumab 400 mg i.v. Q4W
o
Declared futile at interim analysis 1
With protocol amendment 3, a fourth combination arm (Arm 4) was added:
!
Arm 4: Ribociclib 600 mg p.o. QD on Days 1-21 of a 28-day cycle and 
spartalizumab 400 mg i.v. Q4W
o
Declared futile at interim analysis 3
As dose regimens for new additional combinations with spartalizumab become 
established, new combination arms will be added under the same master protocol 
through protocol amendments. Eligible subjects will be randomized with equal 
probability to the arms. A maximum of 10 arms may be active at any given time 
under this master protocol, and any arms active in part 1 will continue to be 
randomized with equal probability. 
At each interim analysis, it will be determined (1) which arm is declared efficacious 
and will be expanded to part 2, (2) and which arms will continue enrollment in part 1 
(up to 45 subjects) or (3) will be dropped for futility, taking into account all available 
efficacy, safety, and biomarker data. 
Part 2 : Expansion phase
In the randomized section of the study, only combination arms that have met the 
pre-specified protocol criteria in part 1 will be eligible for opening of subject’s 
enrollment in part 2. Exact randomization strategies for the arm(s) in part 2 of the 
study compared to arms still open for enrollment in part 1 will be determined at the 
time of the selection of the arm(s) that will be expanded in part 2.
At any time during the study, subjects deemed eligible after the completion of 
screening procedures will be randomized to any open arms in both part 1 and part 
2 for which the subject meets the eligibility criteria using an Interactive Response 
Technology (IRT) system. For each arm, randomization will be stratified by baseline 
LDH. Stratification will occur based on baseline LDH (≤ ULN vs. LDH > ULN).
In both parts, crossover or re-randomization of subjects to other combination arms, 
including better performing arms, is not allowed.
The first four arms evaluated in the randomized section of the study will enroll 
approximately a maximum of 230 subjects in total (for both parts of the study): 
approximately a maximum of 180 subjects in the selection phase (if all four
combination arms enroll the maximum of 45 subjects each) and approximately 50 
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subjects in the expansion phase (assuming that only one of the four initial 
combination arms will be expanded).
- Non-randomized section of the study
Arm 1A will enroll up to approximately 100 subjects in total with LAG-3 positive 
melanoma: 20 subjects in part 1 and up to approximately 80 subjects in part 2.
Study treatment in Arm 1A will be: LAG525 600 mg i.v. Q4W and spartalizumab 
400 mg i.v. Q4W.
Two interim analyses for futility will be conducted for arm1A: based on data from 20 
subjects treated in Part 1 and from 20 additional subjects treated in part 2 (i.e. 40 
subjects in total combined with part 1 subjects).
Population
Randomized section of the study: Adult (≥ 18 years) patients with unresectable or 
metastatic melanoma previously treated with anti-PD-1/PD-L1 single-agent or in 
combination with anti-CTLA-4 therapy (V600BRAF mutant patients must also have 
received prior V600BRAF inhibitor therapy, either single-agent or in combination with 
a MEK inhibitor)
Non-randomized section of the study (Arm 1A): Adult (≥ 18 years) patients with LAG-
3 positive unresectable or metastatic melanoma previously treated with anti-PD-
1/PD-L1 (as monotherapy or in combination with ipilimumab) as last therapy prior to 
enrollment (V600BRAF mutant patients must also have received prior V600BRAF
inhibitor therapy, as monotherapy or in combination with a MEK inhibitor).
Key inclusion 
criteria
Randomized section of the study 
Key inclusion criteria are listed below, please refer to the protocol for the full list of 
inclusion criteria:
!
Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV 
melanoma using AJCC edition 8 
!
Previously treated for unresectable or metastatic melanoma (refer to Section 
5.2.1 in the protocol for details)
!
ECOG performance status 0-2
!
At least one measurable lesion per RECIST v1.1
!
At least one lesion, suitable for sequential mandatory tumor biopsies 
(screening and on-treatment) in accordance with the biopsy guidelines 
specified in protocol. The same lesion must be biopsied sequentially. Note: this 
lesion cannot be used as a target lesion.
!
Screening tumor biopsy must fulfill the tissue quality criteria outlined in the 
protocol, as assessed by a local pathologist
Non-randomized section of the study 
Key inclusion criteria for arm 1A are listed below, please refer to the protocol for the 
full list of applicable inclusion criteria:
!
Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV 
melanoma according to AJCC Edition 8 
!
Previously treated for unresectable or metastatic melanoma (refer to Section 
5.2.2 in the protocol for details)
!
ECOG performance status 0-1
!
At least one measurable lesion per RECIST v1.1
!
Subjects must have baseline tumor sample (fresh tumor biopsy or recent 
archival sample, as described in the protocol) that is positive for LAG-3 per 
central assessment at the Novartis-designated laboratory (Histogenex, 
Antwerp, Belgium)
Key exclusion 
criteria
Key exclusion criteria common to all combination arms are listed below, please 
refer to the protocol for the full list of common and arm-specific exclusion criteria:
!
Subjects with uveal or mucosal melanoma
!
Presence of clinically active or unstable brain metastasis at time of screening. 
Note: Subjects with previously unstable brain lesions who have been 
definitively treated with stereotactic radiation therapy, surgery or gamma knife 
therapy are eligible:
!
Subjects with brain lesions who are untreated (i.e. newly discovered brain 
lesions during screening) or received whole brain radiation must have 
documented stable disease as assessed by two consecutive assessments 
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≥ 4 weeks apart and have not required steroids for at least ≥ 4 weeks prior 
to randomization/enrollment.
!
Use of any live vaccines against infectious diseases within 3 months before 
randomization/enrollment.
!
Subjects with a condition requiring systemic treatment with either 
corticosteroids (> 10 mg daily prednisone equivalent) or other 
immunosuppressive medications within 14 days of randomization/enrollment. 
Inhaled or topical steroids, and adrenal replacement steroid doses > 10 mg 
daily prednisone equivalent, are permitted in the absence of active 
autoimmune disease.
!
Active, known or suspected autoimmune disease or a documented history of 
autoimmune disease. Note: Subjects with vitiligo, controlled type I diabetes 
mellitus on stable insulin dose, residual autoimmune-related hypothyroidism 
only requiring hormone replacement or psoriasis not requiring systemic 
treatment or conditions not expected to recur in the absence of an external 
trigger are permitted.
!
Active infection requiring systemic therapy (i.e. antibiotics, anti-virals, high 
dose steroids, immunosuppressants, or any other systemic therapy) at the time 
of randomization/enrollment.
!
Prior allogenic bone marrow or solid organ transplant
!
History of known hypersensitivity to any of the investigational drugs used in 
this study
!
Known history or current interstitial lung disease or non-infectious pneumonitis
!
Malignant disease, other than that being treated in this study. Exceptions to 
this exclusion include the following: malignancies that were treated curatively 
and have not recurred within 2 years prior to start of study treatment; 
completely resected basal cell and squamous cell skin cancers and any 
completely resected carcinoma in situ
!
Known history of testing positive for Human Immunodeficiency Virus (HIV) 
infection 
!
Active Hepatitis B infection (HBsAg positive). Note: Subjects with antecedent 
of Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible
!
Subject with positive test for hepatitis C virus (HCV) ribonucleic acid (RNA) 
!
Prior systemic therapy for unresectable or metastatic melanoma with any 
investigational agent, or with any other agent, except anti-PD-1/PD-L1 and 
anti-CTLA-4 (and V600BRAF and MEK inhibitors if subject has V600BRAF mutant 
disease). Prior neoadjuvant and or adjuvant therapy for melanoma completed 
less than 6 months before the start of study treatment.
!
Medical history or current diagnosis of myocarditis 
!
Cardiac troponin T or I (TnI) level > 2 x ULN at screening 
Investigational and 
reference therapy
Study treatment is defined as :
!
Arm 1 and Arm 1A: LAG525 and spartalizumab 
!
Arm 2: capmatinib and spartalizumab 
!
Arm 3: canakinumab and spartalizumab 
!
Arm 4: ribociclib and spartalizumab 
Investigational drugs will be administered as follows:
!
All arms: spartalizumab will be administered as 400 mg intravenous (i.v.) 
infusion over 30 minutes (up to 2 hours, if clinically indicated) every four weeks 
(Q4W). 
!
Arm 1 and Arm 1A: LAG525 will be administered as 600 mg i.v. infusion over 
30 minutes (up to 2 hours, if clinically indicated) Q4W.
!
Arm 2: The starting dose of capmatinib will be 400 mg p.o administered on a 
twice daily (BID) dosing (total daily dose: 800 mg) orally from Day 1 till Day 28 
of each 28-day cycle.
!
Arm 3: canakinumab will be administered as 300 mg s.c. injection Q4W.
!
Arm 4: The starting dose of ribociclib will be 600 mg p.o administered once a 
day from Day 1 to Day 21 of each 28-day cycle.
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Efficacy 
assessments
Radiological tumor assessments by local RECIST v1.1
!
At screening
!
During treatment: 12 weeks (± 7 days) after the date of randomization (or after 
the date of first dose of study treatment in arm 1A), then every 8 weeks (± 7 
days) until 52 weeks after randomization/date of first dose of study treatment in 
arm 1A, and every 12 weeks (± 7 days) thereafter until disease progression per 
RECIST v1.1 (as assessed by the investigator), death, lost to follow-up or 
withdrawal of consent. 
!
End of Treatment (EOT): Only to be done if a scan was not conducted within 
30 days prior to end of study treatment.
!
Efficacy follow-up: If subject discontinued study treatment for reason other than 
disease progression per RECIST v1.1, efficacy follow-up must be continued on
the same schedule as during treatment until disease progression per RECIST 
v1.1.
Survival follow up
Every 3 months after safety/efficacy follow-up period.
Safety 
assessments
!
Physical examination
!
ECOG performance status 
!
Weight and vital signs
!
12-lead ECG
!
Laboratory assessments, including hematology, chemistry, thyroid function, 
coagulation, serology, urine and safety cytokines
!
Pregnancy testing for women of childbearing potential 
!
Adverse events (AEs): severity, relationship to study treatment and 
seriousness
!
Immunogenicity: Testing for anti-drug antibodies (ADA) for spartalizumab, 
LAG525 and canakinumab
Other 
assessments
!
Biomarker tissue samples:
!
Baseline tumor sample: Mandatory newly or recently acquired tumor 
biopsy (as defined in protocol section 7.2.3.1.1) at screening and newly 
obtained tumor biopsy at 3-4 weeks on treatment for the evaluation of 
CD8+ T cell infiltration and T cell activation, gene expression analysis 
and/or T cell repertoire/clonality. When screening for arm 1A, centralized 
LAG-3 status assessment will be performed on baseline tumor sample by 
the Novartis-designated laboratory (Histogenex, Antwerp, Belgium).
Data analysis
Interim analyses
- Randomized section of the study 
In part 1, the first interim analysis is planned for ORR once at least ten subjects 
have been randomized into each of the three initial treatment groups (arm 1, arm 2, 
arm 3), and have either completed two post-baseline tumor assessments or have 
discontinued study treatment. Subsequent interim analyses will be conducted 
approximately every five months thereafter. The first interim analysis for arm 4 
(ribociclib and spartalizumab) will be synchonized with the subsequent planned 
interim analyses for the other arms and will occur when at least ten subjects have 
been randomized to that arm and have either completed two post-baseline tumor 
assessments or have discontinued study treatment. Enrollment and assessment at 
subsequent interim analyses for each treatment group will continue until the criteria
for futility/advancement into the expansion phase have been met, or 45 subjects 
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have been randomized into a treatment group.
To determine whether treatment arms have the potential to demonstrate clinically 
meaningful response rates, arms will need to show that they cross a specific 
probability efficacy threshold P(ORR ≥20%) ≥ 70% during the selection phase to 
advance to the expansion phase. Conversely, treatment arms can also be shown to 
cross a specific futility probability threshold P(ORR ≤15%) ≥ 70% and 
consequently will be declared as futile and enrollment in those arms will be 
terminated.
No formal interim analysis is planned for part 2. 
- Non-randomized section of the study 
In part 1, the first interim analysis planned for ORR will occur once all 20 subjects 
treated in arm 1A have either completed two post-baseline tumor assessments or 
have discontinued study treatment.
In part 2, a second interim analysis will be conducted after 20 subjects are treated
in expansion phase (i.e. 40 subjects in total for arm 1A including the 20 treated in 
the selection phase) and followed up for at least two post-baseline efficacy 
assessments or have discontinued study treatment. 
At each interim analysis, it will be determined if arm 1A will be further explored or 
dropped for futility.
Primary analysis
The primary analysis in each of the randomized and non-randomized section of this 
study will be performed once an expanded arm has fully enrolled and all subjects in 
that arm have at least 9 months of follow-up . Formal hypothesis testing of the 
primary endpoint will be performed at the primary analysis taking into account data 
from both the expansion and selection phases.
Key words
Unresectable melanoma, metastatic melanoma, advanced melanoma 
spartalizumab (PDR001), LAG525, capmatinib (INC280), canakinumab (ACZ885), 
ribociclib (LEE011), immunotherapy, platform study, LAG-3
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Amendment 5 (26-Jun-2020) 
Amendment rationale 
As of the date of release of this amendment, 174 subjects have received study treatment in 
part 1 (45 in arm 1, 43 in arm 2, 42 in arm 3 and 44 in arm 4) and all arms have been declared 
futile. No arm has yet been expanded to part 2 of the study.
The main purpose of amendment 5 is to add a new non-randomized single-arm (Arm 1A) in 
this study to evaluate the efficacy and safety of spartalizumab and LAG525 combination in 
LAG-3 positive subjects with previously treated unresectable or metastatic melanoma. 
Preliminary data generated in Arm 1 support further investigation of the spartalizumab plus 
LAG525 combination in order to validate the hypothesis that this combination could be 
effective in subjects with LAG-3 positive melanoma. 
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.
Major changes are:
!
Addition of arm 1A as a non-randomized single-arm:
-
Section 2.2 is updated to add the non-randomized section of the study and 
include the rationale for adding arm 1A outside of the randomized design and 
for the selection of a higher targeted overall response rate for decision-
making in this selected arm.
-
Section 2.4.1.1 is added to provide the rationale for targeting subjects with 
LAG-3 positive melanoma in arm 1A, based on findings in arm 1 following 
interim analysis 2 (IA2).
-
Section 3 is updated to indicate that the objectives and endpoints defined 
apply for all arms.
-
Section 4.1 is updated to add the non-randomized section of the study with 
the addition of arm 1A. Section was also updated to reflect that the 
randomized and non-randomized sections of this study share the same 
objectives for part 1 and part 2. Section 4.1.1 header is created to 
individualize the design for the randomized section of the study from the 
description for the design of the non-randomized section that has been added 
in the newly created Section 4.1.2. The title of Figure 4-1 and text in Section 
4.1.1 are updated to clearly indicate that they apply for the randomized 
section of the study. A new Figure 4-2 is added to provide an overview of 
the study design for the non-randomized section.
-
Section 4.1.3 header is created to individualize the paragraph describing 
subject-level study design and indicate that it will be shared by the 
randomized and non-randomized sections of the study. Regardless of the 
study section and part they are randomized/enrolled into, each subject will 
undergo the same study periods described in the section and will have 
assessments performed as described in Table 7-2. 
-
The text in Section 4.1.3 for the treatment period and the former Figure 4-2 
describing subject level study design (re-numbered Figure 4-3), as well as 
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text in Section 6.1.1, Section 7.1, Table 7-1, Table 7-2, Section 10, are 
updated to reflect “randomization/enrollment” or “randomized/enrolled”
where statements are applicable for subjects randomized and subjects 
enrolled in arm 1A. 
-
A statement is added in Section 4.1.3, Section 7.1, Table 7-2, Table 7-3, and 
Section 7.2.1.2 to indicate that the schedule of RECIST v1.1 tumor 
assessments in arm 1A should be calculated taking the date of first dose of 
study treatment as reference (as this arm is not randomized), whereas the 
reference for this calculation in randomized arms is the date of randomization.
Section 7.2.1.1 is also updated to indicate that imaging assessments obtained 
after date of first dose of study treatment cannot be considered as baseline 
images.
-
Section 4.2.1 header is created to individualize the paragraph on timing of 
interim analyses and design adaptations in the randomized section of the 
study. Former Figure 4-3 is re-numbered Figure 4-4 (no update in the figure).
Section 4.2.2 is created to describe the independent timing of interim 
analyses and design adaptations in the non-randomized section of the study.
-
Section 4.3 is updated to indicate that each section of the study (randomized 
and non-randomized) will have a different timing for the completion of the 
primary analysis. Indeed, primary analysis will occur once all subjects 
randomized/enrolled in an arm expanded in part 2 (whether in the 
randomized or non-randomized section) will have at least 9 months of 
follow-up. This will not occur at the same time for each arm expanded in part 
2 across the two sections of the study.
-
Section 5.2.1 header is created to individualize the inclusion criteria 
applicable for the arms assessed in the randomized section of the study (arms 
1,2, 3, 4)
-
Section 5.2.2 is created to describe all the inclusion criteria that subject must 
meet to be eligible for arm 1A. Some of the inclusion criteria for arm 1A are 
the same as for other arms (those criteria have the same criterion number in 
Section 5.2.1 and Section 5.2.2; Note that inclusion criterion #8a is not 
applicable for arm 1A, which leads to a gap in criteria numbering). The below 
inclusion criteria differ for arm 1A compared to other arms:

Inclusion criterion #4b is adding new requirements for prior anti-
cancer therapies received and prior disease progression compared to 
inclusion criterion #4a: all subjects must have received an anti-PD-1
pembrolizumab or nivolumab) either as monotherapy
or in 
combination with ipilimumab as the last systemic therapy prior to 
enrollment and must have confirmed disease progression as per 
RECIST v1.1 (confirmed on a subsequent scan, which can be the scan 
performed during screening) while on or after this therapy prior to 
enrollment. Those new requirements are added to better assess the 
efficacy of the combination partner of spartalizumab over anti-PD1 
alone and to have a more homogeneous patient population. The 
criteria for confirmed progression is being implemented to ensure 
that progression to prior PD-1 therapy was not a pseudo-progression.
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
Inclusion criterion #5a is changing the requirement on ECOG 
performance status, that must be 0 or 1 for subject to be eligible to 
arm 1A. This change is intended to exclude patients with worst
performance status that in most cases would not even reach the first 
and second post-baseline tumor assessments (approximatively 6% of 
the patients enrolled in the study so far had ECOG performance status 
of 2).

Inclusion criterion #7b is adding a new requirement for subjects to
have a baseline tumor sample (either newly collected during 
screening, or archival sample meeting requirements defined in 
Section 7.2.3.1.1) that is LAG-3 positive per central assessment at the
Novartis-designated laboratory (Histogenex, Antwerp, Belgium). 
This new requirement allows selection of a population of subjects
with LAG-3 positive melanoma who may derive a higher clinical 
benefit from treatment with LAG525 and spartalizumab combination 
based on IA2 findings in arm 1. 
-
Exclusion criteria #2a, #3 and #6a in Section 5.3.1 (listing exclusion criteria 
common to all arms) have minor updates to indicate that the criteria apply 
prior to randomization/enrollment.
-
Section 6.1, Table 6-1 and Table 7-2 are updated to include the study 
treatment regimen received by subjects enrolled into arm 1 A (LAG525 600 
mg Q4W i.v. and spartalizumab 400 mg Q4W i.v.), which is the same as for 
arm 1.
-
Section 6.5.2 is updated to indicate which paragraphs are applicable for the 
randomized section of the study and add reference to Section 4.1.1. A 
statement is also added for the non-randomized section of the study to 
indicate that assignment to arm 1A in IRT (in part 1 or part 2) will be 
systematic in IRT as long as subject fulfills the inclusion/exclusion criteria 
applicable for arm 1A, given the absence of randomization. 
-
Section 7.1.2.3 is updated to reflect that randomization stratification on LDH 
value applies only in the randomized section of the study.
-
Section 7.2.2.5 is updated to indicate that the requirements for subject to be 
fasting for at least 12 hours overnight before each blood collection to obtain 
fasting glucose and for investigators to monitor the potential occurrence of 
auto-immune diabetes for arm 1 also apply for arm 1A, as both arms share 
the same study drugs.
-
Section 7.2.2.5.1, Table 7-2 and Table 7-5 are updated to indicate that the 
requirement for cardiac troponin T (or I) monitoring for arm 1 also apply for 
arm 1A, as both arms share the same study drugs.
-
Table 7-2 and Table 7-6 are updated to indicate that the schedule of ECGs 
for subjects treated in arm 1A will be the same as the schedule for arm 1, as 
both arms share the same study drugs.
-
Table 7-2 and Table 7-8 are updated to indicate that the schedule for 
collection 
of
blood 
samples 
for 
immunogenicity analyses for arm 1A is the same as 
the schedule for arm 1 as both arms share the same study drugs.
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-
Table 7-1, Table 7-2, Section 7.1.2 and Table 7-12 are updated to indicate 
that, when screening for arm 1A, the study informed consent can be signed 
up to 35 days prior to planned enrollment date to allow prompt collection of 
the newly or recently obtained baseline tumor sample after consent is given 
(screening period for arm 1A extended accordingly to up to 35 days in Table 
7-2). As eligibility to arm 1A is dependent upon LAG-3 status assessed 
centrally, sites are requested to submit the baseline tumor sample to the 
Novartis-designated laboratory (Histogenex, Antwerp, Belgium) as early as 
possible and at the latest 20 days prior to planned enrollment date to allow 
sufficient time for central assessment and reporting of LAG-3 status in a 
timely manner. All other screening assessments for arm 1A have to be 
performed according to the timelines applicable for all other arms as 
mentioned in Table 7-1. It is recommended to wait to receive the result of 
LAG-3 status to perform further screening assessments.
-
Centralized assessment of LAG-3 status on mandatory baseline tumor 
sample is added in Table 7-2 and Section 7.2.3.1 as a screening assessment 
specifically for arm 1A and described within the newly created Section 
7.2.3.1.2. As added in Section 7.1.2 and Section 7.2.3.1.2, a subject whose 
baseline tumor biopsy tissue sample does not allow central assessment of 
LAG-3 will be considered a screen failure, unless a new baseline tumor 
sample is submitted and assessed for LAG-3 before the end of the screening 
period. Sample must be reported as LAG-3 positive for subject to be eligible 
to arm 1A. Other biomarkers described in Section 7.2.3.1 will be analyzed 
only if subject is enrolled.
-
Wording on description of biomarker analyses on tumor samples which was 
included in Section 7.2.3, Section 7.2.3.1.1, Section 7.2.3.1.3 and Section 
7.2.3.1.4 has been condensed and moved to Section 7.2.3.1 to avoid 
redundant information across different sections as the randomized and non-
randomized sections of the study share the same secondary 
 
biomarker objectives for all mandatory, optional or archival tumor tissue 
samples. A statement has also been added that tumor samples, including from 
screen failed patients, may be also used to generate data to support 
development of future companion diagnostic tests.
-
Section 7.2.3.1.1 and Table 7-12 are updated to indicate the specific 
requirements for mandatory baseline tumor sample for LAG-3 testing for 
arm 1A which are different than all other arms. Biopsy guidelines for the 
collection of a fresh tumor biopsy (at screening and on treatment) are the 
same for arm 1A as in the other arms, but are not a requirement for eligibility 
to arm 1A. Similarly, the tissue quality criteria described in Table 7-13 are 
only recommendations, but not a requirement for eligibility for arm 1A. 
These requirements allow the enrollment of a subject in arm 1A as long as 
the baseline tumor sample is reported LAG-3 positive (and provided all other 
eligibility criteria for arm 1A are met), even if the sample does not meet 
tissue quality criteria in Table 7-13. Local pathology review of the tissue 
quality criteria defined in Table 7-13 on baseline tumor sample prior to 
enrollment is not required when screening for arm 1A, as the assessment will 
be done centrally as part of LAG-3 testing. Submission of a formalin-fixed 
tissue in ethanol as baseline tumor sample would only be acceptable when 
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screening for arm 1A, although submission of FFPE tumor block remains the 
preferred option.
-
Updated Section 8.6 to indicate that the DMC will review safety data from 
any arm expanded in part 2, whether in the randomized or non-randomized 
section of the study.
-
Section 10 : Introduction paragraph is updated to clarify that Section 10 and 
all sub-sections refer by default to the randomized section of the study and 
the same will apply to the non-randomized section of the study (where only 
arm 1A will be analyzed), unless specified otherwise. It has been added that 
the date of first dose of study treatment will be used as reference date for 
non-randomized section. Sections 10.4.2.1, 10.7.1, 10.8.1 headers were 
created to individualize paragraphs applicable for the randomized section of 
the study from the newly added paragraphs specific to the non-randomized 
section of the study (added in Sections 10.4.2.2, 10.7.2 and 10.8.2). Section 
10.4.4 is updated to indicate that sub-group efficacy analyses on LDH starta 
applies only for arms in the randomized section of the study. Tables 
numbering have been updated accordingly due to addition of the non-
randomized section details.
The other main changes done, not specific to the addition of arm 1A, are the following:
!
Addition of the outcome of IA2 and IA3 and specified the outcome for each study 
treatment arm in Section 4.1.1. 
!
Clarification on interim analyses performed in part 1 in the randomized section of 
the study: Section 4.2.1 and Section 10.7.1. are updated to clarify that interim 
analyses in part 1 of the randomized section of study will continue to be performed 
at the pre-defined frequency until a clinical decision (e.g. arm declared futile or 
efficacy probabilistic thresholds crossed) is made for each arm in part 1. 
Combination arms, even if declared futile, will be analyzed at subsequent interim 
analyses until all subjects have been reported at least once (i.e. had a minimum 
follow-up of 20 weeks). Additional descriptive analyses may be performed if 
required. This update will allow Novartis to report data for all subjects at least once 
(after they have reached a minimum of 20 weeks of follow-up) if needed for 
publication purpose before the primary or final analysis.
!
Removed statement in Section 4.3 that results of primary analysis will be 
summarized in a primary CSR: Generation of a primary CSR is not a regulatory 
requirement, therefore Novartis may not generate a primary CSR for each primary 
analysis performed, in the case where several primary analyses are done if arm(s) 
are expanded in both the randomized and non-randomized section of the study.
!
Allow end of study to be declared in case no arms are expanded in part 2 (in either 
randomized or non-randomized section of the study): Section 4.3 is updated to 
indicate that the end of study can be declared once all subjects randomized/enrolled 
have at least 15 months of follow-up (i.e. 15 months after last subject is 
randomized/enrolled, regardless of the study section/part). Indeed, the completion of 
the primary analysis in each study section is conditioned on the expansion of at least 
one combination arm in part 2. This update in the definition of end of study would 
allow declaring the end of study and completion of the final analysis and generation 
of the final CSR, with a sufficient follow-up for all subjects randomized/enrolled.
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Section 4.3 is also updated to remove the statement that all available data from all 
subjects up to this cut-off date will be analyzed and summarized in a final CSR.
!
Revision of some exclusion criteria that are common to all arms in Section 5.3.1 :
-
Exclusion criterion #4 (re-numbered #4a) is revised to exclude subjects with 
a condition requiring systemic treatment with either corticosteroids (> 10 mg 
daily prednisone equivalent) or other immunosuppressive medications 
within 14 days (instead of 7 days) of randomization/enrollment. Inhaled or 
topical steroids, and adrenal replacement steroid doses > 10 mg daily 
prednisone equivalent, are permitted in the absence of active autoimmune 
disease. This change is done to allow subjects with adrenal replacement 
steroids to be enrolled in the study as they require steroid doses > 10mg in 
case of stress condition (including but not limited to minor dental surgeries,
fever). 
-
Exclusion criterion #6 (re-numbered #6a) is revised to exclude subjects with 
any active infection (bacterial, viral or of any other type) that would require 
systemic therapy (including, but not limited to, antibiotics, anti-virals, high 
dose steroids, immunosuppressants). This change ensures that subjects with 
any type of active infection (including coronavirus infection) requiring 
systemic therapy are excluded from enrollment to ensure subject’s safety.
-
Exclusion criterion #12 (re-numbered #12a) is revised to correct that active 
hepatitis B infection is defined based on HBsAg positivity only and not based 
on positive testing for HBV-DNA. 
-
Exclusion criterion #15 (re-numbered #15a) is revised to clarify that a 
woman should have had bilateral tubal ligation (at least six weeks before 
taking study treatment) to be considered not of child bearing potential.
-
Exclusion criterion #17a is updated to remove the list of examples of prior 
neoadjuvant and/or adjuvant therapy for melanoma, as the list is not 
exhaustive (minor update). Any prior neoadjuvant and/or adjuvant therapy 
for melanoma completed less than 6 months before the start of study 
treatment makes the subject ineligible for the study.
!
Revision of the threshold AST/ALT values for potential drug-induced liver injury 
(DILI) cases and guidance on investigations which can be performed to rule out other 
causes for liver injury in Section 6.3.3.1 (applicable for all arms) to align with current 
best clinical practices and publications: for subjects with elevated AST or ALT or 
total bilirubin at baseline, [AST or ALT > 3.0 × baseline] OR [AST or ALT > 8.0 × 
ULN], whichever is lower, combined with [total bilirubin > 2.0 × baseline AND > 
2.0 × ULN] will require further investigations to exclude any other cause before 
DILI is assumed as the cause of liver injury. Investigations have been detailed in 
Section 6.3.3.1 and a new Table 6-38 is added to provide guidance on specific 
clinical and diagnostic assessments which can be performed to rule out possible 
alternative causes of observed liver abnormalities. All cases confirmed on repeat 
testing meeting the laboratory criteria defined for potential DILI, with no other 
alternative cause for liver test abnormalities identified should be reported as SAE 
using the term “potential treatment-induced liver injury”.
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!
Clarified in Table 7-2, Table 7-12 and Section 7.2.3.1.3 that the provision of an 
archival tumor sample collected prior to the start of any prior anti-PD-1/PD-L1 
mono- or combination therapy is mandatory if such sample is available.
!
Amended tissue quality criteria to indicate that mandatory tumor samples submitted 
should not contain abundant melanin pigmentation, in the footnote of Table 7-13, 
which was a leading cause for tumor samples not being evaluable for LAG-3 and 
other biomarker analyses.
!
Emphasized in Section 8.3 that a female participant becoming pregnant must 
discontinue study treatment and must be proposed the pregnancy consent form to 
allow the investigator to collect and report information regarding the pregnancy if 
consent given. Section 8.3 is also updated to specify that female subjects providing 
consent for pregnancy follow-up will be contacted one month after the estimated 
date of delivery, and 3 and 12 months after the estimated date of delivery for live 
births only. This aligns with information provided in the current pregnancy follow-
up consent form for pregnant participants and pregnant partners of male participants.
!
Population of analysis used for the calculation of the proportion of subjects with a 
favorable biomarker profile (pFBP) has been slightly modified in Section 10.5.5.1 
to include the evaluability on at least two of the biomarker parameters used to define 
a favorable biomarker profile. 
!
BOR definition for stable disease in Section 14.2.3.1 of the RECIST guidelines in 
Appendix 2 has been corrected to reflect the study protocol tumor assessment 
schedule. At time of this protocol amendment, there was no impact on previous 
analyses done since no tumor assessment had been performed between 6 and 11 
weeks that qualified for a BOR stable disease.
The following editorial changes have also been made:
!
New abbreviations added in the list of abbreviations
!
List of abbreviations and Section 1.2.2.1 updated to reflect the new definition for ICH, 
International Council for Harmonization.
!
Glossary of terms updated to indicate that for non-randomized arm 1A, enrollment 
defines the point/time when consented subject is deemed eligible for treatment in this 
arm.
!
Protocol summary updated to align with the changes described above which are 
impacting protocol summary. Details on prior therapies to be received for subjects to be 
eligible to randomized arms have been removed from the section on key inclusion 
criteria and replaced by a reference to the corresponding protocol section, as 
requirements differ in randomized and non-randomized arms. Wording for primary 
analysis was also corrected in the protocol summary as it was not reflecting accurately 
the timing of primary analysis as described in Section 4.3.
!
Section numbers are updated across the document to refer to the adequate sub-paragraph 
for randomized or non-randomized section of the study. Figure and Table numbers are 
updated across the document to account for the new figures and tables added.
!
Clarified in Section 7.2.1. that central imaging is performed by an independent reviewer.
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!
The term “newly obtained tumor biopsy” is replaced across the document with
“mandatory newly or recently obtained tumor biopsy” to account for the fact that the 
mandatory baseline sample to be provided at screening for all arms can be a fresh biopsy 
collected during screening or a recently collected tumor sample (as stated in Section 
7.2.3.1.1)
!
Corrected “Formalin-fixed block in ethanol” to “Formalin-fixed tissue in ethanol” in 
Table 7-12 as the tissue is fixed, not the block.
!
Updated Section 9.4 to clarify that dates of screenings, randomizations/enrollments, 
screen failures and study treatment completion are also tracked using the IRT system, as 
this was omitted by error in this paragraph.
!
Included the list of informed consents available for this study in Section 11.3. A separate 
main study consent will be used for arm 1A.
!
Instructions in italic within the RECIST v1.1 guidelines in Appendix 2 (Section 14.2) 
have been removed, as those are instructions for Novartis teams when developing the 
protocol which were left in the appendix by error.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 4 (24-Jan-2020) 
Amendment rationale 
As of the date of release of this amendment, 168 subjects have received study treatment in 
part 1 (45 in arm 1, 43 in arm 2, 42 in arm 3 and 38 in arm 4) and enrollment is still ongoing 
in arm 4 in part 1 (part 2 of the study is not yet open).
The main purpose of amendment 4 is to amend ribociclib’s dose modification guidelines for 
interstitial lung disease (ILD)/pneumonitis and Toxic Epidermal Necrolysis (TEN), 
following the observation of rare cases of ILD/pneumonitis in subjects receiving CDK4/6 
inhibitors, and the reporting of TEN in the post-marketing setting in a well-documented 
literature case report (no case observed in the clinical trials). Therefore, this protocol 
amendment is implementing mandatory dose modification guidelines for investigators to 
interrupt ribociclib in case of ILD/pneumonitis grade 2 and to permanently discontinue
ribociclib in case of ILD/pneumonitis of grade ≥ 3, and to discontinue ribociclib if TEN is 
diagnosed. Please refer to ribociclib (LEE011) Investigator Brochure Edition 14 for more 
information.
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.
Major changes are:
!
Section 4.1 and protocol summary: Information has been added that enrollment in Part 
1 is closed in the three initials arms (arms 1, 2 and 3) of the study. 
!
Section 4.2 and Section 10.7: Clarification has been added to indicate that combination 
arms will no longer be included in subsequent interim analyses after all subjects 
randomized in this arm had primary endpoint already reported in a previous interim 
analysis.
!
Four exclusion criteria have been revised. Based on the current enrollment status in Arm 
4 (i.e. 38 subjects randomized in Part 1 as of the date of release of this amendment), the 
changes in those exclusion criteria are not expected to affect the study population in Part 
1:
!
Section 5.3.1 and protocol summary: Exclusion criterion #5 (re-numbered #5a) 
has been clarified to indicate that subjects with autoimmune conditions that are 
not expected to recur in the absence of an external trigger may be eligible. 
!
Section 5.3.3: Exclusion criterion #28 (re-numbered #28a) has been corrected to 
remove the requirement to use central interpretation of triplicate ECGs at 
baseline, to align with section 7.2.2.6 stating that eligibility should be assessed 
by the investigator based on local interpretation of screening ECGs. It has also 
been clarified that the QTcF interval value (QT interval using Fridericia’s 
correction) should be used at screening.
!
Section 5.3.3: Exclusion criterion #30 (re-numbered #30a) was revised to add 
uncorrected hypocalcemia as a risk factor for Torsades de Pointe and exclude 
subjects with such condition from receiving treatment with ribociclib, as low 
calcium levels can cause QT prolongation. 
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!
Section 5.3.3: Requirements on sodium and phosphorus values at screening were 
removed from exclusion criterion #33 (re-numbered #33a) as abnormal sodium 
or phosphorus levels have no impact on QT prolongation.
!
Section 6.1.1.5: Recommendations were added for investigators on dosing of ribociclib 
if a visit has to be delayed within the allowed visit window. It has also been clarified 
that shortening the rest period to less than 7 days is not recommended.
!
Section 6.3.1.3.2 and Section 6.3.1.4: Additional mandatory dose modification guideline 
has been added in Table 6-23 for the permanent discontinuation of capmatinib in the 
event of myocarditis of any grade or other cardiac events Grade ≥ 3 following the release 
of the INC280 Investigator Brochure Edition 11 describing a case of myocarditis 
observed in a subject treated with capmatinib and spartalizumab in PDR001J2201 study. 
A reference to Table 14-17 was also added within Table 6-12 (dose modifications for 
spartalizumab and LAG525) and Table 6-23 to refer investigators to recommended 
management guidelines for such cardiac events.
!
Section 6.3.1.6: Mandatory dose modifications were added in Table 6-37 in case of 
interstitial lung disease/pneumonitis event for investigators to interrupt ribociclib for 
grade 2 events, or permanently discontinue ribociclib for grade ≥3 events following 
FDA recommendation for CDK4/6 inhibitors. Table 6-37 is also updated to clearly 
indicate that ribociclib must be permanently discontinued if Toxic Epidermal Necrolysis 
(TEN) is diagnosed.
!
Section 6.4.2.2 and Section 6.4.3: Paragraphs regarding corticosteroids have been
updated in order to allow for treatment of immune-related adverse events or in presence 
of stress conditions in patients with adrenal insufficiency higher doses of corticosteroids 
to be given for limited time as clinically necessary. A reference to Section 6.4.2.2 was 
also added in Section 6.4.3 paragraph on corticosteroids to ensure the investigator takes 
into account the specific restrictions on corticosteroids use during treatment with 
ribociclib in arm 4.
!
Section 6.4.2.2 and Section 13: The list of medications to be used with caution during 
ribociclib treatment in Table 6-39 was updated with latest information available. The 
publication added in the footnote of Table 6-39 was added in the list of references in 
Section 13.
!
Section 6.4.3: Apalutamide was added in the list of strong CYP3A4/5 inducers 
prohibited for use during ribociclib treatment in arm 4 in Table 6-42. This table was also 
updated to clarify that not only herbal preparations/medications but also dietary 
supplements known as strong inducers or inhibitors of CYP3A4/5 or with a known risk 
of QT prolongation are prohibited in arm 4.
The following editorial changes have also been made:
!
Interstitial lung disease (ILD) was added in the list of abbreviations
!
Section 6.3.1.6: The term “bi-weekly” in Table 6-35 was changed to “every 2 weeks” to 
avoid confusion and clarify that liver function tests should be monitored every 2 weeks 
(and not twice a week) in case of low-grade abnormalities in liver parameters.
!
Section 6.6.4: It was clarified that destruction of study drugs at site is possible if allowed 
per local regulations and local Sponsor procedures and agreements.
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!
Section 7.1: Table 7-1 was revised to align the timing and allowed window for EOT visit 
assessments with Section 4.1, as clarification was previously provided that EOT visit 
should be scheduled within 7 days after the discontinuation of the last study drug (i.e. 
within 7 days after the last dose of the last study drug or after the date when decision 
was made to permanently discontinue both study drugs/the last study drug). 
!
Section 7.1.7 and Table 7-1 were revised to provide guidance to sites for the timing of 
30-day safety follow-up visit in cases where the last dose of study drug was more than 
30 days ago when the decision is taken to discontinue study treatment.
!
Section 7.2.2.7.1: Table 7-11 was corrected to remove the second dose reference ID for
C1D1 visit, which is not applicable for this visit.
!
Correction of typographical errors across the document.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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Amendment 3 (29-Apr-2019)
Amendment rationale 
As of the date of release of this amendment, 92 subjects have received study treatment in 
this study in part 1 (part 2 not yet open).
Amendment 3 is required in order to add a new combination arm for evaluation in this study 
(arm 4: ribociclib in combination with spartalizumab). D-cyclin-CDK4/6-p16-pRb pathway 
is often up-regulated in melanoma. Given the magnitude of immune modulatory effects 
observed from CDK4/6 inhibitors, the combination of CDK4/6 inhibitors with check point 
inhibitors such as anti PD-1/PD-L1 may help to overcome resistance to anti PD-1/PD-L1.
The full rationale for addition of this new arm is provided in Section 2.4.4. 
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. 
Major changes are:
!
Addition of arm 4 (ribociclib + spartalizumab) in this study:
-
Added Section 1.2.5 providing non-clinical data, clinical data 
 
 available to date on ribociclib given in combination with 
other agents.
-
Added Section 2.3.4 with rationale for dose and regimen selection for this new 
combination.
-
Added Section 2.4.4 with scientific rationale for choice of this new combination.
-
Added Section 2.6.4 with risks and benefits for this new combination.
-
Updated Section 4.1 and Figure 4-1 to add arm 4 and reflect the revised sample 
size in Part 1 following the addition of this new combination arm.
-
Updated Section 4.2 to reflect changes in the timing of interim analyses with the 
addition of arm 4.
-
Added Section 5.3.3 with exclusion criteria specific to arm 4 to ensure subjects 
randomized in arm 4 do not have any contraindication to receive treatment with 
ribociclib.
-
Updated Section 6.1 and Table 6-1 to add the dose and regimen for ribociclib and 
spartalizumab in arm 4. Table 7-2 was also updated to indicate the starting dose 
and regimen for ribociclib administration in arm 4.
-
Added Section 6.1.1.5 with instructions to be provided to subjects randomized in 
arm 4 for oral intake of ribociclib during the study.
-
Updated Section 6.2 to indicate that dose re-escalation for ribociclib is not allowed.
-
Updated Section 6.3.1 to add ribociclib in the text and updated Table 6-2 to add 
quick reference to tables providing mandatory dose modifications for ribociclib in 
case of event suspected to be related to ribociclib. 
-
Updated Section 6.3.1.1 and added Table 6-4 to indicate that dose reductions are 
allowed for ribociclib in case of adverse events and provide the dose levels for 
ribociclib allowed in the study and the dose reduction steps to be followed. 
-
Updated Section 6.3.1.2 to add the maximum length of time allowed for ribociclib 
interruption.
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-
Added Section 6.3.1.6 and Table 6-34 to 6-37 to provide mandatory dose 
modifications to be followed for ribociclib in case of adverse events suspected to 
be related to ribociclib.
-
Updated Section 6.3.3, Section 6.4, Section 7.1.7, Section 8.1.1 and Section 8.1.2 
to indicate that AEs/SAEs must be followed and concomitant medications must be 
collected in eCRF up to 30 days after the last dose of ribociclib (in the case where 
this timepoint is later than 150 days after the last spartalizumab dose).
-
Added Section 6.4.2.2 with concomitant medications to be used with caution 
during treatment with ribociclib of subjects randomized in arm 4 (including the 
addition of Table 6-39 providing a non-exhaustive list of those medications) and 
updated Section 6.4.3 to add prohibited concomitant medications for ribociclib 
(including the addition of Table 6-42 providing a non-exhaustive list of those 
medications).
-
Updated Section 6.6 with information for ribociclib
-
Revised Table 7-2 and Table 7-6 to add schedule of ECG assessments specific to 
arm 4.
 
 
 
-
Updated chemistry laboratory parameters in Table 7-5 to add GGT in the 
parameters to be tested, as well as calcium corrected on serum albumin required at 
screening for all subjects (and then as clinically indicated), and indicate that fasting 
glucose must be obtained for subjects randomized in arm 4.
-
Revised Section 10.3 to add ribociclib to the treatment calculation section
-
Updated Section 10.4.2 and Table 10-3 to reflect new alpha calculations taking into 
account the addition of the ribociclib arm as well as the number of patients to be 
analyzed in the first interim analysis
-
Revised Section 10.5.3.2 to include ribociclib to investigational drugs that will 
have an AESI list
 
-
Updated Section 10.7 to capture the timing of the first interim analysis for the 
ribociclib and spartalizumab combination arm and specify that the 3 initial 
treatment groups mentioned refer to arm 1, arm 2 and arm 3.
-
Updated Section 10.8 and Table 10-7 to capture the inclusion of the ribociclib and 
spartalizumab arm, the actual randomization of patients in the first interim analysis 
of the first three arms tested in this trial, and the number of patients to be 
randomized before the first interim analysis of the new combination arm 
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-
Section 13: Added references to new publications cited in the rationale sections 
added for ribociclib.
!
Inclusion criterion #4 (Section 5.2, re-numbered #4a) and exclusion criterion #17 
(Section 5.3.1, re-numbered #17a) have been revised in order to further ensure the 
enrollment of an homogenous study population and provide clarification to investigators 
on the requirements regarding prior therapies received in the metastatic setting and prior 
disease progression before study entry.
!
Section 5.2: Inclusion criterion #9 (re-numbered #9a) has been updated to clarify that 
growth factors and/or transfusion support should not be administered within 14 days 
prior to screening blood draw.
!
Section 5.3.1: Exclusion criterion #2 (re-numbered #2a) wording has been clarified, to 
clearly state that subjects with active/unstable brain metastases at time of screening are 
not eligible.
!
Section 5.3.1: Exclusion criterion #19 (re-numbered #19a) has been updated to allow 
enrollment of subjects based on cardiac Troponin I testing (considered as more sensitive 
than Troponin T in some countries). Table 7-2 and Section 7.2.2.5.1 were updated 
accordingly and Table 7-5 has also been updated to indicate that Troponin I local testing 
is acceptable though central Troponin T testing is recommended.
!
Updated Section 6.1.1.4 to provide additional instructions on canakinumab intravenous 
administration and sites of injection. 
!
Implementation of the most recent version for CTCAE grading guidelines (CTCAE 
v5.0) to ensure adequate grading of adverse events and comparability of safety profiles 
with future studies:
-
Section 1.2 and Section 2.6: Added a statement to clarify that adverse events (AEs) 
described in those sections for each study drug are described using CTCAE v4.03 
grading, unless otherwise specified.
-
Section 5.2: Inclusion criterion #10 (re-numbered #10a) has been updated for 
treatment-related toxicities of prior anticancer therapies to be assessed using CTCAE 
v5.0 instead of v4.03.
-
Section 5.3.2: Exclusion criterion #27 (re-numbered #27a) has been updated to add 
the grading system to be used (CTCAE v5.0) for serum amylase.
-
Section 6.1.2: updated to specify that adverse events mentioned should be graded as 
per CTCAE v5.0.
-
Section 6.3.1 and Section 14.3 (Appendix 3): Tables 6-5 to 6-33 and Tables 14-10 
to 14-17 have been updated to indicate that the grading system to be used is CTCAE 
v5.0. Definitions for each grade have been aligned with the definitions from CTCAE 
v5.0 for events for which definition was revised in CTCAE v5.0 compared to v4.03, 
i.e. creatinine alterations, abnormal liver tests (hepatic adverse events), amylase and 
lipase elevations, QTc prolongation.
-
Section 8.1.1 and Section 10.5.3 : Updated CTCAE version to be used for grading 
of adverse events in the study to CTCAE v5.0.
!
Section 7.1.2: Added a statement that re-screened subjects are exempted to re-sign the 
optional pharmocogenetics ICF.
!
Table 7-13: Added language to clarify that instructions for performing mandatory 
biopsies (e.g. size specifications, needle type, etc.) were intended as guidelines rather 
than strict requirements. Specifically the requirement for minimum total tissue volume 
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for mandatory newly collected tumor samples was removed, as the remaining guidelines 
are sufficient and tissue volume may be challenging to estimate for local pathologists.
!
Section 7.2.3.1.1: 
-
Added language to clarify the intent of the requirements and tissue quality criteria 
for mandatory biopsy collection. Specifically, it was clarified that for samples with 
>60% tumor content, total tissue area may be < 30 mm2 but must be ≥15 mm2 to 
expand the tissue quality criteria in Table 7-13.
-
Added a statement to allow mandatory screening biopsy requirement fulfillment 
from subjects who are re-screened or who recently had a biopsy as part of standard 
of care (including prior to signing of main study ICF).
!
Section 8.7: Updated to implement a steering committee on the study. 
!
Section 14.3 (Appendix 3): Recommended management guidelines have been updated 
to align with published guidelines for the management of immune-related adverse events
(Brahmer et al 2018) in case of occurrence of grade 2 immune-related liver abnormality 
results (Table 14-11), grade 3 or 4 immune-related pneumonitis (Table 14-14), immune-
related symptomatic endocrinopathies and autoimmune diabetes grade 3 or 4 (Table 14-
15) and infusion reaction or cytokine release syndrome of any grade (Table 14-16) 
suspected related to spartalizumab and/or LAG525. 
The following editorial changes have also been made:
!
Updated the protocol summary to reflect changes done in this protocol amendment
!
Updated the list of abbreviations with new abbreviations added or missing abbreviations
and removed abbreviations not used in the document
!
Updated numbering of tables included in Section 6 and Section 7 of the protocol to 
reflect the addition of new tables in those sections relating to the addition of arm 4.
!
Section 4.1 and Table 7-1: Updated to clarify that first dose of study treatment must be 
initiated within 3 days maximum after date of randomization. 
!
Section 4.1 and Section 7.1.5: Clarified that EOT visit should be scheduled within 7 days 
after last dose of last study drug or after the date when the decision was made to 
permanently discontinue both study drugs/the last study drug.
!
Section 5.2: Clarified the protocol subsection for investigator reference (Section 
7.2.3.1.1) in inclusion criteria #7 (re-numbered #7a) and #8 (re-numbered #8a).
!
Section 6.3.1.1: Clarification was added that the BID dosing schedule applies only for 
capmatinib. Table 6-3 has also been updated to clearly indicate the number of tablets 
and dosage of tablets to be taken twice in a day for each dose level of capmatinib.
!
Table 7-2 : An “X” was added in the row for “Disposition form”, which is also to be 
completed in eCRF in case of screen failure. The name of this form has been aligned 
with final name in eCRF. 
!
Section 7.2.2.1 and Section 7.2.2.6: Corrected that significant physical examination 
findings meeting the definition of AE, and new or worsened clinically significant 
findings on ECG, occurring after informed consent signature (and not after first dose of 
study treatment) must be recorded in the eCRF as AE.
!
Section 7.2.2.5: Clarified the minimal fasting time and conditions to obtain fasting 
glucose at screening for all patients and for patients randomized in arm 1 and in arm 4.
!
Table 7-7 and Table 7-8: Minor correction in dose reference ID programmed in the 
database from cycle 9 to avoid overlapping numbers.
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!
Section 7.2.3.1.1: Clarified that the tumor sample collected for mandatory on-treatment 
biopsy should be taken from the same anatomical location biopsied at screening, where 
medically feasible. 
!
Section 7.2.3.1.3: Added that, wherever possible, the guidelines and tissue quality 
criteria in Table 7-13 should be followed for optional biopsies. 
!
Throughout protocol, changed references from SAP Appendix to SAP Technical
Appendix
!
Section 10.4.2: Clarified assumption for number of patients enrolled in the selection 
phase
!
Section 10.7: Clarified the timing of the 1st primary analysis
!
Section 10.8: Clarified why the shrinkage estimator may be conservative and clarified 
the observed ORR from the other selection phase arms will be used in the calculation of 
the sample size in the expansion phase
!
Section 10.8: Updated the timing of subsequent interim analyses in the selection phase, 
and the timing of the 1st primary ORR analysis after completion of expansion phase 
enrollment
!
Correction of typographical errors and addition of the meaning of some abbreviations in 
the text across the document
IRBs/IECs/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
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Amendment 2 (06-Feb-2019) 
Amendment rationale 
As of the date of release of this amendment, 55 subjects have received study treatment in 
this study.
Amendment 2 is required to implement feedback from the French HA (Agence Nationale 
de Sécurité du Medicament, ANSM) after their review of protocol amendment 1. Rare cases 
of myocarditis and fatal heart failure have been reported in patients treated with checkpoint 
inhibitors alone and in combination (Varricchi et al 2017). As incidence of myocarditis is 
higher in immune checkpoint inhibitors combination trials, protocol amendment 2 is 
implementing precautionary on-treatment monitoring measures to optimize the detection of 
possible autoimmune myocarditis events in arm 1 combining spartalizumab and LAG525. 
Guidelines for the management of myocarditis events (of any grade) have also been revised.
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. 
Major changes are:
!
Section 6.3.1.3.2 (Table 6-11) and section 14.3 (Table 14-17 in Appendix 3): Table 6-
11 was updated to mandate the permanent discontinuation of spartalizumab (in all 
arms) and LAG525 (in Arm 1) if myocarditis of any grade occurs. Recommended 
management guidelines in Table 14-17 were updated to recommend urgent cardiology 
consult to initiate high dose systemic corticosteroids in case of myocarditis events of 
any grade. References to published guidelines for the management of immune-related 
adverse events, including myocarditis, in patients treated with immune checkpoint 
inhibitor therapy (Brahmer et al 2018, Mahmood et al 2018) have been included in 
Table 14-17.
!
Table 7-2 and Section 7.2.2.5: Table 7-2 and Table 7-5 were updated to add the 
monitoring of cardiac Troponin T level for patients randomized in Arm 1 during the 
first 2 months of study treatment (at C1D15, C2D1 and C3D1).
!
Section 7.2.2.5.1 was added to provide guidance on specific monitoring of cardiac 
troponin T for patients randomized in Arm 1 with additional safety assessments to be 
performed in case of troponin T increase (Central electrocardiogram ECG assessment
and local echocardiogram, Troponin T repeat, and cardiologist consultation if ECG or 
echocardiogram are abnormal and suggestive of myocarditis).
The following editorial changes have also been made:
!
Section 5.3.2: Correction of the numbering of arm-specific exclusion criteria for 
continuity of numbering with common exclusion criteria. 
!
Table 14-9 in Section 14.2.3.2.9: correction of a typo.
IRBs/IECs/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
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The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
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Amendment 1 (24-Jul-2018) 
Amendment rationale 
As of 24-Jul-2018, the study has not started in any of the participating countries/sites.
Amendment 1 is required to implement specific feedback received from the US Food and 
Drug Administration (FDA), the Medicines and Healthcare products Regulatory Agency 
(MHRA), the German Paul -Ehrlich Institute (PEI) and the French health authority (Agence 
Nationale de Sécurité du Medicament, ANSM) upon review of the protocol, as well as 
additional changes. 
Major changes are intended to: 
!
Clarify inclusion criterion #4 and add a new exclusion criterion # 17 to further define 
and homogenize the study population.
!
Extend the time frame for exclusion of the use of any live vaccines before randomization 
in the common exclusion criterion #3 from 4 weeks to 3 months. This is based on the 
recommendation in the canakinumab Investigator’s Brochure (IB) Edition 16 which 
stipulates that patients should complete all immunizations 3 months prior to initiating 
canakinumab therapy. 
!
Add two common exclusion criteria to exclude patients with medical history or current 
diagnosis of myocarditis or with elevated cardiac Troponin T at screening. Myocarditis 
is an immune mediated adverse event which has been associated with immune 
checkpoint inhibitors (CPIs), it is a rare event with an estimated incidence of less than 
1% (Norwood TG et al, 2017). In the absence of consensus guidelines for cardiovascular 
monitoring and management for patients treated with CPI to date, a risk minimization 
approach is thus implemented with these changes as regards to the potential increased 
incidence of myocarditis when combining spartalizumab and LAG525 for early 
detection of myocarditis.
!
Include two additional criteria in Section 6.1.5.1 for continuation of study treatment 
beyond disease progression per RECIST v1.1 to further clarify the population of patients 
who would potentially benefit from continuing treatment beyond progression per 
RECIST v1.1. 
!
Provide additional dose modification guidelines in Table 6-6 for the permanent 
discontinuation of spartalizumab (and LAG525 in Arm 1) in the event of Stevens-
Johnson syndrome (SJS) or toxic epidermal necrolysis (TEN). After the recent 
occurrence of a case of SJS in a study with spartalizumab in combination with another 
investigational agent, the dose modification guidelines for protocols using spartalizumab
were updated to mandate permanent discontinuation of study treatment for patients who 
experience SJS or TEN. This change has been part of an Urgent Safety Measure (USM) 
released on 15 June 2018. This protocol amendment is now formalizing these changes 
in Table 6-6.
Additional instructions are also provided to investigators on 
spartalizumab/LAG525 dose modifications to be implemented in case of skin events 
(other than rash) possibly related to spartalizumab/LAG525.
!
Update section 6.3.1 on dose modifications for spartalizumab and LAG525 and 
management guidelines in Appendix 3 to align with latest published consensus 
guidelines on the clinical management of suspected immune-related toxicities.
!
Remove the requirements for ECGs at C1D1 visit and on treatment visits for patients 
randomized in Arm 3, as regular QT assessment is not required with monoclonal 
antibodies as regards to their low potential for QT prolongation. Patients in Arm 3 will 
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only be required to have an ECG assessment at End of Treatment visit (in addition to 
the ECG performed at screening), and if clinically indicated during study treatment. 
ECG assessment has been retained on Day 1 of the first 3 cycles for Arm 1, but at pre-
dose only (post-dose ECG removed), to monitor for potential immune-related cardiac 
events.
!
Add the collection of additional 
 immunogenicity (IG) samples for spartalizumab 
(all Arms), LAG525 (Arm 1) and canakinumab (Arm 3) at pre-dose every 3 months 
from Cycle 6 through end of treatment to monitor immunogenicity and related drug 
exposure throughout the treatment period.
!
Provide additional guidelines in Section 7.2.2.1 for the monitoring of patients treated in 
Arm 2 with capmatinib. Investigators are asked to monitor any clinical signs indicative 
of neural toxicity to align with the potential risk for central nervous system (CNS) 
toxicity described in capmatinib (INC280) IB Edition 9.
!
Remove visceral metastases as allowable lesion location sites for mandatory biopsies (at 
screening and on treatment between C1D21 and C2D1) (this is applicable to France 
only).
!
Clarify that “Progression of malignancy” should be reported as a SAE in this study if 
the investigator suspects that the study treatment accelerates disease progression.
!
Implement an independent Safety Data Monitoring Committee (DMC) during expansion 
phase (Part 2) of the study who will review relevant safety data on a regular basis and 
will provide recommendations on the continuation of the study.
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. 
Major changes are:
!
Section 5.2: Inclusion criterion #4 has been revised to clarify that all patients must have 
had objective disease progression while on or following prior anti-PD-1/PD-L1 therapy 
(administered alone or in combination with anti-CTLA4 therapy) and that this 
progression must have occurred within 12 weeks before randomization in this study. 
This criterion also provides the minimal time frame which must have elapsed between 
the last dose of those prior anti-cancer therapies and randomization.
!
Section 5.3.1: Exclusion criterion #3 has been revised to exclude the use of any live 
vaccines within 3 months prior to randomization (instead of 4 weeks). Exclusion 
criterion #17 has been added to clarify that subjects who received any other systemic 
therapy for unresectable or metastatic melanoma than the ones listed in inclusion 
criterion # 4 are not eligible to the study. Two common exclusion criteria # 18 and 19 
have also been added to exclude patients with medical history or current diagnosis of 
myocarditis or with elevated cardiac Troponin T level > 2 x ULN at screening. 
!
Section 6.1.5.1: Two additional criteria have been added for the investigator to confirm 
that a patient does not have any symptoms or signs indicative of disease progression and 
does not have a rapidly progressing disease before being allowed to continue study 
treatment beyond RECIST v1.1 disease progression. 
!
Table 6-6 in Section 6.3.1.3.2 and Table 14-12 in Appendix 3: A mandatory instruction 
has been added in Table 6-6 to permanently discontinue spartalizumab (and LAG525 
for arm 1 patients) in the event of Stevens-Johnson syndrome or toxic epidermal 
necrolysis, and a recommendation to hospitalize the patient and have an urgent 
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dermatology consultation if such event occurs has been added in Table 14-12 (Appendix 
3). Further instructions are also added in case of skin events (other than rash).
!
Table 6-10: A recommendation to permanently discontinue spartalizumab/LAG525 has 
been added in case of recurring infusion reaction (despite adequate prophylactic 
measures).
!
Section 6.3.1.3.2, Table 6-11 and Table 14-17 in Appendix 3: Provided clarification to 
investigators on the description of frequent manifestations of immune-related adverse 
events and added further description of rare immune-related adverse events observed 
with anti-PD-1/PD-L1 class agents for information of investigators. Additional 
instructions to investigators on spartalizumab/LAG525 dose modifications to be 
implemented in case of rare immune-related adverse events possibly related to 
spartalizumab/LAG525 have been added in Table 6-11, as well as recommendations on 
the management of those rare immune-related adverse events in Table 14-17. 
!
Table 7-2 and Table 7-6: Post-dose ECGs at C1D1 and C3D1 are no longer required for 
patients randomized in Arm 1 and ECGs at C1D1, C2D1 and C3D1 visits (pre- and post-
dose) are no longer required for patients randomized in Arm 3 (unless clinically 
indicated). 
!
Table 7-2, Table 7-7, Table 7-8 and Table 7-10: Collection of 
 IG samples for 
spartalizumab (all arms), LAG525 (Arm 1) and canakinumab (Arm 3) have been added 
at predose on day 1 of every 3 months from C6D1 through end of treatment.
!
Section 7.2.2.1: Added that investigators should monitor the occurrence of any clinical 
signs indicative of neural toxicity as part of the physical examination at Day 1 of each 
cycle for patients receiving capmatinib in Arm 2, and a neurological examination should 
be performed as clinically indicated.
!
Section 7.2.2.5: Table 7-5 has been updated to add testing of cardiac Troponin T (TnT) 
level at screening for all patients.
!
Section 7.2.3.1.1: Removed visceral lesions as allowable sites for mandatory biopsies 
(this is applicable to France only).
!
Section 8.1.1: Clarified that “Progression of malignancy” should be reported as SAE if 
the investigator suspects that the study treatment accelerates disease progression.
!
Section 8.6: Added description for the Safety DMC reviewing safety data during 
expansion phase (Part 2) of this study.
Other changes are:
!
Section 1.2.1.2: Corrected the global number of patients treated with spartalizumab 
single agent or in combination to align with the numbers in the PDR001 IB Edition 7.1 
(used as a source for data presented for spartalizumab in the background section of this 
protocol).
!
Section 5.3.1 and Section 5.3.2: Clarified that time of randomization should be the 
reference for evaluation of subject’s eligibility in the study as regards to exclusion 
criteria #2, #3, #4, #6, #21, #25 and #27 as this is a randomized study.
!
Section 5.3.1: Exclusion criterion #12 has been revised to exclude patients with positive 
test result for HBV-DNA at screening (which is also indicative of active HBV infection). 
!
Section 5.3.1: Exclusion criterion #16 has been revised to correct the time frame 
requirement for mandatory use of condoms for male participants from 30 days to 7 days 
after the last dose of study treatment. Indeed, recent studies have shown that monoclonal 
antibodies do not disseminate into semen and hence do not require the prolonged use of 
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condoms after the last dose. Capmatinib (INC280) is a small molecule and is able to 
disseminate into semen but has not shown to be genotoxic in preclinical studies (refer to 
INC280 IB Edition 9). Guidelines on birth control requirements for non-genotoxic small 
molecules recommend the use of condoms for male participants for at least five times 
the half-life after the last dose of drug. As the half-life of capmatinib is ranging from 3.5 
to 6.3 hours, the use of condoms for a period of 7 days after the last dose of study 
treatment is considered conservative enough to ensure a complete wash-out of 
capmatinib from the body.
!
Section 5.3.2: Exclusion criterion #27 has been revised to correct an error and clarify 
that patients with serum amylase grade > 2 are not eligible for randomization in arm 2, 
while patients with serum amylase grade 1 or 2 are eligible only if asymptomatic (no 
signs or symptoms suggesting pancreatitis or pancreatic injury).
!
Sections 6.1.1.1, 6.1.1.2, 6.1.1.4 and 6.3.1: The delay allowed for administration of 
spartalizumab, LAG525 and canakinumab dose at scheduled visits has been corrected to 
4 days instead of 7 days to match the visit and dose administration window of +/- 4 days 
defined in Table 7-1.
!
Table 6-2 has been corrected to update table numbering and remove the rows for 
neurological and ocular events, as there is no specific dose modifications for those events. 
Investigators should follow dose modifications for “Other adverse events”.
!
Section 6.3.1: In dose modifications tables (from Table 6-4 to Table 6-32), the 
recommendation to ‘continue treatment at the same dose level’ in case of grade 1 or 
grade 2 events has been deleted from the “Mandatory dose modification” column, as this 
is a recommendation but not a mandatory dose modification.
!
Section 6.3.1.3.2: Table 6-11 describing dose modifications for spartalizumab in case of 
hematological adverse events suspected to be related to spartalizumab has been deleted, 
as it was included in error as hematological events are rare with immuno-oncology 
therapies. Dose modifications to be followed for spartalizumab/LAG525 by 
investigators in case of hematological event are already covered by the table providing 
dose modifications in case of other adverse events suspected to be related to 
spartalizumab/LAG525 (newly numbered Table 6-11). Specific instructions have also 
been added in this table in case of autoimmune hemolytic anemia, hemolytic uremic 
syndrome or acquired hemophilia grade ≥3.
!
Section 6.3.1.4: Wording has been corrected to match information provided in Section 
6.2 that re-escalation of the dose of capmatinib after a previous reduction due to adverse 
event is allowed in this study, provided certain criteria (described in Section 6.2) are met.
!
Section 6.5.2 and Section 7.1.2.3: Removed the requirement to use central laboratory 
LDH result for randomization stratification to align with Section 7.2.2.5 that allows the 
use of local LDH result (if an immediate clinical decision is required). 
!
Section 7.1.6 and Glossary of terms: The definition of Withdrawal of Consent has been 
updated to enforce the protection of patients’ rights on the use and confidentiality of 
their Personal Data (definition of Personal Data has been added to the Glossary of terms) 
and align with the latest regulatory framework as regards to the use of their Personal 
data for patients who withdraw their consent, depending on local applicable law. It has 
been clarified that no further Personal Data will be collected after consent is withdrawn 
(except in the specific situations described and depending on applicable local law).
!
Section 7.2.2.7.1: Replaced instructions provided for the processing of 
 IG 
samples by a reference to the central lab manual to avoid discrepancies between lab 
manual and protocol and updated the volume of blood collected at each planned 
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timepoint for 
 IG analyses for each study drug to match the actual blood 
collection volumes. 
!
Table 7-11: Separated the entries for blood collections for PBMC flow cytometry and 
sequencing analyses to align with the collection methods in the laboratory manual which 
require two blood draws totaling 12.5 mL.
!
Section 13: Addition of a new reference.
!
In addition, editorial revisions, clarifications and corrections are made throughout the 
protocol to improve consistency and understanding.
IRBs/IECs/HA
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes in this amended protocol identified above as being related to the USM have 
already been implemented by a USM letter issued on 15 June 2018. These changes are 
required for patient safety (i.e. necessary to eliminate immediate hazards to the trial subjects 
as per ICH GCP 3.3.8). Therefore, they were required to be implemented prior to 
IRB/IEC/HA approval.
All other changes described in this amended protocol require IRB/IEC/HA approval prior 
to implementation.
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.
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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Melanoma is the most aggressive form of all skin cancers. Worldwide, it is expected that 
over 232,000 people are diagnosed with cutaneous melanoma each year and more than 
55,000 people are expected to die of this disease annually. Usually melanoma is diagnosed 
at an early stage in which surgical excision is curative in most cases. The management of 
patients with unresectable or metastatic melanoma is more difficult, although recent 
advances have led to important improvements of clinical outcomes for this population. 
The primary systemic therapy approaches for patients with unresectable or metastatic 
melanoma are (1) checkpoint inhibitor immunotherapy (anti-PD-1 monotherapy or in 
combination with anti-CTLA-4 therapy) or (2) targeted therapy with V600BRAF and MEK 
inhibitors (e.g. dabrafenib and trametinib) for melanomas harboring a V600BRAF mutation 
(NCCN Guidelines® Melanoma Version 1 2018; Cutaneous Melanoma: ESMO Guideline 
Committee 2015). The optimal sequencing of targeted therapy and checkpoint inhibitor 
therapy in V600BRAF-mutant melanoma has not been definitively established and is under 
investigation in study EA6134 [NCT02224781]. In clinical practice, the choice of treatment 
is driven by the tempo of disease, presence or absence of symptoms, medical history, 
comorbidities and other factors (e.g. patient preference). 
As of today, patients who do not respond to, or progress on, the approved treatments have 
very limited treatment options, and there is no established standard of care. Guidelines 
recommend enrollment in a clinical trial, treatment with ipilimumab (anti-CTLA-4), 
chemotherapy, or high-dose interleukin-2 (IL-2) for selected patients (NCCN Guidelines®
Melanoma Version 1 2018). Based on retrospective data from 47 patients treated in the 
pivotal phase III study KEYNOTE-006, single-agent checkpoint inhibitor therapy with 
ipilimumab has limited anti-tumor activity following failure of pembrolizumab (anti-PD-1) 
with a reported objective response rate (ORR) of 16% (Zimmer et al 2017). As a result, most 
patients are enrolled in clinical studies as there is an urgent need for new treatment options 
for patients who failed the available standard therapies. 
Patients enrolled in this study have failed previous therapies including immune checkpoint 
inhibitors. The mechanisms of primary and acquired resistance to checkpoint inhibitors 
treatment are not well understood and are mainly due to a combination of intrinsic or 
extrinsic resistance mechanisms (see Section 2.1). The combinations tested in this study aim 
to alter the tumor and/or microenvironment in favorable way to overcome treatment 
resistance and restore T cell function.
1.2
Introduction to investigational treatments 
In subsections providing clinical experience with each study drug, all adverse events (AEs) 
described are graded per Common Terminology Criteria for Adverse Events (CTCAE)
v4.03, unless otherwise specified.
1.2.1
Overview of spartalizumab
Spartalizumab (PDR001) is a high-affinity, ligand-blocking, humanized immunoglobulin 
G4 (IgG4) monoclonal antibody directed against the human programmed cell death 1 (PD-
1) receptor. 
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1.2.1.1
Non-clinical experience with spartalizumab
Spartalizumab binds specifically and with high affinity to human PD-1 and enhances IL-2 
production in lymphocyte stimulation assays in-vitro. Spartalizumab does not cross-react 
with rodent PD-1. However, toxicology studies performed in cynomolgus monkeys showed 
acceptable cross reactivity with monkey PD-1. Repeat administration of spartalizumab to 
cynomolgus monkeys was tolerated at all doses tested up to 100 mg/kg/week for 5 weeks in 
the GLP toxicology single-agent study. No drug-related in-life, mortality, organ weight 
changes, or macroscopic findings were noted. 
For further details, please refer to the latest [spartalizumab Investigator’s Brochure].
1.2.1.2
Clinical experience with spartalizumab
As of 19-Jan-2018, a total of 517 patients were exposed to spartalizumab single-agent every 
two weeks (Q2W), every three weeks (Q3W) or every four weeks (Q4W), and 722 patients 
were exposed to spartalizumab in combination with other agents in multiple tumor types 
including unresectable and metastatic melanoma. Based on the available pharmacokinetics 
(PK) and safety data, two recommended phase two doses (RP2D) for spartalizumab single-
agent have been declared: spartalizumab 400 mg Q4W or 300 mg spartalizumab Q3W.
For further details, please refer to the latest [spartalizumab Investigator’s Brochure].
1.2.1.2.1 Clinical experience with spartalizumab single-agent in advanced 
melanoma
Data is available from a phase I/II, open-label, dose escalation/expansion study in advanced 
solid tumors [CPDR001X2101]. As of November 13, 2017, 61 patients with cutaneous and 
non-cutaneous melanoma received 400 mg spartalizumab Q4W. Out of the 61 patients, 36% 
were treatment-naïve and 20% had two or more prior therapies. Spartalizumab was well 
tolerated with a manageable safety profile. The most common treatment-related AEs (all 
grades, ≥5%) were fatigue (15%), decreased appetite (11%), hypothyroidism (8%), rash 
(8%), asthenia (7%), and vitiligo (7%). 
Anti-tumor activity observed was as expected given the level of prior treatment and high 
proportion of patients with PD-L1 negative melanoma. ORR using RECIST v1.1 was 26% 
(16/61), including 1 complete response (CR). 41 patients (67%) had baseline PD-L1 data: 
63% were PD-L1 negative (tumor proportion score <1%). ORR was 40% (6/15) for PD-L1 
positive and 19% (5/26) for PD-L1 negative patients. 
For further details, please refer to the latest [spartalizumab Investigator’s Brochure].
1.2.1.2.2 Clinical pharmacokinetics of spartalizumab
Following administration of spartalizumab via a 30 minute intravenous (i.v.) infusion in 
study [CPDR001X2101], approximately dose-proportional increases in spartalizumab 
exposure were observed from 1 mg/kg to 10 mg/kg as suggested by an approximately 10-
fold increase in exposure for a 10-fold increase in dose. Moderate accumulation (1.0~3.0-
fold) of spartalizumab was observed, as exposure in Cycle 3 was relatively higher than that 
in Cycle 1 following a Q2W or Q4W regimen. Pharmacokinetic (PK) variability was low to 
moderate as illustrated by inter-subject variability (e.g. 15.4 to 46.5% for Cmax during Cycle 
1). The observed median half-life for spartalizumab ranges from 10.0 to 23.2 days.
For further details, please refer to the latest [spartalizumab Investigator’s Brochure].
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1.2.2
Overview of LAG525
LAG525 is a high-affinity, ligand-blocking, humanized anti-LAG-3 immunoglobulin G4 
(IgG4) monoclonal 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.
1.2.2.1
Non-clinical experience with LAG525
In Biacore assays, binding to mouse or rat LAG-3 proteins was undetectable demonstrating 
that LAG525 is not mouse or rat cross-reactive. LAG525 binds specifically and with high 
affinity to human LAG-3. 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 LAG-3 expressing 
human embryonic kidney (HEK 293) cells, LAG525 was binding 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 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 assays 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 epitope mapping studies and crystallography. 
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 (DDI) 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 ABC 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 at doses of 6 mg/kg, 25 mg/kg, 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 mg/kg and 100 mg/kg) were noted in males but these 
changes were not adverse.
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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 day 43 and/or day 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 Council for 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.
For further details, please refer to the latest [LAG525 Investigator’s Brochure].
1.2.2.2
Clinical experience with LAG525
Clinical data is available from study [CLAG525X2101C]: An open-label, multicenter Phase 
I/II study to determine the safety and efficacy of LAG525 single-agent and in combination 
with spartalizumab in patients with advanced solid tumors. The study consists of dose-
escalation parts for LAG525 single-agent, and LAG525 in combination with spartalizumab. 
During dose-escalation, 134 patients were treated with LAG525 single-agent, and 121 
patients were treated with the combination of LAG525 and spartalizumab (data cut-off 
October 18, 2017).
1.2.2.2.1 Clinical experience with LAG525 single-agent
The preliminary safety information was summarized from the ongoing single-agent dose 
escalation part of the study (N=134) using a data cut-off of October 18, 2017.
Four dose limiting toxicities (DLT) were reported and included grade 3 events of localized 
intra-abdominal fluid collection (1 mg/kg Q2W), vomiting (5 mg/kg Q2W), elevated lipase 
(5 mg/kg Q2W) and grade 4 acute kidney injury (10 mg/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-tumor activity, and selection of a RP2D was not informed by anti-tumor activity. 
The RP2D selection was therefore supported by a modeling approach to 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 sLAG3 detected 
in blood samples was utilized as a pharmacodynamic (PD) marker for target engagement. 
Based on the trial simulation of the PK/PD model, 400 mg LAG525 Q3W and 800 mg 
LAG525 Q4W were selected as RP2D for LAG525 single agent (data on file). Simulation 
of the population PK model for LAG525 showed comparable inter-subject 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 
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considered in the PKPD analysis described above for selecting the LAG525 single-agent 
RP2D.
Adverse events (AEs) of all grades and regardless of relationship to study treatment were 
reported in 132/134 subjects (98.5%) overall, with the most frequently reported (in >20% 
of subjects) AEs being fatigue and nausea (26.1% each), constipation (24.6%), decreased 
appetite (23.9%), abdominal pain and anemia (23.1% each), dyspnea and vomiting (20.9% 
each), which are consistent with AEs commonly reported for subjects with advanced solid 
malignancies. The safety profile appeared similar across different dose levels and schedules. 
Of the 134 subjects 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 
subjects were anemia (14 subjects, 10.4%) and dyspnea (7 subjects, 5.2%). Seventy-six of 
the 134 treated (56.7%) experienced AEs (all grades) suspected to be related to study 
treatment. In this subject group, the following grade 3 or 4 AEs were reported (10 subjects, 
7.5%): decreased appetite and vomiting (3 subjects each); fatigue, nausea, amylase 
increased, lipase increased (2 subjects each); abdominal pain, anemia, blood creatinine 
increased and hyperuricemia (1 subject each).
Serious adverse events (SAEs), all grades, and regardless of relationship to study treatment, 
were reported in 53 subjects (39.6%). The majority of SAEs (49 out of 53 subjects who 
experienced SAEs) were Grade 3/4 in severity. Among the 53 subjects who experienced 
SAEs, 18 events among 7 subjects were suspected related to study treatment including intra-
abdominal fluid collection (1 patient, 1 mg/kg Q2W, DLT), abdominal pain and melena (1 
patient, 3 mg/kg Q2W), infection and vomiting, (1 patient, 5 mg/kg Q2W, DLT), increased 
lipase and diarrhea (1 patient, 5 mg/kg Q2W, DLT), diarrhea (1 patient, 5 mg/kg Q2W), and 
nausea, vomiting, anorexia, fatigue, and failure to thrive (1 patient, 240mg Q2W). One 
patient experienced multiple SAEs suspected 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 10 mg/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. 
Single-agent LAG525 demonstrated only minimal anti-tumor activity in solid tumors. No 
RECIST v1.1 responses were seen at any dose level but some subjects (papillary renal cell 
carcinoma [RCC], non-small cell lung cancer [NSCLC], ovarian granulosa tumor, thymoma) 
experienced prolonged stable disease.
For further details, please refer to the latest [LAG525 Investigator’s Brochure].
1.2.2.2.2 Clinical experience with LAG525 in combination with spartalizumab
For the combination rationale of LAG525 with spartalizumab please refer to Section 2.4.1. 
As of October 18, 2017, 186 subjects have been treated with LAG525 in combination with 
spartalizumab in the combination part of study [CLAG525X2101C]. LAG525 doses ranged 
from 0.3 mg/kg to 1000 mg, and spartalizumab doses ranged from 1 mg/kg to 400 mg. The 
combination was tested with a Q3W and 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-
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life for spartalizumab ranged from 7.2 to 23.8 days, which is similar to the results from the 
ongoing [CPDR001X2101] study. There are no human PK data generated to date.
Four subjects experienced DLT which included grade 3 hyperglycemia (80 mg LAG525 
Q2W and 400 mg spartalizumab Q4W), grade 4 autoimmune hepatitis and grade 3 fatigue 
(1000 mg LAG525 Q4W and 400 mg spartalizumab, Q4W), grade 3 brain tumor edema 
(600 mg LAG525 Q3W and 300 mg spartalizumab Q3W), and grade 3 pneumonitis (400 
mg LAG525 and 400 mg spartalizumab, Q4W). 
The preliminary safety information was summarized from the ongoing combination part of 
the study using a data cut-off of October 19, 2017. AEs of all grades and regardless of 
relationship to study treatment were reported in 171 subjects (91.9%) overall, with the most 
frequently reported (in >20% of subjects) AEs being fatigue (27.4%), nausea (27.4%), and 
diarrhea (21.0%). Grade 3/4 AEs regardless of relationship to study treatment were reported 
in 79 subjects (42.5%). The frequency of each grade 3/4 AEs was below 10%. The most 
frequently reported AEs occurring in 2 or more subjects included anemia (5.9%), asthenia 
(2.7%), fatigue (2.2%), dyspnea (2.2%), nausea (1.6%), vomiting (1.6%), decreased appetite 
(1.1%), abdominal pain (1.1%), and back pain (1.1%). Of the 186 subjects with the 
combination, 110 (59.1%) experienced AEs (all grades) suspected to be related to study 
treatment. In this subject group, the following grade 3/4 AEs were reported (16 subjects, 
8.6%): fatigue, diarrhea, asthenia, anemia, aspartate aminotransferase increased, alanine
aminotransferase increased, amylase increased, headache, cough, hyperglycemia, 
pneumonitis, polyarthritis (1 subject each), hypophosphatemia, lipase increased (2 subject 
each). Serious adverse events (SAEs), all grades, regardless of relationship to study drug, 
were reported in 65 subjects (34.9%). The majority of these subjects (53 out of 65) 
experienced SAEs that were Grade 3/4 in severity. Among the 65 subjects who experienced 
SAEs, 17 events in 12 subjects were suspected related to study treatment. SAEs, all grades, 
regardless of relationship, occurring in more than 2 subjects were pyrexia (6 subjects), 
dyspnea, fatigue, nausea (4 subjects each), acute kidney injury, colitis, hypercalcemia, pain, 
pleural effusion and vomiting (2 subjects each). 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.
The combination part of [CLAG525X2101C] included 5 subjects with advanced and heavily 
pre-treated triple negative breast cancer (TNBC). Two of these subjects showed durable 
partial response (PR) with both subjects being on treatment for over a year (data on file). 
Anti-tumor activity was also reported in other solid tumors. One subject with thymoma 
achieved a complete response (CR) and 11/100 evaluable subjects with a variety of solid 
tumors had a confirmed PR. The majority of subjects with confirmed PR have durable 
responses. Several prolonged stable disease (SD) were observed. The study is ongoing and 
these data are therefore preliminary and may be subject to change.
For further details, please refer to the latest [LAG525 Investigator’s Brochure].
1.2.2.2.3 Clinical Pharmacokinetics of LAG525
The preliminary pharmacokinetics of LAG525 have been characterized from 100 patients 
in single-agent and 101 patients in combination in the clinical study [CLAG525X2101C]
(data cut-off date of March 20, 2017).
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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-subject 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. Comparing to a typical 
monoclonal antibody 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 (i.v.). 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 (DDI) are not 
anticipated for LAG525 because it is not expected to interact with drug metabolizing 
enzymes or transporters. Preliminary analysis of immunogenicity in subjects on the 
[CLAG525X2101C] study suggests the presence of ADAs in some subjects. 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.
For further details, please refer to the latest [LAG525 Investigator’s Brochure].
1.2.3
Overview of capmatinib
Capmatinib (INC280) is a small ATP (adenosine triphosphate) competitive, reversible 
inhibitor of the c-MET receptor tyrosine kinase.
1.2.3.1
Non-clinical experience with capmatinib
Capmatinib possesses potent inhibitory activity against the c-MET kinase in vitro and is 
highly specific for c-MET with > 10,000-fold selectivity over several other human kinases 
tested. Potent activity of blocking c-MET activation has been observed in cell-based 
biochemical and functional assays that measure c-MET-mediated signal transduction, as 
well as c-MET-dependent cell proliferation, survival, and migration. In c-MET–dependent 
mouse tumor models (including lung cancer models), capmatinib exhibits dose-dependent 
anti-tumor activity and causes tumor regression at well tolerated doses that exceeded IC90 
coverage (Liu et al 2011). Importantly, plasma levels of capmatinib correlate with both, the 
dose administered and the extent of tumor growth inhibition in vivo. In c-MET/HGF-driven 
mouse xenograft tumor models, oral dosing of capmatinib demonstrated significant in vivo
activity in blocking both c-MET phosphorylation and tumor growth. Collectively, the data 
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suggest that capmatinib possesses potent in vitro and in vivo biological and pharmacologic 
activities. 
For further details, please refer to the latest [capmatinib Investigator’s Brochure].
1.2.3.2
Clinical experience with capmatinib 
As of the cut-off date (September 28, 2017), a total of 1109 cancer patients and 158 non-
cancer subjects have received capmatinib. A total of 622 patients with solid tumors have 
been treated with capmatinib single-agent, and 487 patients have been treated with 
capmatinib in combination with other agents. 
1.2.3.2.1 Clinical experience with capmatinib single-agent
Capmatinib single-agent data is available from the reference study [CINC280X2102]: a 
phase I dose escalation study in patients with c-MET dependent advanced solid tumors with 
an expansion part in hepatocellular carcinoma (HCC), gastric cancer, NSCLC, RCC and 
other solid tumors. 
For further details, please refer to the latest [capmatinib Investigator’s Brochure].
1.2.3.2.2 Clinical experience of capmatinib in combination with spartalizumab
For the combination rationale of capmatinib with spartalizumab please refer to Section 2.4.2. 
Capmatinib in combination with spartalizumab is currently being evaluated in the open-
label phase Ib/II study in patients with advanced HCC [CINC280X2108]. As of the data cut-
off (25-Sep-2017), 20 patients were enrolled and treated with capmatinib in combination 
with spartalizumab within the dose escalation part of the study, using three dose levels (200 
mg bid, 300 mg BID and 400 mg BID) of capmatinib in combination with 300 mg 
spartalizumab Q3W. The expansion part has not started yet.
The median age of patients was 62.5 years (range 47 to 78 years). 16 patients were male and 
4 were females. Eleven patients (55%) had an ECOG performance status of 0 at baseline; 9 
patients (45%) had an ECOG performance status of 1. 13 patients (65%) were still receiving 
treatment and 7 patients (35%) had discontinued treatment. The reasons for end of treatment 
were progressive disease (4 patients, [20%]), adverse event (1 patient, [5%]), 
subject/guardian decision (1 patient, [5%]), and death (1 patient, [5%], due to underlying 
disease). 
Nineteen patients (95%) experienced AEs of any grade, regardless of causality. The most 
common AEs were edema peripheral (10 patients, [50%]), nausea (7 patients, [35%]), blood 
creatinine increased and fatigue (each in 6 patients, [30%]), and rash (5 patients, [25%]).
The most frequent AEs suspected to be related to study treatment were edema peripheral (9 
patients, [45%]), fatigue, rash (each in 5 patients, [25%]), blood creatinine increased, nausea, 
vomiting (each in 4 patients, [20%]). Seven patients (35%) had grade 3/4 AEs suspected to 
be related to study treatment: nausea (2 patients, [10%]), edema peripheral, ALT increased, 
diarrhea, stomatitis, hypotension, platelet count decreased, acute myocardial infarction, 
unstable angina, blood bilirubin increased, dehydration, and neutropenia (each in 1 patient, 
[5%]). Six SAEs regardless of causality have been reported for 4 (20%) patients. Three 
patients (15%) experienced the following SAEs suspected of being related to study 
treatment: unstable angina pectoris, diarrhea, dehydration, and chronic obstructive 
pulmonary disease (COPD) exacerbation.
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There were no DLT observed in cohort 1 (capmatinib 200 mg BID with spartalizumab 300 
mg Q3W) and cohort 2 (capmatinib 300 mg BID with spartalizumab 300 mg Q3W). One 
patient in cohort 3 using capmatinib 400 mg BID in combination with 300 mg Q3W 
spartalizumab experienced Grade 3 diarrhea, suspected to be related to study treatment, 
which was considered a DLT. The dose of spartalizumab 300 mg i.v. Q3W and capmatinib 
400 mg BID is currently under evaluation.
Capmatinib in combination with nivolumab in NSCLC
The phase II [CEGF816X2201C] study is currently enrolling patients with Epidermal 
growth factor receptor (EGFR) wild-type NSCLC to receive the combination of capmatinib
with the approved anti-PD-1 antibody nivolumab. As of February 1, 2017, 9 patients had 
been enrolled in safety monitoring cohorts and treated with capmatinib 400 mg p.o. BID in 
tablet formulation plus nivolumab 3 mg/kg i.v. every 2 weeks, on 28-day cycles. The most 
commonly reported adverse events (occurring in 2 or more patients), regardless of CTCAE 
grade, that were suspected to be related to study treatment were nausea (n=7, 77.8%), 
diarrhea (n =5, 55.6%), increased amylase (n=4, 44.4%), vomiting (n=4, 44.4%), asthenia 
(n=3, 33.3%), fatigue (n=3, 33.3%), arthralgia, increased blood creatinine, decreased 
appetite, increased lipase, and peripheral edema (n=2 each, 22.2%). Four patients (44.4%) 
experienced at least one Grade ∀3 adverse event that was suspected to be related to study 
treatment. These events included asymptomatic increased lipase (n=2, 22.2%) and increased 
amylase, asthenia, lethargy, somnolence, and vomiting (n=1 each, 11.1%). One patient had 
a dose reduction of capmatinib during the first cycle of treatment. Based on these data, the 
decision was made to continue with expansion enrollment using capmatinib 400 mg p.o. 
BID tablet plus nivolumab 3 mg/kg i.v. every 2 weeks.
1.2.3.2.3 Clinical pharmacokinetics of capmatinib
After oral administration, capmatinib was rapidly absorbed with the median time to reach 
maximum drug concentration (Tmax) ranging from 1 to 2 hours for tablets and from 1 to 4 
hours for capsules. The elimination half-life estimated from ranged from 3.5 to 6.3 hours 
across the cohorts. Accumulation in capmatinib exposure following repeated administration 
of 400 mg BID tablets is low, with geometric mean accumulation ratio of 1.4-fold. Steady 
state capmatinib exposure is expected to be reached by the third day of consecutive BID
dosing. The mean plasma exposure increase is roughly dose proportional for capmatinib 
tablet from 200 mg BID to 400 mg BID. 
Based on the tablet PK and safety data, the dosage of capmatinib 400 mg BID in tablet form 
has been declared as the RP2D. Capmatinib can be administered without regard to food, and 
caution is advised with proton pump inhibitors (PPI) as exposure may be decreased. 
Capmatinib is not a CYP3A4 inhibitor, but a moderate CYP1A2 inhibitor. Capmatinib is an 
inhibitor of P-gp as well as BCRP transporters, with clinically relevant DDI potential. The 
concurrent use of strong CYP3A4 inducers with capmatinib should be avoided. Based on 
the available data, capmatinib does not show a risk of QT prolongation.
For more information, please refer to the current [capmatinib Investigator’s Brochure].
1.2.4
Overview of canakinumab 
Canakinumab (ACZ885, ILARIS®) is a high-affinity human anti-interleukin-1β (IL-1β)
monoclonal antibody that belongs to the IgG1/κ isotype subclass. 
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1.2.4.1
Non-clinical experience with canakinumab 
Canakinumab neutralizes the bioactivity of human IL-1β by preventing its binding to the 
IL-1β receptor. Canakinumab specifically binds human IL-1β with a Kd of 40-60 picomolar 
and has no cross-reactivity with human IL-1# (IL-1F1), human IL-1 receptor antagonist (IL-
1Ra, IL-1F3) or other members of the IL-1 family (IL-1F4-IL-1F9). Canakinumab is 
selective for human and marmoset IL-1β (IL-1F2) but does not bind to mouse, rat, rabbit, 
rhesus, or cynomolgus monkey IL-1β. Because canakinumab does not react with rodent IL-
1β, the in vivo activity of canakinumab was demonstrated in models on inflammation 
induced by human IL-1β in rodents. Canakinumab inhibited the IL-1β induced effect.
An extensive program of toxicology studies was performed. The marmoset monkey was 
characterized as an appropriate model to predict human safety. Regarding toxicokinetics, 
exposure to canakinumab was demonstrated. Following i.v. or s.c. administration, 
canakinumab was well tolerated in marmosets at all dose levels investigated without any 
relevant adverse findings. No anti-drug antibodies were detected. Long-term animal studies 
have not been performed to evaluate the carcinogenic potential of canakinumab. The 
mutagenic potential of canakinumab was not evaluated. No significant treatment-related 
effects were observed with respect to male or female fertility in a mouse model using a 
murine analog of canakinumab. 
For further details, please refer to the latest [canakinumab Investigator’s Brochure].
1.2.4.2
Clinical experience with canakinumab 
1.2.4.2.1 Clinical experience with canakinumab single-agent
As of June 20, 2017 a total of 15,902 patients had been enrolled in Novartis sponsored 
interventional canakinumab studies. Canakinumab has demonstrated efficacy in a variety of 
non-oncologic indications: cryopyrin-associated periodic syndromes (CAPS), familial 
Mediterranean fever (FMF), tumor necrosis factor receptor associated periodic syndrome 
(TRAPS), hyper immunoglobulin D syndrome (HIDS), mevalonate kinase deficiency 
(MKD), systemic juvenile idiopathic arthritis (SJIA).
A recent large randomized phase III study (CANTOS) has demonstrated a clinically and 
statistically significant effect of canakinumab 150 mg and 300 mg every 3 months versus 
matching placebo in reducing the risk of major adverse cardiovascular events (MACE) 
(Ridker et al 2017a). The results of the CANTOS study also reported that inhibition of IL-
1β dose dependently reduced the occurrence of lung cancers in post myocardial infarction 
patients with elevated high-sensitivity CRP (hsCRP) suggesting an anti-tumor effect with 
canakinumab treatment (Ridker et al 2017b). A phase III study evaluating the efficacy and 
safety of adjuvant canakinumab versus placebo in NSCLC is ongoing (EUDRACT number 
2017-004011-39).
For further details, please refer to the latest [canakinumab Investigator’s Brochure].
1.2.4.2.2 Clinical experience with canakinumab in combination with spartalizumab
For the combination rationale of canakinumab with spartalizumab please refer to Section 
2.4.3.
Data for the combination of canakinumab with spartalizumab is available from a phase Ib, 
open-label, multi-center study [CPDR001X2103]. As of the data cut-off (July 31, 2017), 16 
patients were enrolled and treated in the dose escalation part of the study, using three dose 
levels: 100 mg canakinumab s.c. Q8W, 300 mg canakinumab Q8W and 600 mg 
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canakinumab Q8W in combination with 400 mg Q4W spartalizumab. Fifteen patients (94%) 
experienced AEs of any grade, regardless of causality. The most common AEs were 
decreased appetite (6 patients, [37%]), fatigue (5 patients, [31%]), anemia and dyspnea 
(each in 4 patients, [25%]), and back pain, dizziness and nausea (each in 3 patients, [18%]). 
The majority of AEs were Grade 1/2. Six (37%) experienced AEs of any grade, suspected 
to be related to study treatment. The most frequent AEs suspected to be related to study 
treatment were fatigue (5 patients, [18%]) and decreased appetite (2 patients, [12%]). Seven 
patients (44%) experienced Grade 3/4 AEs regardless of causality (each 1 patient [6.3%]): 
anemia, dyspnea, back pain, urinary tract infection, acute respiratory failure, aspartate 
aminotransferase increased, cancer pain, cystitis, herpes zoster. No patient had a Grade 3/4 
AEs that was suspected to be related to study treatment. Eight SAEs have been reported for 
5 (31%) patients with none suspected of being related to study treatment.
There were no DLT observed and the Phase I of the study is ongoing.
1.2.4.2.3 Clinical pharmacokinetics of canakinumab 
During the development of canakinumab, four drug formulations were investigated. 
Bioavailability and absorption rate constants of the product types were similar, ranging from 
63-76% and 0.28-0.38 d-1., respectively. The peak serum canakinumab concentration (Cmax) 
occurred approximately 7 days following single s.c. administration of 150 mg canakinumab 
in adult CAPS subjects. Exposure parameters (such as AUC and Cmax) increased in 
proportion to dose over the dose range of 0.3 to 10 mg/kg as intravenous infusions or from 
150 to 600 mg as subcutaneous injection. The serum clearance (CL) and volume of 
distribution of canakinumab varied according to body weight (6.01 L/day and 0.174 L/day 
in a typical CAPS patient weighing 70 kg). The mean terminal half-life was 26 days. After 
accounting for body weight differences, no clinically significant differences in the PK 
properties of canakinumab were observed between CAPS, TRAPS, HIDS/MKD, FMF, 
SJIA and gouty arthritis subjects. There was no indication of accelerated clearance or time-
dependent change in the PK properties of canakinumab following repeated administration.
For further details, please refer to the latest [canakinumab Investigator’s Brochure].
1.2.5
Overview of ribociclib 
1.2.5.1
Non-clinical experience with ribociclib 
Ribociclib inhibits the CDK4/ Cyclin D (CCND1) and CDK6/CCND3 enzyme complexes 
with IC50 values of 0.01 and 0.039 μM in biochemical assays, respectively, while showing 
a high degree of selectivity for CDK4/6 versus other cyclin-dependent kinases. In more than 
40 pRb-positive cell lines derived from diverse cancer types, ribociclib inhibited 
Retinoblastoma protein (pRb) phosphorylation and interfered with G1 to S phase cell cycle 
progression.
Ribociclib has demonstrated in vivo anti-tumor activity in subsets of tumor xenograft models 
including but not limited to breast, melanoma, neuroblastoma, malignant rhabdoid, lung, 
pancreas and hematological malignancies. In addition, ribociclib has shown anti-tumor 
activity when combined with targeted agents which inhibit signaling pathways known to 
regulate D-cyclin levels, including inhibitors of the RAF, mitogen-activated protein kinase 
kinase (MEK), phosphoinositide 3-kinase (PIK3) and mammalian target of rapamycin 
(mTOR) pathways. 
For further details, please refer to the latest [ribociclib Investigator’s Brochure].
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1.2.5.2
Clinical experience with ribociclib
Ribociclib is being investigated in patients with advanced breast cancer (aBC) and other 
solid tumors in multiple clinical trials at different phases of development. Three large phase 
III studies in patients with aBC have led to regulatory approvals in the USA and EU.
For further details, please refer to the latest [ribociclib Investigator’s Brochure].
1.2.5.2.1 Clinical experience with ribociclib in combination with endocrine agents
Clinical Safety:
Clinical safety of ribociclib with endocrine agents such as letrozole, tamoxifen, exemestane, 
fulvestrant, and goserelin has been evaluated in several combination trials. The safety profile 
of ribociclib in combination with Non-Steroidal Aromatase Inhibitor (NSAI) (+/- goserelin) 
was investigated in two phase III trials in aBC (MONALEESA-2 [CLEE011A2301] and 
MONALEESA-7 [CLEE011E2301]).
Study [CLEE011A2301] is a phase III, multicenter study of the combination of ribociclib 
or placebo with letrozole in postmenopausal women with HR-positive, HER2-negative 
advanced (metastatic or loco regionally recurrent) breast cancer. In total, 668 patients were 
randomized; 334 patients each to the ribociclib plus letrozole arm and the placebo plus 
letrozole arm. Median duration of follow up at the second overall survival interim analysis 
(data cut-off 02-Jan-2017) was 26.4 months. As of January 2017, the most commonly (≥ 
30%) reported AEs in ribociclib plus letrozole group, irrespective of causality were: 
neutropenia (64.1%), nausea (53.3%), fatigue (41.3%), diarrhea (38.3%), alopecia (34.4%), 
vomiting (33.5%), and arthralgia (33.2%). The incidence of Serious Adverse Events (SAE)s 
was 25.4% and 15.5% in the ribociclib plus letrozole and placebo plus letrozole arms, 
respectively. The trial reported 12 (3.6 %) patients with at least one > 480 ms post-baseline 
QTcF for the ribociclib arm, and 2 (0.6 %) patients with at least one > 480 ms post-baseline 
QTcF in the placebo arm. One case of sudden death has been observed in a context of grade 
3 hypokalemia and grade 2 QTcF prolongation. Permanent discontinuations due to AEs 
were reported in 16.8% of patients receiving ribociclib plus letrozole and 3.9% in patients 
receiving placebo plus letrozole. The most common AEs leading to treatment 
discontinuation of ribociclib in patients receiving ribociclib plus letrozole were ALT 
increased (4.5%), AST increased (2.7%), vomiting (2.4%) based on data cut off of 04-Jan-
2017. 
For a comprehensive review of the safety profile of ribociclib in combination with endocrine 
agents, please refer to the current [ribociclib Investigator’s Brochure].
Clinical Efficacy:
Efficacy of ribociclib with endocrine agents has been evaluated in three published phase III 
combination trials in patients with aBC, two of them evaluating the combination of 
ribociclib with NSAI (+/- goserelin).
Key efficacy results:
Study [CLEE011A2301] met its primary objective at the primary analysis (29 Jan 2016 data 
cut off), with compelling evidence of clinical benefit in patients with HR-positive, HER2-
negative advanced breast cancer. A 44.4% estimated risk reduction in ribociclib plus 
letrozole treated patients was evident in the primary PFS endpoint as per investigator 
assessment (HR=0.556, 95% CI: 0.429, 0.720; one sided p-value =3.29×10-6). Updated PFS 
analyses (02 Jan 2017 data cut off) demonstrated continued treatment benefit for patients 
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receiving ribociclib and letrozole vs placebo and letrozole (hazard ratio=0.568; 95% CI: 
0.457–0.704; p=9.63×10–8;). Median PFS was prolonged by 9.3 months, from 16.0 months 
(95% CI: 13.4–18.2) in the placebo arm to 25.3 months (95% CI: 23.0–30.3) in the ribociclib 
arm. The 24-month PFS rates were 54.7% in ribociclib plus letrozole arm vs 35.9% in the 
placebo plus letrozole arm. As of 02-Jan-2017 cut off, overall survival data remain immature, 
with 15.0% vs 19.8% of patient deaths in the ribociclib plus letrozole vs placebo plus 
letrozole arm (hazard ratio=0.746; 95% CI: 0.517–1.078; p=0.059).
For more details, please refer to the current [ribociclib Investigator’s Brochure].
1.2.5.2.2 Clinical experience with ribociclib in combination with spartalizumab
[NCT03294694] is an open-label phase I dose escalation study with primary objective to 
determine the safety, tolerability, maximum-tolerated dose (MTD) and recommended phase 
2 dose (RP2D) of the combination of ribociclib and spartalizumab in metastatic HR-positive
breast cancer and advanced ovarian cancer. Nine women with breast cancer and one woman 
with ovarian carcinoma participated in the dose escalation portion of the trial. The median 
age was 57 years (50-70 years); all 10 (100%) had ECOG PS of 0 or 1; all patients had 
metastatic disease. The median number of prior therapies for metastatic breast cancer was 2 
(range 0-4). The median number of prior cytotoxic chemotherapies for metastatic breast or 
ovarian disease was 4 or more (range 0-4+). Eight of the nine participants with breast cancer 
(89%) had prior exposure to a CDK4/6 inhibitor in any setting. 
Three subjects were enrolled to Dose Level 1 (400mg p.o. QD ribociclib + 400 mg i.v. Q4W
spartalizumab) and no DLTs were observed. Three subjects were enrolled to Dose Level 2 
(600mg p.o QD ribociclib + 400mg i.v. Q4W spartalizumab) and no DLTs were observed. 
Four additional subjects were enrolled to this dose level; one was deemed unevaluable due 
to drug compliance issues and was replaced. Among these three evaluable subjects, one 
subject experienced a DLT of grade 3 atrial flutter and grade 3 atrial fibrillation, which were 
determined to be possibly related to both ribociclib and spartalizumab. Based on this 
information, a Maximum Tolerated Dose (MTD) of 600mg p.o QD ribociclib in 
combination with 400mg i.v. Q4W spartalizumab was declared. 
A full listing of all grade toxicity determined to be possibly, probably, or definitely related 
to either ribociclib or spartalizumab are outlined here: alanine aminotransferase increased
(6 patients, 60%), aspartate aminotransferase increased (3 patients, 30%), atrial fibrillation, 
atrial flutter, blood bilirubin increased, hyperglycemia, platelet count decreased, white blood 
cell count decreased (all reported in 1 patient, 10%).
One of ten participants experienced a best response per RECIST 1.1 of SD for <16 weeks; 
8 had a best response of progressive disease; one participant was not evaluable per RECIST 
1.1 but experienced clinical progression; one participant was not evaluable for a response 
assessment altogether. Nine participants were removed from treatment due to progressive 
disease; one was removed for unacceptable toxicity.
Overall the combination demonstrated a favorable safety and tolerability profile. An 
expansion cohort of the doublet later opened for ovarian participants, as well as a safety run-
in with the addition of fulvestrant for breast participants that lead to a dose expansion cohort.
1.2.5.2.3 Clinical pharmacokinetics of ribociclib 
The clinical pharmacokinetics (PK) of ribociclib have been evaluated in a phase I study in 
patients with advanced solid tumors or lymphomas [CLEE011X2101]. Following oral 
dosing, ribociclib was rapidly absorbed with median Tmax ranging from 1 to 4 hours.
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The T1/2 accumulation for ribociclib was 32.0 hours and the mean CL/F (apparent total 
body clearance of drug from the plasma) was 25.5 L/hr at steady-state at 600 mg in patients 
with advanced cancer. Ribociclib is mainly eliminated via hepatic clearance (extensive 
hepatic metabolism via CYP3A), with renal clearance playing a lesser role in humans. 
Concomitant use of ribociclib with strong CYP3A4 inhibitors or strong CYP3A4 inducers 
should be avoided as ribociclib exposure may be markedly affected. Concurrent use of 
sensitive CYP3A4 substrates with a narrow therapeutic index should be avoided. Concurrent 
use of CYP1A2 substrates is not expected to lead to clinically important drug-drug 
interaction (DDI).
No apparent drug-drug interaction (DDI) was observed between ribociclib and the 
combination partner letrozole or anastrozole based on PK data in the MONALEESA-2 and 
-7 trials. Based on the population PK analysis, concomitant use of letrozole or anastrozole 
had no impact on ribociclib exposure.
Food does not affect the PK of ribociclib administered as a capsule or tablet formulation; 
therefore ribociclib capsules or tablets can be taken without regard to meals 
[CLEE011A2111, CLEE011A2103].
Refer to the current [ribociclib Investigator’s Brochure] for additional details.
2
Rationale
2.1
Study rationale and purpose
Patients eligible for this study failed to respond, or progressed while being on standard 
treatment for unresectable or metastatic melanoma which include either targeted therapy 
(for patients with V600BRAF-mutant melanoma) and/or immune checkpoint inhibitors (e.g. 
pembrolizumab, nivolumab with or without ipilimumab) due to either primary or acquired 
resistance (Kim et al 2016, Sharma et al 2017, Jenkins et al 2018).
Patients with primary resistance to treatment with checkpoint inhibitors do not respond 
because of a combination of intrinsic or extrinsic tumor-cell resistance mechanisms. 
Intrinsic mechanisms may include lack of antigen expression, loss of HLA (human 
leukocyte antigen) or B2M (Beta-2-Microglobulin) expression, alterations in antigen 
processing, alterations in signaling pathways (e.g. MAPK, PI3K, WNT, IFN), and 
constitutive PD-L1 expression. Extrinsic mechanisms may include expression of inhibitory 
immune checkpoints (e.g. CTLA-4, PD-1, VISTA, TIM-3, LAG-3), T cell exhaustion, 
immune suppressive cells (e.g. Treg, MDSC, macrophages), and cytokines and metabolites 
release into the tumor microenvironment (e.g. CSF-1, tryptophan, TGF-∃, adenosine) (Kim 
et al 2016, Sharma et al 2017, Jenkins et al 2018).
Approximately one third of patients with metastatic melanoma who have responded to 
checkpoint inhibitor therapy with anti-CTLA-4 or anti-PD-1 will eventually progress due to 
an acquired resistance. Although not well-understood, potential mechanisms for acquired 
resistance include loss of T cell function, lack of T cell recognition by downregulation of 
tumor antigen presentation and development of escape mutation variants in the cancer (Kim 
et al 2016, Sharma et al 2017, Jenkins et al 2018). 
Considering the importance of the inhibitory effect of the PD-1/PD-L1 axis as described 
above, there is rationale to use an anti-PD-1 antibody even in patients who have received
previous checkpoint inhibitor therapy. Furthermore, the established anti-tumor activity of 
anti-PD-1/PD-L1 checkpoint inhibitors as monotherapy in a wide spectrum of cancers 
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together with its favorable toxicity profile provides a strong rationale for its use as a 
backbone for combination strategies. Although the PD-1/PD-L1 checkpoint axis plays a 
critical inhibitory role, secondary immune checkpoints such as LAG-3, TIGIT, and VISTA 
may also play a vital role leading to T cell dysfunction. As a result, targeting these inhibitory 
checkpoint inhibitors (e.g. with the anti-LAG-3 antibody LAG525) may restore T cell 
function (refer to the rationale for combining LAG525 with spartalizumab in Section 2.4.1). 
Neutrophils recruited to T cell-inflamed microenvironments play an immunosuppressive 
role, restraining T cell expansion, effector functions and contribute to resistance to immune 
therapy. High blood neutrophil counts and neutrophil-to-lymphocyte ratios predict poor 
survival in cancer patients (Shen et al 2014, Templeton et al 2014) and poor outcome to 
checkpoint immunotherapy in melanoma patients (Ferrucci et al 2015, Gebhardt et al 2015). 
In cancer patients, high serum levels of the c-MET ligand HGF (hepatocyte growth factor) 
correlated with increasing neutrophil counts and poor responses to checkpoint blockade 
therapies (Glodde et al 2017). In addition, cytokines like IL-1β, derived from the tumor 
microenvironment and secreted by malignant cells, promotes tumor cell proliferation, 
increases invasiveness and dampens anti-tumor immune response, in part by recruiting 
inhibitory neutrophils (Apte et al 2006, Miller et al 2007). Therefore, inhibition of c-MET 
(e.g. with the c-MET inhibitor capmatinib) or the cytokine IL-1β (e.g. with the IL-1∃
antagonist canakinumab) may restore T cell function resulting in tumor response in a 
population with lack of treatment options as of today (refer to the rationale for combining 
capmatinib and canakinumab with spartalizumab in Section 2.4.2 and Section 2.4.3
respectively).
MDSC are a heterogeneous population of immature myeloid cells and represent another 
class of tumor infiltrating cells which are highly immunosuppressive. These cells contribute 
to tumor immune escape by inhibiting cytotoxic T cell proliferation and driving T regulatory 
cell induction. Cytokines such as IL-1∃secreted by tumor cells have been shown to recruit 
MDSC to tumor microenvironment (Guo et al 2016). Therefore, strategies to suppress the 
MDSC population by various ways including inhibition of IL-1∃may offer another 
approach to boost sensitivity to anti PD-1 therapy. 
Using the anti-PD-1 antibody spartalizumab as backbone, this study will evaluate novel 
compounds, which may help alter the tumor microenvironment through different 
mechanisms which may potentially reverse resistance to immune checkpoint blockade and 
restore T cell function.
A specific rationale for each of the combinations tested in is provided in Section 2.4.
2.2
Rationale for the study design
Considering the importance of the inhibitory effect of the PD-1/PD-L1 axis as described in 
Section 2.1, the anti-PD-1 antibody spartalizumab will be used in combination with other 
compounds, which may help alter the tumor microenvironment favorably to potentially
reverse the primary or acquired resistance to checkpoint inhibitor blockade. As outlined in
Section 2.1, there are multiple intrinsic and extrinsic resistance mechanisms, which can be 
targeted to restore T cell activity against the tumor.
Considering the high number of potential targets and available compounds, an open platform 
design is applied for this study. In general, platform designs allow for simultaneous 
assessment of multiple treatments within a single disease under one master protocol (Ventz 
et al 2017, Saville et al 2016). An open platform design starts with a predefined fixed number 
of treatment arms but as new suitable treatments become available during the course of the 
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trial new treatment arms can be added. Those new arms are added based on evolving 
scientific rationale (e.g. mechanism of action), preclinical data and if an acceptable safety 
profile has been established. Furthermore, platform designs offer adaptive features such as 
dropping treatment arms for futility and declaring one or more treatments efficacious. A 
protocol amendment will be needed each time a new arm is added to the study.
The platform study design methodology has been successfully applied as an accelerated 
mechanism to evaluate multiple compounds in various diseases, and has been successfully 
implemented in recent clinical studies (e.g. I-SPY2, STAMPEDE, AML15, AML16) (Ventz 
et al 2017, Saville et al 2016, Renfro 2017, Berry et al 2015, Woodcock et al 2017).
The randomized section of this study is designed as a randomized, open-label, two-part,
multi-center, open platform phase II study to assess the efficacy and safety of novel 
combinations using the anti-PD-1 antibody spartalizumab as a backbone in previously 
treated unresectable or metastatic melanoma. The primary endpoint is confirmed objective 
response rate (ORR) in each combination arm with supportive key secondary endpoint of 
duration of response (DoR) using RECIST v1.1. A study design using those endpoints has 
been utilized as primary means of efficacy evaluation in disease settings with no available 
therapies or in settings where currently available therapy does not provide sufficient 
evidence of benefit. Since there are no available therapies for patients eligible for this study 
(who failed to respond, or progressed while being on standard treatment for unresectable or 
metastatic melanoma), the targeted response rate of 25% is deemed to be clinically 
meaningful and transformative in this patient population and warrants further development.
The non-randomized section of this study is designed to assess the efficacy and safety of 
spartalizumab combined with LAG525 treatment in subjects with previously treated 
unresectable or metastatic LAG-3 positive melanoma. The primary and key secondary
endpoints are similar to the randomized section of this study. The targeted ORR of 30% 
chosen in this arm 1A is deemed to be clinically meaningful and transformative in this 
selected subject population, where the ORR would be expected to be higher than in a 
non-selected population, and warrants further development.
The two sections of the study (randomized and non-randomized) consists of two parts each: 
!
Part 1 (selection phase) to evaluate the preliminary efficacy in terms of ORR of 
spartalizumab in combination with novel agents and to identify combination arm(s) 
that will be expanded to part 2 using Bayesian statistical methodology. Bayesian 
approach is ideally suited for repeated assessment of efficacy data that accrues during 
the course of the study and provides basis for probabilistic decision rules that can 
incorporate prior information.
!
Part 2 (expansion phase) to obtain more precise estimate(s) of ORR in combination 
arm(s) selected for expansion, as well as further investigate their efficacy and safety.
The exploratory ‘selection’ process in Part 1 will be based on the confirmed ORR observed 
in each of treatment combination arms that will be compared against predefined efficacy 
thresholds (discussed in Section 10.4.2.1 for randomized section of this study and in Section 
10.4.2.2 for the non-randomized section) and probabilistic decision rules (also presented in 
Section 10.4.2) to drop arms for futility or advance arms to part 2 will be applied. Hypothesis 
testing approach will be applied after completion of part 2 within each of the arms that were 
expanded to confirm efficacy in those arms (Section 10.4.2). Although, no formal 
comparison among treatment arms is planned, a randomized design is being used in the 
randomized section of this study. Randomization removes the potential of bias in allocation 
of patients in treatment combination arms and ensures comparability of arms in terms of 
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importance of baseline prognostic factors (like baseline level of lactate dehydrogenase 
[LDH]) that allows for meaningful side-by-side comparisons. 
At the time of protocol amendment 5, no arms were enrolling in the randomized section of 
this study (refer to Section 4.1.1). The new arm 1A evaluating the combination of 
spartalizumab with LAG525 is being added as a single arm in the non-randomized section 
of this study. Given the selected LAG3-positive population in non-randomized section, the 
targeted clinically relevant ORR and the ORR corresponding to the null hypothesis will be 
slightly higher than in the randomized section of this study.
The study design as proposed is expected to provide initial preliminary evidence of benefit 
by showing a clinically meaningful magnitude of response rate, which - based on recent 
experience with anti-PD-1 inhibitors - should serve as an appropriate surrogate to predict 
clinical benefit.
It is expected that the suggested study design will allow early identification of successful 
combinations while reducing patient exposure to futile treatments.
2.3
Rationale for dose and regimen selection
2.3.1
LAG525 in combination with spartalizumab
In the phase I/II study [CLAG525X2101C], patients with a variety of advanced solid tumors
have been treated at multiple dose levels of single-agent LAG525 or LAG525 in 
combination with spartalizumab. Overall, single-agent LAG525 and LAG525 in 
combination with spartalizumab were tolerated with safety profiles similar to those of other 
approved checkpoint inhibitors. A maximum tolerated dose was not identified for LAG525. 
Anti-tumor activity was not observed with LAG525 single agent but was seen at several 
dose levels of LAG525 in combination with spartalizumab. There was no clear pattern 
between dose and anti-tumor activity. Therefore, a PK/PD modeling was used to support 
determination of the RP2D. 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 patients [Justification for RP2D report]. Based on the trial simulation of the PK/PD 
model, two RP2Ds were declared for the combination: 400 mg LAG525 Q3W in 
combination with 300 mg spartalizumab Q3W and 800 mg LAG525 Q4W in combination 
with spartalizumab 400 mg Q4W. 
An alternate dose regimen of 600 mg LAG525 Q4W in combination with spartalizumab 400 
mg Q4W was chosen for this study. Even though the LAG525 dose is lower than the 
recommended dose regimen of 800 mg Q4W, the predicted tumor target (LAG-3) 
suppression is similar to the higher dose schedule (88% vs. 92%).
2.3.2
Capmatinib in combination with spartalizumab
In the phase 1b/II study [CINC280X2108], patients with hepatocellular carcinoma (HCC) 
have been treated at multiple dose levels with the combination of capmatinib and 
spartalizumab or spartalizumab single-agent. Based on the observed DLT rate (as described 
in Section 1.2.3.2.2), the BLRM-EWOC model used in this study supports a dose of 400 mg 
capmatinib BID in combination with 300 mg spartalizumab Q3W. In the current study the 
alternate dosing regimen of 400 mg capmatinib BID in combination with spartalizumab 400 
mg Q4W will be used. PK and safety data across dose levels in study [CPDR001X2101]
supported the declaration of two RP2Ds, 300 mg Q3W and 400 mg Q4W, for spartalizumab
as single-agent. Based on the population PK model simulations, both regimens are expected 
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to achieve similar exposure range at steady-state and achieve a mean steady-state Ctrough 
value higher than the in vitro EC50 for antigen-stimulated IL-2 production, a translational 
biomarker for PD-1 blockade [Summary of phase I clinical safety, pharmacokinetic (PK)
and pharmacodynamics (PD) data]. 
2.3.3
Canakinumab in combination with spartalizumab
Data for the combination of canakinumab with spartalizumab is available from a Phase Ib, 
open-label, multi-center study [CPDR001X2103].
From data available as of July 31, 2017 (as described in Section 1.2.4.2.1), there were no 
DLT observed and the Phase I of the study is ongoing. The dose level of canakinumab 600 
mg Q8W in combination with spartalizumab 400 mg Q4W was declared as the RP2D. In 
the current study an alternate dose regimen of canakinumab 300 mg Q4W in combination 
with spartalizumab 400 mg Q4W will be used to align the dosing schedules. Based on the 
population PK model simulations the canakinumab 300 mg Q4W regimen is predicted to 
achieve similar exposure as the canakinumab 600 mg Q8W. Based on the available safety 
data across the doses tested the alternate dose regimen is expected to be well tolerated.
2.3.4
Ribociclib in combination with spartalizumab
The dose (oral administration of 600 mg daily) and regimen (days 1-21 of a 28 day cycle) 
of ribociclib was selected for this study since this dose and regimen were shown to be 
tolerable when combined with endocrine therapy in clinical trials in patients with HR-
positive, HER2-negative advanced BC (see Section 1.2.5.2). A phase I study of the CDK4/6 
inhibitor ribociclib in combination with the PD-1 inhibitor spartalizumab in patients with 
metastatic hormone receptor-positive breast cancer and metastatic ovarian cancer is 
currently ongoing [NCT03294694]. Based on the information from the dose-finding cohort, 
a MTD of 600 mg p.o QD ribociclib in combination with 400mg i.v. Q4W spartalizumab
was declared. An expansion cohort of the doublet later opened for ovarian participants. 
Furthermore, a safety run-in with the addition of fulvestrant for breast cancer 
participants was initiated that led to a dose expansion cohort. Other doses and/or regimens 
of ribociclib in combination with spartalizumab may be explored in this study in the future.
2.4
Rationale for choice of combination drugs
2.4.1
Rationale for LAG525 in combination with spartalizumab
LAG-3 and PD-1 function at multiple levels to control T cell homeostasis, activation, and 
differentiation. Furthermore, they contribute to cell extrinsic regulation by controlling Treg
cell homeostasis and function, and mitigating dendritic cell differentiation and function. As 
a result, simultaneous blockade of LAG-3 and PD-1 may synergistically restore T cell
activation and enhance anti-tumor immunity (Woo et al 2012, Ascierto et al 2017).
In vivo studies have demonstrated a synergistic effect in anti-tumor activity of the dual
blockade of the LAG-3 and PD-1 co-inhibitory receptors when compared to the inhibition 
of either checkpoint alone. CD4+ and CD8+ TIL from Sa1N fibrosarcoma, MC38 colon 
carcinoma and B16 melanoma have previously been shown to co-express PD-1 and LAG-
3.
Combined LAG-3 and PD-1 blockade led to rapid and complete regression of established 
tumors in 70% of Sa1N fibrosarcoma and 80% of MC38 colon carcinoma within 50 days of 
the initiation of therapy. Using the maximum likelihood model, this demonstrated synergy 
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of co-blockade over single agent activity. Both TIL and lymphocytes from draining lymph 
nodes harvested from treated mice had increased numbers of CD8+IFN%+ TIL, further 
supporting the anti-tumor role of co-blockade (Woo et al 2012). Further, data from dual 
LAG-3/PD-1 knockout mice experiments show that compared to wild type, the dual 
knockout mice developed an early onset (4 weeks of age) lethal autoimmune condition that 
resulted in approximately 80% of the mice moribund by approximately 10 weeks. The major 
histopathologic manifestations included diffuse fibrosis, lymphohistiocytic endocarditis, 
myocarditis and pancreatitis. In contrast, LAG-3 and PD-1 single knockout mice lacked any 
disease manifestations or histopathology over this period of observation. These results show 
that the PD-1 and LAG-3 pathways synergistically regulate immune self-reactivity (Woo et 
al 2012).
Taken together, these preclinical data demonstrate that co-blockade of the PD-1 and LAG-
3 pathways leads to synergistic anti-tumor activity superior to blockade of either inhibitory
protein alone (Woo et al 2012). Recently, clinical data showed that patients treated with the 
anti-LAG-3 antibody BMS-986016 in combination with the anti-PD-1 antibody nivolumab 
is well tolerated with a safety profile similar to nivolumab monotherapy and provides 
encouraging efficacy in a heavily pre-treated, advanced melanoma population. Higher 
response rates correlated with higher LAG-3 expression, irrespective of PD-L1 expression 
status (Ascierto et al 2017).
2.4.1.1
Rationale for targeting subjects with LAG-3 positive melanoma in 
arm 1A 
The combination of LAG525 and spartalizumab has been explored in arm 1 within the 
CPDR001J2201 study in unselected metastatic melanoma patients who had progressed on 
prior anti-PD(L)-1 therapy, alone or in combination. Data from the first 35 patients enrolled 
in arm 1 were analyzed as part of the second interim analysis (IA2) and the safety profile of 
spartalizumab plus LAG525 (arm 1) was consistent with the safety profile of the individual 
drugs. The most common adverse events in arm 1 (>20%) were nausea (31.4%) and asthenia 
(22.9%). One subject reported multiple organ dysfunction syndrome as AE leading to 
treatment discontinuation and death. The main reason for treatment discontinuation was 
disease progression (57.1%). The ORR based on local radiology review per RECIST v1.1 
was 8.6% (95% CI:1.8, 23.1) with 3 confirmed responders. The observed responses were 
durable with 2 responders ongoing for 7.4 months at the time of data cut off. The 3rd
responder had brain metastasis and high LDH levels at enrollment and reported a duration 
of response of 3.7 months. LAG-3 status was determined for baseline tumor samples 
collected during screening using immunohistochemistry (IHC) analysis. Of the baseline 
biopsy samples from the 3 clinical responders, 2 samples were positive for LAG-3 and 1 
sample was not evaluable for LAG-3 IHC evaluation but had high LAG3 gene expression as 
analyzed by Nanostring. With only 4 of 35 patients total with positive LAG-3 tumor status,
correlative analyses were limited in arm 1 hence further exploration is warranted to confirm 
these findings. Taken together, the preliminary data support further investigation to validate 
the hypothesis that the spartalizumab plus LAG525 combination could be effective in 
patients with positive LAG-3 tumor status. A centralized IHC assay will be used to select 
patients for arm 1A using a ≥ 5% threshold for positive LAG-3 staining in order to enroll
the same patient population where an enrichment in response was observed in arm 1 during
IA2.
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2.4.2
Rationale for capmatinib in combination with spartalizumab
Stromal release of HGF and increased expression of its receptor c-MET are found in many 
solid tumors including melanoma (Sierra et al 2011; Etnyre et al 2014). c-MET is a receptor 
tyrosine kinase encoded by the MET proto-oncogene that activates several intracellular 
signaling pathways including RAS-MAPK, PI3K-AKT, RAC1, and PAK. As a result, c-
MET signaling regulates proliferation, cell survival, and migration in development, tissue 
regeneration, and tumorigenesis. Further, several studies reported immunosuppressive roles 
for the HGF/c-MET axis such as an impairment of dendritic cell functions and the induction 
of T cell tolerance (Benkhoucha et al 2010, Okunishi et al 2005). High blood neutrophil 
counts and neutrophil-to-lymphocyte ratios predict poor survival in cancer patients and poor 
outcomes to checkpoint inhibitor therapy in melanoma (Ferrucci et al 2015). Current clinical 
studies aim to evaluate the c-MET inhibitors in cancers with deregulated c-MET signaling 
A multitude of effects of HGF/c-MET signaling on identity and function of immune cells 
has been reported in the preclinical literature (Molnarfi et al 2015). A common theme is the 
modulation of dendritic cell function by HGF towards a “tolerogenic” phenotype. Therefore, 
inhibition of c-MET signaling on dendritic cells is expected to improve their T cell 
stimulatory activity, suggesting that capmatinib has the potential to enhance the efficacy of 
immunotherapies such as checkpoint blockade by anti-PD-1 antibodies. Indeed, a recent 
preclinical study showed that inhibition of c-MET with capmatinib or genetic knockout can 
enhance T cell mediated anti-tumor immunity in a variety of treatment regimens and mouse 
models (Glodde et al 2017). The proposed mechanism in this report is different from the 
dendritic cell hypothesis and based on a c-MET dependent reactive neutrophil response: 
when T cells attack and kill tumor cells, the ensuing tissue damage triggers a repair response 
that involves secretion of HGF by the tumor-associated stroma. As a consequence, 
neutrophils with immunosuppressive properties are mobilized and migrate to the tumor, 
dampening the T cell response. This negative feedback can be prevented by capmatinib. 
Both of these preclinical hypotheses suggest that inhibition of c-MET on immune cells may 
be beneficial for T cell mediated anti-tumor immunity.
In order to independently reproduce these results, the combination of anti-PD-1 and 
capmatinib was tested in two syngeneic mouse models at Novartis [RD-2017-00370 draft 
report]: the widely used MC38 colon cancer model was tested, which was originally 
generated by chemical mutagenesis and bears a high mutation burden. Combination 
treatment led to increased T cell infiltration in the short term, and an improved anti-tumor 
immune response with a higher cure rate than either single agent in the long term. MC38 
cells were not sensitive to capmatinib in vitro. The in vivo studies were extended in a second 
model that was generated at Novartis in a genetically engineered mouse strain with error-
prone DNA replication, which also leads to a high mutation burden. Again, addition of 
capmatinib to anti-PD-1 therapy led to an increased cure rate, while the c-MET inhibitor 
was largely inactive on its own.
Besides these direct functional data in mouse models, the reported immunosuppressive 
effects of HGF/MET on dendritic cells (summarized above) further support the rationale for 
combining anti-PD-1 and capmatinib, because both agents have the potential to enhance T 
cell mediated anti-tumor immunity through complementary mechanisms. While inhibition 
of HGF/c-MET signaling is expected to enhance antigen presentation and T cell stimulation 
by dendritic cells, anti-PD-1 antibodies will prevent suppression of T cell function through 
PD-L1 expressed on tumor cells or other immune cells.
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2.4.3
Rationale for canakinumab in combination with spartalizumab
The IL-1 family consists of agonistic and antagonistic molecules as well as receptors. The 
two major agonistic proteins are IL-1# and IL-1∃. IL-1∃is not present under homeostatic 
conditions, but is induced and secreted upon inflammatory signals (Voronov et al 2014).
Solid tumors in which IL-1∃has been shown to be upregulated include breast, colon, lung, 
head and neck cancers and melanoma, and patients with IL-1∃producing tumors have 
generally a poor prognosis (Lewis et al 2006). Secreted IL-1∃, derived from the tumor 
microenvironment and secreted by malignant cells, promotes tumor cell proliferation, 
increases invasiveness and dampens anti-tumor immune response, in part by recruiting 
inhibitory neutrophils (Apte et al 2006, Miller et al 2007). In addition, IL-1β derived from 
inflammasome activation or cancer cell lines expressing high IL-1β promote generation and 
infiltration of immunosuppressive myeloid cells such as myeloid-derived suppressor cells 
(MDSC) and tumor-associated macrophages (TAMs) into tumor microenvironments (Guo 
et al 2016, Lechner et al 2010). Such cells were found to be enriched and activated in 
melanoma, hindering anti-tumor immune responses and leading to the tumor progression
(Umansky et al 2014, Martens et al 2014). Experimentally, inhibition of IL-1∃results in a 
decrease in tumor burden and metastasis (Voronov et al 2003) and also reduced the 
recruitment of myeloid cells in preclinical breast cancer models (Guo et al 2016). 
Importantly, reducing MDSC levels were also shown to increase sensitivity to anti-PD-1 
therapy syngeneic mouse tumor models (lung and renal cell cancer) (Orillion et al 2017).
Canakinumab is a high-affinity human monoclonal antibody against interleukin-1β (IL-1β). 
Recent results from a large randomized, double-blind phase III study of canakinumab in 
patients with cardiovascular disease showed that canakinumab reduced the occurrence of 
lung cancers (Ridker et al 2017b). By inhibiting the pro-inflammatory cytokine IL-1∃, 
canakinumab may alter the inflammation in the tumor microenvironment in a positive way, 
which in combination with spartalizumab could overcome resistance.
2.4.4
Rationale for ribociclib in combination with spartalizumab
The cyclin D-CDK 4/6-p16INK4-pRb signaling pathway plays a key role in mammalian cell 
proliferation, where D cyclins bind to and activate CDK4/6, which phosphorylates pRb and 
drives progression of the cell cycle at the G1/S phase transition checkpoint (Ortega et al 
2002, Shapiro 2006). The majority of cancers (~80%) maintain a functional pRb and alter 
the positive and negative regulators of CDK4/6 to increase activity of these kinases (Ortega 
et al 2002, Shapiro 2006). Copy number variation or overexpression in at least one 
component of the cyclin D-CDK4/6 pathway is seen in approximately 75% of melanoma 
(Young et al 2014).
Pharmacological inhibition of CDK4/6 in vitro are cytostatic causing downregulation of E2F 
target genes, loss of proliferation markers and cell cycle arrest in G1. However, only modest 
clinical benefit was observed in the unselected early clinical phase trials of single agent 
CDK4/6 inhibitors. Based on these findings, synergistic combinations with CDK4/6 
inhibitors are being explored to amplify the efficacy of CDK4/6 inhibitors. CDK4/6 
inhibitors can induce senescence and senescent cells are associated with activation of the 
innate and adaptive immune system as they secrete a collection of inflammatory cytokines, 
chemokines and proteinases, collectively referred to as the senescence associated secretory 
phenotype (SASP) (Xue et al 2007). Additionally, CDK4/6 inhibitors have shown to 
increase cancer cell presentation of tumor neoantigens on major histocompatibility complex 
(MHC) class I molecules. CDK4/6 inhibitors have also been shown to suppress the 
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proliferation of immunosuppressive regulatory T cells, increase nuclear levels of NFAT and 
increased transcriptional activity resulting in a change in the cytokine milieu within the 
tumor microenvironment and increased effector T cell activity (Deng et al 2018). 
The cytotoxic T cell-mediated clearance of tumor cells, along with the efficacy of CDK4/6 
inhibition on tumor growth, have been shown to be further enhanced with immune 
checkpoint blockade (Schaer et al 2018, Jerby-Arnon et al 2018, Goel et al 2017). 
Furthermore, CDK4 was implicated in a tumor cell resistance program including T cell 
exclusion and immune evasion and CDK4/6-inhibition was shown to repress the program 
and overcome resistance to anti-PD1 therapy (Jerby-Arnon et al 2018). Given the magnitude 
of immune modulatory effects observed from CDK4/6 inhibitors, the combination of 
CDK4/6 inhibitors with check point inhibitors such as anti PD1/PDL1 offers a novel 
treatment strategy in patients with relapsed/ refractory melanoma. 
2.5
Rationale for choice of comparators drugs
Not applicable.
2.6
Risks and benefits
Subjects enrolled in this study have not responded to, or progressed on, the approved 
treatments for unresectable or metastatic melanoma (e.g. checkpoint inhibitors and/or 
targeted therapy) and have very limited treatment options. There is no established standard 
of care for this population. The combinations tested in this study may help alter the tumor 
microenvironment through different mechanisms which may potentially reverse the 
observed intrinsic and extrinsic resistance mechanisms (Section 2.1).
Specific risks for each compound and combination are discussed below. Implementation of 
dose modification and stopping rules, appropriate adverse event management, adherence to 
the protocol specific procedures and eligibility criteria, and close clinical monitoring (as 
mandated by the protocol) may further minimize the risk to subjects. As in any clinical study, 
there may be unforeseen risks with any of the combinations studied, which could be serious. 
AE grades indicated in the subsections below for each study combination are using CTCAE 
v4.03, unless otherwise specified.
2.6.1
LAG525 and spartalizumab
Immune checkpoint inhibitors like LAG525 and spartalizumab may be associated with the 
occurrence of immune-mediated adverse events (irAEs). In general, irAEs can potentially 
involve every organ system with gastrointestinal (colitis), dermatologic, hepatic (hepatitis), 
pulmonary (pneumonitis), renal (nephritis) and endocrine toxicities (hypothyroidism, 
hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism and adrenal 
insufficiency) being typically among the most frequent side effects. Other immune mediated 
AEs may rarely include the nervous system (e.g., encephalitis, Guillain-Barre syndrome, 
and myasthenia gravis), eye (e.g., uveitis), musculo-skeletal system (e.g., myositis, arthritis), 
cardiovascular system (e.g., vasculitis, myocarditis) or blood system (e.g., anemia). These 
side effects are generally manageable and reversible with dose interruption and 
administration of corticosteroids. 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 irAE may also occur after discontinuation of study 
treatment (Puzanov et al 2017). While the incidence of immune-related adverse events with 
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single-agent anti PD-1 has been well characterized there may be a higher incidence of 
immune related adverse events with combination immune therapies, including the 
combination of LAG525 with spartalizumab. In addition, monoclonal antibodies such as 
spartalizumab and LAG525 can be associated with infusion-related reactions, which can be 
severe in some cases; these are often immediate and usually occur within minutes of the 
exposure to the study drug. 
Combining immune checkpoint inhibitors targeting distinct inhibitory pathways 
demonstrated greater anti-tumor activity than each of the single-agents alone. In preclinical 
models, dual blockade of LAG-3 and PD-1 eradicated established melanoma and colon 
adenocarcinoma tumors that were largely resistant to single agent 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 [CCLAG525X2101C], treatment with LAG525 single agent and in combination 
with spartalizumab was well tolerated. LAG525 and spartalizumab showed promising 
efficacy, with RECIST responses across all dosage groups.
2.6.2
Capmatinib and spartalizumab
In rat and monkey studies, reversible pancreatic acinar cell vacuolation and/or apoptosis 
without inflammation were observed with capmatinib. Elevations in lipase and/or amylase 
were also seen during clinical development. When capmatinib is administered as a single 
agent, severe pancreatic events are reported in a number of patients. In study
[CINC280A2201] study, grade 3/4 AEs of increased amylase suspected to be related to 
study treatment have been reported in 1 patient (0.5%) and Grade 3/4 increase in lipase 
suspected to be related to study treatment occurred in 9 patients (4.1%). Based on the current 
available data, a direct toxic effect of capmatinib on pancreas could not be definitively 
identified. Routine periodic clinical evaluations including serum amylase and lipase will be 
performed in this study. Further, patients with elevated amylase and/or lipase are excluded 
from this study. 
The safety of the combination of capmatinib with spartalizumab is generally consistent with 
the single-agent experience for both compounds. No unexpected adverse events as 
compared with single agent data were observed. 
In preclinical models, the combination treatment led to increased T cell infiltration in the 
short term, and an improved anti-tumor immune response with a higher cure rate than either 
single agent in the long term. Besides these direct functional data in mouse models, the 
reported immunosuppressive effects of HGF/MET on dendritic cells further support the 
rationale for combining anti-PD-1 and capmatinib, because both agents have the potential 
to enhance T cell-mediated anti-tumor immunity through complementary mechanisms. 
It is hypothesized that the combination of capmatinib with spartalizumab may reverse
resistance to checkpoint inhibitor therapy and restore T cell activity against the tumor in the 
subjects enrolled, which have very limited options.
2.6.3
Canakinumab and spartalizumab
Canakinumab is approved for the treatment of several inflammatory disorders in many 
countries and is marketed under the trade name ILARIS®. No dose-limiting toxicities of 
canakinumab have been observed in subjects receiving doses of up to 600 mg i.v. Q4W for 
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26 weeks (or with chronic dosing of up to 300 mg s.c. Q4W for over 2 years. Due to the 
mode of action of all inhibitors of the IL-1 pathway, infection is an important concern. As a 
result, subjects will be closely monitored for signs or symptoms of infection and appropriate 
treatment instituted in a timely manner (see Section 6.4.1). Monoclonal antibodies such as 
spartalizumab can be associated with infusion-related reactions, which can be severe in 
some cases; these are often immediate and usually occur within minutes of the exposure to 
the study drug.
The combination of canakinumab with spartalizumab was well tolerated (see Section 
1.2.4.2.2). The most frequent AEs suspected to be related to study treatment were fatigue 
and decreased appetite. No patient had a Grade 3/4 AE that was suspected to be related to 
study treatment. There were no DLT observed. 
It is hypothesized that the combination of canakinumab with spartalizumab may reverse
resistance to checkpoint inhibitor therapy and restore T cell activity against the tumor in the 
subjects enrolled, which have very limited options.
2.6.4
Ribociclib and spartalizumab
Based on clinical data, treatment of ribociclib in combination with NSAI appears tolerable 
and toxicities of the treatment are expected to be manageable and reversible with treatment 
interruption, ribociclib dose reduction, or discontinuation. The 600 mg dose of ribociclib in 
combination with an NSAI has been investigated in the MONALEESA-2 and 
MONALEESA-7 Phase III studies in post- and premenopausal women with aBC 
respectively. Further details can be found in the latest [ribociclib Investigator’s Brochure]. 
A phase I study of the CDK4/6 inhibitor ribociclib in combination with the PD-1 inhibitor 
spartalizumab in patients with metastatic hormone receptor-positive breast cancer and 
metastatic ovarian cancer is currently ongoing (NCT03294694). Based on the information 
from the dose finding cohort, a MTD of 600 mg p.o. QD ribociclib in combination with 
400mg i.v. Q4W spartalizumab was declared. An expansion cohort of the doublet later 
opened for ovarian participants. Furthermore, a safety run-in with the addition of fulvestrant 
for breast cancer participants was initiated that led to a dose expansion cohort.
Patients in this study where ribociclib will be given in combination with spartalizumab will 
be carefully monitored for key toxicities that have been observed with ribociclib (refer to 
the current [ribociclib Investigator’s Brochure]) and spartalizumab, and risks will be further 
minimized by adherence to inclusion/exclusion selection criteria, avoidance of prohibited 
medications, close safety monitoring and dose modification guidelines.
As per the inclusion/exclusion selection criteria, 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 must agree that in order to participate in the 
study they must adhere to the contraception requirements outlined in the exclusion criteria. 
If there is any question that the patient will not reliably comply, they should not be entered 
or continue in the study.
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below. These are applicable to 
all arms.
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Table 3-1
Objectives and related endpoints
Primary objective
Endpoint
Analysis
To evaluate the efficacy of each combination arm, as 
measured by confirmed objective response rate 
(ORR)
Confirmed ORR using RECIST v1.1, per local assessment
Refer to Section 10.4
Key secondary objective
Endpoint
Analysis
To evaluate the efficacy of each combination arm in 
terms of duration of response (DoR)
DoR using RECIST v1.1, per local assessment
Refer to Section 10.5.1
Other secondary objectives
Endpoint
Analysis
To evaluate the efficacy of each combination arm as 
measured by progression-free survival (PFS) and
disease control rate (DCR) 
PFS and DCR, assessed using RECIST v1.1, per local assessment
Refer to Section 10.5.2
To evaluate the overall survival (OS) of each 
combination arm
Overall survival (OS)
Refer to Section 10.5.2
To characterize the safety and tolerability of each 
combination arm
Safety: Incidence and severity of AEs including changes in laboratory values, 
vital signs and cardiac assessment. 
Tolerability: Dose interruptions, reductions, and permanent discontinuations of 
study treatments
Refer to Section 10.5.3
To characterize the prevalence and incidence of 
immunogenicity of spartalizumab, LAG525 and 
canakinumab in each combination arm
Anti-drug antibodies (ADA) prevalence at baseline and ADA incidence on 
treatment
Refer to Section 10.5.4
To evaluate changes in levels and phenotype of T cell 
populations in the tumor and tumor microenvironment 
after treatment with combination therapies
Proportion of subjects with a favorable biomarker profile (pFBP), as defined by 
changes in numbers of cells expressing the CD8+ T cell marker and/or T cell 
activation marker(s), T cell clonality and/or gene expression in tumor biopsy 
samples collected at baseline (screening) and compared to on treatment (3-4 
weeks) samples
Refer to Section 10.5.5
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4
Study design
4.1
Description of study design
This is a randomized, open-label, multi-center, two-part, open platform phase II study to 
assess the efficacy and safety of the anti-PD-1 antibody spartalizumab in combination with 
novel agents in previously treated unresectable or metastatic melanoma. A non-randomized
arm 1A has been added with protocol amendment 5 based on findings in arm 1 at IA2. Arm 
1A is assessing the efficacy and safety of spartalizumab in combination with LAG525 in 
subjects with previously treated unresectable or metastatic LAG-3 positive melanoma. 
This study consists of two parts, applicable for both randomized and non-randomized 
sections of the study:
!
Part 1 : Selection phase 
The primary objective of part 1 is to evaluate the preliminary ORR of spartalizumab in 
combination with novel agents in patients with previously treated unresectable or 
metastatic melanoma. 
!
Part 2 : Expansion phase
The primary objective for part 2 is to further characterize ORR of spartalizumab in 
combination with novel agents with relevant preliminary activity, as determined in part 1, 
for patients with previously treated unresectable or metastatic melanoma. 
4.1.1
Randomized section of the study
At any time during the study, subjects deemed eligible after the completion of screening 
procedures will be randomized into any of the combination arms open to enrollment in the 
randomized section of this study (in either part 1 or part 2) for which the subject meets the 
eligibility criteria as described in Section 5 using an Interactive Response Technology (IRT) 
system. For each arm, randomization will be stratified by baseline level of lactate 
dehydrogenase (LDH). Stratification will occur with subjects with baseline LDH ≤ ULN 
(upper limit of normal), and subjects with baseline LDH > ULN.
Crossover or re-randomization of subjects to other combination arms, including better 
performing arms, is not allowed.
The first four arms evaluated in the randomized section of this study will enroll 
approximately a maximum of 230 subjects in total (for both parts of the study): 
approximately a maximum of 180 subjects in the selection phase (if all four combination 
arms enroll the maximum of 45 subjects) and approximately 50 subjects in the expansion 
phase (assuming that only one of the four initial combination arms will be expanded). If 
additional arms are expanded, then the maximum sample size will increase accordingly.
Part 1: Selection phase
The randomized section of this study started with the following three initial combination 
arms among which eligible subjects will be randomized with equal probability:
!
Arm 1: LAG525 600 mg i.v. Q4W and spartalizumab 400 mg i.v. Q4W 
!
Declared futile at interim analysis 2
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!
Arm 2: capmatinib 400 mg p.o BID and spartalizumab 400 mg i.v. Q4W 
!
Declared futile at interim analysis 1 
!
Arm 3: canakinumab 300 mg s.c. Q4W and spartalizumab 400 mg i.v. Q4W 
!
Declared futile at interim analysis 1 
With protocol amendment 3, a fourth combination arm (Arm 4) was added:
!
Arm 4: ribociclib 600 mg p.o QD on Days 1 to 21 of a 28-day cycle and spartalizumab 
400 mg i.v. Q4W 
!
Declared futile at interim analysis 3 
After approval of protocol amendment 3 at each respective study site, eligible subjects will 
be randomized with equal probability across any of the four arms that are still open to 
enrollment within the selection phase.
As dose regimens for additional new combinations with spartalizumab become established, 
new combination arms will be added under the same master protocol through protocol 
amendments. A maximum of 10 arms may be active (open to enrollment) at any given time 
under this master protocol, and any arms active in part 1 will continue to be randomized 
with equal probability.
At each interim analysis, it will be determined which arm(s) (1) is declared efficacious and 
will be expanded to part 2, (2) will continue enrollment in part 1 (up to a maximum of 45 
subjects enrolled in a given arm) or (3) will be dropped for futility, taking into account all 
available efficacy, safety and biomarker data. If a combination arm can be expanded to part 
2, the exact sample size for part 2 will be determined at that time when the decision to 
expand this arm is taken (refer to Section 10.8.1 for further details on sample size 
considerations). The timing of interim analyses and the criteria used for decision-making at 
each interim analysis are detailed in Section 4.2.1and Section 10.
The maximum sample size for the first four arms in part 1 is approximately 180 subjects.
However, based on simulations of sample size detailed in Section 10.8.1, it is expected that 
approximately 92-121 subjects will be enrolled in the first four arms during the selection 
phase. 
Arm 1 (LAG525 plus spartalizumab) did not meet the efficacy nor the futility criterion at 
interim analysis 1, and enrollment was continued until the maximum of 45 subjects were 
randomized, and the arm was declared futile at interim analysis 2. However, findings 
supporting a potentially enriched response in subjects with LAG-3 positive tumor in arm1, 
warrant further development of the LAG525 plus spartalizumab combination in a LAG-3
positive selected patient population (refer to the rationale for arm 1A in Section 2.4.1.1).
Arm 2 (capmatinib plus spartalizumab) and arm 3 (canakinumab plus spartalizumab) were 
declared futile based on protocol specific criteria at interim analysis 1 and enrollment was 
consequently stopped for these arms. Arm 4 (ribociclib plus spartalizumab) was declared 
futile at interim analysis 3 after the enrollment in this arm was stopped at 44 subjects due to 
COVID-19 situation.
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Part 2: Expansion phase
Only combinations arms that have met the pre-specified criteria defined in Section 4.2 and 
Section 10 will be opened for enrollment in part 2.
Exact randomization strategies in the situation when there is one (or more) arms open for 
enrollment in part 2 and there are still arms open for enrollment in part 1 will be determined 
at the time of the selection of the arm that will be expanded in part 2. Four factors will be 
considered at the time of opening an arm in part 2 to determine the exact randomization 
strategy and those are the following:
!
Number of subjects enrolled in part 1 for the arm that meets criteria for expansion 
in part 2
!
Number of subjects that will need to be enrolled in part 2 to have sufficient 
predictive power and alpha control
!
Observed effect size (ORR) for the arm that meets criteria for expansion in part 2
!
Observed effect size of other arms which are open for enrollment in part 1
Based on the sample size assumptions detailed in Section 10.8.1 and the assumption that 
only one of the four initial arms will meet the criteria for efficacy and will be expanded to 
part 2, it is expected that approximately 50 subjects will be enrolled in the expansion phase.
The study design for the randomized section of this study is schematized in Figure 4-1.
Figure 4-1
Overview of study design for randomized section of the study
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4.1.2
Non-randomized section of the study
Subjects meeting the eligibility criteria for arm 1A, as described in Section 5, after the 
completion of screening procedures will be enrolled in this arm (in either part 1 or part 2) 
using the same Interactive Response Technology (IRT) system as used for the randomized 
section of the study. 
Arm 1A will enroll up to approximately 100 subjects in total with LAG-3 positive melanoma 
(for both parts of the study) unless further exploration of this arm is stopped after 1st or 2nd
interim analysis: 20 subjects in the selection phase and up to approximately 80 subjects in 
the expansion phase.
Part 1: Selection phase
After approval of protocol amendment 5, the following non-randomized combination arm 
will be opened for enrollment in part 1:
!
Arm 1A: LAG525 600 mg i.v. Q4W and spartalizumab 400 mg i.v. Q4W, assessed in 
a population selected based on the LAG-3 status of their tumor.
Twenty (20) subjects will be treated in arm 1A in part 1. One interim analysis on these 20 
subjects will be conducted as described in Section 4.2.2 to determine whether the efficacy 
probabilistic threshold is crossed for arm 1A and thus arm 1A may be expanded to part 2 or 
be dropped for futility.
Part 2: Expansion phase
Arm 1A will be opened for enrollment in part 2 only if the pre-specified criterion defined in 
Section 4.2.2 and Section 10.4.2.2 for this arm is met.
Based on the sample size assumptions detailed in Section 10.8.2, it is expected that up to 
approximately 80 subjects will be treated in arm 1A in the expansion phase, unless further 
exploration of this arm is stopped after 2nd interim analysis.
A second interim analysis will be conducted based on data from 20 additional subjects
treated in expansion phase (i.e. 40 subjects in total combined with part 1 subjects) as 
described in Section 10.4.2.2 to support and inform decision-making on whether the arm 1A 
will be further explored or dropped for futility.
Enrollment may be held after 20 subjects are treated in part 2 until the outcome of the 2nd
interim analysis is available.
Novartis may decide at any time during the study to prematurely stop enrollment in arm 1A 
for any reason.The study design for the non-randomized section of the study is schematized 
in Figure 4-2.
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Figure 4-2
Overview of study design for non-randomized section of the study
4.1.3
Subject-level study design (common to randomized and 
non-randomized sections of the study)
Subjects in both part 1 and part 2 will undergo the same study periods as described below
and in Figure 4-3 and will have assessments performed as described in Table 7-2:
Screening period 
Subjects must sign the provided IRB/EC approved study informed consent form (ICF) prior 
to any study specific screening procedure. Refer to Section 7.1.2 for details on screening 
procedures and timing.
Treatment period
The treatment period begins when the first dose of study treatment is administered to the 
subject (on Day 1 of Cycle 1
[C1D1]), maximum 3 days after date of 
randomization/enrollment. 
After randomization in one of the open arms (or enrollment in arm 1A) in part 1 or part 2, 
subjects will receive the study treatment corresponding to their arm on a 28-day cycle basis
as described in Section 6 until disease progression per RECIST v1.1 by local assessment, 
unacceptable toxicity, start of subsequent anti-cancer therapy, withdrawal of consent, 
investigator’s decision, lost to follow-up, death, or study is terminated by the sponsor. 
Subjects will be followed as per the schedule of assessments defined in Section 7.
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The first RECIST v1.1 tumor assessment is scheduled 12 weeks after the date of 
randomization (or after the date of first dose of study treatment in arm 1A) and subsequent 
tumor assessments are detailed in Section 7.2.1.
Subjects may continue study treatment beyond disease progression by RECIST v1.1 if 
considered to be in the best interest of the subject and as long as all the protocol-specific 
criteria defined in Section 6.1.5.1 are met. In this case, the subject will continue assessments 
as defined in Section 7.
End of Treatment
Subjects should be scheduled for an End of Treatment (EoT) visit (refer to Section 7.1.5 for 
assessments to be performed) within 7 days after permanent discontinuation of study 
treatment for any reason (i.e. within 7 days after the last dose of the last study drug or after 
the date when decision was made to permanently discontinue both study drugs/the last study 
drug).
Safety follow-up
After study treatment discontinuation, all subjects must be followed for safety evaluations 
up to 150 days after the last dose of study treatment as outlined in Section 7.1.7.
Efficacy follow-up
In parallel with the safety follow up, subjects who have permanently discontinued study 
treatment for any reason other than disease progression by RECIST v1.1 will continue tumor 
assessments as outlined in Section 7.1.8 until documented disease progression per RECIST 
v1.1 by local assessment, withdrawal of consent, lost to follow-up, death, or study is 
terminated by the sponsor. Every effort will be made to continue collection of tumor 
assessments even after start of another anti-cancer therapy for subjects that have not 
progressed.
Survival follow-up
Survival status and all subsequent anti-cancer therapies initiated after study treatment 
discontinuation (radiotherapies, surgeries and medications, including regimen number, 
names of all medications received within each regimen and start/end dates for each 
medication) will be collected as outlined in Section 7.1.9 until death, withdrawal of consent, 
lost to follow-up or end of study.
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Figure 4-3
Overview of study design at subject level.
4.2
Timing of interim analyses and design adaptations 
4.2.1
Randomized section of the study
The first interim analysis will be conducted in part 1 after approximately 10 subjects have 
been enrolled in each of the first three arms (arm 1, arm 2 and arm 3) and have completed 
the second post-baseline tumor assessment or have discontinued study treatment prior to 
completing the second post-baseline tumor assessment. The requirement to have at least 10 
subjects in each arm is based on simulations showing that 10 is the minimal number of 
subjects to be able to declare futility as per decision rules presented below and also in 
Section 10.4.2.1.
Subsequent interim analyses in part 1 will be conducted approximately every 20 weeks
thereafter (since the first post-baseline assessment occurs at week 12, and the next post-
baseline assessment occurs 8 weeks later) until sufficient subjects have been enrolled to 
assess if a combination is futile or meets the criteria for expansion in part 2. The first interim 
analysis for arm 4 (ribociclib and spartalizumab) will be synchronized with the subsequent 
planned interim analyses for the other arms and will occur when at least 10 subjects have
been randomized to that arm and have either completed two post-baseline tumor 
assessments or have discontinued study treatment. Each interim analysis will be linked to a 
clinical decision point. Although the formal interim decisions rules and statistical thresholds 
(described in the paragraph below and in Section 10) are based on the observed confirmed 
ORR, all available efficacy, safety and biomarker data will be considered at each decision 
point to determine arms which are (1) considered futile, (2) will be expanded in part 2, or
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(3) will continue enrollment in part 1 (until a maximum of 45 subjects).
 
Figure 4-4 presents pre-specified 
criteria for decision-making.
Statistical thresholds for efficacy and futility to be used at each interim analysis are defined 
as P(true ORR ≥ 20%) ≥ 70% and P(true ORR ≤ 15%) ≥ 70%, respectively. These statistical 
thresholds were chosen based on simulations so that clinically meaningful ORR thresholds 
of 10% for futility and 25% for efficacy are achieved with high probability (as presented in 
Table 10-10 in Section 10.8). The targeted ORR of 25% is deemed to be transformative in 
this population, since treatments are very limited for subjects who have not responded to, or 
progressed on the approved therapies for unresectable or metastatic melanoma. The 
probabilities will be calculated at each decision point for each arm based on observed 
confirmed ORR. Further details are provided in Section 10.4.2.1.
No interim analysis is planned for part 2. 
Figure 4-4
Pre-specified criteria for decision making at each decision point
(interim analysis) in part 1 to determine expansion in part 2 or drop 
of a combination arm
Of note, interim analyses will continue to be performed in the randomized section of the 
study at the pre-defined frequency until a clinical decision (e.g. arm declared futile or 
efficacy probabilistic thresholds crossed) on each arm in part 1 has been made. Even if 
declared futile, combination arms will be analyzed at subsequent interim analyses until all 
subjects have been reported at least once (i.e. had a minimum follow-up of 20 weeks). 
Additional descriptive analyses may be performed if required.
4.2.2
Non-randomized section of the study
The first interim analysis will occur in part 1 once all 20 subjects have been treated in arm 
1A (in part 1) and followed up for at least two post-baseline efficacy assessments or have 
discontinued study treatment.
If arm 1A is expanded in part 2, the second interim analysis will be conducted once 20 
additional subjects (i.e. 40 subjects in total combined with part 1 subjects) have been treated
in the expansion phase and followed up for at least two post-baseline efficacy assessments 
or have discontinued study treatment.
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Each interim analysis will be linked to a clinical decision point. Although the formal interim 
decisions rules and statistical thresholds (described in the paragraph below and in Section 
10) are based on the observed confirmed ORR, all available data will be considered at this 
decision point to determine if the arm 1A is (1) considered futile, or (2) the efficacy 
probabilistic threshold is crossed and arm 1A may be expanded in part 2/may continue 
enrollment in part 2 at time of first interim analysis/2nd interim analysis respectively.
Statistical thresholds for efficacy and futility to be used is defined as P(true ORR 
≥20%) > 70% and P(true ORR ≥ 20%) ≤70%, respectively. These statistical thresholds 
were chosen so that there is a sufficient efficacy signal observed before advancing this arm 
to the expansion phase and to ensure that if the true underlying ORR is 30% (clinically 
meaningful ORR) then the probability of crossing the threshold is sufficiently large (as 
presented in Section 10.4.2.2). The targeted ORR of 30% is deemed to be clinically 
meaningful and transformative in this selected patient population, where the ORR would be 
expected to be higher than in a non-selected population. The probabilities will be calculated 
based on observed confirmed ORR. Further details are provided in Section 10.4.2.2.
4.3
Definition of end of study
Timing of the randomized and non-randomized primary analysis is directly driven by the 
enrollment of the expansion arm of each section, and the primary analysis of each section
will be run once the expanded arm has fully enrolled and also after all patients 
randomized/enrolled in that arm had at least 9 months of follow-up. This timing would allow 
for a potential minimum duration of response of 6 months for all subjects 
randomized/enrolled, assuming no delayed response. The exact timing of the randomized 
primary analysis could be revisited if more than one arm ends up being expanded.
Following the cut-off date for the primary analysis, the study will remain open. Ongoing 
subjects will continue to receive study treatment and will be followed as per the schedule of 
assessments, as long as subjects derive benefit from the combination arms in the opinion of 
the investigator. 
The end of study is defined as the earliest occurrence of one of the following:
!
All subjects have died or discontinued from the study
!
Another clinical study (i.e. rollover study) becomes available that can continue to 
provide the appropriate combination treatment in this subject population and all 
subjects ongoing are eligible to be transferred to that clinical study
!
All subjects randomized/enrolled in the study have at least 15 months of follow-up 
(i.e. 15 months after last subject is randomized/enrolled). For subjects still 
receiving study treatment at the time of end of study, every effort will be made to 
continue provision of study treatment outside this study through an alternative 
setting (e.g. Novartis managed access program) to subjects who in the opinion of 
the investigator are still deriving clinical benefit.
The final analysis and the generation of the final CSR will occur at the end of the study.
The timing of primary and final analyses and the definition of end of study will be updated, 
should new arms be added through protocol amendment or if more than one arm is expanded 
to part 2.
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4.4
Early study termination
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the subject should be seen as soon as possible and the same assessments should be performed 
as described in Section 7 for a discontinued or withdrawn subject. 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 subject’s interests. The investigator will be 
responsible for informing IRBs and/or ECs of the early termination of the trial.
5
Population
5.1
Patient population
The investigator or designee must ensure that only subjects who meet all the following 
inclusion and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
5.2.1
Inclusion criteria for arms 1, 2, 3, 4
Subjects eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Male or female must be ≥ 18 years of age at time of providing informed consent. 
3. Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma
using AJCC Edition 8 (refer to Appendix 1)
4a. Previously treated for unresectable or metastatic melanoma:
-
Subjects with V600BRAF wild-type disease:
!
Subjects must have received prior systemic therapy for unresectable or 
metastatic melanoma with anti-PD-1/PD-L1. Additionally, subjects may 
have received anti-CTLA-4 as a single agent or in combination with anti-
PD-1/PD-L1, irrespective of the sequence. No additional systemic treatment 
is allowed for advanced or metastatic melanoma
!
A maximum of two prior lines of systemic therapies for unresectable or 
metastatic melanoma are allowed.
!
The last dose of prior therapy (anti-PD-1, anti-PD-L1 or anti-CTLA-4) must 
have been received more than four weeks before randomization.
-
Subjects with V600BRAF mutant disease:
!
Subjects must have received prior systemic therapy for unresectable or 
metastatic melanoma with anti-PD-1/PD-L1, and V600BRAF inhibitor. 
Additionally, subjects may have received anti-CTLA-4 as a single agent or 
in combination with anti-PD-1/PD-L1, or MEK inhibitor (in combination 
with V600BRAF inhibitor or as a single agent), irrespective of the 
sequence. No additional systemic treatment is allowed for advanced or 
metastatic melanoma 
!
A maximum of three prior lines of systemic therapies for unresectable or 
metastatic melanoma are allowed
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!
The last dose of prior therapy must have been received more than 4 weeks 
(for anti-PD-1, anti-PD-L1 or anti-CTLA-4) or more than 2 weeks (for 
V600BRAF or MEK inhibitor) prior to randomization
-
For all subjects with V600BRAF wild-type disease and with V600BRAF mutant 
disease: Subject must have documented disease progression as per RECIST v1.1 
while on/after the last therapy received prior to study entry and while on/after 
treatment with anti-PD1/PD-L1. The last progression must have occured within 
12 weeks prior to randomization in the study
5. ECOG performance status 0-2
6. At least one measurable lesion per RECIST v1.1 (refer to Appendix 2)
7a. At least one lesion, suitable for sequential mandatory tumor biopsies (screening and on-
treatment) in accordance with the biopsy guidelines specified in protocol Section 
7.2.3.1.1. The same lesion must be biopsied sequentially. Note: this lesion cannot be 
used as a target lesion.
8a. Screening tumor biopsy must fulfill the tissue quality criteria outlined in Section 
7.2.3.1.1, as assessed by a local pathologist 
9a. Subject must meet the following laboratory values at the screening visit in the absence 
of growth factors and/or transfusion support within 14 days prior to screening blood draw:
Hematological
!
Hemoglobin ≥9 g/dL
!
Absolute neutrophil count ≥1.5 × 109/L
!
Platelets ≥75 × 109/L
Renal
!
Serum creatinine < 1.5 mg/dL
Hepatic
!
Total bilirubin ≤ 1.5 × ULN (upper limit of normal)
!
AST ≤ 3.0 × ULN, except for subjects with liver metastasis, who may only be 
included if AST ≤ 5.0 × ULN
!
ALT ≤ 3.0 × ULN, except for subjects with liver metastasis, who may only be 
included if ALT ≤ 5.0 × ULN
10a. Subjects must have recovered from treatment-related toxicities of prior anticancer 
therapies to grade ≤ 1 (CTCAE v 5.0). 
5.2.2
Inclusion criteria for arm 1A (LAG525/spartalizumab)
Subjects eligible for inclusion in arm 1A in this study must meet all of the following criteria:
1. Written informed consent must be obtained prior to any screening procedures.
2. Male or female must be ≥ 18 years of age at time of providing informed consent. 
3. Histologically confirmed unresectable or metastatic stage IIIB/C/D or IV melanoma 
according to AJCC Edition 8 (refer to Appendix 1)
4b. Previously treated for unresectable or metastatic melanoma:
-
All subjects must have received anti-PD-1 checkpoint inhibitor therapy (ie. 
pembrolizumab or nivolumab) either as monotherapy or in combination with 
ipilimumab as the last systemic therapy prior to enrollment and must have 
confirmed disease progression as per RECIST v1.1 (confirmed on a subsequent 
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scan, which can be the scan performed during screening) while on or after this 
therapy prior to enrollment.
-
Subjects with V600BRAF wild-type disease must have received no more than 2 
prior systemic therapies including prior anti-PD-1/PD-L1 (as monotherapy or in 
combination with ipilimumab)
-
Subjects with V600BRAF mutant disease must have received no more than 3 prior 
systemic therapies including anti-PD-1/PD-L1
(as monotherapy
or in 
combination with ipilimumab), and V600BRAF inhibitor (as monotherapy or in 
combination with a MEK inhibitor)
-
The last dose of anti-PD-1 based therapy must have been received more than 
four weeks prior to first dose of study treatment.
-
The last documented disease progression must have occured within 12 weeks 
prior to first dose of study treatment
-
No additional systemic treatment is allowed for advanced or metastatic 
melanoma (this includes for example tumor infiltrating lymphocyte therapy)
5a. ECOG performance status 0-1
6. At least one measurable lesion per RECIST v1.1 (refer to Appendix 2)
7b. Subjects must have baseline tumor sample (fresh tumor biopsy or recent archival sample, 
as described in Section 7.2.3.1.1) that is positive for LAG-3 per central assessment at the
Novartis-designated laboratory (Histogenex, Antwerp, Belgium)
9a. Subject must meet the following laboratory values at the screening visit in the absence 
of growth factors and/or transfusion support within 14 days prior to screening blood draw:
Hematological
!
Hemoglobin ≥9 g/dL
!
Absolute neutrophil count ≥1.5 × 109/L
!
Platelets ≥75 × 109/L
Renal
!
Serum creatinine < 1.5 mg/dL
Hepatic
!
Total bilirubin ≤ 1.5 × ULN (upper limit of normal)
!
AST ≤ 3.0 × ULN, except for subjects with liver metastasis, who may only be 
included if AST ≤ 5.0 × ULN
!
ALT ≤ 3.0 × ULN, except for subjects with liver metastasis, who may only be 
included if ALT ≤ 5.0 × ULN
10a. Subjects must have recovered from treatment-related toxicities of prior anticancer 
therapies to grade ≤ 1 (CTCAE v 5.0). 
5.3
Exclusion criteria
5.3.1
Exclusion criteria for all arms
Subjects eligible for this study must not meet any of the following criteria:
1. Subjects with uveal or mucosal melanoma
2a. Presence of clinically active or unstable brain metastasis at time of screening. Note: 
Subjects with previously unstable brain lesions who have been definitively treated with 
stereotactic radiation therapy, surgery or gamma knife therapy are eligible.
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!
Subjects with brain lesions who are untreated (including newly discovered brain 
lesions during screening) or received whole brain radiation must have documented 
stable disease as assessed by two consecutive assessments ≥ 4 weeks apart and have 
not required steroids for at least ≥ 4 weeks prior to randomization/enrollment.
3. Use of any live vaccines against infectious diseases within 3 months before
randomization/enrollment.
4a. Subjects with a condition requiring systemic treatment with either corticosteroids (> 10 
mg daily prednisone equivalent) or other immunosuppressive medications within 14 
days of randomization/enrollment. Inhaled or topical steroids, and adrenal replacement 
steroid doses > 10 mg daily prednisone equivalent, are permitted in the absence of 
active autoimmune disease.
5a. Active, known or suspected autoimmune disease or a documented history of 
autoimmune disease. Note: Subjects with vitiligo, controlled type I diabetes mellitus on 
stable insulin dose, residual autoimmune-related hypothyroidism only requiring hormone 
replacement or psoriasis not requiring systemic treatment or conditions not expected to recur 
in the absence of an external trigger are permitted.
6a. Active infection requiring systemic therapy (i.e. antibiotics, anti-virals, high dose 
steroids, immunosuppressants, or any other systemic therapy) at time of 
randomization/enrollment.
7. Prior allogenic bone marrow or solid organ transplant
8. History of known hypersensitivity to any of the investigational drugs used in this study
9. Known history or current interstitial lung disease or non-infectious pneumonitis
10. Malignant disease, other than that being treated in this study. Exceptions to this 
exclusion include the following: malignancies that were treated curatively and have not 
recurred within 2 years prior to start of study treatment; completely resected basal cell 
and squamous cell skin cancers and any completely resected carcinoma in situ
11. Known history of testing positive for Human Immunodeficiency Virus (HIV) infection 
12a. Active Hepatitis B infection (HBsAg positive). Note: Subjects with antecedent of 
Hepatitis B (anti-HBc positive, HBsAg and HBV-DNA negative) are eligible
13. Subject with positive test for hepatitis C virus (HCV) RNA
14. Pregnant or nursing (lactating) women confirmed by a positive hCG laboratory test 
within 72 hours prior to initiating study treatment. Note: Low levels of hCG may also 
be considered a tumor marker, therefore if low hCG levels are detected, another blood 
sample at least 4 days later must be taken to assess the kinetics of the increase and 
transvaginal ultrasound must be performed to rule out pregnancy.
15a. Women of childbearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 150-days after last dose of study treatment. Highly effective contraception 
methods include:
!
Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject). 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 bilateral tubal ligation at least six weeks 
before taking study treatment. In case of oophorectomy alone, only when the 
reproductive status of the woman has been confirmed by follow up hormone level 
assessment
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!
Male sterilization (at least 6 months prior to screening). The vasectomized male 
partner should be the sole partner for that subject
!
Use of oral, injected or implanted hormonal methods of contraception or placement 
of an intrauterine device (IUD) or intrauterine system (IUS), or other forms of 
hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
NOTE: In case of use of oral contraception women should have been stable on the same 
pill for a minimum of 3 months before taking study treatment. 
Note: Women are considered post-menopausal 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 bilateral 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.
16. Sexually active males unless they use a condom during intercourse while on treatment 
and for 7 days after the last dose of study treatment and should not father a child in this 
period. A condom is required to be used by vasectomized men as well during intercourse 
in order to prevent delivery of the drug via semen.
17a.Prior systemic therapy for unresectable or metastatic melanoma with any investigational 
agent, or with any other agent, except anti-PD-1/PD-L1 and anti-CTLA-4 (and 
V600BRAF and MEK inhibitors if subject has
V600BRAF mutant disease). Prior 
neoadjuvant and/or adjuvant therapy for melanoma completed less than 6 months before 
the start of study treatment.
18. Medical history or current diagnosis of myocarditis 
19a. Cardiac Troponin T (TnT) or I (TnI) level > 2 x ULN at screening 
5.3.2
Exclusion criteria specific for arm 2 (capmatinib/spartalizumab)
Subject must not meet any of the following criteria to be eligible for randomization in arm
2:
20. History or current diagnosis of ECG abnormalities indicating significant risk of safety 
for subjects participating in the study such as:
!
Concomitant clinically significant cardiac arrhythmias, e.g., sustained ventricular 
tachycardia, and clinically significant second or third degree AV block without a 
pacemaker
!
History of familial long QT syndrome or known family history of ‘Torsades de 
Pointes’
21. History of myocardial infarction, angina pectoris, coronary artery bypass graft (CABG) 
within 6 months prior to randomization.
22. Resting QTcF > 480 msec (as a mean of triplicate ECG)
23. Use of agents known to prolong the QT interval unless it can be permanently 
discontinued for the duration of study
24. Impairment of gastrointestinal function or gastrointestinal disease that may significantly 
alter the absorption of capmatinib (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, or malabsorption syndrome).
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25. Subjects receiving strong inducers of CYP3A4 that cannot be discontinued or switched 
at least 1 week prior to randomization and for the duration of the study
26. Serum lipase > ULN
27a. Serum amylase grade > 2 (CTCAE v5.0). Note: Subjects with grade 1 or grade 2 serum 
amylase elevations at the time of randomization are eligible for Arm 2 if they are 
confirmed to have no signs or symptoms suggesting pancreatitis or pancreatic injury 
(e.g., elevated P-amylase, abnormal imaging findings of pancreas, etc)
5.3.3
Exclusion criteria specific for arm 4 (ribociclib/spartalizumab)
Subject must not meet any of the following criteria to be eligible for randomization in arm 
4:
28a. Standard 12-lead ECG values defined as the mean of the triplicate ECGs:
!
QTcF interval at screening > 450 ms (QT interval using Fridericia’s correction)
!
Mean resting heart rate > 90 bpm (determined from the ECG)
29. Subject with a known hypersensitivity to any of the excipients of ribociclib (eg. 
ribociclib tablets coating contains soya lecithin, and therefore should not be taken by 
subjects who are allergic to peanuts or soya).
30a. Subject has clinically significant, uncontrolled heart disease and/or cardiac 
repolarization abnormality, including any of the following:
!
History of documented myocardial infarction (MI), angina pectoris, symptomatic 
pericarditis, or coronary artery bypass graft (CABG) within 6 months prior to 
study entry
!
Documented cardiomyopathy
!
Left Ventricular Ejection Fraction (LVEF) < 50% as determined by the multiple 
gated acquisition (MUGA) scan or echocardiogram (testing is not mandatory)
!
Long QT syndrome or family history of idiopathic sudden death or congenital 
long QT syndrome, or any of the following:
-
Risk factors for Torsades de Pointe (TdP) including uncorrected 
hypocalcemia, hypokalemia or hypomagnesemia, history of cardiac failure, or 
history of clinically significant/symptomatic bradycardia
-
Concomitant medication(s) with a known risk to prolong the QT interval 
and/or known to cause Torsades de Pointe that cannot be discontinued or 
replaced by safe alternative medication (e.g. within 5 half-lives or 7 days prior 
to starting study drug, whichever is longer)
-
Inability to determine the QTcF interval
!
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)
!
Systolic blood pressure (SBP) >160 or <90 mmH
31. Patient has impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of ribociclib (e.g., uncontrolled ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, or small bowel 
resection). 
32. Subject is currently receiving any of the following substances and cannot be 
discontinued 7 days prior to Cycle 1 Day 1:
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!
Concomitant medications, herbal supplements, and/or fruits (e.g. grapefruit, 
pomelos, star fruit, Seville oranges) and their juices that are strong inducers or 
inhibitors of CYP3A4/5;
!
Medications that have a narrow therapeutic window and are predominantly 
metabolized through CYP3A4/5.
33a. Subject has the following laboratory values outside of normal limits (and uncorrected
after the use of supplements) before the first dose of study drug:
!
Potassium
!
Magnesium
!
Total calcium (corrected for serum albumin)
34. Subject has one of the following laboratory values before the first dose of study drug:
!
Total bilirubin ≥ULN (for subjects with Gilbert’s syndrome: total bilirubin is >
3.0 × ULN or direct bilirubin > 1.5 × ULN).
!
Aspartate transaminase (AST) ≥2.5 × ULN (for subjects with liver metastasis: 
AST is ≥5 × ULN)
!
Alanine transaminase (ALT) ≥2.5 × ULN (for subjects with liver metastasis: ALT 
is ≥5 × ULN)
6
Treatment
6.1
Study treatment
For this study, the terms ‘investigational drugs’ and ‘study drugs’ refer to spartalizumab, 
LAG525, capmatinib, canakinumab and ribociclib. 
Eligible subjects will be randomized into one of the following arms and will receive the 
study treatment, defined as spartalizumab in combination with another investigational drug 
as described below and in Table 6-1:
!
Arm 1: LAG525 600 mg Q4W i.v. and spartalizumab 400 mg Q4W i.v.
!
Arm 2: Capmatinib 400 mg BID p.o and spartalizumab 400 mg Q4W i.v.
!
Arm 3: Canakinumab 300 mg Q4W s.c. and spartalizumab 400 mg Q4W i.v.
! Arm 4: Ribociclib 600 mg QD p.o on days 1 to 21 of a 28-day cycle and spartalizumab 
400 mg Q4W i.v.
If a subject does not meet the specific eligibility criteria of an arm the subject will be 
randomized to an open arm he is eligible for with probability according to the active 
randomization block.
As dose-regimens for new combinations with spartalizumab become established and a 
RP2D has been determined, arm(s) will be added under the same master protocol upon 
protocol amendment. A maximum of 10 arms may be active at any given time under this 
master protocol. 
Subjects eligible for enrollment in the non-randomized arm 1A will receive the following 
study treatment (also refer to Table 6-1):
! Arm 1A: LAG525 600 mg Q4W i.v. and spartalizumab 400 mg Q4W i.v.
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All dosages prescribed and dispensed to subjects and all dose modifications (interruption, 
reduction/escalation, delay) during the study and the reason for the dose modification must 
be recorded in the eCRF (electronic Case Report Form).
Administration of i.v. investigational drugs (i.e. LAG525, spartalizumab) must take place 
during in-clinic visits as per the schedule defined in Section 7 and Table 6-1, in a facility 
with appropriate resuscitation equipment and a physician readily available during the period 
of drug administration. 
Administration of s.c. investigational drugs (i.e. canakinumab) must take place during in-
clinic visits as per the schedule defined in Section 7 and Table 6-1.
Oral investigational drugs (capmatinib, ribociclib) will be dispensed by sites to the subjects 
at study visits scheduled on Day 1 of each 28-day cycle, as per Table 7-2.
6.1.1
Dosing regimen
After randomization/enrollment, subjects will receive the study treatment corresponding to 
the arm they were randomized/enrolled into as per the dose and schedule of administration
defined in Table 6-1 for each investigational drug.
Patient must start study treatment within 3 days after randomization/enrollment.
Each treatment cycle is 28 days. 
In-clinic intravenous infusions and s.c. injections of investigational drugs must be scheduled
according to the appropriate number of calendar days from the day of first study treatment 
administration on C1D1.
Table 6-1
Dose and schedule of administration for investigational drugs 
used in the study
Investigational drug
Arm
Route 
Dose
Frequency and/or Regimen (28-day 
cycles)
Spartalizumab (PDR001)
All arms
i.v.
400 mg 
Q4W, on Day 1 of each 28-day cycle
LAG525
Arm 1
and
Arm 1A
i.v.
600 mg
Q4W, on Day 1 of each 28-day cycle
Capmatinib (INC280)
Arm 2
p.o.
400 mg 
BID (total daily dose 800 mg)
Canakinumab (ACZ885)
Arm 3
s.c.
300 mg 
Q4W, on Day 1 of every 28-day cycle
Ribociclib (LEE011)
Arm 4
p.o.
600 mg
QD, on Days 1-21 of each 28-day cycle
6.1.1.1
Spartalizumab
Spartalizumab will be administered via intravenous infusion over 30 minutes (up to 2 hours, 
if clinically indicated) Q4W (on Day 1 of each 28-day cycle). A dose may be delayed by up 
to four days. If a dose cannot be administered within the planned window then the dose on 
that cycle should be skipped.
Guidance on dose modification is provided in Section 6.3. Please refer to Section 6.3.1.2 for 
the maximum duration allowed for a dose interruption. 
The safety assessments should be performed as outlined in Section 7 according to the actual 
day of infusion.
Patients should be monitored for potential infusion-related reactions including rigors, chills, 
wheezing, pruritus, flushing, rash, hypotension, hypoxemia, and fever, for at least 2 hours 
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after the first two infusions. Patients should be instructed how to notify study personnel if 
symptoms of infusion reaction occur. The same may apply for the subsequent infusions if 
clinically indicated. Subjects should not receive pre-medication to prevent an infusion 
reaction before the first infusion of study treatment, in order to determine if pre-medication 
is necessary.
For premedication guidance after occurrence of potential infusion reactions, please refer to
Section 6.1.2.
For further information on spartalizumab, refer to [PDR001J2201 Pharmacy Manual].
6.1.1.2
LAG525
LAG525 will be administered via intravenous infusion over 30 minutes (up to 2 hours, if 
clinically indicated) Q4W (on Day 1 of each 28-day cycle). A dose may be delayed by up 
to four days. If a dose cannot be administered within the planned window then the dose on 
that cycle should be skipped.
The LAG525 infusion should be given prior the spartalizumab infusion. The spartalizumab
infusion should start at least 30 minutes and up to 4 hours maximum after the completion of 
LAG525 infusion. LAG525 must be administered using separate infusion materials (bag, 
lines, filters) from spartalizumab, however the same access site may be used for both 
infusions.
Guidance on dose modification is provided in Section 6.3. Please refer to Section 6.3.1.2 for 
the maximum duration allowed for a dose interruption. 
Patients should be monitored for potential infusion-related reactions following LAG525 
infusion in the same way as described for spartalizumab in Section 6.1.1.1.
For premedication guidance after occurrence of potential infusion reactions, please refer to
Section 6.1.2.
For further information on LAG525, refer to [PDR001J2201 Pharmacy Manual].
6.1.1.3
Capmatinib
Capmatinib will be administered orally on a twice daily (BID) dosing schedule from Day 1 
till Day 28 of each 28-day cycle. The starting dose of capmatinib will be 400 mg BID (total 
daily dose: 800 mg).
On days of co-administration of capmatinib with spartalizumab, subjects should be 
instructed to take the morning dose of capmatinib during the clinic visit, when instructed by 
site personnel. The sequence of administration of capmatinib and spartalizumab is left at the 
investigator’s discretion. 
 
 
 
 
Guidance on dose modification is provided in Section 6.3. Please refer to Section 6.3.1.2 for 
the maximum duration allowed for a dose interruption.
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!
Subjects should take capmatinib twice daily at approximately the same time each day 
in the morning and in the evening
. The morning and 
the evening doses should be taken 12 (± 4) hours apart, although 12-hour interval is 
highly recommended. If a dose is not taken within 4 hours of the planned dosing time, 
the missed dose should not be replaced.
!
Capmatinib can be administered with or without food. Each dose of capmatinib is to be 
taken with a glass of water (at least 8 ounces – approximately 250 mL) and consumed 
over as short a time as possible (i.e. not slower than 1 tablet every 2 minutes). 
!
Subjects should be instructed to swallow the tablets whole and not to chew them.
!
Subjects should be instructed not to make up for missed doses or partial doses (i.e. 
when the entire dose is not taken as instructed). A missed or partial dose will be 
defined as a case when the full dose is not taken within 4 hours of the scheduled twice 
daily dosing. If that occurs, then the dose (or part remaining dose) should not be taken 
and dosing should restart with the next scheduled dose. If vomiting occurs, no attempt 
should be made to replace the vomited dose before the next scheduled dose. Subjects 
should be instructed to inform the investigational site staff of any missed or delayed 
doses.
!
During the whole duration of treatment with capmatinib, precautionary measures 
should be taken against ultraviolet exposure (e.g. sunscreen, protective clothing, avoid 
sun exposure or solarium).
6.1.1.4
Canakinumab
Canakinumab will be administered as subcutaneous injection in the abdomen, upper outer 
thigh or upper outer arm Q4W (on Day 1 of every 28-day cycle). To administer a target dose 
of ACZ885 of 300 mg, two separate subcutaneous injections (of 1.0 mL each) must be 
administered to the patient at a visit and should not be injected in the same site (e.g. if first 
injection was done in the thigh, the second injection should be done in the opposite thigh). 
Alternate injection sites should be used throughout the study. A dose may be delayed by up 
to four days. If a dose cannot be administered within the planned window then the dose on 
that cycle should be skipped.
The sequence of administration of canakinumab and spartalizumab is left at the 
investigator’s discretion.
Guidance on dose modification is provided in Section 6.3. Please refer to Section 6.3.1.2 for 
the maximum duration allowed for a dose interruption.
For further information on canakinumab, refer to [PDR001J2201 Pharmacy Manual]. 
6.1.1.5
Ribociclib
Ribociclib will be administered orally once a day (QD) on Days 1-21 of each 28-day cycle. 
Days 22-28 will be a “rest period” from ribociclib. The starting dose of ribociclib will be 
600 mg QD (total daily dose: 600 mg).
Ribociclib should be taken as follows:
!
Ribociclib is dosed for the first 21 days out of each 28-day cycle. The visit schedule 
should be adhered to, as far as possible. If a cycle x day 1 visit has to be delayed for any 
reason (within the + 4 day window allowed from planned date per protocol), the rest 
period of the previous cycle (x-1) can be extended to a maximum of 11 days and the 
number of days of ribociclib dosing for the cycle x should be adjusted accordingly to 
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maintain the visit schedule (subject will receive ribociclib for a few days less than 21 
days for this cycle). Shortening the rest period to less than 7 days is not recommended.
!
Patients should be instructed to take ribociclib with a large glass of water (at least 8
ounces – approximately 250 mL) at the same time each day (Day 1 to 21 of each 28-day 
cycle).
 
 
 
!
On scheduled visit days at the clinic, subjects must be instructed to take their dose of 
ribociclib in the clinic, under the supervision of the investigator or designee, when 
instructed by site personnel. The sequence of administration of ribociclib and 
spartalizumab is left at the investigator’s discretion. On all other days, subjects may take 
ribociclib at home. Ribociclib can be administered with or without food. 
!
 
 
 
 If a subject vomits within 4 hours of 
ribociclib dosing, it should be documented in the subject’s source documents.
!
On a day of chemistry panel, hepatic safety markers and/or lipid panel sampling, subjects 
must be fasting from all food and drink for at least 12 hours overnight. Water is allowed 
during all fasting periods; however coffee, tea and juice are not permitted during the 
fasting period.
!
Patients should be instructed to swallow the ribociclib tablets whole and not to chew or 
crush them.
!
If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose (no attempt should be made to replace the vomited dose). 
The occurrence and frequency of any vomiting during a treatment cycle must be 
documented. 
!
Any doses that are missed (not taken within 6 hours of the intended time) should be 
skipped and should not be replaced or made up on a subsequent day.
!
Patients must avoid consumption of grapefruit, grapefruit hybrids, pomelos/pummelos, 
starfruit, Seville oranges or products containing their juice during the entire study and 
preferably 7 days before the first dose of study medications. These foods are known as 
CYP3A4 inhibitors and have a potential to increase exposure to ribociclib.
Herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4/5 or 
those with a known risk of QT prolongation are not permitted. Multivitamins are 
permitted.
6.1.2
Ancillary treatments for potential infusion reactions with 
spartalizumab or LAG525
Subjects should not receive pre-medication to prevent an infusion reaction before the first
infusion of study treatment, in order to determine if pre-medication is necessary. If a subject
experiences an infusion reaction, he/she may receive pre-medication on subsequent dosing
days. The pre-medication should be chosen per institutional standard of care, at the 
discretion of the treating physician. Recommendations for management for infusion 
reactions can be found in Appendix 3.
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Acute allergic reactions should be treated as needed per institutional standard of care. In the
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore
normal cardiopulmonary status. If a subject experiences a grade 3 (per CTCAE v5.0)
anaphylactic/anaphylactoid reaction, the subject will be permanently discontinued from 
LAG525/spartalizumab.
The NCI-CTCAE v5.0 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.
Guidelines on management of infusion reactions are provided in Table 6-11 (Mandatory 
Dose Modifications).
6.1.3
Rescue medication 
Not applicable.
6.1.4
Guidelines for continuation of treatment 
Please refer to Section 6.3 for interruption and discontinuation criteria.
6.1.5
Treatment duration
All subjects will start study treatment on C1D1 and will receive study treatment on a 28-day 
cycle basis until disease progression per RECIST v1.1 (by local assessment), or 
unacceptable toxicity, start of a subsequent anti-cancer therapy, withdrawal of consent, 
investigator’s decision, lost to follow-up, death, or study is terminated by the sponsor. 
Subjects may continue study treatment beyond disease progression by RECIST v1.1 if they 
derive clinical benefit and if the protocol-specific criteria defined in Section 6.1.5.1 are met. 
Subjects should be scheduled for an End of Treatment (EoT) visit within 7 days after 
permanent discontinuation of the last study drug for any reason to have EoT assessments 
performed as defined in Section 7.
6.1.5.1
Treatment beyond disease progression
Subjects who derive clinical benefit may continue study treatment beyond RECIST v1.1 
disease progression until loss of clinical benefit, unacceptable toxicity, start of subsequent 
anti-cancer therapy, withdrawal of consent, physician’s decision, lost to follow-up, death or 
study is terminated by sponsor, provided they meet all the following criteria:
!
Absence of symptoms and signs (including worsening of clinically relevant laboratory 
values) indicating disease progression
!
Absence of rapid progression of disease
!
Continuation will not delay an imminent intervention to prevent serious complications 
of disease progression (e.g. CNS metastases) 
!
Subject exhibits adequate tolerance to study treatment
!
Subject remains with stable performance status
All study procedures must continue as outlined in Section 7 for subjects who continue 
treatment beyond disease progression per RECIST v1.1. In case of clinical deterioration or 
suspicion of disease progression, a follow-up imaging assessment should be performed 
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promptly rather than waiting for the next scheduled assessment. Subjects who are no longer 
deriving clinical benefit will be discontinued.
6.2
Dose escalation guidelines
Dose escalations for spartalizumab, LAG525 and canakinumab are prohibited.
If the dose of ribociclib has been reduced per the mandatory dose modification (Section 
6.3.1.6), no dose re-escalation is permitted.
If the dose of capmatinib has been reduced per the mandatory dose modification (Section 
6.3.1.4), escalation to the previous dose level is permitted if the following criteria are met:
!
A period of 4 weeks of treatment has passed since restarting dosing at the reduced dose 
level and there is no recurrence of the AE.
!
The subject is deriving clinical benefit.
6.3
Dose modifications
6.3.1
Mandatory dose modification and dose delay
For subjects who do not tolerate the protocol-specified dosing schedule, dose interruptions 
and/or reductions are mandated for treatment-related adverse events in order to manage 
subject safety and allow subjects to continue the study treatment.
Dose reductions are only allowed for capmatinib and ribociclib (refer to Section 6.3.1.1). 
Dose changes for spartalizumab, LAG525 and canakinumab are prohibited.
Table 6-2 summarizes the mandatory dose modifications for specific treatment-related 
adverse events. If the specific adverse event is not listed, the guideline for ‘Other adverse 
events’ must be followed. AEs are to be graded according to NCI-CTCAE v5
(ctep.cancer.gov) and all dose modifications should be based on the worst preceding toxicity. 
Deviations to mandatory dose interruptions and/or reductions are not allowed. Permanent 
treatment discontinuation is mandatory for specific events indicated as such in Table 6-5 to 
Table 6-37 and in Section 6.3.1.5 or listed in Section 7.1.5.
The investigator must follow the dose modifications for the study drug suspected to be 
related to the event:
!
If the event is suspected to be related to spartalizumab, the investigator must follow the 
dose modifications specific for spartalizumab.
!
If the event is suspected to be related to LAG525 or capmatinib or canakinumab or 
ribociclib, the investigator must follow the dose modifications specific for the 
suspected study drug.
!
If it cannot be distinguished which of the study drugs within the combination is 
suspected to be related to the event, the investigator must follow the dose 
modifications specific to both study drugs within the combination.
Recommended management guidelines for suspected immune-related adverse events are 
provided in Appendix 3 and can be amended according to the local or institutional guidelines.
Except for arm 1 where spartalizumab and LAG525 must be permanently discontinued at 
the same time, it is allowed for the other arms to discontinue one of the two study drugs 
within the combination. Permanent study treatment discontinuation is defined as the 
permanent discontinuation of both study drugs within the combination arm. 
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Scheduled dosing of spartalizumab, LAG525 and canakinumab may, at the discretion of the 
investigator, be delayed by up to 4 days if subjects present with conditions that require 
withholding of dose. Outside of this 4 day window, the dose will be considered missed. 
After a dose is missed, every effort should be made to return to the original schedule of 
administration. 
Please refer to Section 6.3.1.2 for the maximum duration allowed for a dose interruption for 
each study drug. 
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Table 6-2
Reference of AE and specific dose management criteria
Adverse event
Spartalizumab/LAG525
capmatinib
canakinumab
ribociclib
Colitis/Diarrhea
Table 6-5
Table 6-18
Table 6-30
Hepatic 
Table 6-6
Table 6-15
Table 6-27
Table 6-35
Skin
Table 6-7
Table 6-19
Table 6-31
Renal
Table 6-8
Table 6-14
Table 6-26
Interstitial lung disease like 
events/Pneumonitis
Table 6-9
Table 6-20
Endocrinopathies
Table 6-10
Infusion reaction and cytokine 
release syndrome
Table 6-11
Hematological 
Table 6-12
Table 6-13
Table 6-25
Table 6-34
Pancreatitis, amylase and/or 
lipase elevations
Table 6-16
Table 6-28
QTc prolongation
Table 6-17
Table 6-36
Vomiting/Nausea
Table 6-18
Fatigue/Asthenia
Table 6-21
Table 6-32
Peripheral edema
Table 6-22
Infections
Table 6-24
Hypertension
Table 6-29
Other adverse events
Table 6-12
Table 6-23
Table 6-33
Table 6-37
6.3.1.1
Dose reductions
Dose reductions for spartalizumab, LAG525 and canakinumab are prohibited.
Dose reductions are only allowed for capmatinib and ribociclib. All dose reductions should 
be based on the worst preceding toxicity demonstrated at the last dose. Dose reduction must 
follow the dose reduction steps described in Table 6-3 for capmatinib and in Table 6-4 for 
ribociclib. For each subject, a maximum of 2 dose level modifications are allowed after 
which the subject must be discontinued from treatment with capmatinib/ribociclib
(reduction below dose level -2 is not allowed: subjects on dose level -2 necessitating further 
dose reduction due to an adverse event must permanently discontinue capmatinib/ribociclib).
Altering from BID dosing schedule for capmatinib is not allowed.
Table 6-3
Dose reduction steps for capmatinib
Capmatinib dose levels
Capmatinib daily dose
Starting dose level 
400 mg BID (= 2 x 200 mg tablets twice in a day; 800 
mg total daily dose)
Dose level -1 
300 mg BID (= 2 x 150 mg tablets twice in a day; 600 
mg total daily dose)
Dose level -2 
200 mg BID (= 1 x 200 mg tablets twice in a day; 400 
mg total daily dose)
Table 6-4
Dose reduction steps for ribociclib
Ribociclib dose levels
Ribociclib daily dose
Starting dose level 
600 mg QD (= 3 x 200 mg tablets once in a day; 600 
mg total daily dose)
Dose level -1 
400 mg QD (= 2 x 200 mg tablets once in a day; 400 
mg total daily dose)
Dose level -2 
200 mg QD (= 1 x 200 mg tablets once in a day; 200 
mg total daily dose)
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6.3.1.2
Maximum duration of study drug(s) interruption
If the treatment with spartalizumab is interrupted for more than 12 weeks (counted from the 
time the AE reaches a grade that leads to spartalizumab interruption), spartalizumab must 
be permanently discontinued.
If the treatment with LAG525 is interrupted for more than 12 weeks (counted from the time 
the AE reaches a grade that leads to LAG525 interruption), LAG525 must be permanently 
discontinued.
If the treatment with capmatinib is interrupted for more than 3 consecutive weeks (counting 
from the first day when a dose was interrupted), then capmatinib must be permanently 
discontinued.
If the treatment with ribociclib is interrupted for more than 28 consecutive days due to 
ribociclib-related toxicity (counting from the first day when a dose was interrupted, 
including the 7 days of planned interruption of dosing between Day 22-28 of a cycle), then 
ribociclib must be permanently discontinued.
If the treatment with canakinumab is interrupted for more than 4 weeks (counted from the 
intended day of the next scheduled dose), canakinumab must be permanently discontinued.
6.3.1.3
Mandatory dose modification for spartalizumab and LAG525
No changes in dose of spartalizumab and LAG525 are allowed. Overall, subjects with AE
suspected to be related to spartalizumab and LAG525 including those of potential immune-
mediated etiology (irAEs) may need to interrupt or permanently discontinue spartalizumab
or/and LAG525 as outlined below, in Section 6.3.1.3.2 and in Table 6-5 to Table 6-12 or as 
listed in Section 7.1.5.
In general, spartalizumab or/and LAG525 must be permanently discontinued in case of:
!
Any life-threatening adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy)
!
Persistent grade 2 or 3 adverse reactions (excluding endocrinopathies controlled with 
hormone replacement therapy) that do not recover to ≤ Grade 1 within 12 weeks 
!
Inability to reduce the dose of steroids (for the management of irAEs) to ≤ 10 mg/day 
prednisone or equivalent within 12 weeks. 
!
Any severe or grade 3 recurring treatment-related adverse reaction
!
Any grade 4 irAE
Note: the 12 week timeframe will begin from the time the irAE reaches a Grade that leads 
to spartalizumab/LAG525 interruption.
6.3.1.3.1 Guidance for corticosteroids tapering for management of immune-related 
AEs
Steroids should be tapered slowly and based on response/recovery of clinical symptoms. 
Consider to complete tapering over a period of at least 4 weeks. Slower tapering of 
corticosteroids therapy may be recommended if the adverse event is not showing 
improvement. If dose level of ≤ 10 mg of prednisone (or equivalent) is achieved, 
spartalizumab or/and LAG525 can be restarted as indicated in Table 6-5 to Table 6-12.
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6.3.1.3.2 Dose modification for potential immune-mediated adverse events (irAEs)
Adverse events of special interest include irAEs
that are associated with 
spartalizumab/LAG525 treatment. An irAE may be experienced by subjects treated with 
spartalizumab or/and LAG525 due to their mechanism of action and predicted based on the 
reported experience with other checkpoint inhibitors that have a similar mechanism of action. 
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 adequate 
management and resolution. 
Immune-related adverse events may be of low grade and self-limited, most frequently 
involving the gastrointestinal tract (e.g. diarrhea/colitis), skin (e.g. rashes, pruritus), liver 
(e.g. hepatitis), lung (e.g. pneumonitis), kidneys (e.g. nephritis) and endocrine systems (e.g. 
hypothyroidism, hyperthyroidism, type I diabetes, hypophysitis including hypopituitarism 
and adrenal insufficiency). Other immune-related 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 patients 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 treatment discontinuation. Serological, immunological and histological 
assessments should be performed as deemed appropriate by the investigator, to verify the 
potential immune-mediated nature of the AE, and exclude neoplastic, infectious or 
metabolic origin of the AE. 
Severe grade or persistent lower grade irAEs typically require treatment interruption or 
permanent discontinuation of treatment and administration of systemic steroids, and 
sometimes other immunosuppressive medications (i.e. TNF# antagonists, mycophenolate 
or tacrolimus, etc.). 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 to 
avoid recurrence or worsening of irAE (Section 6.3.1.3.1). The management of irAEs may 
further include initiation of antibiotics for prophylaxis against opportunistic infections.
Subjects 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. 
Subjects who experience a new or worsening irAE should be contacted and/or evaluated by 
the study site more frequently as applicable. 
Table 6-5
Colitis/diarrhea suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory dose modification 
Grade 2
If diarrhea is grade 2, despite loperamide at 2 mg every 2 hours for > 
48h: Interrupt spartalizumab/LAG525 until recovery to grade ≤ 1 
!
Restart spartalizumab/LAG525 at the same dose level
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Grade (CTCAE v5)
Mandatory dose modification 
Grade 3
1st occurrence 
Interrupt spartalizumab/LAG525 until recovery to grade ≤ 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level
2nd occurrence
Permanently discontinue spartalizumab/LAG525
Grade 4
Permanently discontinue spartalizumab/LAG525 
Table 6-6
Abnormal liver tests suspected to be related to spartalizumab or 
LAG525/spartalizumab
Grade (CTCAE v5)
Mandatory dose modification 
Grade 2
Interrupt LAG525/spartalizumab until recovery to grade ≤ 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level
Patients with baseline grade 2 AST/ALT values may continue 
spartalizumab/LAG525
Grade 3 or 4
Permanently discontinue spartalizumab/LAG525
Patients with baseline grade 2 AST/ALT values must permanently 
discontinue spartalizumab/LAG525 treatment if value increased to grade 
3 with increase ∀2 × baseline
Table 6-7
Rash/skin events suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory Dose Modifications 
Grade 2 (e.g. rash 10 to 30% 
BSA, pruritus)
If tolerable: continue spartalizumab/LAG525
If intolerable (or in case of bullous dermatitis, acute generalized 
exanthematous pustulosis or Drug Reaction with Eosinophilia and 
Systemic Symptoms): interrupt spartalizumab/LAG525 until tolerable or 
recovery to grade ≤ 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level 
Grade 3 (e.g. rash > 30% BSA, 
pruritus)
Other severe cutaneous 
adverse reactions
Bullous dermatitis
1st occurrence 
Interrupt spartalizumab/LAG525 until recovery to grade ≤ 1 or baseline
!
Restart spartalizumab/LAG525 treatment at the same dose level. 
For patients with severe cutaneous adverse reaction or bullous 
dermatitis, risk/benefit before resuming treatment should be 
carefully considered.
2nd occurrence 
Permanently discontinue spartalizumab/LAG525
Grade 4: Life-threatening
Permanently discontinue spartalizumab/LAG525
Stevens-Johnson syndrome
(SJS), toxic epidermal 
necrolysis (TEN)
Permanently discontinue spartalizumab/LAG525
Table 6-8
Creatinine alterations suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory Dose Modification 
Grade 2 (> 1.5 - 3.0 x ULN, 
or >1.5-3.0 x baseline if 
baseline was elevated)
Interrupt spartalizumab/LAG525 until recovery to ≤ grade 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level
Grade 3 (> 3.0 - 6.0 x ULN; 
or >3x baseline if baseline was 
elevated)
Permanently discontinue spartalizumab/LAG525
Grade 4 (> 6.0 x ULN)
Permanently discontinue spartalizumab/LAG525
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Table 6-9
Pneumonitis suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory dose modification 
Grade 2
1st occurrence
Interrupt spartalizumab/LAG525 until recovery to grade ≤ 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level
2nd occurrence
Permanently discontinue spartalizumab/LAG525 
Grade 3 or 4
Permanently discontinue spartalizumab/LAG525
Table 6-10
Endocrinopathies suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory dose modification 
Symptomatic endocrinopathies 
(e.g. hypophysitis, adrenal 
insufficiency, hypothyroidism, 
hyperthyroidism)
Interrupt spartalizumab/LAG525 until recovery to mild or no symptoms, 
and controlled with hormone replacement therapy
!
Once recovered or controlled with hormone replacement, restart 
spartalizumab/LAG525 at the same dose level 
Hypothyroidism may be managed with replacement therapy without 
study treatment interruption (unless life-threatening) 
Permanently discontinue spartalizumab/LAG525 for any life-threatening 
endocrinopathies (i.e. hyperthyroidism, adrenal insufficiency, 
hypophysitis) or recurring severe/life-threatening events which cannot 
be controlled with replacement therapy
Autoimmune diabetes 
(Grade 3 or symptomatic 
hyperglycemia)
1st occurrence
Interrupt spartalizumab/LAG525 until recovery to grade 1 or baseline
!
Restart spartalizumab/LAG525 at the same dose level
2nd occurrence
Permanently discontinue spartalizumab/LAG525
Autoimmune diabetes
(Grade 4 hyperglycemia or life-
threatening complications)
Permanently discontinue spartalizumab/LAG525
Table 6-11
Infusion reactions and cytokine release syndrome suspected to be 
related to spartalizumab or spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory dose modification 
Grade 2
Permanently discontinue spartalizumab/LAG525 in case of recurring 
infusion reaction despite adequate premedication and prolonged 
infusion/slow infusion rate
Grade 3 or 4
Permanently discontinue spartalizumab/LAG525
Table 6-12
Other adverse events suspected to be related to spartalizumab or 
spartalizumab/LAG525
Grade (CTCAE v5)
Mandatory dose modification
Grade 3
1st occurrence 
Interrupt spartalizumab/LAG525 until recovery to ≤ grade 1 or baseline 
!
Restart spartalizumab/LAG525 treatment at the same dose level
2nd occurrence
Permanently discontinue spartalizumab/LAG525
Grade 4
Permanently discontinue spartalizumab/LAG525
Encephalitis (any Grade) or 
aseptic meningitis
Guillain-Barre
Severe peripheral or autonomic 
neuropathy, or transverse 
myelitis
Permanently discontinue spartalizumab/LAG525
Myasthenia gravis
Grade 2
!
Interrupt spartalizumab/LAG525 until recovery to ≤ Grade 1 or 
baseline 
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Grade (CTCAE v5)
Mandatory dose modification
Grade ≥3
!
Permanently discontinue spartalizumab/LAG525
Myocarditis (any grade) or 
other cardiac events Grade ∀3
Permanently discontinue spartalizumab/LAG525 (refer to Table 14-17
for recommended management guidelines for those events)
Pancreatitis
Amylase/lipase elevation
Grade 2 acute pancreatitis
!
Interrupt spartalizumab/LAG525 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
Permanently discontinue spartalizumab/LAG525
Ocular events
Grade 2
!
Interrupt spartalizumab/LAG525 until recovery to ≤ Grade 1 or 
baseline
Grade 3 and 4
!
Permanently discontinue spartalizumab/LAG525
6.3.1.4
Mandatory dose modifications for capmatinib
All dose modifications should be based on the worst preceding toxicity. Capmatinib dose 
reduction must follow the dose reduction steps described in Table 6-3 in Section 6.3.1.1. 
Dose escalation after previous dose reduction due to an adverse event is allowed as described 
in Section 6.2.
Table 6-13
Hematological adverse events suspected to be related to capmatinib 
Grade (CTCAE v5)
Mandatory dose modifications 
Neutrophil count decreased (ANC)
Grade 3 
Interrupt capmatinib until recovery to grade ≤ 2
! If resolved ≤ 7 days, restart at the same dose level 
! If not resolved within 7 days, restart at reduced dose level 
Grade 4 
Interrupt capmatinib until recovery to ≤ grade 2, then restart at reduced
dose level 
Febrile neutropenia
Interrupt capmatinib 
! If resolved in ≤ 7 days, restart at reduced dose level 
! If not resolved within 7 days, permanently discontinue capmatinib
Thrombocytopenia
Grade 3 without clinically 
significant bleeding
Continue capmatinib at the same dose level
Grade 3 with clinically 
significant bleeding
Interrupt capmatinib until recovery to grade ≤ 2
! If resolved ≤ 7 days, restart at the same dose level 
! If not resolved within 7 days, restart at reduced dose level 
Grade 4 
Interrupt capmatinib until recovery to grade ≤ 2, then restart at reduced 
dose level. If toxicity recurs, permanently discontinue capmatinib 
Table 6-14
Creatinine alterations suspected to be related to capmatinib
Grade (CTCAE v5)
Mandatory dose modifications
Grade 2 (> 1.5 - 3.0 x ULN;
or >1.5-3.0 x baseline if 
baseline was elevated) 
OR
Grade 3 (> 3.0 - 6.0 x ULN;
or >3x baseline if baseline was 
elevated )
Interrupt capmatinib until recovery to grade ≤ 1 or baseline
! If resolved in ≤ 7 days: restart capmatinib at reduced dose level 
! If not resolved within 7 days, permanently discontinue capmatinib 
Grade 4 (> 6.0 x ULN)
Permanently discontinue capmatinib
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Table 6-15
Abnormal liver test results suspected to be related to capmatinib
Grade (CTCAE v5)
Mandatory dose modifications
Isolated total bilirubin elevation - For patient’s whose baseline total bilirubin is ≤ ULN
Grade 1 (>ULN - 1.5 x ULN)
Maintain dose level of capmatinib and monitor liver enzymes
Grade 2 (>1.5 - 3.0 x ULN)
Interrupt capmatinib until recovery to grade ≤ 1 
! If resolved in ≤ 7 days, restart at the same dose level
! If not resolved within 7 days, restart at reduced dose level 
Grade 3 (>3.0 - 10.0 x ULN) c
Interrupt capmatinib until recovery to grade≤ 1, 
! If resolved in ≤ 7 days, restart at reduced dose level 
! If not resolved within 7 days, permanently discontinue capmatinib 
Grade 4 (>10.0 x ULN)
Permanently discontinue capmatinib 
Isolated total bilirubin elevation - For patient’s whose baseline total bilirubin is > ULN b
Grade 1 > 1.0 - 1.5 x baseline 
if baseline was abnormal
Maintain dose level of capmatinib and monitor liver enzymes.
Grade 2 >1.5 – 3.0 × above 
baseline if baseline was 
abnormal
Interrupt capmatinib until recovery to baseline
! If resolved in ≤ 7 days, restart at the same dose level 
! If not resolved within 7 days, restart at reduced dose level 
Grade 3 >3.0 -10x above 
baseline if baseline was 
abnormal
Interrupt capmatinib until recovery to baseline 
! If resolved in ≤ 7 days, resume treatment at reduced dose level 
! If not resolved within 7 days, permanently discontinue capmatinib
Grade 4 (> 10.0 × ULN) b if 
baseline was abnormal
Permanently discontinue capmatinib 
Isolated AST or ALT elevation for patient’s baseline AST/ALT are ≤ ULN
Grade 1 and 2 (> ULN - 5.0 × 
ULN)
Maintain dose level of capmatinib 
Grade 3 (> 5.0 – 20.0 × ULN)
Interrupt capmatinib until recovery to grade ≤ 1, 
! If resolved in ≤ 7 days, restart treatment at reduced dose level 
! If not resolved within 7 days, permanently discontinue capmatinib 
Grade 4 (>20.0 × ULN)
Permanently discontinue capmatinib
Isolated AST or ALT elevation for patient’s baseline AST or ALT are > ULN
Grade 2 (> 3.0 – 5.0 × 
baseline value)
Interrupt capmatinib until recovery to grade ≤ 1 or baseline
! If resolved in ≤ 7 days, restart at reduced dose level
! If not resolved within 7 days, permanently discontinue capmatinib 
Grade ≥3 (> 5.0 × baseline
value)
Permanently discontinue capmatinib
Combined a, d elevations of AST or ALT and total bilirubin
For patients with normal 
baseline ALT or AST or total 
bilirubin value:
AST or ALT >3.0 × ULN 
combined with total 
bilirubin >2.0 × ULN without 
evidence of cholestasis c
OR
For patients with elevated 
baseline AST or ALT or total 
bilirubin value [AST or ALT>2 
× baseline AND > 3.0 × ULN] 
OR [AST or ALT > 8.0 × ULN], 
combined with [total 
bilirubin >2x baseline] 
AND >2.0 × ULN without 
evidence of cholestasis c
Permanently discontinue capmatinib in the absence of signs of 
cholestasis, hemolysis, and alternative causes of the liver injury have 
been excluded (e.g., concomitant use of hepatotoxic drug(s), alcoholic 
hepatitis, etc.). 
a ‘Combined’ defined as: total bilirubin increase to the defined threshold concurrently with ALT/AST 
increase to the defined threshold.
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Grade (CTCAE v5)
Mandatory dose modifications
b If total bilirubin > 3.0 x ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g. review of peripheral blood smear and 
haptoglobin determination), then ↓ 1 dose level and continue treatment at the discretion of the 
Investigator.
c ‘Cholestasis’ defined as: ALP elevation (> 2 x ULN and R value (ALT/ALP in x ULN) < 2) in patients 
without bone metastases, or elevation of ALP liver fraction in patients with bone metastases. 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 cholestasis (R≤2), hepatocellular (R≥5), 
or mixed (R>2 and <5) liver injury.
d If combined elevations of AST or ALT and total bilirubin do not meet the defined thresholds, please 
follow the instructions for isolated elevation of AST/ALT, and take a conservative action based on the 
degree of the elevations (e.g., discontinue treatment at the situation when omit dose is needed for one 
parameter and discontinue treatment is required for another parameter). After all elevations resolve to the 
defined thresholds that allow treatment re-initiation, re-start treatment either at the same dose or one 
dose lower if meeting a criterion for dose reduction.
Table 6-16
Pancreatitis, amylase and lipase elevations suspected to be related 
to capmatinib 
Grade (CTCAE v5)
Mandatory dose modification
Pancreatitis
Grade ≥ 3
Permanently discontinue capmatinib
Asymptomatic amylase and/or lipase elevation
Grade 3 (> 2.0 - 5.0 × ULN
with signs or symptoms; >5.0 x
ULN and asymptomatic)
Interrupt capmatinib until resolved to grade ≤ 2
! If resolved in ≤ 14 days, restart at same dose level 
! If not resolved within 14 days, restart at reduced dose level 
Grade 4 (> 5.0 × ULN and with 
signs or symptoms)
Permanently discontinue capmatinib
Symptomatic elevations
Any grade
Permanently discontinue capmatinib
Table 6-17
QTc prolongations suspected to be related to capmatinib (Further 
guidance is provided in Section 6.3.2)
Grade (CTCAE v5)
Mandatory dose modification
Grade 3 (Average QTcF ≥ 501 
ms; >60ms change from 
baseline)
Interrupt capmatinib until resolved to grade ≤ 2, 
! If resolved ≤ 7 days, restart at the same dose level 
! If not resolved within 7 days, restart at reduced dose level 
Grade 4 (Torsades de pointes 
or polymorphic ventricular 
tachycardia or signs/symptoms 
of serious arrhythmia)
Permanently discontinue capmatinib 
Table 6-18
Diarrhea, vomiting or nausea suspected to be related to capmatinib 
Grade (CTCAE v5)
Mandatory dose modification
Diarrhea 
Grade 2 (despite maximal anti-
diarrheal medication)
Interrupt capmatinib until resolved to grade≤ 1, then restart at same 
dose level
! If diarrhea returns as grade ≥ 2, interrupt capmatinib until resolved 
grade ≤ 1, then restart at reduced dose level
Grade 3 or 4 (despite maximal 
anti-diarrheal medication)
Interrupt capmatinib until resolved to grade ≤ 1, then restart at reduced
dose level 
Vomiting
Grade 2 (despite standard 
anti-emetics)
Interrupt capmatinib until resolved to grade ≤ 1, then restart at same 
dose level
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Grade (CTCAE v5)
Mandatory dose modification
If vomiting returns as grade ≥ 2, interrupt capmatinib until resolved to 
grade≤ 1, then restart at reduced dose level
Grade 3 and 4 (despite 
standard anti-emetics)
Interrupt capmatinib until resolved to grade ≤ 1, then restart at reduced
dose level 
Nausea
Grade 3 (despite standard 
anti-emetics)
Interrupt capmatinib until resolved to grade ≤ 1, then restart at reduced
dose level 
Table 6-19
Skin events suspected to be related to capmatinib
Grade (CTCAE v5)
Mandatory dose modification
Grade 3, despite skin toxicity 
therapy
Interrupt capmatinib until resolved to grade ≤ 1, 
! If resolved in ≤ 7 days, restart at reduced dose level 
! If not resolved within 7 days (despite appropriate skin toxicity 
therapy), permanently discontinue capmatinib
Grade 4, despite skin toxicity 
therapy
Permanently discontinue capmatinib 
* During the whole duration of treatment with capmatinib, the patient is recommended to use 
precautionary measures against ultraviolet exposure (e.g., use of sunscreen, protective clothing and 
avoid sunbathing or using a solarium extensively).
Table 6-20
Pneumonitis or interstitial lung disease (ILD) suspected to be 
related to capmatinib
Grade (CTCAE v5)
Mandatory dose modification
Grade 1
Interrupt capmatinib during diagnostic workup for pneumonitis/ILD
If ILD/pneumonitis is confirmed permanently discontinue capmatinib
Restart at reduced dose level upon resolution 
! If pneumonitis does not resolve within 6 weeks, permanently 
discontinue capmatinib.
2nd recurrence
Interrupt capmatinib until resolved, then restart at reduced dose level. 
! If pneumonitis does not resolve within 6 weeks, permanently 
discontinue capmatinib.
3rd recurrence
Permanently discontinue capmatinib. 
Grade 2
Interrupt capmatinib dose during diagnostic workup until improvement 
to ≤ grade1. 
If ILD/pneumonitis is confirmed permanently discontinue capmatinib
If ILD/pneumonitis is NOT confirmed:
! if symptoms resolve to ≤ grade 1 in ≤ 7 days, restart at reduced dose 
level 
! If symptoms do not resolve within 7 days or recur after dose 
reduction, permanently discontinue capmatinib.
Grade 3 or 4
Permanently discontinue capmatinib
Table 6-21
Fatigue/asthenia suspected to be related to capmatinib
Grade (CTCAE v5)
Mandatory dose modification
Grade 3
Interrupt capmatinib until resolved to Grade≤ 1
! If resolved in ≤ 7 days, restart at same dose level 
! If not resolved within 7 days, restart at reduced dose level 
Grade 4
Permanently discontinue capmatinib 
Table 6-22
Peripheral edema suspected to be related to capmatinib
Grade (CTCAE v5)
Mandatory dose modification
Grade 3
Interrupt capmatinib until resolved to grade ≤ 1, then restart at reduced
dose level
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Grade (CTCAE v5)
Mandatory dose modification
Grade 4
Permanently discontinue capmatinib 
Table 6-23
Other adverse events suspected to be related to capmatinib 
Grade (CTCAE v5)
Mandatory dose modification
Grade 1 or 2
Maintain dose level of capmatinib, consider initiating appropriate 
support medication 
For any intolerable grade 2 (e.g. limiting instrumental ADL), consider 
interrupting the dose until resolved to grade ≤ 1, then restart at reduced 
dose level
Grade 3
Interrupt capmatinib until resolved to grade ≤ 2, then restart at reduced 
dose level
Grade 4
Permanently discontinue capmatinib 
Myocarditis (any grade) or 
other cardiac events Grade ∀3
Permanently discontinue capmatinib (refer to Table 14-17 for 
recommended management guidelines for those events)
6.3.1.5
Mandatory dose modifications for canakinumab
Table 6-24
Infections suspected to be related to canakinumab 
Grade (CTCAE v5)
Mandatory dose modifications
Grade 3
Interrupt canakinumab until resolved to ≤ grade 2, then restart at the 
same dose level
Grade 4
Permanently discontinue canakinumab
Table 6-25
Hematological adverse events suspected to be related to 
canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Neutropenia 
Grade 3 (ANC < 1000 -
500/mm3)
Interrupt canakinumab until resolved to ≤ grade 2, then restart at the 
same dose level
Grade 4 (ANC < 500/mm3)
Permanently discontinue canakinumab
Febrile neutropenia 
ANC <1.0 × 109/L, fever ≥ 
38.5°C
Permanently discontinue canakinumab
Thrombocytopenia
Grade 3 (< 50,000 -
25,000/mm3)
Interrupt canakinumab until resolved to ≤ grade 1
! If resolved in ≤ 7 days, restart at same dose 
! If not resolved within 7 days, permanently discontinue canakinumab
Grade 4 (< 25,000/mm3)
Permanently discontinue canakinumab
Table 6-26
Creatinine alterations suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Grade 3 (> 3.0 - 6.0 × ULN; 
or >3.0 x baseline if baseline 
was elevated)
Interrupt canakinumab until resolved to ≤ grade 2 or baseline
! If resolved in ≤ 14 days, then restart at the same dose level
! If not resolved within 14 days, permanently discontinue canakinumab 
Grade 4 (> 6.0 x ULN)
Permanently discontinue canakinumab 
Table 6-27
Hepatic adverse events suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modifications
Isolated total Bilirubin elevation
Grade 2 (> 1.5 - 3.0 × 
ULN; >1.5 - 3.0 x baseline if 
baseline was abnormal)
Interrupt canakinumab and monitor liver testa weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 × ULN
! If resolved in ≤ 14 days, restart at same dose level
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Grade (CTCAE v5)
Mandatory dose modifications
! If not resolved within 14 days, permanently discontinue canakinumab
Grade 3 (> 3.0 - 10.0 × 
ULN*; >3.0 - 10.0 x baseline if 
baseline was abnormal)
Interrupt canakinumab and monitor liver testa weekly, or more 
frequently if clinically indicated, until resolved to ≤ 1.5 × ULN
! If resolved in ≤ 14 days, then restart at the same dose level
! If not resolved within 14 days, permanently discontinue canakinumab. 
The subject should be monitored weekly (including liver testa), or 
more frequently if clinically indicated, until total bilirubin have resolved 
to baseline or stabilization over 4 weeks. 
Grade 4 (> 10.0 × ULN*; >10.0 
x baseline if baseline was 
abnormal)
Permanently discontinue canakinumab. The subject should be 
monitored weekly (including liver testa), or more frequently if clinically 
indicated, until total bilirubin have resolved to baseline or stabilization 
over 4 weeks.
Isolated AST or ALT elevation 
Grade 2 (> 3.0 - 5.0 × 
ULN; >3.0 - 5.0 x baseline if 
baseline was abnormal)
Continue canakinumab at the same dose level
Repeat liver testa within 48-72 hours; if abnormal values are confirmed 
upon the repeat test, then monitor liver testa weekly, or more frequently 
if clinically indicated, until resolved to ≤ 3.0 × ULN
Grade 3 > 5.0 - 10.0 × 
ULN; >5.0 – 10 x baseline if 
baseline was abnormal
Interrupt canakinumab. Repeat liver testa within 48-72 hours; monitor 
liver testa weekly, or more frequently if clinically indicated, until resolved 
to ≤ 3.0 × ULN. 
! If resolved in ≤ 28 days, restart canakinumab at same dose 
! If not resolved within 28 days, permanently discontinue canakinumab
> 10.0 - 20.0 × ULN’ >10 - 20 x 
baseline if baseline was 
abnormal
Permanently discontinue canakinumab
Repeat liver testa within 48-72 hours. Monitor liver testa weekly, or more 
frequently if clinically indicated, until resolved to ≤ baseline
Grade 4 (> 20.0 × ULN; >20.0 
x baseline if baseline was 
abnormal)
Permanently discontinue canakinumab 
Repeat liver testa within 48-72; monitor liver testa weekly, or more 
frequently if clinically indicated, until resolved to ≤ 3 × ULN
Combined b elevations of AST or ALT and total bilirubin
For subjects with normal 
baseline ALT and AST and 
total bilirubin value:
AST or ALT >3.0 × ULN 
combined with total 
bilirubin >2.0 × ULN without 
evidence of cholestasisc
Permanently discontinue canakinumab
Repeat liver testa within 48-72; monitor liver testa weekly or more 
frequently if clinically indicated, until AST, ALT, or bilirubin have 
resolved to baseline or stabilization over 4 weeks. 
aCore liver tests consist of ALT, AST, GGT, total bilirubin (fractionated [direct and indirect], if total 
bilirubin > 2.0 × ULN), and alkaline phosphatase (fractionated [quantification of isoforms], if alkaline 
phosphatase > 2.0 × ULN.)
b “Combined” defined as total bilirubin increase to the defined threshold concurrently with ALT/AST 
increase to the defined threshold. If combined elevations of AST or ALT and total bilirubin do not meet the 
defined thresholds, please follow the instructions for isolated elevation of total bilirubin and isolated 
elevation of AST/ALT, and take a conservative action based on the degree of the elevations (e.g. 
discontinue treatment at the situation when omit dose is needed for one parameter and discontinue 
treatment is required for another parameter). After all elevations resolve to the defined thresholds that 
allow treatment re-initiation, re-start the treatment either at the same dose or at one dose lower if meeting 
a criterion for dose reduction.
c “Cholestasis” defined as ALP elevation (>2.0 × ULN and R value <2 ) in subjects without bone 
metastasis, or elevation of ALP liver fraction in subjects 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.
* If total bilirubin > 3.0 × ULN is due to the indirect (non-conjugated) component only, and hemolysis as 
the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood smear and 
haptoglobin determination), continue treatment at the discretion of the investigator.
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Table 6-28
Pancreatitis, amylase and/or lipase elevations suspected to be 
related to canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Pancreatitis
Grade ≥ 3
Permanently discontinue canakinumab
Asymptomatic amylase and/or lipase elevation*
Grade 3 (> 2.0 - 5.0 x ULN with 
signs or symptoms; >5.0 x ULN 
and asymptomatic)
Interrupt canakinumab until resolved to grade≤ ,1 or baseline 
! If resolved in ≤ 7 days, restart at same dose level
! If not resolved within 7 days, permanently discontinue 
canakinumab
Grade 4 (> 5.0 x ULN and with 
signs or symptoms)
Permanently discontinue canakinumab
* A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. If asymptomatic Grade 2 
elevations of lipase and/or amylase occur again at the reduced dose, subjects will be discontinued 
permanently from study treatment.
Table 6-29
Hypertension suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Grade 3
Interrupt canakinumab until resolved ≤ grade 1, then restart at same 
dose level
Grade 4
Permanently discontinue canakinumab
Table 6-30
Diarrhea suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modifications
Grade 2
Interrupt canakinumab until resolved to ≤ Grade1, then restart at 
same dose level
Grade 3
Permanently discontinue canakinumab
Grade 4
Permanently discontinue canakinumab
Table 6-31
Skin related toxicities suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Grade 3, despite skin toxicity 
therapy
Interrupt canakinumab until resolved to Grade≤ 1
! If resolved in ≤ 7 days, restart at same dose level
! If not resolved within 7 days (despite appropriate skin toxicity 
therapy), permanently discontinue canakinumab
Grade 4, despite skin toxicity 
therapy
Permanently discontinue canakinumab
Table 6-32
Fatigue/asthenia suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modifications
Grade 3
Interrupt canakinumab until resolved to ≤ grade1
! If resolved in ≤ 14 days, restart at same dose level
! If not resolved within 14 days, permanently discontinue 
canakinumab
Table 6-33
Other adverse events suspected to be related to canakinumab
Grade (CTCAE v5)
Mandatory dose modification
Grade 3
Interrupt canakinumab until resolved to ≤ grade 1, restart at the 
same dose level
Grade 4, except alopecia
Permanently discontinue canakinumab
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6.3.1.6
Mandatory dose modifications for ribociclib 
Table 6-34
Hematological adverse events suspected to be related to ribociclib
Grade (CTCAE v5)
Mandatory dose modification
Thrombocytopenia
Grade 2 (≥50 x 109/L – <75 x 
109/L)
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the same dose.
Grade 3 (≥25 x 109/L – <50 x 
109/L)
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until recovery to 
grade ≤1 and reduce ribociclib to the next lower dose level.
Grade 4 (<25 x 109/L)
Dose interruption until recovery to grade ≤1.
Re-initiate ribociclib at the next lower dose level.
If toxicity recurs at grade 4: discontinue ribociclib
Absolute neutrophil count (ANC)
Grade 3 (≥0.5 x 109/L – <1.0 x 
109/L)
Dose interruption until recovery to ≥1.0 x 109/L.
Re-initiate ribociclib at the same dose level.
If toxicity recurs at grade 3: temporary dose interruption until recovery to 
≥ 1.0 x 109/L.
If resolved in ≤7 days, then maintain dose level.
If resolved in >7 days, then reduce ribociclib dose to the next lower 
dose level.
Grade 4 (<0.5 x 109/L)
Dose interruption until recovery to ≥ 1.0 x 109/L.
Re-initiate ribociclib at the next lower dose level.
Febrile neutropenia
Grade 3 
ANC <1.0 x 109/L with a single 
temperature of >38.3 ºC (101 
ºF) or a sustained temperature 
of ≥38 ºC (100.4 ºF) for more 
than one hour
Dose interruption until improvement of ANC ≥ 1.0 x 109/L and no fever. 
Restart at the next lower dose level.
If febrile neutropenia recurs, discontinue ribociclib.
Grade 4 
Life-threatening 
consequences;
urgent intervention indicated
Discontinue ribociclib.
Anemia (Hemoglobin)
Grade 3 (<8.0 g/dL)
Dose interruption until recovery to grade ≤ 2.
Re-initiate ribociclib at the same dose.
Grade 4 
Life-threatening 
consequences;
urgent intervention indicated
Discontinue ribociclib.
Table 6-35
Abnormal liver tests suspected to be related to ribociclib
Grade (CTCAE v5)
Mandatory dose modification
TOTAL BILIRUBIN without ALT/AST increase above baseline value
Grade 1 (> ULN – 1.5 x ULN)
(confirmed 48-72h later)
No dose adjustment required with LFTs monitored every 2 weeks
Grade 2 (> 1.5 – 3.0 x ULN)
Dose interruption of ribociclib
If resolved to ≤ grade 1 in ≤ 21 days, then maintain dose level
If resolved to ≤ grade 1 in > 21-28 days or toxicity recurs, then reduce to 
the next lower dose level
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption
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If toxicity recurs after two dose reductions, or recovery to ≤ grade 1 is > 
28 days, discontinue ribociclib
Grade 3 (> 3.0 – 10.0 x ULN)
Dose interruption of ribociclib, until resolved to ≤ grade 1 , then reduce 
to the next lower dose level
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption
If resolved to ≤ grade 1 in > 28 days or toxicity recurs, discontinue 
ribociclib
Grade 4 (> 10.0 x ULN)
Discontinue ribociclib
Confounding factors and/or alternative causes for increase of total bilirubin should be excluded before dose
interruption/reduction. They include but are not limited to: evidence of liver metastases, evidence of
obstruction, such as elevated ALP and GGT typical of gallbladder or bile duct disease, hyperbilirubinemia 
due to the indirect component only (i.e. direct bilirubin component ≤ 1 x ULN) due to hemolysis or Gilbert
Syndrome, other pharmacologic treatment, viral hepatitis, alcoholic or autoimmune hepatitis, other
hepatotoxic drugs.
For patients with Gilbert Syndrome, these dose modifications apply to changes in direct bilirubin only.
Bilirubin will be fractionated if elevated.
AST or ALT without bilirubin elevation > 2 x ULN
Same grade as baseline or 
increase from baseline grade 0 
to grade 1
(confirmed 48 – 72 h later)
No dose adjustment required with LFTs monitored per protocol if same 
grade as baseline or every 2 weeks in case of increase from baseline 
grade 0 to 1
Increase from baseline grade 0 
or 1 to grade 2 (> 3.0 – 5.0 x 
ULN)
Dose interruption of ribociclib
If resolved to ≤ baseline grade in ≤ 21 days, then maintain dose level
If resolved to ≤ baseline grade in > 21 days or toxicity recurs, then 
reduce to the next lower dose level
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption
If toxicity recurs after two dose reductions or recovery to ≤ baseline 
grade is > 28 days, discontinue ribociclib
Increase from baseline grade 0 
or 1 to grade 3 (> 5.0 – 20.0 x 
ULN)
Dose interruption of ribociclib until resolved to ≤baseline grade, then 
reduce to the next lower dose level
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption
If recovery to ≤ baseline grade is > 28 days, discontinue ribociclib
If toxicity recurs, discontinue ribociclib
Increase from baseline grade 2 
to grade 3 (> 5.0 – 20.0 x ULN)
Dose interruption of ribociclib until resolved to ≤baseline grade, then
reduce to the next lower dose level
Repeat liver enzyme and bilirubin tests twice weekly for 2 weeks after 
dose resumption
If toxicity recurs after two dose reductions or recovery to ≤ baseline 
grade is > 28 days, discontinue ribociclib.
Grade 4 (> 20.0 x ULN)
Discontinue ribociclib
AST or ALT and concurrent Bilirubin
For patients with normal ALT 
and AST and total bilirubin at 
baseline: AST or ALT >3.0 x 
ULN combined with total 
bilirubin > 2 x ULN without 
evidence of cholestasis
OR
For patient with elevated AST 
or ALT or total bilirubin at 
baseline: [AST or ALT >2 x 
baseline AND >3.0x ULN] OR 
[AST or ALT > 8.0 x ULN]-
whichever is lower- combined 
with [total bilirubin > 2 x 
baseline AND >2.0 x ULN]
Discontinue ribociclib
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Table 6-36
QTcF prolongation suspected to be related to ribociclib
Grade (CTCAE v5)
Mandatory dose modification
For All Grades
1. Check the quality of the ECG and the QT value and repeat if needed.
2. Perform analysis of serum electrolytes (K+, Ca++, Phos, Mg++). If outside 
of the normal range, interrupt ribociclib administration, correct with 
supplements or appropriate therapy as soon as possible, and repeat
electrolytes until documented as normal.
3. Review concomitant medication usage for the potential to inhibit CYP3A4 
and/or to prolong the QT interval.
4. Check compliance with correct dose and administration of ribociclib.
 
Grade 1*
QTcF 450-480 ms
Perform steps 1-4 as directed in “For All Grades.” No dose adjustment 
required.
Grade 2*
QTcF 481-500 ms
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” Perform 
a repeat ECG within one hour of the first QTcF of ≥ 481 ms.
Repeat ECG as clinically indicated until the QTcF returns to < 481 ms, Restart 
ribociclib with dose reduced by 1 dose level.
If QTcF ≥ 481 ms recurs, ribociclib should be reduced again by 1 dose level.
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patients who had therapy interrupted due to QTcF ≥ 481 
ms.
Grade 3*
QTcF ≥ 501 ms; or > 
60 ms change from 
baseline
Interrupt ribociclib. Perform steps 1-4 as directed in “For All Grades.” Transmit 
ECG immediately and confirm prolongation/abnormalities with central
assessment.
Perform a repeat ECG within one hour of the first QTcF of ≥ 501 ms. If QTcF 
remains ≥ 501 ms, consult with a cardiologist (or qualified specialist) and 
repeat cardiac monitoring as indicated until the QTcF returns to < 481 ms.
!
If QTcF returns to < 481 ms, ribociclib will be reduced by 1 dose level.
!
If QTcF remains ≥ 481 ms after performing steps 1-4 as directed in “For
All Grades,” discontinue ribociclib.
Repeat ECGs 7 days and 14 days after dose resumption (then as clinically 
indicated) for any patients who had therapy interrupted due to QTcF ≥ 501 
ms
If QTcF of ≥ 501 ms recurs, discontinue ribociclib.
Grade 4*
Torsades de pointes 
or polymorphic 
ventricular 
tachycardia, or 
signs/symptoms of 
i
h th
i
Discontinue ribociclib. Perform steps 1-4 as directed in “For All Grades.”
!
Obtain local cardiologist (or qualified specialist) consultation and repeat 
cardiac monitoring as indicated until the QTcF returns to <481 ms.
*All values refer to the average of triplicate measurements if study protocol requires triplicate ECG collections.
Table 6-37
Other adverse events suspected to be related to ribociclib
Consider performing an analysis of serum potassium, calcium, phosphorus, and magnesium for all adverse 
reactions, if indicated. If electrolyte values are outside of the normal range, interrupt ribociclib administration, 
correct electrolytes with supplements or appropriate therapy as soon as possible, and repeat electrolyte 
testing until documented normalization of the electrolytes.
Grade (CTCAE v5)
Mandatory dose modification
Renal impairment (not due to other contributing factors)
Grade 2 or higher
Discontinue ribociclib.
Interstitial lung disease/pneumonitis
Grade 1 (asymptomatic)
No dose adjustment required.
Initiate appropriate medical therapy and monitor as clinically indicated
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Grade 2 (symptomatic)
Interrupt ribociclib dose until recovery to Grade ≤1, then resume ribociclib
at the next lower dose level (An individualized benefit-risk assessment 
should be performed before resuming ribociclib). 
Grade 3 or 4 (severe)
Discontinue ribociclib.
Other adverse events
Grade 2
Dose interruption until recovery to grade ≤ 1. Initiate appropriate medical 
therapy and monitor.
Re-initiate ribociclib at the same dose.
If the same toxicity recurs at grade 2, interrupt ribociclib until recovery to 
grade ≤ 1. Re-initiate ribociclib at the next lower dose level.
Grade 3
Dose interruption until recovery to grade ≤ 1. Initiate appropriate medical 
therapy and monitor.
Re-initiate ribociclib at the next lower dose level.
If toxicity recurs at grade 2: temporary dose interruption until recovery to 
grade ≤ 1 and reduce ribociclib dose the next lower dose level.
If toxicity recurs at grade 3, discontinue ribociclib.
Grade 4 (including Toxic 
Epidermal Necrolysis, TEN)
Discontinue ribociclib and treat with appropriate medical therapy.
6.3.2
Dose adjustments for QTcF prolongation suspected to be related to 
capmatinib 
In case of QTcF >500 msec, (or QTcF prolongation >60 msec from baseline):
1. Assess the quality of the ECG recording and the QT value and repeat if needed
2. Interrupt capmatinib 
3. Determine the serum electrolyte levels (in particular hypokalemia, hypomagnesemia). If 
abnormal, correct abnormalities before resuming capmatinib.
4. Review concomitant medication associated with QT prolongation, including drugs with 
a ‘Known’, ‘Possible’, or ‘Conditional’ risk of Torsades de Pointes” (refer to 
qtdrugs.org), and drugs with the potential to increase the risk of study drug exposure 
related QT prolongation 
5. Check capmatinib dosing schedule and treatment compliance
 
After confirming ECG reading at site, if QTcF > 500 msec
!
Interrupt capmatinib 
!
Repeat ECG and confirm ECG diagnosis by a cardiologist or central ECG lab
!
If QTcF confirmed > 500 msec:
!
Correct electrolytes, eliminate culprit concomitant treatments, and identify and 
address clinical conditions that could potentially prolong the QT interval.
!
Consult with a cardiologist (or qualified specialist)
!
Increase cardiac monitoring as indicated, until the QTcF returns to ≤ 480 msec.
!
After resolution to ≤ 480 msec, consider re-introducing capmatinib at reduced dose, 
and increase ECG monitoring for the next cycle(s):
!
If QTcF remains ≤ 500 msec after dose reduction, continue planned ECG 
monitoring during subsequent treatment
!
If QTcF recurs > 500 msec after dose reduction, discontinue subject from 
capmatinib.
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6.3.3
Follow-up for toxicities
All subjects must be followed-up for AEs and SAEs for 150 days following the last dose of 
spartalizumab/LAG525, or up to 130 days after the last dose of canakinumab, or up to 30 
days after the last dose of capmatinib or ribociclib, whichever is later. Suspected SAEs will 
continue to be collected beyond those timeframes. However, if the subject begins 
subsequent anti-cancer therapy before the 150-Day safety visit, the collection of new SAEs
and AEs unrelated to study medication will stop and thereafter only suspected SAEs and 
suspected AEs will continue to be collected up to 150 days following the last dose of 
spartalizumab. If SAEs suspected to be related to study medication occur beyond Day 150, 
information should also be collected.
The emergence of irAEs may be anticipated based on the mechanism of action of checkpoint 
inhibitor therapies. Serologic, histologic (tumor sample) and immunological assessments 
should be performed as deemed appropriate by the Investigator to verify the immune-related 
nature of the AE and to exclude alternative explanations. Recommendations have been 
developed to assist investigators in assessing and managing the most frequently occurring 
irAEs (refer to Appendix 3). If cytokine release syndrome is suspected, the assessments 
outlined in Section 7.2.2.5 must be performed.
Subjects whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 30 days, and 
subsequently at approximately 30-day intervals (or more frequently if required by 
institutional practices, or if clinically indicated), until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed 
necessary.
Refer to Section 6.3 and Appendix 3 for the follow-up evaluations recommended for 
selected toxicities.
6.3.3.1
Follow up on potential drug-induced liver injury cases (all arms)
Transaminase increase combined with total bilirubin increase may be indicative of 
potentially severe drug-induced liver injury (DILI), and should be considered as clinically 
important events and assessed appropriately to establish the diagnosis. The required clinical 
information, as detailed below, should be sought to obtain the medical diagnosis of the most 
likely cause of the observed laboratory abnormalities.
The threshold for potential DILI may depend on the subject’s baseline AST/ALT and total 
bilirubin values; subjects meeting any of the following criteria will require further follow-
up as outlined below:
!
For subjects with normal ALT and AST and total bilirubin at baseline: AST or ALT > 
3.0 × ULN combined with total bilirubin > 2.0 × ULN
!
For subjects with elevated AST or ALT or total bilirubin at baseline: [AST or ALT > 
3.0 × baseline] OR [AST or ALT > 8.0 × ULN], whichever is lower, combined with 
[total bilirubin > 2.0 × baseline AND > 2.0 × ULN]
As DILI is essentially a diagnosis of exclusion, other causes of abnormal liver tests should 
be considered and their role clarified before DILI is assumed as the cause of liver injury.
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A detailed history, including relevant information such as review of ethanol consumption, 
concomitant medications, herbal remedies, supplement consumption, history of any pre-
existing liver conditions or risk factors, should be collected.
Laboratory tests should include ALT, AST, total bilirubin, direct and indirect bilirubin, GGT, 
GLDH (Glutamate dehydrogenase), prothrombin time (PT)/INR, alkaline phosphatase, 
albumin, and creatine kinase.
Evaluate status of liver metastasis (new or exacerbation) or vascular occlusion – e.g. using 
CT, MRI, or duplex sonography.
Perform relevant examinations (Ultrasound or MRI, ERCP) as appropriate, to rule out an 
extrahepatic cause of cholestasis, defined as an ALP elevation > 2.0 × ULN with R value < 
2 in subjects without bone metastasis, or elevation of the liver-specific ALP isoenzyme in 
subjects 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.
Table 6-38 provides guidance on specific clinical and diagnostic assessments which can be 
performed to rule out possible alternative causes of observed LFT abnormalities.
Table 6-38
Guidance on specific clinical and diagnostic assessments which can 
be performed to rule out possible alternative causes of observed LFT abnormalities
Disease
Assessment
Hepatitis A, B, C, E
!
IgM anti-HAV; HBsAg, IgM & IgG anti-HBc, HBV DNA; anti-
HCV, HCV RNA, IgM & IgG anti-HEV, HEV RNA
CMV, HSV, EBV infection
!
IgM & IgG anti-CMV, IgM & IgG anti-HSV; IgM & IgG anti-EBV
Autoimmune hepatitis
!
ANA & ASMA titers, total IgM, IgG, IgE, IgA
Alcoholic hepatitis
!
Ethanol history, GGT, MCV, CD-transferrin
Nonalcoholic 
steatohepatitis
!
Ultrasound or MRI
Hypoxic/ischemic 
hepatopathy
!
Medical history: acute or chronic congestive heart failure, 
hypotension, hypoxia, hepatic venous occlusion. Ultrasound or 
MRI.
Biliary tract disease
!
Ultrasound or MRI, ERCP as appropriate.
Wilson disease (if <40 yrs 
old)
!
Ceruloplasmin
Hemochromatosis
!
Ferritin, transferrin
Alpha-1-antitrypsin 
deficiency
!
Alpha-1-antitrypsin
Other causes should also be considered based upon subjects’ medical history 
(hyperthyroidism / thyrotoxic hepatitis – T3, T4, TSH; cardiovascular disease / ischemic 
hepatitis – ECG, prior hypotensive episodes; Type 1 diabetes / glycogenic hepatitis).
Following appropriate causality assessments, as outlined above, the causality of the 
treatment is estimated as “probable” i.e. >50% likely, if it appears greater than all other 
possible causes of liver injury combined. The term “treatment-induced” indicates probably 
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caused by the treatment, not by something else, and only such a case can be considered a 
DILI case and should be reported as an SAE.
All cases confirmed on repeat testing meeting the laboratory criteria defined above, with no 
other alternative cause for liver test abnormalities identified should be considered as 
“medically significant”, thus, met the definition of SAE (Section 8.1.2) and be reported as 
SAE using the term “potential treatment-induced liver injury”. All events should be 
followed up with the outcome clearly documented.
6.4
Concomitant medications
The subject must be told to notify the investigational site about any new medications he/she 
takes after the start of the study treatment. 
All medications (other than study treatment), including, surgeries, radiotherapies, or other 
medical procedures and significant non-drug therapies (blood transfusions, physical therapy, 
herbal/natural medications and) administered within 30 days prior to starting study treatment 
until 150 days following the last dose of spartalizumab/LAG525, or up to 130 days after the 
last dose of canakinumab, or up to 30 days after the last dose of capmatinib or ribociclib, 
whichever is later, must be recorded in the eCRF. If a new anti-cancer therapy is started then 
only medications relative to the suspected AE/SAE that are reported should be collected.
Each concomitant drug must be individually assessed against all exclusion 
criteria/prohibited medication. If in doubt the investigator should contact the Novartis before 
randomizing a subject or allowing a new medication to be started. If the subject is already 
enrolled, the investigator should contact Novartis to determine if the subject should be 
discontinued from the study treatment or the study.
6.4.1
Permitted concomitant therapy
!
In general, concomitant medications and therapies deemed necessary for the supportive 
care (e.g. such as anti-emetics, anti-diarrhea) and safety of the subject are allowed except 
those prohibited in Section 6.4.3.
!
Limited-field palliative radiotherapy may be allowed (refer to Section 6.4.4) after 
documented discussion with Novartis. 
!
Immune-suppressive therapy (e.g. steroids) to treat (suspected) immune-mediated 
adverse events are allowed (see also Section 6.4.3).
!
Treatment with bisphosphonates or denosumab for pre-existing bone metastases is 
allowed. If therapy needs to be initiated while on study, subjects should be evaluated for 
disease progression. 
!
Inactivated vaccines are allowed
6.4.2
Permitted concomitant therapy requiring caution and/or action 
!
Anticoagulation and anti-aggregation agents are permitted if the subjects 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.
!
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration 
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should be given to withholding anti-hypertensive medications for 12 hours prior to 
infusion with spartalizumab and/or LAG525.
6.4.2.1
For subjects receiving capmatinib in combination arm 2
The following cautions should be taken:
!
Capmatinib is a moderate CYP1A2 inhibitor. Co-administration of capmatinib increased 
sensitive CYP1A2 probe substrate (caffeine) AUC by 135%. The dose of CYP1A2 
substrates with narrow therapeutic index may need to be reduced when used 
concurrently with capmatinib as capmatinib may increase their exposure. Consult the 
product information of concomitant drug for dose adjustment.
!
Co-administration of capmatinib increased Pgp substrate (digoxin) exposure (AUC and 
Cmax by 47% and 74%, respectively) and BCRP substrate (rosuvastatin) exposure (AUC 
and Cmax by 108% and 204%, respectively). Monitor subjects closely for symptoms of 
increased exposure to Pgp or BCRP substrates. Consult the concomitant Pgp or BCRP 
substrate product information when considering dose adjustment.
!
Co-administrating capmatinib with strong CYP3A4 inhibitor (itraconazole) increased 
capmatinib AUC by 40%. There is no change in capmatinib Cmax. Execute caution when 
use strong CYP3A4 inhibitor concurrently with capmatinib.
!
While the data on the concurrent use of PPI and food have to be considered preliminary 
as they have been generated in a small cohort of subjects of the study CINC280A2108, 
the decrease in exposure imposes caution on the use of PPI when capmatinib is taken.
!
Short acting gastric acid modulators containing aluminum hydroxide and magnesium 
hydroxide, or calcium carbonate can be taken. However, it is recommended to take these 
drugs at least 3 hours before or 3 hours after administration of capmatinib. H2 receptor 
antagonists should be avoided. If subjects are using H2 receptor antagonists during the 
course of this study, subjects should not take capmatinib within 2 hours of taking H2 
receptor antagonists. In addition, the next scheduled dose of capmatinib should be 
administered at least 8 hours after taking H2 receptor antagonists.
!
Capmatinib is a weak to moderate inhibitor of CYP2C8, CYP2C9 and CYP2C19 in vitro. 
Substrates of CYP2C8, CYP2C9 and CYP2C19 with a narrow therapeutic window 
should be administered with caution.
Refer to Table 6-39 below for a list of the medications that require caution when 
concomitantly used with capmatinib. 
Table 6-39
List of medications to be used with caution while on treatment with 
capmatinib (arm 2) 
Mechanism of Interaction
Drug Name
Strong CYP3A inhibitor
ombitasvir/paritaprevir/dasabuvir/ritonavir (Viekira Pak), 
indinavir/ritonavir, tipranavir/ritonavir, ritonavir, cobicistat, indinavir, 
ketoconazole, troleandomycin, telaprevir, danoprevir/ritonavir, 
elvitegravir/ritonavir, saquinavir/ritonavir, lopinavir/ritonavir, itraconazole, 
voriconazole, mibefradil, posaconazole, telithromycin, grapefruit juice, 
conivaptan, nefazodone, nelfinavir, idelalisib, boceprevir, 
atazanavir/ritonavir, darunavir/ritonavir
CYP1A2 substrate with NTI
theophylline, tizanidine
CYP2C9 substrate with NTI
warfarin
CYP2C19 substrate with NTI
(S)-mephenytoin
P-gp substrates
afatinib, alfuzosin, aliskiren, alogliptin, ambrisentan, apixaban, 
apremilast, aprepitant, boceprevir, bosentan, carvedilol, carvedilol, 
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Mechanism of Interaction
Drug Name
caspofungin, ceritinib, colchicine, cyclosporine, dabigatran, digoxin, 
doxepin, doxorubicin, eribulin, everolimus, fidaxomicin, fluvastatin, 
fosamprenavir, idelalisib, iloperidone, indacaterol, irbesartan, 
lacosamide, lapatinib, levetiracetam, linagliptin, losartan, maraviroc, 
mirabegron, naloxegol, nateglinide, nintedanib, olodaterol, pantoprazole, 
paroxetine, pazopanib, posaconazole, pravastatin, quinine, ranolazine, 
riociguat, risperidone, rivaroxaban, saquinavir, silodosin, simeprevir, 
sirolimus, sitagliptin, sorafenib, telaprevir, tenofovir, ticagrelor, tipranavir, 
tolvaptan, topotecan, umeclidinium, valsartan, vardenafil, vincristine, 
voriconazole, atorvastatin, docetaxel, fentanyl, fexofenadine, linezolid, 
loperamide, nadolol, nevirapine, paclitaxel, proguanil, ritonavir, 
simvastatin, sofosbuvir, tacrolimus
BCRP substrates
atorvastatin, daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, methotrexate, mitoxantrone, paritaprevir, pitavastatin, 
rosuvastatin, irinotecan, ethinyl estradiol, simvastatin, sofosbuvir, 
sulfasalazine, tenofovir, topotecan, venetoclax
Proton pump inhibitor
omeprazole, pantoprazole, lansoprazole, esomeprazole, rabeprazole, 
dexlansoprazole
Short acting gastric acid 
modulator and H2 receptor 
antagonist
ranitidine, nizatidine, famotidine, cimetidine, aluminum hydroxide, 
aluminum carbonate, calcium hydroxide, calcium carbonate, bismuth 
subsalicylate
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum 
(Jan 2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University 
School of Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, 
Drug Interaction Studies” This may not be an exhaustive list, will be updated periodically.
NTI: narrow therapeutic index
6.4.2.2
For subjects receiving ribociclib in combination arm 4
Medications to be used with caution during treatment with ribociclib are listed below and in 
Table 6-40 (This list is not comprehensive and is only meant to be used as a guide. Please 
contact the medical monitor with any questions). These medications should be excluded 
from patient use if possible. If they must be given based on the investigator’s judgment, then 
use with caution and consider a ribociclib interruption if the concomitant medication is only 
needed for a short time.
!
Moderate inhibitors or inducers of CYP3A4/5 (may increase or decrease ribociclib 
exposure, respectively)
!
Sensitive substrates of CYP3A4/5 that do not have narrow therapeutic index 
(ribociclib may increase exposure to these medications)
!
Strong inhibitors of bile salt export pump (based on in vitro data co-administration 
with ribociclib may lead to intrahepatic cholestasis)
!
Medications that carry a possible risk for QT prolongation (may precipitate QT 
prolongation and TdP)
!
Sensitive substrates of the renal transporters MATE1/2 and OCT1/2 (ribociclib has a 
potential to increase exposure to substrates of these transporters, although no animal or 
clinical data are available to support these statements)
!
Sensitive substrates of transporter BCRP (ribociclib has a potential to increase 
exposure to substrates of this transporter, although no animal or clinical data are 
available to support these statements)
!
Corticosteroids: Chronic dosing of corticosteroids such as dexamethasone and 
prednisone is known to lead to induction of CYP3A enzymes, thereby potentially 
reducing ribociclib drug exposure to sub-therapeutic levels. Systemic corticosteroid 
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treatment should be avoided during the study treatment with ribociclib, unless 
clinically required.
Topical applications (e.g. for rash), inhaled sprays (e.g. for obstructive airways 
diseases), eye drops or local injections (e.g. intra-articular) are allowed.
Table 6-40
List of medications to be used with caution during ribociclib 
treatment (arm 4)
Category
Drug Name
Moderate CYP3A4/5 inhibitors
Aprepitant, amprenavir, asafoetida resin (Ferula asafoetida), 
cimetidine, 
crizotinib, 
diltiazem, 
faldaprevir,
imatinib,
isavuconazole, netupitant, nilotinib, tofisopam, Schisandra 
sphenanthera (nan wu wei zi), verapamil
Moderate CYP3A4/5 inducers
Bosentan, 
dabrafenib, 
efavirenz, 
etravirine, 
genistein,lopinavir5, modafinil, nafcillin,telotristat
Sensitive CYP3A4/5 substrates1
Alpha-dihydroergocryptine, apixaban, aprepitant, atorvastatin, 
avanafil, bosutinib, brotizolam, budesonide, buspirone, 
cannabinoids6, 
cannabidiol6,
cobimetinib,
darifenacin, 
dasatinib, ebastine, eletriptan, eplerenone, everolimus, 
felodipine, fluticasone, grazoprevir, ibrutnib, isavuconazole, 
ivabradine, ivacaftor, lumefantrine, lurasidone, maraviroc, 
midazolam, midostaurin, naloxegol, neratinib, perospirone, 
quetiapine, ridaforolimus, rivaroxaban, sildenafil, simeprevir, 
ticagrelor, tilidine, tolvaptan, triazolam, ulipristal, vardenafil, 
venetoclax, vicriviroc, voclosporin
Bile salt export pump inhibitors
Alectinib, atorvastatin, bromocriptine, candesartan, clobetasol, 
clofaziminie, dabigatran, dipyridamole, glyburide, grazoprevir, 
ledipasvir, mifepristone,pioglitazone, reserpine, rifamycin, 
simeprevir, telmisartan, timcodar, troglitazone, velpatasvir
Medications that carry a 
possible risk for QT 
prolongation2
Alfuzosin, apomorphine, aripiprazole, artenimol+piperaquine, 
asenapine,
atazanavir, 
atomoxetine,
bedaquiline, 
bendamustine, 
bortezomib, 
bosutinib,
buprenorphine, 
cabozantinib, 
capecitabine, ceritinib, clomipramine, crizotinib, clozapine, 
cyamemazine 
(cyamepromazine), 
dabrafenib, 
dasatinib, 
degarilix, 
delamanid, 
desipramine, 
dexmedetomidine, 
dolasetron, efavirenz, eliglustat, epirubicin, eribulin mesylate, 
ezogabine(retigabine), famotidine, felbamate, fingolimod, 
flupentixol,
gemifloxacin, 
granisetron, 
hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, ketanserin, 
lapatinib, 
lenvatinib, 
leuprolide, 
loperamide, 
lithium, 
melperone, 
midostaurin, 
mifepristone, 
mirabegron, 
mirtazapine, 
moexipril/HCTZ, 
necitumumab, 
, 
nilotinib, 
norfloxacin, 
nortriptyline, 
nusinersen, 
ofloxacin, 
olanzapineosimertinib, oxytocin, paliperidone, palonosetron,
panabinostat, 
pasireotide, 
pazopanib, 
perflutren 
lipid 
microspheres, 
perphenazine, 
pilsicainide, 
pimavanserin, 
pipamperone, 
promethazine, 
prothipendyl, 
quetiapine, 
ranolazine, rilpivirine, risperidone, romidepsin, sertindole, 
sorafenib, sunitinib, tamoxifen, telavancin, tetrabenazine, 
tipiracil/trifluridine, 
tizanidine, 
tolterodine, 
toremifene, 
trimipramine, 
tropisetron, 
vardenafil, 
vemurafenib, 
venlafaxine, vorinostat, ziprasidone
MATE1/2 substrates3
Acyclovir, cephalexin, cimetidine, fexofenadine, ganciclovir, 
glycopyrronium, metformin, pindolol, plisicainide, ranitidine, 
topotecan, varenicline
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OCT1/2 substrates4
Amantadine, carboplatin, cisplatin, cephalexin, cephradine, 
ipratropium, lamivudine, linagliptin, metformin, oxaliplatin, 
oxybutynin, phenformin, picoplatin, pilsicainide, pindolol, 
ranitidine, sorafenib, tropisetron, trospium, umeclidinium, 
zidovudine
BCRP substrates
Daunorubicin, dolutegravir, doxorubicin, hematoporphyrin, 
imatinib, 
methotrexate, 
mitoxantrone, 
pitavastatin, 
rosuvastatin, irinotecan, ethinyl estradiol, sulfasalazine, 
sofosbuvir, tenofovir, topotecan, venetoclax
1 Sensitive substrates include drugs whose plasma AUC values have been shown to increase 5-
fold or higher when co-administered with a potent inhibitor. 
2 The list provided is as of January 2018. Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list.
3 MATE1 and MATE2 share considerable substrate specificity.
4 OCT1 and OCT2 share considerable substrate specificity.
5Lopinavir and atazanavir are prohibited when combined with ritonavir (see Table 6-43)
6 Based on data that exposure of cannabidiol (CBD), tetrahydrocannabinol (THC), 11-hydroxy 
THC, increased by ~2-3 folds when co-administered with ketoconazole (CYP3A4 inhibitor) (Stott 
et al 2013)
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana 
University “Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction 
Database, and FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers.
6.4.3
Prohibited concomitant therapy while receiving study drug(s)
The following concomitant therapies are prohibited for all subjects in all combination arms 
during the course of study treatment:
!
Any other anti-cancer therapies (e.g. tumor infiltrating lymphocytes [TIL], checkpoint 
inhibitor therapy or other immunotherapies, chemotherapy, small molecules, other 
investigational drugs or devices,) or any other therapies that may be active against 
cancer or modulate the immune responses. For radiation please refer to Section 6.4.4. 
!
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed 
except for the treatment of infusion reaction, immune related adverse events, imaging 
contrast dye allergy, substitution for adrenal insufficiency, or transient exacerbations 
of other underlying diseases such as chronic obstructive pulmonary disease (COPD).
Please refer to Section 6.4.2.2 for specific cautions on corticosteroids use during 
treatment with ribociclib in arm 4.
!
The use of live vaccines is not allowed through the whole duration of the study. 
Inactivated vaccines are allowed.
!
For subjects in arm 2, co-administrating capmatinib with strong CYP3A4 inducer 
(rifampicin) decreased capmatinib AUC by 66% and Cmax by 56%. Concurrent use of 
strong CYP3A4 inducers (refer to Table 6-41) is prohibited as decreased capmatinib
exposure may lead to reduced efficacy.
Table 6-41
List of strong CYP3A4 inducers prohibited while on treatment with 
capmatinib (Arm 2)
Mechanism of Interaction
Drug Name
Strong CYP3A4 inducer
carbamazepine, enzalutamide, lumacaftor, phenobarbital, phenytoin, 
rifabutin, rifampicin, mitotane, St. John’s wort (Hypericum perforatum)
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Mechanism of Interaction
Drug Name
Source: The list is adapted from the Novartis Institutes for Biomedical PK Sciences internal memorandum 
(Jan 2018): drug-drug interactions (DDI) database, which is compiled primarily from the Indiana University 
School of Medicine’s “Clinically Relevant” Table (medicine.iupui.edu/flockhart/table.htm), the University of 
Washington’s Drug Interaction Database (druginteractioninfo.org), and the FDA’s “Guidance for Industry, 
Drug Interaction Studies” This may not be an exhaustive list, will be updated periodically.
!
For subjects in arm 2: As far as possible avoid co-administering drugs with a 
“Known”, “Possible”, or “Conditional” risk of QT prolongation and/or Torsades de 
Pointes (TdP) (refer to qtdrugs.org) during the course of the treatment with capmatinib:
!
If concomitant administration of drugs with a “Known risk of QT prolongation 
and/or TdP” (refer to Table 6-42) is required and cannot be avoided, study drug 
must be interrupted. If, based on the investigator assessment and clinical need, 
study treatment is resumed, close ECG monitoring is advised. 
!
If during the course of the study, concomitant administration of a drug with 
“Possible risk“ or “Conditional risk of QT prolongation and/or TdP“ is required, 
based on the investigator assessment and clinical need, study treatment may be 
continued under close ECG monitoring to ensure subject safety.
A list of drugs associated with QT prolongation and/or TdP is available online at qtdrugs.org.
Table 6-42
Drugs with a known risk of QT prolongation and/or ‘Torsades de 
Pointes’ prohibited while on treatment with capmatinib 
Class of medication
Drug Name
With Known risk of QT 
prolongation and/or 
‘Torsades de Pointes’
amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, bepridil, 
chloroquine, chlorpromazine, cilostazol, ciprofloxacin, cisapride, citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, flecainide, fluconazole, 
gatifloxacin, grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, levomethadyl, levosulpiride, mesoridazine, methadone, 
moxifloxacin, ondansetron, oxaliplatin, papaverine HCl (intra-coronary), 
pentamidine, pimozide, probucol, procainamide, propofol, quinidine, 
roxithromycin, sevoflurane, sotalol, sparfloxacin, sulpiride, sultopride, 
terfenadine, terlipressin, terodiline, thioridazine, vandetanib
This may not be an exhaustive list.
Check crediblemeds.org/healthcare-providers/drug-list for the most updated list.
!
For subjects in arm 4, co-administration of any medication listed below and in Table 
6-43 with ribociclib is prohibited :
-
co-administration of strong inhibitors or inducers of CYP3A4/5 (may significantly 
increase or decrease ribociclib exposure, respectively).
-
co-administration of substrates of CYP3A4/5 with a narrow therapeutic index 
(ribociclib may increase exposure to these medications resulting in toxicity from 
these medications).
-
co-administration of medications with a known risk for QT prolongation and/or 
TdP (may precipitate QT prolongation and TdP in combination with ribociclib). As 
far as possible, avoid co-administration of QT prolonging drugs or any other drugs 
with the potential to increase the risk of drug-related QT prolongation (e.g., via a 
potential DDI that increases the exposure of ribociclib or the exposure of the QT 
prolonging drug). A definitive list of drugs with a known risk, possible risk, or 
conditional risk of QT prolongation and/or Torsades de Pointes (TdP) is available 
online at qtdrugs.org.
-
co-administration or ingestion of herbal medications/preparations or dietary 
supplements that are strong inhibitors or inducers of CYP3A4/5 or those with a 
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known risk of QT prolongation. These include, but are not limited to: St. John’s 
wort, Kava, ephedra (ma huang), gingko biloba, dehydroepiandrosterone (DHEA), 
yohimbe, saw palmetto, black cohosh and ginseng. Patients should stop using these 
preparations/medications at least 7 days prior to first dose of study treatment.
Table 6-43
List of prohibited medications while on treatment with ribociclib
(arm 4)
Category
Drug Name
Strong CYP3A4/5 inhibitors
Atazanavir/ritonavir, 
boceprevir, 
clarithromycin, 
cobicistat, 
conivaptan, 
danoprevir/ritonavir, 
darunavir/ritonavir, 
elvitegravir/ritonavir, 
grapefruit 
juice, 
idelalisib, 
indinavir, 
indinavir/ritonavir, itraconazole, ketoconazole, lopinavir/ritonavir, 
mibefradil, 
nefazodone, 
nelfinavir,ombitasvir/paritaprevir/dasabuvir/ritonavir 
(VIEKIRA 
PAK), posaconazole, ritonavir, saquinavir/ritonavir, telaprevir, 
telithromycin, tipranavir/ritonavir, troleandomycin, voriconazole
Strong CYP3A4/5 inducers
Apalutamide, carbamazepine3, enzalutamide, lumacaftor, mitotane, 
phenobarbital, phenytoin3, rifabutin, rifampin (rifampicin)3, St. 
John's wort (hypericum perforatum)2,3
CYP3A4/5 substrates with NTI1
Alfentanil, astemizole, cisapride, cyclosporine, diergotamine 
(dihydroergotamine), ergotamine, fentanyl, lomitapide5, lovastatin, 
nicardipine, nisoldipine, pimozide, quinidine, simvastatin, sirolimus, 
tacrolimus
Medications with a known risk for QT 
prolongation4
Amiodarone, anagrelide, arsenic trioxide, astemizole, azithromycin, 
bepridil, 
chloroquine, 
cocaine, 
chlorpromazine, 
cilostazol, 
ciprofloxacin, cisapride, citalopram, clarithromycin, disopyramide, 
dofetilide, domperidone, donepezil, dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, fluconazole, gatifloxacin, 
grepafloxacin, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomepromazine, 
levosulpiride, 
levomethadyl, 
mesoridazine 
methadone, moxifloxacin, ondansetron, oxaliplatin, papaverine HCl 
(intra-coronary), pentamidine, pimozide, probucol, procainamide, 
propofol, 
quinidine, 
roxithromycin, 
sevoflurane, 
sotalol, 
sparfloxacin, 
sulpiride, 
sultopride, 
terlipressin, 
terodiline, 
terfenadine, thioridazine, vandetanib
Herbal preparations/ medications or 
dietary supplements
Herbal preparations/medications or dietary supplements known as 
strong inducers or inhibitors of CYP3A4/5 or those with a known risk 
of QT prolongation are prohibited throughout the study. These 
include, but are not limited to: St. John’s wort, Kava, ephedra (ma 
huang), gingko biloba, dehydroepiandrosterone (DHEA), yohimbe, 
saw palmetto, black cohosh, and ginseng. Patients should stop 
using these herbal medications or dietary supplements 7 days prior 
to first dose of study drug.
1 NTI = narrow therapeutic index drugs whose exposure-response indicates that increases in their 
exposure levels by the concomitant use of potent inhibitors may lead to serious safety concerns 
(e.g., Torsades de Pointes) or drugs which have <2-fold difference in the minimum toxic 
concentrations and effective concentrations in the blood
2 Herbal product
3 P-gp inducer
4 The list provided is as of December 2019. Check https www crediblemeds.org/healthcare-
providers/drug-list for the most updated list.
5 Drug has warning for risk of hepatotoxicity.
Source: Novartis PK Sciences Memorandum: Drug-Drug Interactions (DDI) and Co-medication 
Considerations for Novartis Clinical Trials (January 2018), which is compiled from Indiana 
University “Clinically Relevant” Flockhart Table™, University of Washington Drug Interaction 
Database, and FDA Drug Development and Drug Interactions: Table of Substrates, Inhibitors 
and Inducers.
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6.4.4
Radiotherapy
Limited-field palliative radiotherapy may be allowed after documented discussion with 
Novartis. Such local therapies administered during the study treatment must be recorded in 
the eCRF.
6.5
Subject numbering, treatment assignment or randomization
6.5.1
Subject numbering
Each subject is identified in the study by a Subject Number (Subject No.), that is assigned 
when the subject is first enrolled for screening and is retained as the primary identifier for 
the subject throughout his/her entire participation in the trial. The Subject No. (7-digit 
number) consists of the Center Number (Center No.) (4-digit, as assigned by Novartis to the 
investigative site) with a sequential 3-digit subject number suffixed to it, so that each subject 
is numbered uniquely across the entire database. 
Upon signing the informed consent form, the subject is assigned to the next sequential 
Subject No. available to the investigator.
The investigator or designated staff will contact the IRT and provide the requested 
identifying information for the subject to register them into the IRT.
Once assigned, the Subject No. must not be reused for any other subject and the Subject No. 
for that individual must not be changed, even if the subject is re-screened. 
6.5.2
Treatment assignment or randomization
In the randomized section of the study, prior to dosing, all subjects who fulfill all 
inclusion/exclusion criteria will be randomized via IRT to one of the treatment arms open 
to enrollment in part 1 and part 2 (Section 4.1.1 and Section 6.1). The investigator or his/her 
delegate will call or log on to the IRT and confirm that the subject fulfills all the 
inclusion/exclusion criteria
for each arm.
If the subject
does not fulfill the 
inclusion/exclusion criteria specific to one or more arms, the IRT system will exclude those
arms for randomization. For each arm , randomization will be stratified by baseline level of 
LDH (baseline LDH ≤ ULN and baseline LDH > ULN).
The IRT will assign a randomization number to the subject, which will be used to link the 
subject to a treatment arm and will specify a unique medication number for the first package 
of study treatment to be dispensed to the subject. The randomization number will not be 
communicated to the caller.
The randomization numbers will be generated using the following procedure to ensure that 
treatment arm assignment is unbiased and concealed from subjects and investigator staff. A 
subject randomization list will be produced by the Interactive Response Technology (IRT) 
provider using a validated system that automates the random assignment of subject numbers 
to randomization numbers. These 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.
In the non-randomized section of the study, no randomization will be performed. Prior to 
dosing, all subjects who fulfill the inclusion/exclusion criteria applicable for arm 1A will be 
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enrolled via IRT and systematically assigned to this arm (in part 1 or part 2, refer to Section 
4.1.2 and Section 6.1).
6.5.3
Treatment blinding
Not applicable.
6.6
Study drug preparation and dispensation
Study drug(s) will be dispensed to the subject by authorized site personnel only. 
Administration of spartalizumab and LAG525 i.v. infusions must take place in a facility 
with appropriate resuscitation equipment available and a physician readily available during 
the period of drug administration. Clinical monitoring during and post infusion should be 
performed according to local practice and institutional guidelines, and as outlined in Section 
6.1. 
Capmatinib and ribociclib will be administered orally. Capmatinib or ribociclib tablets (in 
bottles), including instructions for administration, are dispensed by study personnel on an 
outpatient basis. Subjects will be provided with adequate supply of capmatinib or ribociclib 
for self-administration at home until at least their next scheduled visit. The investigator or 
responsible site personnel must instruct the subject or caregiver to take capmatinib or 
ribociclib as per protocol. 
Canakinumab will be administered subcutaneously by site personnel. 
Further instructions for the preparation and dispensation of spartalizumab, LAG525 and 
canakinumab are described in the [PDR001J2201 Pharmacy Manual].
6.6.1
Study treatment packaging and labeling
All study drugs will be provided as global clinical open supply and will be packed and 
labeled under the responsibility of Novartis, Drug Supply Management.
Spartalizumab will be supplied in vials containing 100 mg spartalizumab (PDR001) as a 
liquid concentrate solution for infusion.
LAG525 will be supplied in vial containing 100 mg LAG525 as a liquid concentrate solution 
for infusion.
Capmatinib (INC280) film-coated tablets for oral use will be supplied at 200 mg and 150 
mg dosage strengths in bottles of 30 tablets to accommodate the initial dose as well as dose 
reduction steps.
Ribociclib (LEE011) film-coated tablets for oral use will be supplied at 200 mg dosage 
strength in bottles of 75 tablets to accommodate the initial dose as well as dose reduction 
steps.
Canakinumab will be supplied in vial containing 150 mg canakinumab (ACZ885) as a liquid 
solution for subcutaneous injection.
Study drugs labels will comply with the legal requirements of each country and will include 
storage conditions, a unique medication number (corresponding to study drug and strength). 
Responsible site personnel will identify the study drug package(s) to dispense by the 
medication number(s) assigned by IRT to the subject. Site personnel will add the subject
number on the label. If the label has 2-parts (base plus tear-off label), immediately before 
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dispensing the package to the subject, site personnel will detach the outer part of the label 
from the package and affix it to the subject’s source document.
6.6.2
Drug supply and storage
Study drugs must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, the study drugs should be stored 
according to the instructions specified on the drug labels and in the current Investigator’s 
Brochures.
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each subject visit 
and information provided by the subject and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each 
subject visit.
Compliance will be assured by administration of the study treatment under the supervision 
of investigator or his/her designee.
6.6.3.2
Study drug accountability
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Drug accountability will be noted 
by the field monitor during site visits and at the completion of the study. Subjects will be 
asked to return all unused study treatment and packaging on a regular basis, at the end of 
the study or at the time of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to the Novartis monitor or to the Novartis address 
provided in the investigator folder at each site.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate, or at site if allowed per local regulations and local Sponsor 
procedures and agreements.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-2 lists all of the assessments to be performed for all subjects (regardless of the study 
part, part 1 or part 2, they were randomized/enrolled into) and indicates with an “X”, the 
visits when they are performed. All data obtained from these assessments must be supported 
in the subject’s source documentation. The table indicates which assessments produce data 
to be entered into the database (D) or remain in source documents only (S) (“Category” 
column).
Additional assessments may be performed as clinically indicated.
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No CRF will be used as a source document.
Study treatment will begin on C1D1 with the first administration of the assigned study 
treatment, depending on the arm the subject has been randomized/enrolled into. 
Each treatment cycle is 28 days. All study visits, assessments and study treatment 
administration are to be scheduled according to the appropriate number of calendar days 
from the day of first study treatment administration on C1D1 (except for tumor assessments 
in randomized arms which have to be scheduled as per the scheduled number of weeks after
the date of randomization) whenever possible as per the allowable visit window specified in 
Table 7-1 below. If one of the investigational drugs is interrupted or permanently
discontinued, at any time during the study, all study visits and safety assessments should 
continue according to the appropriate number of calendar days from C1D1 as per the 
schedule of assessments, and efficacy assessments must continue as per the scheduled 
number of weeks from the date of randomization (or from the date of first dose of study 
treatment in arm 1A) as described in Table 7-2. Missed or rescheduled visits should not lead 
to automatic discontinuation.
Safety follow-up visits are to be scheduled according to the appropriate number of calendar 
days after the date of last dose of study drug administered (refer to Section 7.1.7). 
Every effort must be made to follow the schedule of assessments within the windows 
outlined in the protocol.
The preferred sequence for assessments during study visits is ECG collection first, followed 
by vital signs, and blood sampling.
Table 7-1
Allowable visit windows 
Visit name
Assessments
Window allowed
Screening
Physical examination (complete), 
Performance Status, weight, vital 
signs, hematology, chemistry, 
coagulation
≤ 14 days before C1D1
Serum pregnancy test
≤ 72 hours before C1D1
For Arm 1A: Collection/submission
of newly or recently obtained
baseline tumor biopsy sample (as 
defined in Section 7.2.3.1.1) for 
LAG-3 status central assessment
≤ 35 days before enrollment (tumor sample 
should be submitted as early as possible and 
at the latest 20 days prior to planned 
enrollment date to allow sufficient time for 
central testing)
Other screening assessments
≤ 28 days before C1D1
C1D1
Administration of first dose of study 
treatment
All visit assessments
Maximum 3 days after date of 
randomization/enrollment
NA
(if screening laboratory assessments and 
physical examination were performed ≤ 72
hours before first dose of study treatment, 
they do not need to be repeated on C1D1)
Day 1 visit of all 
subsequent cycles
All visit assessments (except tumor 
assessment)
± 4 days
Administration of i.v. and s.c. 
investigational drugs
± 4 days
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Visit name
Assessments
Window allowed
During Treatment 
and Efficacy 
follow-up periods
Tumor assessments 
± 7 days
EoT
All assessments
+ 7 days after the discontinuation of the last 
study drug (i.e. within 7 days after the last dose 
of the last study drug or after the date when 
decision was made to permanently discontinue 
both study drugs/the last study drug) 
(tumor assessments do not need to be 
repeated if performed within 30 days prior to 
last study treatment administration)
30-day safety 
follow-up visit
All assessments
30 days (+ 7 days) after last dose of study 
treatment (if last dose was more than 30 days 
ago when the decision is taken to discontinue 
study treatment, then 30-day safety follow-up 
to be performed as soon as possible) 
60-, 90-, 120-Day 
follow-up phone 
call/onsite visit
All assessments
± 7 days
150-Day follow-up 
visit
All assessments
+ 14 Days
Survival follow up 
All assessments
± 14 days
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Table 7-2
Visit evaluation schedule (applicable for all subjects, in both part 1 and part 2)
Category
Protocol section
Screenin
g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Obtain Informed Consent (ICF)
Study ICF
D
7.1.2, 
11.3
X
Eligibility and subject's history
Demography
D
7.1.2.3
X
Inclusion/exclusion
D
5.2, 5.3 X
Relevant medical history D
7.1.2.3
X
Diagnosis and extent of 
cancer, including 
V600BRAF status
D
7.1.2.3
X
HIV history
S
7.1.2.3
X
Prior anti-cancer therapies 
(medications, surgery, 
radiation)
D
7.1.2.3
X
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Protocol section
Screenin
g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Prior/concomitant 
medications
D
7.1.2.3, 
6.4
From 30 days prior to starting study treatment until 150-Day safety follow-up or start of subsequent anti-
cancer therapy, whichever occurs first. If subsequent anti-cancer therapy is started then only medications 
relative to the suspected AE/SAE that are reported should be collected. 
Investigator must ensure that no prohibited medication(s) (refer to Section 6.4.3) is given to the subject 
while on study treatment.
Subsequent anti-cancer 
therapy since
discontinuation of study 
treatment
D
7.1.9
X
Enrollment-Randomization
IRT Registration (after 
Study ICF signature)
S
6.5.1
X
IRT –
Randomization/enrollment
S
6.5.2
X
Disposition form
D
7.1.5, 
7.1.8
X
X
X
Physical examination
Physical examination 
(complete)
S
7.2.2.1
X
Physical examination 
(short)
S
7.2.2.1
X
X
X
X
X
X
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Protocol section
Screenin
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
Height
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X
X
Performance status 
(ECOG)
D
7.2.2.4
X
X
X
X
X
X
X
12-lead ECG (Arm 1, Arm 
2, Arm 1A)
D
7.2.2.6
X
X
X
X
X
12-lead ECG (Arm 3) 
D
7.2.2.6
X
If clinically indicated
X
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Protocol section
Screenin
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
12-lead ECG (Arm 4)
D
7.2.2.6
X
X
X
X
X
X
All subjects: 
at C4D1, 
C5D1, 
C6D1.
Only for 
subjects 
with QTcF ≥
481 ms at 
any time 
prior to 
cycle 7: Day 
1 of all 
cycles from 
Cycle 7 until 
EoT
X
Laboratory assessments
Hematology 
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Chemistry 
D
7.2.2.5
X
X
X
X
X
X
X
X
X
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Cardiac troponin T (or I)
D
7.2.2.5
X
Arms
1 
and 
1A 
only 
Arms 1
and 1A
only
Arm
s 1 
and 
1A 
only
Coagulation
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Thyroid function - TSH
D
7.2.2.5
X
X
X
X
X
X
Thyroid function - free T3 
and Free T4
D
7.2.2.5
X
Only if TSH is abnormal
Urinalysis - Local testing
S
7.2.2.5
X
X
X
X
X
X
Serum pregnancy test 
- Local testing
S
7.2.2.5
X
X
X
X
Urine pregnancy test -
Local testing
S
7.2.2.5
X
X
X
X
X
X
Hepatitis B and C Testing D
7.2.2.5
X
Safety cytokines (for 
cytokine release 
syndrome)
D
7.2.2.5
X
Anytime when a suspected cytokine release syndrome occurs, immediately after the AE, and 
one week after occurrence of the AE
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Protocol section
Screenin
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Local HIV testing, if 
required per local 
requirements
S
7.2.2.5
X
Tumor imaging and assessment per RECIST v1.1
CT/MRI scan (chest, 
abdomen, pelvis) with IV 
contrast enhancement
D
7.2.1
X
During treatment: 12 weeks (± 7 days) after the date of randomization (or after the date of first dose of study 
treatment in arm 1A), then every 8 weeks (± 7 days) until 52 weeks after randomization/date of first dose of study 
treatment in arm 1A then every 12 weeks until disease progression per RECIST v1.1. In case of continuation of 
study treatment beyond initial disease progression per RECIST v1.1: continue assessment with the same 
schedule. Refer to Section 6.1.5.1 and Section 7.2.1 for details.
End of Treatment (EOT): Only to be done if a scan was not conducted within 30 days prior to end of study 
treatment.
Efficacy follow-up: If subject discontinued study treatment for reason other than disease progression per 
RECIST v1.1, efficacy follow-up must be continued on the same schedule as during treatment until disease 
progression per RECIST v1.1.
Refer to Section 7.2.1.2 for details on additional tumor assessments required for confirmation of response per 
RECIST 1.1 
.
Brain CT/MRI
D
7.2.1
X
If clinically indicated or if lesions were documented at screening, follow same schedule as CT/MRI of chest, 
abdomen, and pelvis.
Whole-body bone scan
D
7.2.1
If clinically indicated
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Protocol section
Screenin
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
CT/MRI of other 
metastatic sites (e.g. 
neck)
D
7.2.1
If clinically indicated or if lesions were documented at screening, follow same schedule as CT/MRI of chest, abdomen, and 
pelvis. 
Localized bone CT,
MRI or X-ray
D
7.2.1
Only for lesions on whole body scan that are not visible on the chest, abdomen and pelvis scans. If lesions were 
documented at screening, follow same schedule as CT/MRI of chest, abdomen and pelvis
Color Digital Photography 
(including a metric ruler) 
D
7.2.1
X 
If clinically indicated or if cutaneous lesions were documented at screening, follow same schedule as 
CT/MRI of chest, abdomen, and pelvis. 
Collection of body 
fluid/tissue data
D
7.2.1
Record needle aspiration, biopsy or any other form of collection (e.g., paracentesis, puncture) performed for any 
clinically indicated reason
Safety
Adverse events (AEs)
D
8.1.1
Suspected AEs up to 150 days after last spartalizumab dose regardless of the start of subsequent anti-
cancer therapy; non-suspected AEs up to 150 days after last spartalizumab dose or start of subsequent 
anti-cancer therapy, whichever is sooner.
Serious adverse events 
(SAEs)
D
8.1.2
Suspected SAEs up to 150 days after last spartalizumab dose and beyond, regardless of the start of 
subsequent anti-cancer therapy; non-suspected SAEs up to up to 150 days after last spartalizumab dose or 
start of subsequent anti-cancer therapy, whichever is sooner.
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Protocol section
Screenin
g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Arm 1 and Arm 1A: 
Immunogenicity (IG) 
sampling for 
spartalizumab (see Table 
7-7) and LAG525 (see 
Table 7-8)
D
7.2.2.7
X
X
X
X – at 
C4D1, 
C5D1 and 
C6D1, then 
every 3 
months 
(C9D1, 
C12D1, 
C15D1, etc)
X
X
X
Arm 2 and Arm 4: 
Immunogenicity (IG) 
sampling 
for spartalizumab (see 
Table 7-7)
D
7.2.2.7
X
X
X
X – at 
C4D1, 
C5D1 and 
C6D1, then 
every 3 
months 
(C9D1, 
C12D1, 
C15D1, etc)
X
X
X
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Protocol section
Screenin
g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Arm 3: Immunogenicity 
(IG) sampling 
for spartalizumab (see 
Table 7-7) and 
canakinumab (see Table 
7-10)
D
7.2.2.7
X
X
X
X – at 
C4D1, 
C5D1 and 
C6D1, then 
every 3 
months 
(C9D1, 
C12D1, 
C15D1, etc)
X
X
X
Safety follow-up
D
7.1.7
visit visit or 
phone 
call
visit or 
phone 
call
visit or 
phone 
call
visit
Tumor tissue samples
Mandatory newly or 
recently obtained tumor 
biopsy
D
7.2.3.1.1X
Between 
C1D21 and 
C2D1 
 
 
 
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Screenin
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Arm 1A only: Centralized 
assessment of LAG-3 
status on baseline tumor 
sample
D
7.2.3.1.2
X
Mandatory, if available: 
Provision of archival FFPE 
block or slides from a 
tumor sample collected 
prior to start of any prior 
anti-PD-1/PD-L1 mono- or 
combination therapy
D
7.2.3.1.3
X
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Protocol section
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Study treatment administration
All arms: spartalizumab 
infusion
D
6.1.1.1
400 mg i.v. Q4W
Arm 1 and Arm 
1A: LAG525 infusion
D
6.1.1.2
600 mg i.v. Q4W
Arm 2: capmatinib 
administration
D
6.1.1.3
400 mg BID p.o.
Arm 3: canakinumab 
injection
D
6.1.1.4
300 mg s.c. Q4W
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Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Arm 4: ribociclib 
administration
D
6.1.1.5
600 mg QD, on Days 1-21 of each 28-day cycle (Days 
22-28 are a “rest period” from ribociclib)
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Protocol section
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g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Survival
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Protocol section
Screenin
g period Treatment Period (Cycle = 28 days)
Follow-up (FU) Period
Survival
Screening
Cycle 1
Cycle 2 Cycle 3
Subsequent 
Cycles Day 1
End of Treatment 
(EoT)
Safety FU
Efficacy FU
(Not applicable 
if EoT due to 
progression)
30-day 
Safety FU
60-day 
Safety FU
90-day 
Safety FU
120-day 
Safety FU
150-day 
Safety FU
Efficacy FU
End of post-
treatment FU
Day of cycle
-28 (-35 
for arm
1A) to -1 1
8
15
21
1
1
8
15
1
Survival status
D
7.1.9
Every 
3 
month
s
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7.1.1
Molecular pre-screening 
Not applicable.
7.1.2
Screening
The screening period begins once written informed consent is provided and ends after 28 
days (or after 35 days for subjects screened for Arm 1A) or when subject is 
randomized/enrolled, whichever comes first.
Screening assessments to confirm eligibility into the study, as described in Table 7-2, should 
be performed within 1 to 28 days prior to the first dose of study treatment, unless otherwise 
specified in Table 7-1.
Serum pregnancy test must be confirmed negative prior to the first dose of study treatment. 
In the randomized section of the study, a subject whose baseline tumor biopsy tissue sample 
does not meet the tumor sample quality criteria outlined in Section 7.2.3.1.1 will be 
considered a screen failure. In the non-randomized section of the study, the collection of a 
baseline tumor sample should be performed as soon as possible after consent is obtained and 
submitted to Novartis- designated laboratory as early as possible and at the latest 20 days 
prior to planned enrollment date to allow sufficient time for receipt of central LAG-3 results
and to complete screening assessments (refer to Section 7.2.3.1.1 and Section 7.2.3.1.2 for 
details). It is recommended to wait to receive the result of LAG-3 status to perform further 
screening assessments (as per allowed window defined in Table 7-1 for each assessment).
A subject whose baseline tumor biopsy tissue sample does not allow central assessment of 
LAG-3 will be considered a screen failure, unless a new baseline tumor sample is submitted 
and assessed for LAG-3 before the end of the screening period. Sample must be reported as 
LAG-3 positive for subject to be eligible to arm 1A.
A subject 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 approximately 3 weeks of the original screening 
visit date. In this case, the subject will not be required to sign another ICF, and the original 
subject ID number assigned by the investigator will be used. In the event that the laboratory 
test(s) cannot be performed within 3 weeks of the original screening visit, or the re-test(s) 
do not meet the entrance criteria, or other eligibility criteria have changed and are not met 
anymore, the subject is considered a screen failure.
A new ICF will need to be signed if the investigator chooses to re-screen the subject after a 
subject has screen failed, however, the subject ID number will remain the same. All required 
screening activities (i.e. screening assessments required to confirm eligibility; however, the 
optional pharmocogenetics ICF does not need to be re-signed) must be performed when the 
subject is re-screened for participation in the study to satisfy the requirements defined in 
Table 7-1.
An individual subject may only be re-screened once for the study. Once the number of 
subjects screened and enrolled is likely to ensure target enrollment, the Sponsor may close 
the study to further screening. In this case, the subjects who screen failed will not be 
permitted to re-screen.
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7.1.2.1
Eligibility screening 
Following registering in the IRT for screening, subject eligibility will be checked once all 
screening procedures are completed. The eligibility check will be embedded in the IRT 
system. Please refer and comply with detailed guidelines in the IRT manual.
7.1.2.2
Information to be collected on screening failures
Subjects who sign the study ICF but are subsequently found to be ineligible prior to 
randomization/enrollment will be considered a screen failure. The demographic information, 
informed consent, and Inclusion/Exclusion pages must also be completed for screen failure 
subjects. No other data will be entered into the clinical database for subjects who are screen 
failures, unless the subject experienced a serious adverse event during the screening phase 
(see SAE section for reporting details). If the subject fails to be randomized/enrolled, the 
IRT must be notified within 2 days of the screen fail that the subject was not 
randomized/enrolled.
Subjects who are randomized/enrolled and fail to start study treatment for any reason will 
be considered an early terminator. The reason for early termination should be recorded on 
the appropriate Case Report Form.
7.1.2.3
Subject demographics and other baseline characteristics
The following data on subject characteristics will be collected at screening:
!
Demographic information: age at consent, sex, ethnicity and race
!
Relevant medical history (including medical conditions present at time of ICF 
signature)
!
Melanoma histology, V600BRAF status and staging using AJCC staging edition 8 (refer 
to Appendix 1)
!
All prior anti-cancer therapies (medications, surgeries, radiation)
!
Prior and current concomitant medications: All medications and significant non-drug 
therapies taken within 30 days prior to the first dose of study treatment must be 
recorded in the eCRF. They will be updated on a continuous basis if there are any new 
changes to the medications.
!
HIV history (If mandated per local requirements, a local HIV testing is to be done 
during screening)
In the randomized section of the study, the LDH value closest to the randomization date
must be used in the IRT system for the stratification of randomization in each arm.
7.1.3
Run-in period 
Not applicable.
7.1.4
Treatment period
After randomization/enrollment of the subject in an arm via the IRT system, the site 
personnel will have to report in the eCRF the arm in which the subject has been 
randomized/enrolled.
The treatment period begins when the first dose of study treatment is administered to the 
subject (on Day 1 of Cycle 1). Table 7-2 describes the assessments to be performed at each 
visit during treatment period (refer to Table 7-1 for windows of assessments).
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Physical examination and laboratory assessments (hematology, chemistry and coagulation) 
performed as part of the screening evaluations will not require to be repeated on C1D1 prior 
to dosing if performed ≤ 72 hours prior to the first dose of study treatment. 
In some circumstances (see Section 6.1.5.1), subjects may be allowed to continue to receive 
study treatment beyond disease progression as per RECIST v1.1 criteria. These subjects will 
continue assessments as outlined in Table 7-2 until discontinuation of study treatment.
7.1.5
Discontinuation of study treatment
Subjects who discontinue study treatment (i.e. when both investigational drugs are 
discontinued) at any time during the study for any reason should be scheduled for an End of 
Treatment (EoT) visit within 7 days after the discontinuation of the last study drug (i.e. 
within 7 days after the last dose of the last study drug or after the date when decision was 
made to permanently discontinue both study drugs/the last study drug), at which time all of 
the assessments for EoT will be performed as described in Table 7-2.
At this EoT visit, all dispensed investigational drugs should be reconciled and the adverse 
event and concomitant medications recorded in the eCRF.
In addition to mandatory permanent discontinuation of study treatment in case of 
unacceptable toxicity (as described in Section 6.3), study treatment must also be discontinued 
under the following circumstances:
!
Pregnancy of the female subject
!
Use of a prohibited concomitant therapy (refer to Section 6.4.3).
!
Any other protocol deviation that results in a significant risk to the subject’s safety
The investigator may discontinue the study treatment for a given subject if he/she believes
that continuation would be detrimental to the subject’s well-being.
Subjects may voluntarily discontinue from the study treatment for any reason at any time.
If a subject decides to discontinue from the study treatment, the investigator should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this
decision and record this information in the subject’s chart and in the eCRF. 
All subjects who discontinue study treatment should return for the safety assessments 
indicated in Section 7.1.7, and if applicable, for the efficacy assessments indicated in Section 
7.1.8. 
Subjects should NOT be considered withdrawn from the study, unless they state an intention
to withdraw consent for all study assessments including follow up (see Section 7.1.6) or
become lost to follow-up for any other reason (see Section 7.1.10).
The investigator must also contact the IRT to register the subject’s discontinuation
from study treatment. Site personnel will also have to record the End of Treatment in the 
Disposition page in the eCRF.
Crossover or re-randomization of subjects to other arms, including better performing arms, 
is not allowed.
7.1.5.1
Replacement policy
Not applicable.
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7.1.6
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a subject:
!
Does not want to participate in the study anymore, and
!
Does not allow further collection of personal data
In this situation, the investigator should make a reasonable effort (e.g. telephone, e-mail, 
letter) to understand the primary reason for the subject’s decision to withdraw his/her 
consent and record this information. 
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 subject are not allowed unless safety findings require 
communicating or follow-up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data 
resulting from the analysis of a subject’s samples until their time of withdrawal) according 
to applicable law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may 
still be used for further testing/analysis in accordance with the terms of this protocol and of 
the informed consent form. 
For EU and Rest of World (RoW): All biological samples not yet analyzed at the time of 
withdrawal will no longer be used, unless permitted by applicable law. They will be stored 
according to applicable legal requirements.
7.1.7
Follow up for safety evaluations (Safety follow up)
After study treatment discontinuation for any reason (except death), all subjects must be 
followed for safety evaluations as outlined in Table 7-2.
Due to the extended half-life of spartalizumab and LAG525 and the potential occurrence of 
side effects with checkpoint inhibitors, all subjects will be followed for safety up to 150 
days after the last dose of spartalizumab or LAG525. In the case that spartalizumab is 
permanently discontinued, but the combination agent is continued (i.e capmatinib or 
canakinumab), subjects will have to be followed for safety evaluations up to 150 days 
following the last dose of spartalizumab/LAG525, or up to 130 days after the last dose of 
canakinumab, or up to 30 days after the last dose of capmatinib or ribociclib, whichever is 
longer. The 30-day safety follow-up visit should be scheduled 30 days after last dose of 
study treatment (if last dose was more than 30 days ago when the decision is taken to 
discontinue study treatment, then 30-day safety follow-up should be performed as soon as 
possible).
If a subsequent anti-cancer therapy is initiated, only adverse events suspected to be related 
to study treatment will be collected. 
After the 30-day onsite safety follow-up visit, subjects will be followed (via telephone call 
or onsite visit if subject happens to be visiting the site) at 60, 90, 120 and 150 days after the 
last dose of spartalizumab/LAG525 (refer to Table 7-1 for visit windows). All safety 
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assessments should be completed as per Table 7-2. However, if the subject begins post 
treatment anti-cancer 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. Data collected should be recorded 
in the eCRF. 
For female subjects of child bearing potential, a pregnancy test will be performed at the time 
points listed in Table 7-2. After the 30-Day Safety Follow-up visit, women of childbearing 
potential will perform at-home urine pregnancy testing every 30 days using kits provided 
until the 120-Day follow-up telephone call visit. Every effort must be made for the women 
of child bearing potential to return to the site for the 150-day Safety Follow-up visit for the 
final serum pregnancy test
 samples. However, if the subject is unable to return then 
the subject will administer the urine pregnancy test at home using the kit provided. For all 
pregnancy tests performed at home, the site personnel will follow-up with the subject via 
telephone call to collect the date and the test results and document the information in the 
subject’s source documents. If the subject returns to the site for the serum pregnancy test at 
the 150 day safety follow up the results must be documented in the subject’s source 
documents. 
Data collected for AEs/SAEs and concomitant medications must be recorded in the eCRF.
7.1.8
Follow-up for efficacy evaluations (Efficacy follow up)
In addition to safety follow up, subjects who discontinue study treatment for any reason 
other than documented disease progression as per RECIST v1.1 (per investigator 
assessment), death, lost to follow-up, or withdrawal of consent should continue tumor 
assessments as outlined in Section 7.2.1 until documented disease progression as per 
RECIST v1.1 (per investigator assessment), withdrawal of consent, lost to follow-up, death, 
or study is terminated by the sponsor. Every effort will be made to continue collection of 
tumor assessments even after the start of subsequent anti-cancer therapy for subjects that 
have not progressed.
Site personnel will have to record the End of Post-Treatment Follow up in the Disposition 
page in the eCRF at the end of efficacy follow-up, when subject meets one of the criteria 
described above. 
7.1.9
Survival follow-up
Subjects will enter the survival follow-up period once they complete the safety follow-up 
and efficacy follow-up after study treatment discontinuation (whichever is longer). Subjects 
will then be contacted by telephone every 12 weeks (± 1 week) until death, withdrawal of 
consent, lost to follow-up or end of study to follow-up on their survival status. Any new 
anti-cancer therapies that have been started since study treatment was discontinued will also 
be collected (radiotherapies, surgeries and medications, including regimen number, names 
of all medications received within each regimen and start/end dates for each medication) 
and any change or new anti-cancer therapy initiated since the last telephone contact date
will be captured in the eCRF.
7.1.10
Lost to follow-up
For subjects whose status is unclear because they fail to appear for study visits without 
stating an intention to withdraw consent, the investigator should show "due diligence" by 
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contacting the subject, family or family physician as agreed in the informed consent and by 
documenting in the source documents steps taken to contact the subject, e.g. dates of 
telephone calls, registered letters, etc. A subject should not be considered lost to follow-up 
until due diligence has been completed. Subjects lost to follow up should be recorded as 
such in the Disposition eCRF page.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be assessed locally and centrally according to the Novartis guideline 
version 3.2 (Appendix 2) based on RECIST 1.1 (Eisenhauer et al 2009). The imaging 
assessment collection plan is presented in Table 7-3. Details of the central review process 
will be described in the independent review charter.
Imaging data will be centrally collected and checked for quality by an imaging Contract 
Research Organization (CRO) designated by Novartis. 
The local investigator’s tumor assessment as per RECIST 1.1 will be used for primary 
endpoint analysis purposes and for treatment decision making. Blinded independent central 
review (BIRC) of the imaging data per RECIST 1.1 will be performed by the designated 
imaging CRO and results will be included for primary and final analyses as a supportive 
analysis.
 
Information regarding prior interventions (e.g. radiotherapy), pre-existing radiographic 
findings that mimic metastatic disease at baseline/screening and prior interventions will be 
collected in the eCRF and transmitted electronically to the imaging CRO for review by the 
independent radiologist. Sites must ensure the data is entered in the eCRF prior to image 
submission to the CRO.
Information regarding cytology results (e.g. needle aspiration, biopsy or any other form of 
collection, paracentesis, puncture) obtained during the study for any clinically indicated 
reason will be also collected in the eCRF and transmitted electronically to the imaging CRO 
when applicable, for review by the independent radiologist. Sites must ensure the data is 
recorded in the eCRF prior to image submission to the CRO.
Clinical data such as physical exam, photography, biopsy results, pathology/histology and 
cytology results, as well as, information regarding prior interventions, pre-existing 
radiographic findings that could mimic metastatic disease at baseline/screening and on-
study interventions will be transmitted electronically to the imaging CRO for review by an 
independent reviewer. Sites must ensure the data is entered in the eCRF prior to image 
submission to the CRO.
Table 7-3
Imaging Assessment Collection Plan
Procedure
Screening/Baseline
Day -28 to Day -1)
During Treatment/Follow-up (± 7 days window)
Chest, abdomen and 
pelvis CT or MRI (with 
intravenous contrast 
enhancement) 
(for PET/CT please 
see Section 7.2.1.2)
Mandatory
During treatment: 12 weeks (± 7 days) after the 
date of randomization (or after the date of first dose 
of study treatment in arm 1A), then every 8 weeks 
(± 7 days) until 52 weeks after randomization/date 
of first dose of study treatment in arm 1A then every 
12 weeks until disease progression per RECIST 
v1.1 by local assessment.
End of Treatment (EOT): Only to be done if a scan 
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Procedure
Screening/Baseline
Day -28 to Day -1)
During Treatment/Follow-up (± 7 days window)
was not conducted within 30 days prior to end of 
study treatment.
Efficacy follow up: subjects who discontinue study 
treatment for reason other than disease progression 
per RECIST v1.1 must continue to have scans
performed on the same schedule as during 
treatment until disease progression per RECIST 
v1.1.
In case of continuation of study treatment beyond 
initial disease progression per RECIST v1.1, follow 
the same schedule for scans as during treatment 
until criteria defined in Section 6.1.5.1 are met. 
Refer to Section 7.2.1.2 for details on additional 
tumor assessments required for confirmation of 
response per RECIST 1.1 
 
.
Brain CT or MRI
Mandatory
If clinically indicated or if lesions were documented 
at screening, follow same schedule as CT/MRI of 
chest, abdomen, and pelvis.
Whole body bone 
scan
If clinically indicated
If clinically indicated
CT or MRI of other 
metastatic sites (e.g. 
neck)
If clinically indicated 
If clinically indicated or if lesions were documented 
at screening, follow same schedule as CT/MRI of 
chest, abdomen, and pelvis.
Localized bone CT,
MRI or X-ray
If clinically indicated
If clinically indicated or if lesions were documented 
at screening, follow same schedule as CT/MRI of 
chest, abdomen, and pelvis.
Color Digital 
photography (with 
metric ruler) of 
cutaneous lesions 
Mandated for any 
cutaneous lesions present
If clinically indicated or if cutaneous lesions were 
documented at screening, follow same schedule as 
CT/MRI of chest, abdomen, and pelvis.
7.2.1.1
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 subject
within 28 days prior to start of treatment, including before signing the main study ICF, can 
be considered as the baseline images for this study. Any imaging assessments obtained after
randomization (or after the date of first dose of study treatment in arm 1A) cannot be 
considered baseline images. The following assessments are required at screening/baseline:
!
Chest, abdomen and pelvis CT or MRI (with intravenous contrast enhancement)
!
Brain CT or MRI
!
Whole body bone scan, 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
!
Color photography (with metric ruler) for any skin lesions present
!
CT or MRI of other metastatic sites (e.g., neck), if clinically indicated
If a subject has a contraindication to intravenous CT 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 
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performed instead) plus a contrast-enhanced MRI (if possible) of the abdomen and pelvis 
should be performed.
Brain MRI or CT must be completed at screening. Contrast enhanced brain MRI is preferred, 
however, if MRI contrast is contraindicated, then MRI without contrast or CT with/without 
contrast is acceptable. If clinically indicated, a whole body bone scan must 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 must 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.
If skin lesions are present at screening, color photography should be acquired using a digital 
camera in clear focus, including a scale/ruler, in such a way that the size of the lesion(s) can 
be determined from the photograph.
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.
Any potential lesion that could mimic metastatic disease must be confirmed negative for 
melanoma as confirmed by biopsy/pathology and cannot be considered as measurable or 
non-measurable lesions.
Chest x-rays and ultrasound should not be used to measure tumor lesions.
7.2.1.2
Post-baseline imaging assessments
Imaging assessments as described in Table 7-3 should be performed at the time points 
specified using the same imaging modality used at baseline, irrespective of study treatment 
interruption or actual dosing (see Table 7-2). Imaging assessments for response evaluation 
will be performed 12 weeks (± 7 days) after the date of randomization (or after the date of 
first dose of study treatment in arm 1A), then every 8 weeks (± 7 days) until 52 weeks after 
randomization/date of first dose of study treatment in arm 1A, and every 12 weeks (± 7 days) 
thereafter until disease progression per RECIST 1.1 (as assessed by the investigator), death, 
lost to follow-up or withdrawal of consent. Imaging assessments should be scheduled using 
the randomization date (or after the date of first dose of study treatment in arm 1A) as the 
reference 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.
An additional tumor assessment must be performed to confirm response (complete response 
CR or partial response PR) as per RECIST v1.1, no less than 4 weeks after the criteria for 
response are first met.
For subjects who discontinue study treatment without disease progression per RECIST v1.1
(as assessed by the investigator), imaging assessments must be performed as part of efficacy 
follow up as described in Table 7-2 and Table 7-3 until disease progression per RECIST 
v1.1 (as assessed by the investigator), death, lost to follow-up or withdrawal of consent.
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Every effort will be made to continue collection of tumor assessments even after the start of 
subsequent anti-cancer therapy for subjects that have not progressed.
For all subjects (including those who continue study treatment beyond disease progression 
per RECIST v1.1), at least two additional tumor assessments that are at least 4 weeks apart 
are recommended subsequent to disease progression per RECIST v1.1 
 
 no less than 4 weeks after criteria for disease progression per RECIST 
v1.1 are first met. Tumor assessments after start of new anti-cancer therapy are 
recommended.
Additional imaging assessments may be performed at any time during the study at the 
investigator’s discretion to support the efficacy evaluations for a subject, 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.
Any imaging exams submitted to the imaging CRO are expected to have a local RECIST 
v1.1 assessment completed and recorded in the eCRF. Scans done for safety and/or off 
protocol imaging should not be submitted to the imaging CRO and/or have a corresponding 
local RECIST v1.1 assessment.
Each lesion that is measured at baseline must be measured by the same method (either same 
imaging method or by photography, including a metric ruler) and when possible, by the 
same local radiologist/physician throughout the study so that the comparison is consistent. 
If an off-schedule imaging assessment is performed because progression is suspected, 
subsequent imaging assessments should be performed in accordance with the original 
imaging schedule.
Combined PET/CT with diagnostic CT may be used only if the CT is of similar diagnostic 
quality as a CT performed without PET, including the utilization of IV contrast media. At 
the discretion of the Investigators, PET scans may be performed to document progressive 
disease per RECIST v1.1. (Appendix 2).
All study imaging done for efficacy or for suspicion of progression, including assessments 
done after PD per RECIST v1.1 and any on protocol off-schedule imaging studies, must be 
submitted to the designated imaging CRO for quality control and central review.
7.2.2
Safety and tolerability assessments
Safety will be monitored as described in Table 7-2 by assessing physical examination, 
performance status, vital signs, weight, laboratory evaluations and ECG as specified below, 
as well as collecting of the adverse events at every visit. For details on AE collection and 
reporting, refer to Section 8.
More frequent examinations may be performed at the investigator’s discretion, if clinically 
indicated.
7.2.2.1
Physical examination
A complete physical examination will be performed at screening (and if clinically indicated 
thereafter) and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, 
vascular, and neurological. If indicated based on medical history and/or symptoms, rectal, 
external genitalia, breast, and pelvic exams will be performed.
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A short physical exam will be performed as per schedule in Table 7-2 and will include the 
examination of general appearance. Based on the safety profiles of the study drugs, special 
attention should be given to any signs or symptoms suggestive for infections, pneumonitis 
or interstitial lung disease. Patients receiving capmatinib in Arm 2 should be monitored for 
any clinical signs indicative of neural toxicity, and a neurological examination should be 
performed as clinically indicated.
Information for all physical examinations must be included in the source documentation at 
the study site. 
Clinically relevant findings that are present prior to signing informed consent must be 
recorded on the eCRF that captures medical history. Significant findings made after signing 
informed consent which meet the definition of an Adverse Event (refer to Section 8) must 
be recorded in the eCRF as an adverse event.
7.2.2.2
Vital signs
Vitals signs will be collected as per the schedule in Table 7-2. 
Vital signs include blood pressure (Systolic blood pressure [SBP] and diastolic blood 
pressure [DBP], supine position preferred when ECG is collected), pulse measurement, and 
body temperature.
7.2.2.3
Height and weight
Height will be measured at screening.
Body weight (in indoor clothing, but without shoes) will be measured at screening and at 
subsequent time points as specified in Table 7-2.
7.2.2.4
Performance status
ECOG Performance status scale will be used as described in Table 7-4.
Table 7-4
ECOG Performance Status
ECOG status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about 
more than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
5
Dead
7.2.2.5
Laboratory evaluations
A central laboratory will be used for analysis of all specimens listed in Table 7-5, except for 
urinalysis, HIV testing (to be performed only if required per local regulations) and 
urine/serum pregnancy tests, which will be performed locally. The laboratory assessments 
must be performed as per the schedule in Table 7-2.
At screening, all subjects must be fasting for at least 12 hours overnight before each blood 
collection to obtain fasting glucose.
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Subjects randomized in Arm 1 or enrolled in Arm 1A (spartalizumab in combination with 
LAG525) and in Arm 4 (spartalizumab in combination with ribociclib) are required to be 
fasting for at least 12 hours overnight before each blood collection to obtain fasting glucose
and investigators should monitor the potential occurrence of auto-immune diabetes (for Arm 
1 and Arm 1A).
Note on fasting conditions: Subjects must be fasting from all food and drink. Water is 
allowed during all fasting periods; however coffee, tea and juice are not permitted during 
the fasting period.
Details on the collections, shipment of samples and reporting of results by the central 
laboratory will be provided to investigators in a separate Laboratory Manual.
Laboratory results from the central laboratory will be used to determine subject’s eligibility 
(except for laboratory assessments performed locally). If an immediate clinical decision 
needs to be made, locally unscheduled testing may be performed and used to determine 
eligibility.
If local laboratory testing is performed during the study, the results of the local laboratory 
will be recorded in the eCRF if at least one of the following criteria is met:
!
local results were used to determine subject’s eligibility (including local LDH result 
used for stratification of randomization), or
!
a treatment decision was made based on the local results, or
!
local abnormal laboratory values or test results meet one of the criteria for adverse 
event(s), as defined in Section 8.1.1. In this case, local results supporting start/end date 
of adverse event and changes in grade should be recorded in the eCRF.
Sites will be requested to provide the local laboratory reference ranges and a copy of the 
laboratory certification to Novartis for all local laboratory results recorded in the eCRF.
Clinically significant laboratory abnormalities must be recorded as either medical 
history/current medical conditions or adverse events (if meeting the criteria for reporting as 
AE as defined in Section 8.1.1), as appropriate.
Samples for safety cytokine panel at screening will be stored below -70°C and analyzed 
only if post-screening samples are received.
Table 7-5
Clinical laboratory parameters collection plan 
Test Category
Test Name
Hematology
Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils, Bands, Other) 
Chemistry
Albumin, Alkaline phosphatase, ALT , AST, GGT, LDH, Calcium, corrected calcium
(corrected on serum albumin; mandatory at screening for all subjects, and then as 
clinically indicated), Magnesium, Phosphorus, Chloride, Sodium, Potassium, 
Creatinine, Creatine kinase, Direct Bilirubin, Total Bilirubin, Total Cholesterol, Blood 
Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase, Glucose (At screening: 
fasting glucose for all subjects; at subsequent time points: fasting glucose for 
subjects in Arm 1 and Arm 1A receiving LAG525 and for subjects in Arm 4 receiving 
ribociclib, non-fasting for other arms) 
Cardiac Troponin T (TnT) level must be tested at screening (for all patients), and 
then at C1D15, C2D1 and C3D1 for patients randomized into Arm 1 and Arm 1A
only (also refer to Section 7.2.2.5.1 for monitoring guidance in Arm 1/Arm 1A). 
Central TnT testing is recommended, but if site is unable to assay TnT centrally (or 
locally), local Troponin I (TnI) is acceptable.
Urinalysis (local)
Macroscopic Panel (Dipstick) (Color, Bilirubin, Blood, Glucose, Ketones, Leukocytes 
esterase, Nitrite, pH, Protein, Specific Gravity, Urobilinogen). 
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Test Category
Test Name
If dipstick is abnormal, then perform local lab microscopic panel (Red Blood Cells, 
White Blood Cells, Casts, Crystals, Bacteria, Epithelial cells)
Coagulation
International normalized ratio [INR]), Activated partial thromboplastin time (APTT)
Thyroid function
At baseline: TSH, Free T3 and Free T4 
At the subsequent visits, as indicated in Table 7-2: TSH only. If TSH is abnormal, 
central lab will test Free T3 and Free T4
Hepatitis serology
HBV-DNA, HbsAg, HbsAb, HbcAb, HCV RNA-PCR
Safety cytokines
(for cytokine 
release syndrome)
IFN-%, IL-6, IL-1 beta, TNF-#
HIV serology (local)
If required per local regulations: local HIV testing at screening
Pregnancy Test 
(local) for women 
of childbearing 
potential
At screening: A local serum pregnancy test must be performed ≤ 72 hours before 
first dose of study treatment.
Local serum and urine pregnancy tests must then be performed as per Table 7-2
7.2.2.5.1 Troponin monitoring guidance
Cardiac enzyme Troponin T (or I) level must be tested at screening for all patients. 
For patients randomized in Arm 1 and Arm 1A (spartalizumab + LAG525), additional 
cardiac troponin T (or I) assessments will be done during the first two months at C1D15, 
C2D1 and C3D1. If Troponin level is above ULN during the first two months, or if the level 
is above the screening value (if the screening value was 1-2 fold ULN), a central ECG
assessment (as described in Section 7.2.2.6) and a local echocardiogram must be performed. 
If ECG and echocardiogram are normal, Troponin must be repeated the following day. 
However, if ECG or echocardiogram are abnormal and suggestive of myocarditis, a 
cardiologist must be consulted. Results of local echocardiogram (or any other local 
assessments performed for cardiac evaluation, as well as conclusions of any cardiologist 
consulted) will be documented in subject’s source documents.
7.2.2.6
Electrocardiogram (ECG)
Standard 12 lead ECG (triplicate, unless otherwise stated) recording will be performed at 
each ECG collection time point as indicated in Table 7-6 using the ECG machine provided 
by central core ECG laboratory designated by Novartis. 
ECGs must be recorded after 10 minutes rest in the supine position to ensure a stable 
assessment and according to the [ECG investigator manual]. 
The individual triplicate ECGs should be recorded approximately 2 minutes apart. The mean
Fridericia QT correction formula (QTcF) value for each visit will be calculated from the 
triplicate ECGs for each subject and should be used for clinical decisions.
Subject’s eligibility to the study should be assessed by the investigator based on the local 
interpretation of results from the triplicate ECG recordings performed on the machine 
provided. Clinically significant abnormalities present at screening should be reported as 
Medical History in the eCRF. Clinically significant findings must be discussed with 
Novartis prior to randomizing the subject in the study.
Interpretation of the ECG tracing must be made by a qualified physician. Each ECG tracing 
should be printed, labeled with the study number, subject number, date, and kept in the 
source documents at the study site. 
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New or worsened clinically significant findings occurring after informed consent is signed
must be recorded as Adverse Events in the eCRF.
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 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.
If an unscheduled ECG is performed at an external medical facility, a copy of the ECG 
should be obtained and forwarded to the ECG core laboratory, and a copy kept in the source 
documents at the study site.
All ECGs performed during the study, including unscheduled triplicate ECGs with clinically 
relevant findings, 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.
Table 7-6
Central ECG collection plan
Visit /Cycle
Time
ECG Type
Arm 1 and 
Arm 1A
Arm 2
Arm 3
Arm 4
Screening
Any time
Any time
Any time
Any time
12 Lead, triplicate, 
central
C1D1
Pre-dose
Pre-dose
Not applicable Pre-dose
12 Lead, triplicate, 
central
Not applicablePost dose: 4 
hours after 
capmatinib 
administration
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
Not applicableNot applicable
Not applicable 4 h post-dose (± 15 min) 12 Lead, triplicate, 
central
C1D15
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
Not applicableNot applicable
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
Not applicableNot applicable
Not applicable 4 h post-dose (± 15 min) 12 Lead, triplicate, 
central
C2D1
Pre-dose
(single)
Pre-dose (single) Not applicable Pre-dose (triplicate)
12 Lead, central
C3D1
Pre-dose
Pre-dose
Not applicable Pre-dose
12 Lead, triplicate, 
central
Not applicablePost dose: 4 
hours after 
capmatinib 
administration
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
C3D15
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
Not applicableNot applicable
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
C4D1
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
C5D1
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
C6D1
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
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Visit /Cycle
Time
ECG Type
Arm 1 and 
Arm 1A
Arm 2
Arm 3
Arm 4
Not applicableNot applicable
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
Day 1 of all 
other cycles 
(only for 
patients with 
QTcF ≥
481 ms at any 
time prior to 
cycle 7)
Not applicableNot applicable
Not applicable Pre-dose
12 Lead, triplicate, 
central
Day 1 of cycle 9 
and every third 
cycle (only for 
patients with 
QTcF ≥ 481 ms
at any time 
prior to cycle 7)
Not applicableNot applicable
Not applicable 2h post-dose (± 15 min)
12 Lead, triplicate, 
central
EoT
Anytime
Anytime
Anytime
Anytime
12 Lead, triplicate, 
central
Unscheduled 
Anytime
Anytime
Anytime
Anytime
12 Lead, triplicate, 
central
7.2.2.7
 immunogenicity
7.2.2.7.1
 immunogenicity (IG) blood collection and 
handling
Blood samples for 
 
 IG analysis of spartalizumab, LAG525 and canakinumab will be collected 
according to the relevant time points described in Table 7-7, Table 7-8, Table 7-9, Table 7-
10 and Table 7-11.
Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted 
in a forearm vein. Please refer to the CPDR001J2201 Central Lab Manual for instructions 
on processing of samples.
!
A total of 3.5 mL of blood (serum) will be collected at specified time points for 
spartalizumab IG analysis. 
!
A total of 5 mL of blood (serum) will be collected at specified time points for LAG525 
IG analysis. 
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!
A total of 3.5 mL of blood (serum) will be collected at specified time points for 
canakinumab IG analysis. 
The exact date and time of drug administration and blood draws for 
 IG assessment 
will be recorded in the eCRF.
 
If subject experience an SAE or an AE leading to the discontinuation of the study treatment. 
 
 
 If subjects experience suspected immunologically related AEs 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 of the 
occurrence. 
 
 
 
Table 7-7
Blood
(serum)
collection 
schedule
for 
spartalizumab
 immunogenicity samples (applicable for all 
subjects)
Cycle
Da
y
Scheduled Time Point c
Dose 
reference 
ID
IG 
Sample 
number
1
1
Pre-infusion C1D1a
1
301
1
1
1 hr post end of C1D1 infusion (± 5 
min)
1
-
1
8
168 hr post C1D1 infusion (± 8 hr)
1
-
1
15
336 hr post C1D1 infusion (± 24 hr)
1
-
2
1
Pre-infusion C2D1 a
2
305
2
1
1 hr post end of C2D1 infusion (± 5 
min)
2
-
3
1
Pre-infusion C3D1 a
3
307
3
1
1 hr post end of C3D1infusion (± 5 
min)
3
-
3
8
168 hr post C3D1 infusion (± 8 hr)
3
-
3
15
336 hr post C3D1 infusion (± 24 hr)
3
-
4
1
Pre-infusion C4D1 a
4
311
5
1
Pre-infusion C5D1 a
5
312
6
1
Pre-infusion C6D1 a
6
313
9, 12, 15, 
etc 
(every 3 
months)
1
Pre-infusion a
101, 102, 
103, etc
317, 318, 
319, etc
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Cycle
Da
y
Scheduled Time Point c
Dose 
reference 
ID
IG 
Sample 
number
EOT
-
Anytime
N/A
314
30-day safety 
follow-up visit
Anytime
N/A
315
150-day safety 
follow-up visit d
Anytime
N/A
316
-
-
Unscheduled b
N/A
3000+
a Take samples within 30 min before the infusion begins
 
c Time is relative to the beginning of the infusion; it will be recorded as both days and hours on the eCRF 
but only as hours in the database (1 day = 24 hrs)
d for women with child bearing potential
Note 1: Immunogenicity samples are collected together with 
. Blood samples are to be 
collected from the arm opposite from infusion site.
Table 7-8
Blood (serum) collection schedule for LAG525
 
immunogenicity samples (only applicable for subjects enrolled in 
arm 1 and arm 1A)
Cycle
Da
y
Scheduled Time Point c
Dose 
reference 
ID
IG 
Sample 
number
1
1
Pre-infusion C1D1 a
11
501
1
1
1 hr post end of C1D1 infusion (± 5 
min)
11
-
1
8
168 hr post C1D1 infusion (± 8 hr)
11
-
1
15
336 hr post C1D1 infusion (± 24 hr)
11
-
2
1
Pre-infusion C2D1 a
12
505
2
1
1 hr post end of C2D1 infusion (± 5 
min)
12
-
3
1
Pre-infusion C3D1 a
13
507
3
1
1 hr post end of C3D1 infusion (± 5 
min)
13
-
3
8
168 hr post C3D1 infusion (± 8 hr)
13
-
3
15
336 hr post C3D1 infusion (± 24 hr)
13
-
4
1
Pre-infusion C4D1 a
14
511
5
1
Pre-infusion C5D1 a
15
512
6
1
Pre-infusion C6D1 a
16
513
9, 12, 15, 
etc (every 
3 months)
1
Pre-infusion a
201, 202, 
203, etc
515, 
516,
517, etc
EOT
-
Anytime
N/A
514
-
-
Unscheduled b
N/A
5000+
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Cycle
Da
y
Scheduled Time Point c
Dose 
reference 
ID
IG 
Sample 
number
a Take samples within 30 min before the infusion begins
Unscheduled IG 
blood samples will be uniquely, sequentially numbered 5000, 5001 etc.
c Time is relative to the beginning of the infusion; it will be recorded as both days and hours on the eCRF 
but only as hours in the database (1 day = 24 hrs)
Note 1: Immunogenicity samples are collected together with 
. Blood samples are to be 
collected from the arm opposite from infusion site.
Table 7-10
Blood 
(serum) 
collection 
schedule 
for 
canakinumab
 immunogenicity samples (only applicable for 
subjects enrolled in arm 3)
Cycle
Day
Scheduled Time Point
Dose 
reference 
ID
IG 
Sample 
number
1
1
Pre-dose C1D1 a
31
701
1
8
168 hr post C1D1 dose (± 8 hr)
31
-
1
15
336 hr post C1D1 dose (± 24 hr)
31
-
2
1
Pre-dose C2D1 a
32
704
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Cycle
Day
Scheduled Time Point
Dose 
reference 
ID
IG 
Sample 
number
3
1
Pre-dose C3D1 a
33
705
3
8
168 hr post C3D1 dose (± 8 hr)
33
-
3
15
336 hr post C3D1 dose (± 24 hr)
33
-
4
1
Pre-dose C4D1 a
34
708
5
1
Pre-dose C5D1 a
35
709
6
1
Pre-dose C6D1 a
36
710
9, 12, 
15, etc 
(every 3 
months)
1
Pre-dose a
37, 38, 39, 
etc
712, 713, 
714,etc
EOT
-
Anytime
N/A
711
-
-
Unscheduled b
N/A
7000+
a Take samples within 30 min before the injection is administered
Unscheduled IG 
blood samples will be uniquely, sequentially numbered 7000, 7001 etc.
Note 1: Immunogenicity samples are collected together with 
. Blood samples are to be
collected from the arm opposite from infusion site.
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7.2.2.7.2 Analytical method
Bioanalysis for 
 IG determination will employ validated assays:
The assay to quantify LAG525, capmatinib, spartalizumab and ribociclib will be validated 
LC-MS/MS (Liquid chromatography–mass spectrometry) methods respectively.
The assay to quantify canakinumab will be using a validated competitive ELISA method.
The assay to assess the IG against LAG525 and spartalizumab will be using validated 
homogeneous ELISA methods respectively.
The assay to assess the IG against canakinumab will be a validated Meso Scale Discovery 
(MSD) electrochemiluminescence assay.
7.2.3
Biomarkers
During the study, both blood and tumor samples will be collected for biomarker analyses as 
described in Table 7-12. 
All assessments will be performed by a Novartis designated laboratory. Instructions for 
collection, storage and shipment of all biomarker samples will be provided in the laboratory 
manual. Required sample collection information must be entered in the eCRF and 
requisition forms.
While the goal of the biomarker study is to provide supportive data for the clinical study, 
there may be circumstances when a decision is made to stop a collection, or not perform or 
discontinue an analysis due to either practical or strategic reasons. For example, there may 
be inadequate sample number, issues related to the quality of the sample or issues related to 
the assay that preclude analysis. Alternatively, there may be insufficient efficacy to allow 
for correlative analyses. Therefore, depending on the results obtained during the study, 
collection/analysis of some samples may be omitted at the discretion of the sponsor.
Table 7-12
Biomarker sample collection plan 
Sample Type
Volume
Visit
Time point
Tumor samples
Mandatory, if available: 
Provision of archival 
formalin fixed paraffin 
embedded (FFPE)
block or slides from a 
tumor sample collected 
prior to start of any prior 
anti-PD-1/PD-L1 mono-
or combination therapy
FFPE block (preferred)
or 15 archival slides
(leftover block can be 
returned upon request)
C1D1
Any time 
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Sample Type
Volume
Visit
Time point
Mandatory
Newly or recently 
obtained (as defined in 
Section 7.2.3.1.1) 
tumor biopsy 
FFPE tumor block
(Formalin-fixed tissue
in ethanol is 
acceptable for arm 1A 
only)
Screening
Day -28 to Day -1
(for screening in arm 
1A, sample can be 
collected from Day -35 
and should be 
submitted as early as 
possible and at the 
latest by Day -20 for 
central LAG-3 
assessment)
Mandatory
Newly obtained tumor 
biopsy
FFPE tumor block
C1D21 +7 day window
Any time between 
C1D21 and C2D1, 
pre-dose
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7.2.3.1
Biomarker assessments in tumor tissue
In the non-randomized section of the study, mandatory screening tumor samples will be 
centrally assessed to determine LAG-3 status for enrollment into arm 1A.
For all arms (randomized or non-randomized), biomarker analyses in mandatory tumor 
samples to assess changes in levels, phenotype and activation of T cell populations in the 
tumor and tumor microenvironment will support the decision making at each interim 
analysis as a part of the secondary objectives (Table 3-1). Secondary objective biomarker 
analyses may include but are not limited to CD8+ T cell infiltration and T cell activation by 
IHC, gene expression analysis by Nanostring and/or T cell repertoire/clonality by TCR-
sequencing 
 Analyses will be performed on an on-
going basis, such that the data will be readily available for decision making purposes at each 
interim analysis.
 
 
 
 
 
 
 
 
7.2.3.1.1 Mandatory baseline and on-treatment tumor sample collections
Sequential tumor biopsies at screening and 3-4 weeks on treatment are mandatory. The same 
lesion should be biopsied sequentially whenever feasible. Biopsies of the target lesions are 
not allowed. A biopsy sample must be provided during screening prior to the first dose of 
study treatment and at 3 to 4 weeks on treatment (between C1D21 and C2D1). The biopsy 
guidelines for collection of biopsy specimens are described in Table 7-13.
In all arms except arm 1A: For the mandatory screening biopsy specimen, local pathology 
analysis is required to take place prior to randomization. If the tissue quality criteria listed 
in Table 7-13 are not met, the subject should be re-biopsied in order to meet eligibility 
requirements.
For arm 1A: Baseline tumor sample must be submitted directly to the Novartis-designated 
laboratory (Histogenex, Antwerp, Belgium) for central assessment of LAG-3 status. Local 
pathology review of tissue demonstrating that sample meets tissue quality criteria (Table 7-
13) is not required for baseline sample (refer to Section 7.2.3.1.2 for details). 
Table 7-13
Guidelines for mandatory biopsy collection (applicable for all 
arms) and tissue quality criteria (recommended for arm 1A, 
mandatory for other arms)
Biopsy guidelines
! Minimum three core samples per biopsy using an 18G or larger diameter needle 
or other biopsy method which results in tissue of comparable or larger size
! Minimum size per tissue core should be ~10 mm in length and ~1 mm diameter
Tissue quality criteria*
! Minimum tumor content of 30%
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! Minimum total tumor tissue area 30 mm2
* Criteria are to be measured in one tissue section during local pathologist review. Total tumor tissue area 
excludes non-tumoral areas (i.e. necrosis, fatty, hemorrhagic tissue) and sample should not contain abundant 
melanin pigmentation. For samples with >60% tumor content, total tumor tissue area may be < 30 mm2 but 
must be ≥15 mm2.
Entire tissue sample (3 cores or comparably sized tissue sample, taken from the same lesion)
should be submitted, embedded into a single block (or for arm 1A only, submission of 
formalin-fixed tissue in ethanol is also acceptable). Further instructions on the collection 
and submission of samples is found in the central laboratory manual.
Mandatory biopsies may be taken from cutaneous, subcutaneous, nodal or visceral lesions.
For France only: Mandatory biopsies should be taken from cutaneous, subcutaneous or 
nodal lesions. 
CNS and bone metastasis are excluded for biopsy. Fine needle aspirates cannot be accepted.
For cases of re-screening OR if a biopsy was recently completed as part of standard of care 
(including before signing the main study ICF), the tissue sample can be submitted as 
baseline tumor sample as long as the following criteria are met:
!
Recommended for arm 1A, mandatory for other arms: Biopsy date must be within 8
weeks of start of treatment
!
Patient must not have received any therapy for unresectable or metastatic melanoma 
between collection of biopsy sample and start of study treatment
!
Same lesion should be amenable for on-treatment biopsy 
!
Entire block must be available for submission
!
Recommended for arm 1A, mandatory for other arms: Biopsy must meet tissue QC 
criteria (Table 7-13)
For the mandatory on-treatment biopsy specimen in all arms, every effort should be made 
to adhere with the biopsy guidelines and the resulting sample should meet the tissue quality
criteria (Table 7-13). Where medically feasible, the on-treatment biopsy should be taken 
from the same anatomical location that was biopsied at baseline. 
If the on-treatment biopsy is not taken, medical justification should be documented in the 
eCRF, i.e. the lesion shrank to an extent biopsy is no longer possible or there is a new or 
increased medical risk of biopsy since baseline, such as bleeding. If tissue quality criteria in 
Table 7-13 are not met for the on-treatment biopsy specimen, re-biopsy should be performed 
where medically feasible.
7.2.3.1.2 Mandatory central assessment of LAG-3 status for eligibility for arm 1A
Newly or recently obtained biopsy samples (as defined in Section 7.2.3.1.1) should be 
submitted directly to the Novartis-designated central testing laboratory (Histogenex, 
Antwerp, Belgium) for LAG-3 assessment as early as possible and at the latest 20 days prior 
to planned first treatment date (Day -20) to allow LAG-3 analysis and reporting of results 
within the 35-day screening period. The LAG-3 results will be reported directly to the 
clinical site and the sample must be reported as LAG-3 positive by the central lab for the 
subject to be eligible to arm 1A. Local LAG-3 results are not accepted for eligibility. Details 
for sample submission are found in the central laboratory manual.
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To ensure tissue samples are evaluable for LAG-3 assessment, the tissue quality criteria in 
Table 7-13 should be followed and samples must not contain abundant melanin 
pigmentation.
If the submitted sample is not evaluable for LAG-3 assesment for any reason at the Novartis-
designated central laboratory (Histogenex, Antwerp, Belgium), another newly or recently 
obtained tumor biopsy (as defined in Section 7.2.3.1.1) will be requested. The sample must
be centrally analyzed to determine LAG-3 status for eligibility before the end of the 35-day 
screening period or else the subject will be considered as a screen failure.
LAG-3 status will be assessed by immuohistochemistry by a qualified pathologist at the 
Novartis-designated central testing laboratory (Histogenex, Antwerp, Belgium). Samples
which have ≥5% LAG-3 positive staining will be reported as positive for LAG-3 and 
samples with <5% LAG-3 positive staining will be reported as negative. Once LAG-3 
testing is completed, the remainder of the tumor tissue sample will be analyzed for 
biomarkers for subjects enrolled as described in Section 7.2.3.1.
Upon request, samples determined to be LAG-3 negative will be returned to site. Some
tissue material may be retained for potential companion diagnostic development.
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8
Safety monitoring and reporting
8.1
Definition of adverse events and reporting requirements
8.1.1
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 subject 
or clinical investigation subject 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.
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The investigator has the responsibility for managing the safety of individual subject 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 subject 
at each visit during the study. Adverse events also may be detected when they are 
volunteered by the subject during or between visits or through physical examination findings, 
laboratory test findings, or other assessments.
Adverse events must be recorded under the signs, symptoms or diagnosis associated with 
them, accompanied by the following information (as far as possible). For serious adverse 
event refer to Section 8.1.2):
1. The Common Toxicity Criteria (CTC) AE grade: Adverse events will be assessed and 
graded according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 5.0. 
2. Relationship to the study treatment. If the event is due to lack of efficacy or progression 
ofunderlying illness (i.e. progression of the study indication) the assessment of causality 
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 arms, not on a 
single subject
3. 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 a SAE (see Section 8.1.2 for definition of SAE) and which 
seriousness criteria have been met
5. Action taken regarding with each individual study drug, if the adverse event is 
considered related to study treatment. Action taken may include one or more of the 
following:
!
Dose not changed
!
Dose reduced/increased
!
Drug interrupted/withdrawn
6. Whether concomitant medication or non-drug therapy was given. 
7. its outcome i.e., its recovery status or whether it was fatal
If the event worsens the event should be reported a second time in the eCRF 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 eCRF 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 subject.
Adverse events (including lab abnormalities that constitute AE) should be described using 
a diagnosis whenever possible, rather than individual underlying signs and symptoms.
Adverse event monitoring should be continued for at least 30 days after the last dose of 
capmatinib or ribociclib, or at least 130 days after the last dose of canakinumab, or at least
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150 days after the last dose of spartalizumab/LAG525, whichever is longer. If a subject
starts a subsequent anti-cancer therapy, then only adverse events suspected to be related to 
study treatment should be collected out to 150 days after discontinuation of 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 the interventions required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST criteria for solid tumors), should not be reported as a 
serious adverse event, except if the investigator considers that progression of malignancy is 
related to study treatment.
Adverse events separate from the progression of malignancy (example, deep vein 
thrombosis at the time of progression or hemoptysis concurrent with finding of disease 
progression) will be reported as per usual guidelines used for such events with proper 
attribution regarding relatedness to the drug.
Information about adverse drug reactions for the investigational drug can be found in the 
Investigator Brochure (IB) of each study drug.
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
!
they require changes (reduction, delay or interruption/discontinuation) of study drug(s)
8.1.2
Serious adverse events
8.1.2.1
Definitions
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 a SAE refers to a reaction in which 
the subject 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
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-
social reasons and respite care in the absence of any deterioration in the subject’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 subject 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 
subject 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. Please refer to the ICH-E2D Guidelines.
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 (refer to Section 8.5).
8.1.2.2
SAE reporting
To ensure subject safety, every SAE, regardless of causality, occurring after the subject has 
provided informed consent and until at least 30 days after the last dose of capmatinib or 
ribociclib or at least 130 days after the last dose of canakinumab, or at least 150 days after 
the last dose of spartalizumab/LAG525, whichever is longer, must be reported to Novartis
safety within 24 hours of learning of its occurrence. If a subject starts a subsequent anti-
cancer therapy, then only SAE suspected to be related to study treatment should be collected 
out to 150 days after discontinuation of spartalizumab. SAE suspected to be related to 
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.
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, a 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.
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Suspected Unexpected Serious Adverse Reactions (SUSAR) 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 SAE experienced after the 150 day safety evaluation follow-up period should only be 
reported to Novartis if the investigator suspects a causal relationship to the study treatment.
For screen failures, SAE occurring after the subject has provided informed consent until the 
time the subject is deemed a Screen Failure must be reported to Novartis.
8.2
Emergency unblinding of treatment assignment
Not applicable. 
8.3
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 pregnancy consent form to allow the 
investigator to collect and report information regarding the pregnancy. To ensure subject 
safety, each pregnancy occurring after signing the informed consent must be reported to 
Novartis within 24 hours of learning of its occurrence. In consented subjects, 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. Follow-ups will be done one
month after the estimated date of delivery and 3 and 12 months after the estimated date of 
delivery for live births only.
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 any 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.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the Investigator 
Brochure provided for each study drug. Additional safety information collected between IB 
updates will be communicated in the form of Investigator Notifications. This information 
will be included in the subject informed consent and should be discussed with the subject
during the study as needed.
8.5
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, subject or 
consumer (EMA definition).
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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 recorded 
in the 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 8-1
Guidance for capturing the study treatment errors including 
misuse/abuse
Treatment error type
Document in Dosing 
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.
8.6
Data Monitoring Committee 
This study will include a safety data monitoring committee (DMC) to be activated when a 
combination arm (from the randomized or non-randomized section of the study) reaches
Part 2 of the study (expansion phase) which will function independently of all other 
individuals associated with the conduct of this clinical trial, including the site investigators 
participating in the study. The DMC will assess relevant safety data in the expansion phase 
of the study at defined intervals and recommend to the sponsor whether to continue, modify 
or terminate any or all combination arms in the expansion phase.
Specific details regarding composition, responsibilities, data monitoring and meeting 
frequency, and documentation of DMC reports, minutes, and recommendations will be 
described in a separate charter that is established between the sponsor and the DMC.
8.7
Steering Committee 
The Steering Committee (SC) will be established comprising of investigators participating 
in the trial, i.e. not being members of the DMC, and Novartis/sponsor representatives from 
the Clinical Trial Team.
The SC will ensure transparent management of the study according to the protocol through 
recommending and approving 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 including authorship rules. 
The details of the role of the steering committee will be defined in the Steering Committee 
charter.
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9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:
!
What protected health information (PHI) will be collected from subjects in this study
!
Who will have access to that information and why
!
Who will use or disclose that information
!
The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of 
subject authorization. For subjects that have revoked authorization to collect or use PHI, 
attempts should be made to obtain permission to collect follow-up safety information (e.g. 
has the subject experienced any new or worsened AE) at the end of their scheduled study 
period.
The data collection system for this study uses built-in security features to encrypt all data 
for transmission in both directions, preventing unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of 
individually assigned user identification codes and passwords, made available only to 
authorized personnel who have completed prerequisite training.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and eCRFs with the investigators 
and their staff. Novartis employs several methods of ensuring protocol and Good Clinical 
Practice (GCP) compliance and the quality/integrity of the sites’ data. During the study, the 
field monitor will visit the site regularly to check the completeness of subject records, the 
accuracy of entries on the eCRFs, the adherence to the protocol to Good Clinical Practice, 
the progress of enrollment, and to ensure that study treatment is being stored, dispensed, and 
accounted for according to specifications. Key study personnel must be available to assist 
the field monitor during these visits. Continuous remote monitoring of each site’s data may 
be performed by a centralized Novartis/CRA organization. Additionally, a central analytics 
organization may analyze data and identify risks and 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 subject in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical information, laboratory data, electrocardiograms, and the results of any other tests 
or assessments. All information recorded on eCRFs must be traceable to source documents 
in the subject's file. The investigator must also keep the original signed informed consent 
form (a signed copy is given to the subject).
The investigator must give the monitor access to all relevant source documents to confirm 
their consistency with the eCRF entries. Novartis monitoring standards require full 
verification for the presence of informed consent, adherence to the inclusion/exclusion 
criteria, documentation of SAE, and of data that will be used for all primary variables. 
Additional checks of the consistency of the source data with the eCRFs are performed 
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according to the study-specific monitoring plan. No information in source documents about 
the identity of the subjects will be disclosed.
9.3
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 Electronic Data Capture (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 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
All data should be recorded, handled and stored in a way that allows its accurate reporting, 
interpretation and verification.
9.4
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 is 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 WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA) terminology.
Samples and/or data will be processed centrally and the results will be sent electronically to 
Novartis (or a designated CRO).
Dates of screenings, randomizations/enrollments, screen failures and study treatment 
completion, as well as randomization codes and data about all study treatments dispensed 
to the subject and all dosage changes will be tracked using an Interactive Response 
Technology. The system will be supplied by a vendor, who will also manage the database. 
The data will be sent electronically to Novartis personnel (or designated CRO).
At the conclusion of the study, the occurrence of any emergency code breaks will be 
determined after return of all code break reports and unused drug supplies to Novartis 
personnel (or designated CRO). The occurrence of any protocol violations will be 
determined. After these actions have been completed and the data has been verified to be 
complete and accurate, the database will be declared locked and the treatment codes will be 
unblinded and made available for data analysis. Authorization is required prior to making 
any database changes to locked data, by joint written agreement between the Global Head 
of Biostatistics and Data Management and the Global Head of Clinical Development.
After database lock, the investigator will receive copies of the subject data for archiving at 
the investigational site.
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10
Statistical methods and data analysis
By default Section 10 and all the sub-sections below refer to the randomized section of the 
study: the same analysis timing, definitions and analysis conventions apply to the 
non-randomized section of the study, unless specified otherwise. Only arm 1A 
(spartalizumab + LAG525) will be analyzed in the non-randomized section of the study. In 
the non-randomized section of the study, the date of first dose of study treatment is used as 
reference date instead of the randomization date.
For the selection phase (part 1) and expansion phase (part 2), efficacy, safety, and biomarker
analysis will be conducted on all subject data at the time that each part is completed. The 
primary analysis of each randomized and non-randomized section will be performed once 
the expanded arm has fully enrolled and also after all patients randomized/enrolled had at 
least 9 months of follow-up. This timing would allow for a potential minimum duration of 
response of 6 months for all subjects randomized/enrolled, assuming no delayed response.
The exact timing of the primary analysis of the randomized section of the study could be 
revisited if more than one arm is expanded to part 2. 
The additional data for any subjects continuing to receive study treatment past this time, as 
allowed by the protocol, will be further summarized in a final study report once these 
subjects complete the study.
Categorical data will be presented as contingency tables (frequencies and percentages). For 
continuous data summary statistics of mean, standard deviation, median, minimum, and 
maximum will be presented. For selected parameters, 25th and 75th percentiles will also be 
presented.
Screen failure subjects are those who signed the informed consent, but never started the 
study treatment for any reason. For these subjects, the eCRF data collected will not be 
included in analyses, but will be reported in CSR as separate listings.
10.1
Analysis sets
All below defined analysis sets will be used to analyze data from both the selection phase 
(part 1) and the expansion phase (part 2).
10.1.1
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 they have been assigned to during the randomization 
procedure regardless of whether or not treatment was administered. This population will be 
the primary population for efficacy analysis.
For non-randomized section of the study, the full analysis set (FAS) will be identical to the 
safety set. 
10.1.2
Safety set
The Safety Set includes all subjects who received at least one dose of study treatment. 
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.
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10.1.3
Per-Protocol set
Not applicable.
10.1.4
Dose-determining analysis set
Not applicable.
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10.1.6
Other analysis sets 
10.1.6.1 Biomarker analysis set
The biomarker analysis set, as it pertains to the secondary objective (Section 10.5.5), 
consists of all subjects in the safety set with an evaluable baseline tumor biopsy 
sample and at least one evaluable post-baseline tumor biopsy sample. 
 
 
10.2
Subject demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be listed and
summarized descriptively by treatment group and for all subjects in the FAS and the Safety 
Set.
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 at baseline will be summarized separately 
by system organ class and preferred term, by treatment group and for all subjects.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
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 months to spartalizumab, LAG525, capmatinib, canakinumab
and ribociclib 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 duration of exposure will also be presented for 
the study treatment by treatment group.
The number of subjects with dose adjustments (reductions, interruption, or permanent 
discontinuation) and the reasons will be summarized by treatment group and for all subjects,
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 and for all subjects.
10.4
Primary objective
The primary objective of this study is to evaluate the preliminary efficacy (in part 1) and 
efficacy (in part 2) of spartalizumab in combination with novel agents in subjects with 
previously treated unresectable or metastatic melanoma.
10.4.1
Variable
Objective response rate (ORR) is defined as the proportion of subjects with best overall 
response (BOR) of either confirmed complete response (CR) or confirmed partial response 
(PR), as per local review and according to RECIST v1.1 (see Appendix 2 for details).
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ORR will be calculated based on the FAS. ORR and its 95% confidence interval will be 
presented by treatment group. 
As a supportive analysis, ORR as per blinded independent central review (BICR) will be 
presented by treatment group; along with 95% confidence intervals (see Section 10.4.4).
10.4.2
Statistical hypothesis, model, and method of analysis
10.4.2.1 Randomized section of the study
Part 1: Selection Phase
No formal hypothesis testing will be conducted in part 1. The objective of this part of the 
study is to explore the anti-tumor activity of the combination of spartalizumab with novel 
agents as measured by ORR per RECIST v1.1, and to select an arm(s) with promising 
efficacy that will be advanced to the expansion phase.
To determine whether arms have the potential to demonstrate clinically meaningful response 
rates, arms will need to show that they cross a specific efficacy probability threshold during 
the selection phase to advance to the expansion phase. Conversely, arms can also be shown 
to cross a specific futility probability threshold and consequently will be declared as futile 
and enrollment in those arms will be terminated. These thresholds and probabilities are 
highlighted in Table 10-1.
Table 10-1
Probabilities thresholds used to declare efficacy or futility for an 
arm
Decision rule
Action
P(ORR ≤15%) ≥ 70%
Drop arm for futility
P(ORR ≥20%) ≥ 70%
Efficacy declared; Advance arm to expansion phase (part 2)
The futility decision rule was determined based on simulations such that arms with response 
rate that is not considered clinically meaningful (i.e. ORR < 10%) will be dropped with high 
probability (as illustrated in Table 10-10 in Section 10.8.1). Similarly, the decision criterion 
for advancement to the expansion phase was determined so that arms with clinically 
meaningful response rate that warrants further development (i.e. ORR>25%) will be 
advanced with high probability (‘power’) (see also Table 10-10).
To calculate these probabilities, a beta-binomial posterior distribution will be used as shown 
below:
~ 	
( + 1,  − + 1)
where  are the number of confirmed responses in a combination arm (i), and  are the 
number of subjects enrolled in a combination arm (i). In calculation of the posterior 
distribution uninformed prior Beta[1,1] will be taken into account for each arrm. The 
posterior probability will be calculated separately for each arm based on the observed ORR
based on RECIST v1.1 criteria at each decision point, i.e. at each interim analysis as 
described in Section 10.7.1.
No formal comparisons will be made between the combination arms for ORR in this 
‘selection’ phase, instead each of the arms will be evaluated against efficacy and futility 
thresholds as presented above.
The final decision on whether an arm will be selected for advancement to the expansion 
phase will primarily be based on the observed ORR using decision rule described above but 
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other efficacy (in particular duration of response), safety, and biomarker data will be 
considered as well. Further considerations related to the design and execution of the 
selection phase will be captured in the SAP Technical Appendix.
Part 2: Expansion Phase
For the arms which show promise for efficacy in part 1 (based on pre-defined criteria), these 
arms may be expanded.
After completion of the expansion phase and within each arm separately, the following 
statistical hypothesis will be tested based on objective response rate (ORR):
!
The null hypothesis is that the response rate is not clinically meaningful (≤ 10%).
!
The alternative hypothesis is that the response rate is clinically meaningful (>10%). 
The target response rate that warrants further development is ≥ 25% 
The null hypothesis will be formally rejected if the lower bound of exact 95% CI for ORR 
is above 10%. The primary analysis of ORR at the end of part 2 will be based on a combined 
pool of part 1 and part 2 data for given arm.
For example, assuming 24 subjects enrolled in an arm of interest in part 1 (see Section 10.8.1
for sample size estimates when true ORR = 0.25 in the selection phase), assuming this arm
met criteria for expansion and finally assuming 50 subjects are enrolled in the expansion 
phase, then combined among 74 subjects enrolled in this arm in total and followed 
sufficiently, 14 or more responses need to be observed to reject the null hypothesis. With 
those 14 responders among 74 subjects, the point estimate for ORR will be 18.9% with an 
exact 95% confidence interval of (10.8%, 29.7%). Since the lower bound of the exact 95% 
CI will be > 10%, this leads to rejection of null hypothesis. The exact 95% CIs for potential 
observed ORR in 74 subjects are shown in Table 10-2:
Table 10-2
Exact binomial 95% confidence intervals around potential 
observed ORR for N=74
Number of responders
Observed ORR (%)
95% exact CI (%)
10
13.5
6.7, 23.5
11
14.9
7.7, 25.0
12
16.2
8.7, 26.6
13
17.6
9.7, 28.2
14
18.9
10.8, 29.7
15
20.3
11.8, 31.2
16
21.6
12.9, 32.7
17
23.0
14.0, 34.2
18
24.3
15.1, 35.7
19
25.7
16.2, 37.2
20
27.0
17.4, 38.6
21
28.4
18.5, 40.1
22
29.7
19.7, 41.5
23
31.1
20.8. 42.9
24
32.4
22.0, 44.3
Fifty subjects enrolled in the expansion phase considered in the example above also 
correspond to the number of subjects needed to ensure that the hypothesis to be tested after 
completion of part 2 has sufficient predictive power conditioned on the ORR observed in 
the selection phase (part 1) (see Section 10.8.1). 
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Alpha control considerations:
For each arm (treatment combination cohort) included in the study the potential for alpha 
inflation arises from the adaptive nature of the design and, in particular, from the presence 
of a selection process based on probabilistic decision rules described in Section 10.4.2.1.
To assess whether alpha is controlled for each combination treatment arm separately, 
simulations were conducted. Below in Table 10-3, simulation results for scenarios that 
include one or more arms with the true ORR of 0.10 corresponding to the null hypothesis 
threshold (see also Scenarios 1 and 2 in Section 10.8.1), are presented. Scenario 2 is
investigated to assess a potential impact of shrinkage estimator on type I error inflation. In 
simulations, the focus was on assessing type I error for each of the ‘null hypothesis’ arm 
separately defined as the proportion of significant results after completion of part 2 for given 
arm (successful arm). The technical details for the simulations will be summarized in the 
SAP Appendix:
As shown in Table 10-3, for each of the ‘null hypothesis’ arms with the true ORR=0.10 the 
probability is less than 0.025 (ranging between 0. 0097 and 0. 0149) and therefore alpha is 
well-controlled. Even though there is no explicit alpha control measure used, alpha within 
each arm is still well-controlled due to the use of the futility criterion in the selection phase, 
as well as the adaptive nature of the sample size of part 2, based on the shrinkage estimator. 
Further simulation results for alpha for other scenarios and under a wide variety of samples 
sizes for the expansion arm will be presented in the SAP Technical Appendix. 
Table 10-3
Type I error assessment: Probability of a successful result for 
scenario where the true ORR equals 0.10 for each arm and sample 
size of the expansion arm is 50 subjects
Scenario
Arm
True ORR
Probability of significant result
1
1
0.10
0. 0102
1
2
0.10
0. 0104
1
3
0.10
0. 0136
1
4
0.10
0.0097
2
1
0.10
0. 0101
2
2
0.10
0.0111
2
3
0.10
0.0149
2
4
0.25
NA*
3
1
0.10
0.0102
3
2
0.25
NA*
3
3
0.25
NA*
3
4
0.25
NA*
*NA=not applicable in the context of type I error assessment; applicable only to the arms with true 
ORR=0.10 corresponding to the null hypothesis 
Note: No type I error rate control measures will be used to address the testing across several 
treatment arms considering that each combination treatment included in the design 
represents a stand-alone scientific question of interest leading to a stand-alone null 
hypothesis independent of other arms and thus allowing for one specific claim of statistical 
significance for the given arm.
10.4.2.2 Non-randomized section of the study
Part 1: Selection Phase
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No formal hypothesis testing will be conducted in part 1. The objective of this part of the 
study is to explore the anti-tumor activity of the combination of spartalizumab with LAG525 
agent in subjects with LAG-3 positive melanoma as measured by ORR per RECIST v1.1, 
and to expand this new arm if it shows promising efficacy.
To determine whether the arm has the potential to demonstrate clinically meaningful 
response rate, a specific efficacy probabilistic threshold should be met during the selection 
phase to advance to the expansion phase. If not, the arm will be declared as futile and won’t 
be expanded. These thresholds and probabilities are highlighted in Table 10-4.
Table 10-4
Probabilities thresholds used to declare efficacy or futility for arm
1A
Decision rule
Action
P(ORR ≥20%) ≤70%
Drop arm for futility
P(ORR ≥20%) > 70%
Efficacy signal - Consider advancing arm to expansion phase (part 2) 
The efficacy probabilistic threshold and decision criterion was determined so that a 
sufficient signal of efficacy needs to be observed before advancing this arm to the expansion 
phase and to ensure that if the true underlying ORR is 30% (clinically meaningful ORR) 
then the probability of crossing the threshold is sufficiently large (refer to Table 10-12).
To calculate the posterior probabilities, a beta-binomial posterior distribution will be used 
as shown below:
 ~ 	
( + 1,  − + 1)
Where  is the number of confirmed responses in arm 1A and  is the number of subjects 
treated. In calculation of the posterior distribution, uninformed prior Beta[1,1] will be taken 
into account. The posterior probability will be calculated based on the observed ORR using 
RECIST v1.1 criteria at interim analysis as described in Section 10.7.2.
The final decision on whether the arm will be selected for advancement to the expansion 
phase will primarily be based on the observed ORR using decision rule described above but 
other efficacy (in particular duration of response), safety, and biomarker data will be 
considered as well. Novartis may decide to not expand the arm despite the efficacy 
probability threshold crossed.
With 20 treated patients, 5 or more responders need to be observed to meet the efficacy 
probabilistic threshold as illustrated in Table 10-5. 
Table 10-5
Posterior probability ORR≥20% given observed ORR at time of 1st
interim analysis of selection phase
# of Responders out of 20
ORR observed (%)
PP(ORR≥20% | observed ORR) (%)
0
0
0.9
1
5
5.8
2
10
17.9
3
15
37.0
4
20
58.6
5
25
76.9
6
30
89.1
7
35
95.7
8
40
98.9
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# of Responders out of 20
ORR observed (%)
PP(ORR≥20% | observed ORR) (%)
9
45
99.6
10
50
99.9
Part 2: Expansion Phase
If the pre-defined efficacy probabilistic threshold is met after the selection part, the arm 1A 
might be expanded.
A second interim analysis will be conducted including 20 additional patients treated in the 
expansion phase as described in Section 4.2.2, i.e. based on the total of 40 patients. The 
objective of this second interim analysis is to support and inform decision-making on 
whether arm 1A will be : (1) further explored (2) stopped for futility . To determine whether 
arm 1A has the potential to demonstrate clinically meaningful ORR, an efficacy 
probabilistic threshold same as in part 1 will need to be crossed (see Table 10-4). If not, the 
arm 1A will be declared futile and further exploration/enrollment will be stopped in this 
combination.With 40 subjects at time of 2nd interim analysis treated in arm 1A (combining 
part 1 and part 2), 9 responders will have to be observed to cross the efficacy probabilistic
threshold (see Table 10-6 below).
Table 10-6
Posterior probability ORR≥20% given observed ORR at time of 2nd
interim analysis in expansion phase
# of responders at 2nd IA out 
of 40 pts
ORR observed (%)
PP(ORR≥20% | observed ORR) (%)
5
12.5
14.4
6
15.0
26.1
7
17.5
40.7
8
20.0
56.2
9
22.5
70.4
10
25.9
81.8
Of note, 5 responders have to be seen at the 1st interim analysis to advance in the expansion 
and reach the point of 2nd interim analysis
If efficacy probabilistic threshold is met at the 2nd interim analysis enrollment may continue 
in expansion up to approximately 80 subjects (i.e. 100 subjects in total adding the subjects 
in part 1). 
After completion of the expansion phase, the following statistical hypothesis will be tested 
based on objective response rate (ORR): 
!
The null hypothesis: ORR ≤ 15%.
!
The alternative hypothesis: ORR >15%
The null hypothesis will be formally rejected if the lower bound of exact 95% CI for ORR 
is above 15%. The primary analysis of ORR at the end of part 2 will be based on a combined 
pool of part 1 and part 2 data.
For example, assuming the scenario when 20 subjects are treated in part 1, efficacy 
probabilistic thresholds at 1st and 2nd interim analysis are met and the total of 80 subjects is 
treated in the expansion phase then among 100 subjects treated in this arm in total and 
followed sufficiently, 23 or more responses need to be observed to reject the null hypothesis. 
With those 23 responders among 100 subjects, the point estimate for ORR will be 23% with 
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an exact 95% confidence interval of (15.2, 32.5). The exact 95% CIs for potential observed 
ORR in 100 subjects are shown in Table 10-11 of Section 10.8.2.
10.4.3
Handling of missing values/censoring/discontinuations
For the computation of ORR, all confirmed responses (CR or PR) reported up to the analysis 
cut-off will be included. Subjects with no valid radiological assessment or unconfirmed 
responses will be considered as non-responders. Subjects who were non-responders before 
initiation of subsequent anti-cancer therapy will still be non-responders. In particular, 
subjects with CR or PR at the last radiological assessment prior to cut-off and no response 
at the previous assessment are by definition unconfirmed and will be considered as non-
responders for the primary analysis.
10.4.4
Supportive and Sensitivity analyses
As a supportive analysis, ORR based on RECIST v1.1 criteria as per BICR will be analyzed 
with the same analysis conventions as the primary efficacy analysis, and the treatment effect 
will be summarized by the ORR with its 95% confidence interval using the Clopper-Pearson 
method. 
As sensitivity analyses for ORR in the FAS, data from part 2 will be combined with data 
from part 1 to assess efficacy within the following sub-groups:
!
LDH (≤ ULN vs. > ULN) 
!
ECOG PS (0 vs. 1 vs. 2) 
10.5
Secondary objectives
The secondary objectives in this study are to evaluate efficacy in terms of duration of 
response (DoR), progression-free survival (PFS), disease control rate (DCR), and overall 
survival (OS) of spartalizumab in combination with novel agents in patients with previously 
treated unresectable or metastatic melanoma. DOR, PFS, and DCR will be based on 
investigator assessment and a BICR process will be conducted as a supportive analysis.
10.5.1
Key secondary objective
The key secondary objective is to determine duration of response treatment with 
spartalizumab in combination with novel agents in patients with previously treated 
unresectable or metastatic melanoma.
Duration of response (DOR) only applies to subjects whose best overall response is 
complete response (CR) or partial response (PR) according to RECIST v1.1, per local 
review. 
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. DOR will be listed and summarized by treatment group for 
all subjects in the FAS with confirmed best overall response (BOR) of CR or PR.
10.5.2
Other secondary efficacy objectives
All secondary efficacy endpoints according to RECIST v1.1 will be based on tumor 
assessments as per local assessment.
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Progression-free survival 
Progression-free survival (PFS) is defined as the interval of time (in months) between the 
date of randomization to the date of event defined as the first documented disease 
progression (according to RECIST v1.1 criteria) or death due to any cause (whichever comes 
first). If a subject has not had an event before leaving study or initiation of subsequent anti-
cancer therapy, progression-free survival is censored at the date of last adequate tumor 
assessment. Censoring of subjects who have not had an event before initiation of subsequent
anti-cancer therapy corresponds to option F(2) presented in Table 14-9 in Appendix 2 and 
is used in this study in order to obtain PFS estimates that are not confounded by subsequent 
therapies. 
PFS based on RECIST v1.1 will be analyzed in the FAS population. 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.
Disease Control Rate 
Disease control rate (DCR) is defined as the proportion of subjects with best overall response 
of CR, PR, or SD according to RECIST v1.1 criteria and as per local review.
DCR will be calculated based on the FAS. DCR and its 95% confidence interval will be 
presented for each treatment group.
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Overall Survival 
Overall survival (OS) is defined as the time from date of randomization to date of death due 
to any cause. 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).
OS will be analyzed in the FAS population. 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.
10.5.3
Safety objectives
10.5.3.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented 
by treatment group. In addition, pooled safety analysis based on all subjects will be produced.
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 dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
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. 
Additional summaries will be displayed to report deaths, all AE, AE related to study 
treatment, all SAE and SAE related to study treatment collected up to 150 days after last 
administration of spartalizumab.
Safety will be assessed based on all treated subjects; toxicities will be defined by CTCAE 
v5. Incidence and severity of adverse events, causality attribution to drug, time to event 
onset, duration of the event, its resolution and concomitant medications administered will 
be recorded. Additional safety assessments will include laboratory safety assessment, vital 
signs, and cardiac assessment. 
10.5.3.2 Adverse events 
Summary tables for AE will include only AE that started or worsened during the on-
treatment period, the treatment-emergent AE.
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 v5 
grades), type of adverse event, and 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. The list of AESI will also include 
relevant events for spartalizumab, LAG525, capmatinib, canakinumab and ribociclib which 
will be defined in the SAP.
Project-specific AESI should be defined in the case retrieval strategy (CRS) with regular 
updates whenever necessary.
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All deaths (on-treatment and post-treatment) will be summarized.
All AE, deaths and serious adverse events (including those from the pre and post-treatment 
periods) will be listed and those collected during the pre-treatment and post-treatment period 
will be flagged.
10.5.3.3 Laboratory abnormalities
Grading of laboratory values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) v5. 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 v5, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry 
tests:
!
Listing of all laboratory data with values flagged to show the corresponding CTCAE v5 
grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v5
!
Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will 
be counted only once for the worst grade observed post-baseline.
!
Shift tables using CTCAE v5 grades to compare baseline to the worst on-treatment value
For laboratory tests where grades are not defined by CTCAE v5
!
Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
to the worst on-treatment value.
 
 
10.5.3.4 Other safety data
ECG
12-lead ECG including PR, QRS, QT, QTcF, and RR intervals will be obtained for each 
subject during the study. ECG data will be read and interpreted centrally.
Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these subjects will be produced by treatment group.
Vital signs
Data on vital signs will be tabulated and listed, notable values will be flagged.
10.5.3.5 Supportive analyses for secondary objectives 
Not applicable.
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10.5.3.6 Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions, dose reductions, and permanent discontinuations of study treatments. Reasons 
for dose interruptions, dose reductions, and permanent discontinuations will be listed and 
summarized (see Section 10.3).
10.5.4
Immunogenicity
Immunogenicity will be characterized descriptively tabulating antidrug antibodies (ADA) 
prevalence at baseline and ADA incidence on-treatment. 
The impact of ADA on the occurrence of safety endpoints, efficacy endpoints, 
 
 may be assessed as appropriate. Further 
details will be provided in the SAP.
10.5.5
Biomarkers
Changes in levels, phenotype and/or activation of T cell populations in the tumor and tumor 
microenvironment will be analyzed on an on-going basis. Every effort will be made to make 
this data available for decision making purposes. Such analyses may include, but are not 
limited to CD8+ T cell infiltration and T cell activation by IHC and gene expression analysis,
and T cell repertoire/clonality by TCR-sequencing.
Biomarker-related hypotheses may be compared with results found in literature as well as 
verified with data derived from previous or concurrent clinical trials. 
 
There may be circumstances when a decision is made to stop sample collection, or not 
perform or discontinue the analysis of blood / fresh tumor biopsies due to either practical or 
strategic reasons (e.g., issues related to the quality and/or quantity of the samples or issues 
related to the assay). Under such circumstances, the number of samples may be inadequate 
to perform a rigorous data analysis and only the available data will be listed and potentially 
summarized.
10.5.5.1 Outline of the data analysis
The proposed data analysis is aligned with the secondary biomarker objectives of the 
protocol. Several biomarker parameters (Table 10-7) will be periodically analyzed for each 
subject.
Table 10-7
Parameter definitions for categorization of biomarker outcome at 
subject level
Biomarker parameter
Analysis
Criteria for 
favorable biomarker 
result
Number of tumor infiltrating T 
cells (TIL)
Changes of CD8+ T cell numbers as assessed 
by IHC in tumor/ tumor microenvironment with 
treatment
Increase
Activation level of TIL
Change of T cell activation marker level(s) as 
assessed by IHC in tumor/tumor 
microenvironment with treatment
Increase
TIL repertoire/specificity of T 
cell response to tumor
TCR clonality changes as assessed by TCR-
sequencing in tumor/tumor microenvironment 
with treatment
Increase
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Biomarker parameter
Analysis
Criteria for 
favorable biomarker 
result
Changes in immune response 
gene expression signatures
Changes in expression of genes and/or gene 
signatures as assessed by mRNA analysis in 
tumor/tumor microenvironment with treatment
Defined per 
gene/gene signature
The following analyses may be used to determine the biomarker parameters for supporting
the decision-making criteria to expand or not an arm in part 2:
!
Assessment changes from baseline of the number of CD8+ T cells present in the tumor
and/or tumor microenvironment for spartalizumab in combination with novel agents
!
Assessment of changes from baseline of T cell repertoire/clonality in the tumor and/or 
tumor microenvironment as assessed by TCR sequencing when combining 
spartalizumab with novel agents 
!
Assessment of changes from baseline of T cell activation markers as assessed by IHC 
present in the tumor and/or tumor microenvironment as assessed by IHC when 
combining spartalizumab with novel agents 
!
Assessment of changes from baseline of mRNA levels for expression of genes and/or 
gene signatures corresponding to immune activation in the tumor and/or tumor 
microenvironment
The overall biomarker result for each subject will be formulated according to the available 
biomarker data and by determining if each parameter is favorable or not according to the 
indicated criteria in Table 10-7. If an individual subject has two or more favorable 
parameters from Table 10-7 then that subject will be considered to have a favorable
biomarker profile. For each arm, the proportion of subjects with a favorable biomarker 
profile (pFBP) are then defined as the number of subjects with favorable biomarker profiles 
divided by the number of subjects enrolled into the arm which are included in the “paired” 
biomarker analysis set for that particular interim analysis. The “paired” biomarker analysis 
set include all subjects in the safety set with an evaluable baseline tumor biopsy sample and 
at least one post-baseline tumor biopsy sample with evaluable results for 2 or more 
biomarker parameters listed in Table 10-7. If other biomarker data are available at the time 
of an interim analysis, these may also be considered. More details will be provided in the 
Statistical Analysis Plan or Biomarker Analysis Plan.
10.5.5.2 Data handling principles
Data preprocessing and transformations will be described in detail in the Programming 
Dataset Specifications document.
10.5.5.3 Data analysis principles
10.5.5.3.1
Analysis sets
Unless otherwise specified, all statistical analyses of biomarker data will be performed on 
subjects with biomarker data (Biomarker analysis set).
10.5.5.3.2
Basic tables, figures and listings
Unless otherwise stated, as project standard, all biomarker data collected will be listed and 
summarized. In the event of the collection of large biomarker data such as next generation 
sequencing, gene expression or protein expression panels, some pragmatic considerations 
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will be applied to limit output, as these may easily top thousands, if not tens of thousands of 
pages offering little to no scientific value.
Depending on the endpoint of interest, graphical displays such as box plots or strip plots 
may be used to assess the relationship of different biomarkers with clinical benefit. These 
may be separated by treatment arm and include either baseline or change from baseline 
values, where applicable.
For categorical markers such as mutation status, 2x2 contingency tables may be used to 
assess the relationship with clinical benefit and or Kaplan–Meier curves may be generated 
given the number of number of PFS events warrant such an assessment.
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10.7
Interim analysis
10.7.1
Randomized section of the study
Part 1: Selection phase
As described in Section 4.2.1, the first interim analysis is planned for ORR once at least ten 
subjects have been randomized into each of the three initial treatment groups (arm 1, arm 2, 
arm 3), and have either completed two post-baseline tumor assessments or have 
discontinued study treatment. Subsequent interim analyses will be conducted approximately 
every five months thereafter since that is the scheduled timeframe to have two post-baseline 
scans. The first interim analysis for arm 4 (ribociclib and spartalizumab) will be synchonized 
with the subsequent planned interim analyses for the other arms and will occur when at least 
10 subjects have been randomized to that arm, and have either completed two post-baseline 
tumor assessments or have discontinued study treatment. Enrollment and assessment at 
subsequent interim analyses for each treatment group will continue until the criteria for 
futility or advancement into the expansion phase have been met, or 45 subjects have been 
randomized into a treatment group using decision rules presented in Section 10.4.2.1.
Of note, interim analyses will continue to be performed in the randomized section of the 
study at the pre-defined frequency until a clinical decision (e.g. arm declared futile or 
efficacy probabilistic threshold crossed) on each arm in part 1 has been made. Even if 
declared futile, combination arms will be analyzed at subsequent interim analyses until all 
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subjects have been reported at least once (i.e. had a minimum follow-up of 20 weeks). 
Additional descriptive analyses may be performed if required.
Part 2: Expansion phase
No formal interim analysis is planned for this part of the trial. The first primary analysis will 
be performed once the first expanded arm has fully enrolled and also after all patients 
randomized had at least 9 months of follow-up. This timing would allow for a potential 
minimum duration of response of 6 months for all subjects randomized. Formal hypothesis 
testing of the primary endpoint (as described in Section 10.4.2.1) will be performed at the 
primary analysis. The final analysis will be performed at the end of the study as described 
in Section 4.3.
10.7.2
Non-randomized section of the study
Part 1 : Selection phase 
As described in Section 4.2.2, there will be one interim analysis planned for ORR once all 
patients treated in arm 1A have either completed two post-baseline tumor assessments or 
have discontinued study treatment. 
Part 2: Expansion phase
A 2nd interim analysis will be conducted once 40 patients have been treated within selection 
and expansion phases and have either completed two post-baseline tumor assessments or 
have discontinued study treatment.The primary analysis of this non-randomized section of 
the study will be performed once all patients treated in arm 1A had at least 9 months of 
follow-up. This timing would allow for a potential minimum duration of response of 6 
months for all subjects enrolled. Formal hypothesis testing of the primary endpoint (as 
described in Section 10.4.2.2) will be performed at this primary analysis. The final analysis 
will be performed at the end of the study as described in Section 4.3.
10.8
Sample size calculation
10.8.1
Randomized section of the study
In this section, sample size will be presented based on specific potential scenarios for true 
ORR in the first four combination arms evaluated. In particular, for selection phase (part 1), 
since one can consider a wide variety of potential true ORR scenarios, the sample size will 
not be based on an exact calculation leading to one fixed number, but will instead be 
characterized by simulation based on average number of subjects enrolled into these arms 
under each individual scenario for true ORR. It is important to emphasize that the true 
underlying efficacy activity (in terms of ORR) of the four initial arms will have a substantial 
bearing on the total sample size needed in part 1. Subsequently, and given the adaptive 
nature of the study design, the sample size needed in expansion phase (part 2) to ensure 
sufficient power will depend on the ORR observed in part 1 and in particular on the rate 
observed in the arm that qualifies for expansion to part 2.
The sample size calculation for parts 1 and 2 were performed using SAS 9.4 software, based 
on the probabilities of first determining a efficacious treatment and a futile (non-efficacious) 
treatment in the selection phase (part 1), and then determining the number of subjects needed 
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to reject the null hypothesis (part 2). The following assumptions were made in the estimation 
of the required sample size:
Part 1: Selection phase:
Simulation based determination of the sample size needed for part 1 considers the following:
!
The interim analyses will be performed with frequency described in Section 10.7.1.
!
Decisions rules for declaring an efficacious or non-efficacious (futile) treatment 
described in Section 10.4.2.1 are used at each of the interim analyses
!
Considers at least two interim analyses for the first three arms before the initiation of 
an interim analysis for arm 4 (ribociclib + spartalizumab)
!
Takes into account the actual randomization in the first three arms for the first interim 
analysis (13 subjects for arm 1 [LAG525 + spartalizumab], 10 subjects for arm 2
[capmatinib + spartalizumab], and 12 subjects for arm 3 [canakinumab + 
spartalizumab])
!
Allows for a random allotment of subjects (between 10 and 16) in arm 4 before the 
first interim analysis is conducted for that arm. Random allotment is necessary since 
the timing of the first interim analysis in this combination arm is controlled by the 
timing of the previous interim analyses before this arm begins randomization. 
!
Enrolling a cap of 45 subjects for combination arms that cannot be selected either to be 
an efficacious or non- efficacious treatment.
!
An accrual rate of 8 subjects per month
!
1000 simulations for each scenario of true ORR
Taking into account the efficacy/futility criterions discussed in Section 10.4.2.1, below are 
results of simulations assuming a variety of scenarios for the ‘true’ underlying ORR. Table 
10-10 below presents average sample size (‘N’) along with percentages for declaring ‘futile’ 
and ‘promising/efficacious’ combination arms.
Table 10-10
Simulation based sample size (N) with percentages for declaring 
‘futile’ and ‘efficacious’ combination arms in the selection phase
Scenario
Arm
True ORR
Avg. N
Futility %
Efficacious %
1
1
0.10
31.6
75.35
4.57
2
0.10
25.8
75.55
8.63
3
0.10
27.7
72.91
11.53
4
0.10
30.6
74.10
7.06
2
1
0.10
31.5
75.11
4.51
2
0.10
25.9
75.77
8.59
3
0.10
27.7
72.92
11.74
4
0.25
26.5
5.99
71.24
3
1
0.10
32.6
75.11
4.29
2
0.25
23.7
7.45
73.91
3
0.25
21.6
5.40
78.86
4
0.25
26.5
5.52
71.67
4
1
0.25
28.1
4.82
71.07
2
0.05
19.5
97.38
0.97
3
0.07
25.8
89.85
4.90
4
0.15
32.7
38.17
21.91
5
1
0.25
29.2
4.40
69.59
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Scenario
Arm
True ORR
Avg. N
Futility %
Efficacious %
2
0.30
20.3
2.94
89.50
3
0.35
15.7
0.67
97.62
4
0.25
26.6
5.66
70.84
6
1
0.17
34.2
26.73
28.70
2
0.19
27.6
22.24
44.67
3
0.18
27.4
23.11
46.05
4
0.16
31.7
33.27
26.97
The simulation results for part 1 demonstrate that in an efficacious arm with the true ORR 
of, for example 25%, the sample size will be approximately 22-29 subjects. In an arm with 
even higher efficacy, e.g. ORR of 35%, the sample size will be approximately 16 subjects 
since this arm will have a higher likelihood of being stopped earlier and declared as 
efficacious. On the other hand, an arm that is clearly futile, e.g. an arm with the true ORR 
of 5%, the sample size will be approximately 20 subjects. Based on the simulations results 
presented in Table 10-10, the expected average sample size in part 1 for all four arms 
together range between 92 and 121 subjects. The maximum sample size in part 1 for all four 
arms together is 180 subjects corresponding to the scenario when all four arms will be 
capped at 45 subjects. 
The simulation results also demonstrate that decision rules described in Section 10.4.2.1 are 
adequate to detect efficacious and futile arms with high probabilities. For example, an arm
with the true ORR of 25% will be declared as efficacious with approximately 70-79% 
probability. Similarly, an arm with the true ORR of, for example, 10% will be declared as 
futile with probability of 73-76% and declared as efficacious with probability of 4-12%. Of 
note, the probabilities for efficacy and futility estimated for each scenario and each arm do 
not add up to 100% since there is a possibility for each particular row in the table that given 
arm will fail to satisfy either of the criteria and its enrollment will subsequently be stopped 
using the cap of 45 subjects. Further simulation results for the selection phase will be
summarized in the SAP Technical Appendix.
Part 2: Expansion phase
Considering the null hypothesis value of 10% and targeted response rate of 25% (see Section 
10.4.2.1), the standard approach to sample size and power calculations that would not 
condition on part 1 result, would lead to the following sample sizes for part 2; n = 64, 49, 
40, would provide power of 90%, 80%, and 70% respectively to reject the null hypothesis 
assuming the targeted response rate.
However, a more meaningful approach would be to utilize the information obtained in part 
1 and then condition on the part 1 results to determine the sample size for part 2 with an 
adaptive approach. At the time when a decision to expand one ‘promising’ arm is taken (at 
any of the preplanned interim analyses as discussed in Section 4.2.1), the part 2 sample size 
for this ‘promising’ arm will be determined using a Bayesian predictive power approach. 
Predictive power is defined as probability of obtaining a statistically significant result based 
on the combined data from part 1 and part 2 for the selected ‘promising’ arm. The decision 
about the statistical significance is based on the lower bound of exact 95% CI for ORR as 
described in Section 10.4.2.1. The value used for conditioning in the predictive power 
calculation will be calculated on the basis of a shrinkage estimator of ORR. Use of the 
shrinkage estimator is considered conservative since it takes into account part 1 ORR results 
from all arms eligible for selection phase assessment (since at least one of the 1st 3 arms 
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could advance to part 2 before the 4th arm has enough subjects for assessment) and thus 
reduces bias of the ORR estimate of the ‘promising’ arm that might arise from the selection 
process that can lead to random high or random low values. The part 2 sample size for 
‘promising’ arm will then be determined such that predictive power is at least 70%.
A more detailed description of steps needed to calculate the sample size of part 2 is provided 
below:
!
Observed ORR for the ‘promising’ arm as well as observed ORR in the other selection 
phase eligible arms will be calculated
!
Shrinkage estimator for the ‘promising’ arm as well as for the other selection phase 
eligible arms will be calculated based on 20000 iterations of the Markov chain Monte 
Carlo (MCMC).
!
Shrinkage estimator for the ‘promising’ will be used as a value used for conditioning 
of the predictive power calculation
!
Predictive power distribution is then formed based on the following:
!
Distribution of the observed ORR adjusted by the shrinkage estimator evaluated 
using MCMC
!
From this distribution, for a given number of responses and subjects in part 1, 
calculating the number of responses needed in part 2 to reject the null hypothesis 
for a predefined alpha at final analysis
!
For each sample of MCMC, the corresponding power is calculated. Predictive 
power is then the average of power over the MCMC samples.
!
For the ‘promising’ arm, predictive power will be calculated for several sample size 
scenarios.
!
The sample size for the efficacious arm to be enrolled in part 2 will be chosen such that 
the mean predictive power calculated from the 1000 simulations is at least 70%
Based on the simulation results (that will be further detailed in the SAP Technical Appendix, 
a sample size of 50 subjects in part 2 for the selected efficacious arm for which the true ORR 
is 25% is sufficient to achieve the predictive power of at least 70%.
In summary, a maximum of 230 subjects could be enrolled into the study, with 
approximately a maximum of 180 subjects in the selection phase (if all four combination 
arms enroll the maximum of 45 subjects) and approximately 50 subjects in the expansion 
phase (assuming that only one of the four initial combination arms will be expanded.
However, based on the above assumptions and the current enrollment already in this trial, a 
total of approximately 142 to 171 subjects (approximately 92-121 subjects in part 1 for four 
arms and approximately 50 subjects in part 2 assuming just one expanded arm) will be 
expected to be enrolled in order to analyze data from the selection phase (part 1) and 
expansion phase (part 2) of this study. With this calculation, it is important to note that the 
true efficacy activity of the four initial arms will have a substantial bearing on the total 
sample size. For instance and considering the most extreme futility example, if all four arms 
meet the criterion for futility at the first interim analysis in part 1 and the fourth arm is
assessed at its first interim analysis when 10 subjects are randomized to that arm, the total 
sample size of part 1 would be approximately 45, and no subjects would be enrolled into 
part 2. For another example, if the true efficacy activity is similar to scenario 5 presented in 
Table 10-10, for the case where the true ORR is 0.35 in part 1, only 16 subjects will be 
needed in part 1, and approximately 20 subjects will be needed in part 2 to have adequate 
predictive power.
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Finally, this sample size takes into account only the three arms enrolled into the study. If 
more arms are eventually added to the study, then the sample size will increase accordingly.
Taking into account the first three initial arms and an enrollment rate of approximately 8 
subjects per month, as well as 20 weeks to reach the second post-baseline assessment, the 
first interim analysis is expected to occur at approximately 9 months after the start of the 
study. Subsequent interim analyses will occurr approximately every 5 months afterwards 
until all arms either advance, stop, or reach the cap numbers of subjects in the selection 
phase. The first primary ORR analysis is estimated to occur approximately 28 months after 
the start of the study (taking into account the minimum follow-up time needed to assess 
DoR).
Shrinkage estimator
The estimates of ORR observed in part 1 can potentially be biased due to random high or 
random low values and thus the arm(s) to be expanded can potentially be selected based on 
a random-high ORR observed in part 1. Consequently the estimated sample size and power 
can potentially be affected as well. Therefore, a shrinkage estimator based on a hierarchical 
model that takes into account the ORR from all the combination arms will be used. The 
shrinkage estimator for ORR will be calculated using the observed ORR from each available 
arm at the time when an efficacious combination arm can be determined in part 1 so that 
predictive power can be determined. 
For the shrinkage estimate the ORR for each treatment arm is determined by the hierarchical 
model of the logit of ORR:
ℎ
 	
	 =
(	
0 + 	
{		})
1 + (	
0 + 	
{		})
where beta0 is the mean logit ORR amongst the treatment, and delta{trt} is the random 
effect of the hierarchical model between arms .
The prior distribution for beta0 
	
0 ~ 
 (−1, "
 = 0.25)
where -1 is the mean of the normal distribution with variance of 0.25. This is equivalent to 
median ORR rate of about 0.25. 
For the random effects of the hierarchical model between treatments, the parameters to 
incorporate the random effects are shown below:
	
 ~ 
(0, "
 = 2)
2 ~ 

(2,  = 1, & = 2)
where 2 is the shape parameter of the inverse-gamma distribution and 1 is the scale 
parameter of the inverse-gamma distribution with truncation when the distribution reaches 
a value of 2.
With these priors, the shrinkage estimator model is developed with the following equations:
~ 	'(	
0 + 	
)
 ~ 
( = (,  = )
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Parameters from the model to be used in the shrinkage estimator will be assessed using a 
Markov chain Monte Carlo (MCMC) method with 20000 iterations after a burn-in period of 
2000 iterations.
Further considerations for the execution of the expansion phase will be presented in the SAP 
Appendix.
10.8.2
Non-randomized section of the study
Using a standard (naïve) sample size approach for a single stage study with ORR as the 
primary endpoint : to ensure 80% power to reject H0 ORR≤15% and considering clinically 
meaningful ORR of 30%, 80 subjects would be needed. However, given the proposed 3-
stage design, the power and sample size calculations need to be adjusted as discussed below.
In arm 1A included in the non-randomized section of the study, 20 patients will be treated
in the selection phase. If based on the data from those 20 patients the efficacy probabilistic
threshold presented in Section 10.4.2.2 is met, up to 80 additional subjects will be treated in 
the arm 1A in the expansion phase (assuming the efficacy probabilistic threshold is met at 
the 2nd interim analysis as well).
The exact 95% CIs for various sample sizes and observed ORR are shown in Table 10-11
below. 
Table 10-11
Exact binomial 95% confidence intervals for various sample size in 
expansion phase and observed ORR
Sample size 
(N=Nsel+Nexp)
No of responders
Observed ORR
95% exact CI (%)
50
11
22.0
11.5, 36.0
50
12
24.0
13.1, 38.2
50
13
26.0
14.6, 40.3
50
14
28.0
16.2, 42.5
50
15
30.0
17.9, 44.6
70
14
20.0
11.4, 31.3
70
15
21.4
12.5, 32.9
70
16
22.9
13.7, 34.5
70
17
24.3
14.8, 36.0
70
18
25.7
16.0, 37.6
100
20 
20.0
12.7, 29.2
100
23
23.0
15.2, 32.5
100
25 
25.0
16.9, 34.7
100
30 
30.0
21.2, 40.0
Eighty patients treated in the expansion phase, resulting in 100 subjects in total when 
combining with subjects treated in the selection phase, provide sufficient power (>70%) to 
reject the null hypothesis of ORR ≤ 15% assuming the true ORR is 30% (refer to Table 10-
12).
Taking into account the efficacy/futility criteria discussed in Section 10.4.2.2 of the protocol, 
the Table 10-12 below shows probability of crossing efficacy probabilistic threshold (being 
“efficacious”) at first and second interim analysis and probability of a positive study with 
statistically significant result after completion of expansion phase (e.g. not stopped at 
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selection nor at 2nd interim analysis for futility and success criteria met at the end of 
expansion phase) under different underlying true ORR. 
Table 10-12
Operating characteristics for different sample size in expansion 
and under true underlying ORR
Sample size
True 
ORR (%)
Efficacious 
(%) at 1st
interim 
analysis in 
selection*
Efficacious (%) at 
2nd interim 
analysis among 
40 subjects **
Probability of 
positive study 
(power) *** at the 
end of expansion
Selection
Expansion
Total
20
30
50
20
37.0
27.2
9.0
25
58.5
52.1
30.7
30
76.2
73.5
59.3
40
94.9
94.7
93.2
20
60
80
20
37.0
27.2
10.6
25
58.5
52.1
38.4
30
76.2
73.5
68.7
40
94.9
94.7
94.7
20
80
100
20
37.0
27.2
14.1
25
58.5
52.1
45.0
30
76.2
73.5
72.1
40
94.9
94.7
94.7
* Post. Prob (ORR≥20% | observed ORR)>70%, under true ORR xx%
** Post.Prob (ORR≥20%| observed ORR)>70% at 2nd IA and efficacy threshold met at selection
*** Probability to cross efficacy thresholds at 1st IA in selection and 2nd IA in expansion and 
probability to reject H0 at the end of expansion over the combined selection and expansion 
treated subjects
The operating characteristics with 20 subjects treated in selection phase and 40 subjects at 
time of 2nd interim analysis demonstrate that decision rules described in Section 10.7.2 are 
adequate to meet efficacy probabilistic threshold with high probability:
-
For example, if the true ORR is 30%, the efficacy probabilistic threshold will be
crossed at the first interim analysis at the end of selection and qualify the arm for 
expansion with approximately 76% probability. Under the same underlying true 
ORR, the probability of crossing the efficacy probabilistic threshold at the 1st and 
2nd interim analysis in selection and expansion parts is approximately 74%.
-
When the true ORR is 20%, the efficacy probabilistic threshold will be crossed at 
the first interim analysis with approximately 37% (e.g futile with 63% probability) 
and with 27% at time of 2nd interim analysis (e.g. futile with 73% probability).
If the efficacy probabilistic thresholds are crossed at selection and 2nd interim analysis (e.g. 
at least 5 responders over 20 subjects in selection and at least 9 responders over 40 subjects 
in selection and expansion phases are observed), under a true ORR of 30%, the probability 
of rejecting null hypothesis at the end of the expansion with 80 patients in expansion phase
(e.g. 100 patients in total) is approximately 72%. This sample size provides adequate power 
to reject H0 and robust results for safety to allow adequate risk-benefit assessment.
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10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is 
required to sign a protocol signature page confirming his/her agreement to conduct the study 
in accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRB/IEC/REB and regulatory authorities as required.
11.3
Informed consent procedures
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent.
If applicable, in cases where the subject's representative(s) gives consent (if allowed 
according to local requirements), the subject must be informed about the study to the extent 
possible given his/her understanding. If the subject 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 (i.e. all 
of the procedures described in the protocol). The process of obtaining informed consent 
must be documented in the subject source documents. The date when a subject’s Informed 
Consent was actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the 
investigator must be agreed to by Novartis before submission to the IRB/IEC/REB, and a 
copy of the approved version must be provided to the Novartis monitor after IRB/IEC/REB 
approval.
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 subject 
informed consent and should be discussed with the subject 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 subject.
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Women of child bearing potential should 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 requirement 
for the duration of the study. If there is any question that the subject will not reliably comply, 
they should not be entered in the study.
Male subjects 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.
The following informed consents 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. A separate main study consent is used 
for the non-randomized section of the study that includes only arm 1A.
!
Pregnancy Outcomes Reporting Consent for female subjects or the female partners 
of any male subjects who took study treatment
 
 
 
 
 
 
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the 
clinical study agreement. Specific conditions for terminating the study are outlined in 
Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this 
protocol will be posted on the publicly accessible database, e.g. clinicaltrials.gov before 
study start. In addition, results of interventional clinical trials in adult subjects are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 
year of study completion (i.e., LSLV), those for interventional clinical trials involving 
pediatric subjects within 6 months of study completion.
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines 
of the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
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present poster or oral presentation at scientific congress; however, there will be no 
honorarium provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored 
Research, please refer to novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, 
in compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
Novartis-sponsored study, each site will permit authorized representatives of the sponsor(s) 
and regulatory agencies to examine (and when required by applicable law, to copy) clinical 
records for the purposes of quality assurance reviews, audits and evaluation of the study 
safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. 
Examples of these original documents and data records include, but are not limited to, 
hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ diaries 
or evaluation checklists, pharmacy dispensing records, recorded data from automated 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision 
of the site Principal Investigator. The study case report form (CRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, 
completeness, legibility, and timeliness of the data reported in the CRFs and all other 
required reports. Data reported on the CRF, that are derived from source documents, should 
be consistent with the source documents or the discrepancies should be explained. All data 
requested on the CRF must be recorded. Any missing data must be explained. Any change 
or correction to a paper CRF should be dated, initialed, and explained (if necessary) and 
should not obscure the original entry. For electronic CRFs an audit trail will be maintained 
by the system. The investigator should retain records of the changes and corrections to paper 
CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take measures 
to prevent accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
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11.7
Confidentiality of study documents and subject records
The investigator must ensure anonymity of the subjects; subjects must not be identified by 
names in any documents submitted to Novartis. Signed informed consent forms and subject
enrollment log must be kept strictly confidential to enable subject identification at the site.
11.8
Audits and inspections
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities.
11.9
Financial disclosures
Financial disclosures should be provided by study personnel who are directly involved in 
the treatment or evaluation of subjects at the site - prior to study start.
12
Protocol adherence
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the 
study to request approval of a protocol deviation, as no authorized deviations are permitted. 
If the investigator feels a protocol deviation would improve the conduct of the study this 
must be considered a protocol amendment, and unless such an amendment is agreed upon 
by Novartis and approved by the IRB/IEC/REB it cannot be implemented. All significant 
protocol deviations will be recorded and reported in the CSR.
12.1
Amendments to the protocol
Any change or addition to the protocol can only be made in a written protocol amendment 
that must be approved by Novartis, Health Authorities where required, and the 
IRB/IEC/REB. Only amendments that are required for subject safety may be implemented 
prior to IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the 
safety of any subject included in this study, even if this action represents a deviation from 
the protocol. In such cases, Novartis should be notified of this action and the IRB/IEC at the 
study site should be informed according to local regulations (e.g. UK requires the 
notification of urgent safety measures within 3 days) but not later than 10 working days.
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13
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14
Appendices
14.1
Appendix 1: AJCC Melanoma Staging System (Edition 8)
Refer to the full publication for further details (Gershenwald et al 2017).
Table 14-1
Definition of Primary Tumor (T)
T Category
Thickness
Ulceration status
TX Primary tumor thickness cannot be assessed (eg, diagnosis by curettage)
T0
No evidence of primary tumor (eg, unknown primary or completely regressed melanoma)
Tis 
(melanoma in situ)
T1
≤1.0 mm
Unknown or unspecified
    T1a
<0.8 mm
Without ulceration
    T1b
<0.8 mm
With ulceration
0.8-1.0 mm
With or without ulceration
T2
>1.0-2.0 mm
Unknown or unspecified
   T2a
>1.0-2.0 mm
Without ulceration
   T2b
>1.0-2.0 mm
With ulceration
T3
>2.0-4.0 mm
Unknown or unspecified
    T3a
>2.0-4.0 mm
Without ulceration
   T3b
>2.0-4.0 mm
With ulceration
T4
>4.0 mm
Unknown or unspecified
   T4a
>4.0 mm
Without ulceration
   T4b
>4.0 mm
With ulceration
Table 14-2
Definition of Regional Lymph Node (N)
Extent of regional lymph node and/or lymphatic metastasis
N Category
No. of tumor-involved regional lymph nodes
Presence of in-
transit, satellite, 
and/or microsatellite 
metastases
NX
Regional nodes not assessed (eg, sentinel lymph node [SLN] 
biopsy not performed, regional nodes previously removed for 
another reason); Exception: pathological N category is not 
required for T1 melanomas, use clinical N information
No
N0
No regional metastases detected
No
N1
One tumor-involved node or any number of in-transit, satellite, 
and/or microsatellite metastases with no tumor-involved nodes
   N1a
One clinically occult (ie, detected by SLN biopsy)
No
   N1b
One clinically detected
No
    N1c
No regional lymph node disease
Yes
N2
Two or 3 tumor-involved nodes or any number of in-transit, 
satellite, and/or microsatellite metastases with one tumor-involved 
node
    N2a
Two or 3 clinically occult (ie, detected by SLN biopsy)
No
     N2b
Two or 3, at least one of which was clinically detected
No
   N2c
One clinically occult or clinically detected
Yes
N3
Four or more tumor-involved nodes or any number of in-transit, 
satellite, and/or microsatellite metastases with 2 or more tumor-
involved nodes, or any number of matted nodes without or with in-
transit, satellite, and/or microsatellite metastases
    N3a
Four or more clinically occult (ie, detected by SLN biopsy)
No
   N3b
Four or more, at least one of which was clinically detected, or the 
presence of any number of matted nodes
No
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Extent of regional lymph node and/or lymphatic metastasis
N Category
No. of tumor-involved regional lymph nodes
Presence of in-
transit, satellite, 
and/or microsatellite 
metastases
   N3c
Two or more clinically occult or clinically detected and/or presence 
of any number of matted nodes
Yes
Table 14-3
Definition of Distant Metastasis (M)
M criteria
M Categoryb
Anatomic site
LDH level
M0
No evidence of distant metastasis
Not applicable
M1
Evidence of distant metastasis
See below
    M1a
Distant metastasis to skin, soft tissue including 
muscle, and/or nonregional lymph node
Not recorded or unspecified
         M1a(0)
Not elevated
         M1a(1)
Elevated
   M1b
Distant metastasis to lung with or without M1a sites of 
disease
Not recorded or unspecified
       M1b(0)
Not elevated
         M1b(1)
Elevated
    M1c
Distant metastasis to non-CNS visceral sites with or 
without M1a or M1b sites of disease
Not recorded or unspecified
         M1c(0)
Not elevated
         M1c(1)
Elevated
       M1d
Distant metastasis to CNS with or without M1a, M1b, 
or M1c sites of disease
Not recorded or unspecified
         M1d(0)
Not elevated
         M1d(1)
Elevated
CNS indicates central nervous system; LDH, lactate dehydrogenase. b Suffixes for M category: (0) LDH not 
elevated, (1) LDH elevated. No suffix is used if LDH is not recorded or is unspecified.
Table 14-4
AJCC pathological (pTNM) prognosis stage groups
When T is...
And N is...
And M is...
Then the pathological stage group is...
Tis 
N0a
M0
0
T1a
N0
M0
IA
T1b
N0
M0
IA
T2a
N0
M0
IB
T2b
N0
M0
IIA
T3a
N0
M0
IIA
T3b
N0
M0
IIB
T4a
N0
M0
IIB
T4b
N0
M0
IIC
T0
N1b, N1c
M0
IIIB
T0
N2b, N2c, N3b or 
N3c
M0
IIIC
T1a/b-T2a
N1a or N2a
M0
IIIA
T1a/b-T2a
N1b/c or N2b
M0
IIIB
T2b/T3a
N1a-N2b
M0
IIIB
T1a-T3a
N2c or N3a/b/c
M0
IIIC
T3b/T4a
Any N ≥N1
M0
IIIC
T4b
N1a-N2c
M0
IIIC
T4b
N3a/b/c
M0
IIID
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When T is...
And N is...
And M is...
Then the pathological stage group is...
Any T, Tis
Any N
M1
IV
a Pathological stage 0 (melanoma in situ) and T1 do not require pathological evaluation of lymph nodes to 
complete pathological staging; use clinical N information to assign their pathological stage.
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14.2
Appendix 2: Guidelines for Response, Duration of Overall 
Response, TTF, TTP, Progression-Free Survival and Overall 
Survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
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
Authors (Version 3.2):
 
 
Authors (Version 3.1):
 
 
Authors (Version 3):
 
 
Authors (Version 2):
 
 
Authors (Version 1):
 
14.2.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for 
a consistent and efficient analysis of efficacy for oncology studies in solid tumors. This 
document is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the 
revised RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.2.2 and the definition of best response in
Section 14.2.3.1 are based on the RECIST 1.1 criteria but also give more detailed 
instructions and rules for determination of best response. Section 14.2.3.2 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 14.2.4 of this guideline describes data handling and programming rules. This section 
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is to be referred to in the SAP (Statistical Analysis Plan) to provide further details needed 
for programming.
14.2.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000) and revised 
RECIST guidelines (version 1.1) (Eisenhauer et al 2009).
14.2.2.1 Definitions
14.2.2.1.1
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.
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 ∀15 mm in short axis can 
be considered for selection as target lesions. Lymph nodes measuring ∀10 mm and <15 
mm are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.
!
Cystic lesions: 
-
Lesions that meet the criteria for radiographically defined simple cysts (i.e., 
spherical structure with a thin, non-irregular, non-nodular and non-enhancing wall, 
no septations, and low CT density [water-like] content) should not be considered 
as malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.
-
‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same subject, these are preferred 
for selection as target lesions.
!
Non-measurable lesions - all other lesions are considered non-measurable, including 
small lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph 
nodes with ∀10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., 
blastic bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable by 
reproducible imaging techniques.
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14.2.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the subject 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 subjects be excluded from trials where the main focus is 
on the Overall Response Rate (ORR). Guidance on how subjects with just non-measurable 
disease at baseline will be evaluated for response and also handled in the statistical analyses 
is given in Section 14.2.3.2.8.
14.2.2.1.3
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 anti-tumor effect of a treatment.
!
For optimal evaluation of subjects, 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 subject is known to have a 
medical contraindication to CT contrast or develops a contraindication during the trial, 
the following change in imaging modality will be accepted for follow up: a non-
contrast CT of chest (MRI not recommended due to respiratory artifacts) plus contrast-
enhanced MRI of abdomen and pelvis.
!
A change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use 
or vice-versa, regardless of the justification for the change) or a 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 
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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.
!
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 subject 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.
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14.2.2.2 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).
14.2.2.2.1
Minimum target lesion size at baseline
!
Nodal target: See Section 14.2.2.1.1.
!
Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 
10 mm in longest diameter. See Section 14.2.2.1.1.
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 a group and recorded as a single item (i.e. multiple liver metastases). Each 
non-target lesion identified at baseline must be followed at each subsequent evaluation 
and documented on eCRF.
14.2.2.3 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-5) and non-target lesions (Table 14-6) identified at baseline. These 
evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-7) as well as the presence or absence of new 
lesions.
14.2.2.3.1
Follow-up and recordings 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.
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Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are 
not expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead 
of the actual measurement. This default value is derived from the 5 mm CT slice thickness 
(but should not be changed with varying CT slice thickness).Actual measurement should be 
given for all lesions larger than 5 mm in short axis irrespective of slice 
thickness/reconstruction interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the 
image reconstruction interval. Lesions smaller than twice the reconstruction interval are 
subject to substantial “partial volume” effects (i.e., size may be underestimated because of 
the distance of the cut from the longest diameter; such lesions may appear to have responded 
or progressed on subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 
mm, instead of the actual measurement. This default value is derived from the 5 mm CT 
slice thickness (but should not be changed with varying CT slice thickness). Actual 
measurement should be given for all lesions larger than 5 mm in longest diameter 
irrespective of slice thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size 
(e.g., borders of the lesion are confounded by neighboring anatomical structures), no 
measurement should be entered and the lesion cannot be evaluated.
14.2.2.3.2
Determination of target lesion response
Table 14-5
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
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Response Criteria
Evaluation 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 14.2.2.2.
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 14-5 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 subjects who have not achieved target response of CR. For 
subjects who have achieved CR, please refer to last bullet in this section.
!
For those subjects 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.
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!
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.
!
Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.
!
Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions.
!
Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 
mm and there is at least 20% increase in sum of the diameters of all nodal target 
lesions relative to nadir with at least 5 mm increase in the absolute sum of the 
diameters. 
!
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 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.
14.2.2.3.3
Determination of non-target lesion response
Table 14-6
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.
1. 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..
2. 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)
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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. ∀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 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 14.2.2.3.2 for assigning PD following a CR for the non-target lesion response 
in the presence of non-target lesions nodal lesions should be applied.
14.2.2.3.4
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
!
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 subject in which case the response should be UNK, as for any of this subject's 
assessment (see Section 14.2.2.3.5).
!
A lymph node is considered as a “new lesion” and, therefore, indicative of 
progressive disease if the short axis increases in size to ∀10 mm for the first time in 
the study plus 5 mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible 
for ‘new’ disease).
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14.2.2.3.5
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 14-7.
Table 14-7
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 14.2.2.3.3.
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.
14.2.3
Efficacy definitions
The following definitions primarily relate to subjects who have measurable disease at 
baseline. Section 14.2.3.2.8 outlines the special considerations that need to be given to 
subjects with no measurable disease at baseline in order to apply the same concepts.
14.2.3.1 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 subject'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.
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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 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 
where confirmation required or one determination of CR prior to progression where 
confirmation not required
!
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) > 11 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 11 weeks or early progression within the first 12 weeks)
The time durations specified in the SD/PD/UNK definitions above are based on the first 12-
week tumor assessment frequency taking into account time windows for assessment. E.g. if 
the first assessment occurs at week 12 with a time window of +/- 7 days, a BOR of SD would 
require a SD or better response longer than 11 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 subject 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 subject has a single PR (∀30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from 
baseline at the next assessment (but not ∀20% increase from previous smallest sum), the 
objective status at that assessment should be SD. Once a confirmed PR was seen, the overall 
lesion response should be considered PR (or UNK) until progression is documented or the 
lesions totally disappear in which case a CR assignment is applicable. In studies where 
confirmation of response is not required after a single PR the overall lesion response should 
still be considered PR (or UNK) until progression is documented or the lesion totally 
disappears in which case a CR assignment is applicable.
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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 subject. 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 subject progressed but continues study treatment, further assessments are not 
considered for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a subject 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 overall lesion responses.
Based on the subjects’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of subjects 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 subjects with a best overall response of CR 
or PR or SD. The objective of this endpoint is to summarize subjects 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 subjects 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 subjects 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 2001) and counts 
all subjects 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. Subjects 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 
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disease control, subjects with a best overall response assessment of unknown (UNK) will 
not be regarded as “responders” but may be included in the denominator for ORR and DCR 
calculation depending on the analysis population (e.g. populations based on an ITT 
approach).
14.2.3.2 Time to event variables
14.2.3.2.1
Progression-free survival
Usually in all Oncology studies, subjects 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 subject 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. 
14.2.3.2.2
Overall survival
All subjects should be followed until death or until subject has had adequate follow-up time 
as specified in the protocol whichever comes first. The follow-up data should contain the 
date the subject was last seen alive / last known date subject 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 subject is not known to have died, survival will be 
censored at the date of last known date subject alive.
14.2.3.2.3
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 subject has not had an event, time to progression is censored at the date of last adequate 
tumor assessment.
14.2.3.2.4
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 
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discontinuation due to reasons other than ‘Protocol violation’ or ‘Administrative problems’. 
The time to treatment failure for subjects who did not experience treatment failure will be 
censored at last adequate tumor assessment.
14.2.3.2.5
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 subjects: a good risk group 
and a poor risk group. Good risk subjects tend to get into response readily (and relatively 
quickly) and tend to remain in response after they have a response. Poor risk subjects 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 subjects. Less potent agents induce a response mainly in good risk subjects only. This 
is described in more detail by (Morgan 1988).
It is recommended that an analysis of all subjects (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 subjects (i.e. not restricting to “responders” only) using appropriate 
statistical methods such as the techniques described in Ellis, et al (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-subject analysis of these endpoints are not appropriate since 
the status of subjects throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For subjects 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 subjects 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 subjects with a CR or PR (which may have 
to be confirmed) or SD the start and end date as well as censoring is defined the same as 
that for time to progression.
14.2.3.2.6
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.
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Although an analysis on the full population is preferred a descriptive analysis may be 
performed on the “responders” subset only, in which case the results should be interpreted 
with caution and in the context of the overall response rates, since the same kind of selection 
bias may be introduced as described for duration of response in Section 14.2.3.2.5. It is 
recommended that an analysis of all subjects (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 subjects should definitely be included 
in the analysis to ensure the statistical test is valid. For analysis including all subjects, 
subjects 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. FSFV to LSLV used for the analysis) for subjects 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 subject 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 FSFV to LSLV)
!
at last adequate tumor assessment date otherwise. In this case subjects have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start 
of treatment until first documented CR. Similar analysis considerations including (if 
appropriate) censoring rules apply for this endpoint described for the time to overall
response endpoint.
14.2.3.2.7
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest 
of all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that 
assessment is CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the 
assessment date is calculated as the earliest date of all measurement dates at that evaluation 
number.
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:
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!
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.
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 subject 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 subject 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) anti-cancer therapy or surgery.
14.2.3.2.8
Handling of subjects with non-measurable disease only at baseline
It is possible that subjects 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 subjects 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 
subjects with measurable disease at baseline, subjects without measurable disease should 
also be incorporated in an appropriate manner. The overall response for subjects with non-
measurable disease is derived slightly differently according to Table 14-8.
Table 14-8
Overall lesion response at each assessment: subjects 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
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Non-target lesions
New Lesions
Overall lesion response
Any
Yes
PD
1 As defined in Section 14.2.2.3.
In general, the non-CR/non-PD response for these subjects is considered equivalent to an 
SD response in endpoint determination. In summary tables for best overall response subjects 
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 subjects 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 subjects with 
only non-measurable disease at baseline, handling subjects with a best response of CR as 
“responders” with respect to ORR and all other subjects as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include 
all subjects with only non-measurable disease at baseline, with possible sensitivity analyses 
which exclude these particular subjects. Endpoints such as PFS which are reliant on the 
determination and/or timing of progression can incorporate data from subjects with only 
non-measurable disease.
14.2.3.2.9
Sensitivity analyses
This section outlines the possible event and censoring dates for progression, as well as 
addresses the issues of missing tumor assessments during the study. For instance, if one or 
more assessment visits are missed prior to the progression event, to what date should the 
progression event be assigned? And should progression event be ignored if it occurred after 
a long period of a subject being lost to follow-up? It is important that the protocol and RAP 
specify the primary analysis in detail with respect to the definition of event and censoring 
dates and also include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.2.3.2.7, 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 14-9
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
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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
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
(1) Ignore the new anticancer therapy and
follow situations above (ITT approach) 
(2) 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 14.2.3.2.7
2.
=After the last adequate tumor assessment. “Date of next scheduled assessment” is 
defined in Section 14.2.3.2.7.
3.
=The rare exception to this is if the subject dies no later than the time of the second 
scheduled assessment as defined in the protocol in which case this is a PFS event at the 
date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.
!
(C1) taking the actual progression or death date, in the case of only one missing 
assessment.
!
(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered 
jointly with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity 
analysis consists of backdating the date of event to the next scheduled assessment as 
proposed with option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without 
documented progression: By default, option (1) is used for situation E as subjects 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 
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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 
anti-cancer 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 anti-cancer therapy. It is strongly 
recommended that a tumor assessment is performed before the subject 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 14-8 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 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response 
rather than the calculated response. The need for these types of sensitivity analyses will 
depend on the individual requirements for the specific study and disease area and have to be 
specified in the protocol or RAP documentation.
14.2.4
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).
14.2.4.1 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).
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14.2.4.2 End of treatment phase completion
Subjects 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 subjects 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 subject, 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. 
Subjects may discontinue study treatment for any of the following reasons:
!
Adverse event(s)
!
Lost to follow-up
!
Physician decision
!
Pregnancy
!
Protocol deviation
!
Technical problems
!
Subject/guardian decision
!
Progressive disease
!
Study terminated by the sponsor
!
Non-compliant with study treatment
!
No longer requires treatment
!
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 subject from trial.
14.2.4.3 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.
Subjects may provide study phase completion information for one of the following reasons:
!
Adverse event
!
Lost to follow-up
!
Physician decision
!
Pregnancy
!
Protocol deviation
!
Technical problems
!
Subject/guardian decision
!
Death
!
Progressive disease
!
Study terminated by the sponsor
14.2.4.4 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 
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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.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only subjects with documented deterioration 
of symptoms indicative of progression of disease should have this reason for discontinuation 
of treatment or study evaluation.
14.2.4.5 Programming rules
The following should be used for programming of efficacy results:
14.2.4.5.1
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.
14.2.4.5.2
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 14.2.3.2.7). 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.
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14.2.4.5.3
Incomplete dates for last known date subject alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.2.4.5.4
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)’.
14.2.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.2.4.5.6
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:
!
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 
14-8)
!
Death due to reason other than underlying cancer (only used for TTP and duration of 
response)
!
Initiation of subsequent anti-cancer therapy
* Adequate assessment is defined in Section 14.2.3.2.7. 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 subjects 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.
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14.2.4.6 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.
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14.3
Appendix 3: Recommended management of suspected 
immune-related adverse events related to spartalizumab 
and/or LAG525
Table 14-10
Recommended clinical management for suspected immune-related 
diarrhea/colitis
Diarrhea/colitis (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 1 (Increase of < 4 
stools per day over baseline) 
mild increase in ostomy 
output compared to baseline.
Grade 2 (Increase of 4 - 6 
stools per day over baseline; 
moderate increase in ostomy 
output compared to baseline; 
limiting instrumental ADL) 
and/or abdominal pain/ mucus 
or blood in stool.
!
Diet & Hydration
!
Loperamide: initially 4 mg, followed by 2 mg every four 
hours or after every unformed stool; maximum 16 mg/d. 
Continue until free of diarrhea for 12h
!
Diarrhea > 24h: loperamide 2 mg every two hours; 
maximum 16 mg/d. Consider adding oral antibiotics.
!
Diarrhea > 48h: loperamide 2 mg every two hours; 
maximum 16 mg/d. Consider other second-line therapies for 
diarrhea (e.g. (octreotide, oral diphenoxylate) and oral 
antibiotics
!
If grade 2 and no improvement in 5 days: consider oral 
steroids
!
If grade 2 diarrhea persists > 1 week consider 
gastroenterologist consultation and endoscopy to evaluate 
for colitis
!
If grade 2 persists for 5 days and worsening of symptoms or 
diffuse ulcerations and bleeding seen on endoscopy, initiat
steroids (0.5 - 1 mg/kg/d of prednisone or equivalent) and 
continue until symptoms improve to grade 1. 
!
If no improvement occurs, manage as per grade 3. Steroids 
should be tapered slowly (see Section 6.3.1.3.1).
!
Sigmoidoscopy and biopsy can be considered and may 
assist in determining the duration of steroid taper based on 
the evidence of macroscopic and microscopic inflammation.
Grade 3 diarrhea: Increase of 
≥ 7 stools per day over 
baseline; incontinence; 
hospitalization indicated;
severe increase in ostomy 
output compared to baseline;
limiting self-care ADL;
Grade 3 colitis: Severe 
abdominal pain; change in 
bowel habits; medical 
intervention indicated; 
peritoneal signs
!
Clinical evaluation and hospitalization indicated; rule out 
bowel perforation and intravenous hydration.
!
Consider consultation with gastroenterologist and biopsy 
with endoscopy.
!
In addition to symptomatic treatment (diet, hydration, 
loperamide, antibiotics if indicated); initiate immediate 
treatment with intravenous steroids (methylprednisolone 
125 mg) followed by high dose oral steroids (prednisone 1 
to 2 mg/kg once per day or dexamethasone 4 mg every 4 
hours) is recommended. 
!
When symptoms improve to ≤ grade 1, taper steroids slowly 
(see Section 6.3.1.3.1). Taper over 6 to 8 weeks in patients 
with diffuse and severe ulceration and/or bleeding.
!
If no improvement in 2-3 d: consider initiating infliximab 5
mg/kg and continue steroids. Note: infliximab is 
contraindicated in patients with sepsis or a perforation. 
Upon symptomatic relief initiate a prolonged steroid taper 
over 6 to 8 weeks. 
!
If symptoms worsen during steroid reduction, initiate a re-
tapering of steroids starting at a higher dose of 80 or 100 
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Diarrhea/colitis (NCI-CTCAE v5)
Grade 
Recommended management 
mg/d followed by a more prolonged taper and administer 
infliximab.
!
If symptoms persist despite the above treatment a surgical 
consult should be obtained.
Grade 4: Life-threatening 
consequences; urgent 
intervention indicated
Same as grade 3
Table 14-11
Recommended clinical management for suspected immune-related liver 
laboratory alterations
Abnormal liver tests (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 2: 
AST or ALT > 3 × ULN to 
≤ 5.0x ULN; or if 
baseline 
abnormal >3.0 – 5.0 
x baseline
or bilirubin > 1.5 × ULN 
to ≤ 3 × ULN ; or if 
baseline 
abnormal >1.5 – 3.0 
x baseline
(if patient meets criteria 
for Hy’s law refer to 
Section 6.3.3.1)
!
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
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Abnormal liver tests (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 3 or 4: AST or ALT > 
5.0 × ULN; or if baseline 
abnormal >5.0 x baseline.
bilirubin > 3.0 × ULN; or if 
baseline abnormal >3.0 x 
baseline.
!
Monitor hepatic laboratory tests more frequently (every 2-3 
days) until returned to baseline values. 
!
Consider viral serology (i.e. hepatitis A/B/C, CMV, and rule 
out other potential cause of liver injury such as concomitant 
medications or alcohol), consultation with hepatologist and 
liver biopsy to establish etiology of hepatic injury
!
If after 2-3 days new liver assessment shows worsening of 
laboratory test consider to initiate treatment with steroids 
prednisone 1-2 mg/kg/day or i.v. equivalents.
!
Add prophylactic antibiotics for opportunistic infections as 
appropriate
!
When symptoms/liver tests improve to grade ≤1, taper 
steroids over at least 4 weeks.
!
If serum transaminase levels or bilirubin do not decrease 
48-72 hours after initiation of systemic steroids, oral 
mycophenolate mofetil 500 mg every 12 hours may be 
given as per institutional guidelines.
!
Infliximab is not recommended due to its potential for 
hepatotoxicity
Table 14-12
Recommended clinical management for suspected immune-related rash 
and other skin events
Rash and other skin Events (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 1: rash covering < 10% 
Body Surface Area (BSA)
!
Initiate prophylactic and symptomatic treatment measures.
!
Consider use of topical corticosteroids or urea containing 
creams in combination with oral antipruritics or moderate 
strength topical steroid (hydrocortisone 2.5% cream or 
fluticasone propionate 0.5% cream)
!
Reassess after 2 weeks.
Grade 2: 10-30% of BSA
!
If tolerable, treat as per grade 1; 
!
If intolerable, initiate systemic steroids (e.g. oral 
prednisolone 0.5-1 mg/kg/d) and consider dose interruption 
until tolerable or recovery to grade ≤ 1 or baseline
!
If symptoms persist or recur consider skin biopsy.
Grade 3: More than 30% of 
BSA
!
Obtain a skin biopsy and dermatology consult. 
!
Initiate systemic steroids with 1mg/kg/d of prednisone or 
equivalent. 
Grade 4: Life-threatening
Same as grade 3; additional measures as per local institutional 
guidelines 
Other skin events
Stevens-Johnson syndrome, 
toxic epidermal necrolysis 
! Hospitalization and urgent dermatology consultation
! Institute supportive care immediately as per institutional 
guidelines
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Table 14-13
Recommended clinical management for suspected immune-related 
nephritis
Nephritis (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 1: Creatinine > ULN to 
≤ 1.5 × ULN); or if baseline 
abnormal >1 – 1.5 x baseline
!
Monitor creatinine weekly
!
If creatinine return to baseline resume routine creatinine 
monitoring per protocol
!
Promote hydration and cessation of nephrotoxic drugs
Grade 2: Creatinine > 1.5 to ≤ 
3 × ULN; or if baseline 
abnormal >1.5 – 3.0 x 
baseline
!
Monitor creatinine every 2 to 3 days
!
Initiate 0.5 to 1 mg/kg/d prednisone or equivalents
!
If worsening or no improvement: 1 to 2 mg/kg/day 
prednisone or equivalents 
!
Promote hydration and cessation of nephrotoxic drugs
!
Consult with specialist and consider renal biopsy
Grade 3: Creatinine >3.0 to ≤ 
6.0 × ULN; or if baseline 
abnormal >3.0 – 6.0 x 
baseline
!
Monitor creatinine every 1 to 2 days
!
Start 1 to 2 mg/kg/day prednisone or equivalents 
!
Consult with nephrologist and consider renal biopsy 
Grade 4: Creatinine > 6.0 × 
ULN
!
Monitor creatinine daily
!
Initiate steroids with 1 to 2 mg/kg/d prednisone or 
equivalent
!
Consult with nephrologist and consider renal biopsy
Table 14-14
Recommended clinical management for suspected immune-related 
pneumonitis
Pneumonitis (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 1: Asymptomatic; 
clinical or diagnostic 
observations only; 
intervention not indicated
!
High-resolution CT with lung windows recommended, with 
serial imaging to monitor for resolution or progression. 
Repeat at least every 3 weeks
!
Monitor for symptoms every 2-3 days - Clinical evaluation 
and laboratory work-up for infection
!
Monitoring of oxygenation via pulse oximetry recommended
!
Consultation of pulmonologist recommended
Grade 2: Symptomatic-
medical intervention indicated; 
limits instrumental ADLs
!
Perform high-resolution CT with lung windows
!
Monitor symptoms daily, consider hospitalization
!
Clinical evaluation and laboratory work up for infection
!
Consult pulmonologist
!
Pulmonary function tests - if normal at baseline, repeat 
every 8 weeks 
!
Bronchoscopy with biopsy and/or BAL recommended
!
Symptomatic therapy including corticosteroids if clinically 
indicated (1 to 2 mg/kg/d prednisone or equivalent as 
clinically indicated).
Grade 3: Severe symptoms; 
limits self-care ADLs; oxygen 
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 
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Pneumonitis (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 4: Life- threatening 
respiratory compromise; 
urgent intervention required
!
If no improvement within 48 hours, consider infliximab 
and/or other immune-suppressive therapy, or i.v. Ig as per 
local guidelines
!
Empiric antibiotics
Table 14-15
Recommended clinical management for suspected
immune-related 
endocrinopathies
Endocrine events (NCI-CTCAE v5)
Grade 
Recommended management 
Asymptomatic, intervention 
not indicated (e.g. 
hyperthyroidism or 
hypothyroidism)
!
If TSH < 0.5 × LLN, or TSH > 2 × ULN, or consistently out 
of range in 2 subsequent measurements, include free T4 at 
subsequent cycles as clinically indicated
!
Consider endocrinologist consult
!
If hypophysitis is considered, pituitary gland imaging should 
be considered (MRIs with gadolinium and selective cuts of 
the pituitary can show enlargement or heterogeneity and 
confirm the diagnosis)
!
Repeat labs in 1 to 3 weeks/MRI in 1 month if laboratory 
abnormalities persist but normal lab/pituitary scan
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 initiate
Autoimmune diabetes
(Grade 3 or symptomatic 
hyperglycemia)
!
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)
Autoimmune diabetes
(Grade 4 hyperglycemia or 
life-threatening complications)
Same as grade 3
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Amended Protocol Version 05 (Clean)
Protocol No. CPDR001J2201
Table 14-16
Recommended clinical management for suspected infusion reaction or
cytokine release syndrome 
Infusion reaction (NCI-CTCAE v5)
Grade 
Recommended management 
Grade 1
Mild reaction; infusion 
interruption not indicated; 
intervention not indicated
!
Increase monitoring of vital signs as medically indicated 
until the patient is deemed medically stable in the opinion of 
the investigator.
!
Consider slowing infusion rate until recovery of symptoms
!
May continue spartalizumab
Grade 2
Requires infusion interruption 
but responds promptly to 
symptomatic treatment (e.g., 
antihistamines, NSAIDS, 
narcotics, IV fluids); 
prophylactic medications 
indicated for < =24 hrs
!
Stop infusion
!
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 as medically indicated 
until the patient is deemed medically stable in the opinion of 
the investigator.
!
If symptoms resolve within one hour of stopping drug 
infusion, the infusion may be restarted at 50% of the original 
infusion rate (e.g. from 100 mL/hr to 50 mL/hr). Otherwise 
dosing will be held until symptoms resolve and the patient 
should be re-premedicated for the next scheduled dose.
!
Patient may be premedicated 1.5h (± 30 minutes) prior to 
infusion with diphenhydramine 50 mg p.o. (or equivalent 
dose of antihistamine) and acetaminophen 500-1000 mg 
p.o. (or equivalent dose of analgesic).
!
Consider permanent discontinuation of study treatment in 
case of recurring infusion reaction despite premedication 
and prolonged infusion
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 subject is deemed medically 
stable.
!
Hospitalization as indicated
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Amended Protocol Version 05 (Clean)
Protocol No. CPDR001J2201
Table 14-17
Recommended clinical management guidelines for suspected other
potential immune-related events
Other (i.e. Autoimmune neuropathy, Demyelinating polyneuropathy, Guillain Barre, 
Myasthenia Gravis-like syndrome, non-infectious myocarditis, pericarditis, pancreatitis, 
encephalitis, and Grade 3 Fatigue with rapid onset in absence of disease progression) 
(NCI-CTCAE v5)
Grade 
Recommended management
Mild (Grade 1)
Provide symptomatic treatment
Moderate (Grade 2)
!
Consider treatment interruption until recovery to ≤ grade 1 or 
baseline. 
!
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
Severe (Grade 3)
!
Initiate systemic corticosteroids (prednisone or equivalent) at a 
dose of 1-2 mg/kg/d and other therapies as appropriate
!
Monitor closely and consult with a specialist
Grade 4
!
Hospitalization and consult with specialist
!
Initiate systemic corticosteroids (prednisone a dose of 1-2 mg/kg/d 
or equivalent) and other therapies as appropriate
Encephalitis (any 
grade) 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/d prednisone equivalents.
Guillain-Barre
Severe peripheral or 
autonomic neuropathy, 
or transverse myelitis
!
Hospitalization and consult with specialist
Myasthenia gravis
!
Consult with specialist
!
Consider pyridostigmine and systemic corticosteroids (prednisone 
or equivalent) at a dose of 1-2 mg/kg/d; other therapies as 
appropriate (e.g. IVIG)
!
Hospitalization in case of severe cases
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). Hospitalization as indicated
Pancreatitis
Amylase/lipase 
elevation
•
Evaluate for pancreatitis (clinical assessment, abdominal imaging 
and/or magnetic resonance cholangiopancreatography as appropriate)
•
Treatment may be continued in case of asymptomatic, isolated 
enzyme elevations without evidence for pancreatitis
•
Initiate steroids in case of ≥ grade 2 acute pancreatitis
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
Ocular events
•
Consult with ophthalmologist
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SAP_001.pdf: 
Clinical Development
Spartalizumab (PDR001), LAG525, capmatinib (INC280), 
canakinumab (ACZ885)
CPDR001J22011&7
A randomized, open-label, phase II open platform study 
evaluating the efficacy and safety of novel spartalizumab 
(PDR001) combinations in previously treated unresectable 
or metastatic melanoma
Statistical Analysis Plan (SAP)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
5-Oct-2018
Number of pages:
66
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
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Template Document History – Changes compared to previous version
Date
Version 
number
Summary of changes
01-Jul-2015
1.0
N/A - First version
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted 
(Current)
5-
Oct-
2018
Prior 
to 
DB 
lock
Creation of 
final 
version
N/A - First version
NA


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.1.1
Study design: Part 1: Selection phase .....................................................7
1.1.2
Study design: Part 2: Expansion phase ...................................................8
1.1.3
Timing of interim analyses and design adaptations................................8
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.2
Analysis sets ..........................................................................................................16
2.2.1
Subgroup of interest ..............................................................................18
2.3
Patient disposition, demographics and other baseline characteristics ...................19
2.3.1
Patient disposition.................................................................................20
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................21
2.4.1
Study treatment / compliance................................................................22
2.4.2
Prior, concomitant and post therapies...................................................26
2.5
Analysis of the primary objective..........................................................................28
2.5.1
Primary endpoint...................................................................................29
2.5.2
Statistical hypothesis, model, and method of analysis..........................29
2.5.3
Handling of missing values/censoring/discontinuations.......................32
2.5.4
Supportive analyses...............................................................................32
2.6
Analysis of the key secondary objective ...............................................................34
2.6.1
Key secondary endpoint........................................................................34
2.6.2
Statistical hypothesis, model, and method of analysis..........................34
2.6.3
Handling of missing values/censoring/discontinuations.......................35
2.7
Analysis of secondary 
 efficacy objective(s)................................36
2.7.1
Secondary 
 efficacy endpoints .....................................36
2.7.2
Statistical hypothesis, model, and method of analysis..........................38
2.7.3
Handling of missing values/censoring/discontinuations.......................40
2.8
Safety analyses.......................................................................................................41
2.8.1
Adverse events (AEs)............................................................................41
2.8.2
Deaths....................................................................................................43
2.8.3
Laboratory data .....................................................................................43
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2.8.4
Other safety data ...................................................................................45
46
2.10
PD and
PD analyses.........................................................................................48
2.10.1
Immunogenicity ....................................................................................48
2.11
Patient-reported outcomes .....................................................................................50
2.12
Biomarkers.............................................................................................................50
2.12.1
Introduction...........................................................................................50
2.12.2
Secondary biomarker objectives ...........................................................51
2.12.3
Biomarker data......................................................................................51
2.12.4
General data handling and preprocessing .............................................52
2.12.5
Secondary biomarker objectives ...........................................................52
55
56
2.14
Interim analysis......................................................................................................56
3
Sample size calculation .....................................................................................................57
4
Change to protocol specified analyses ..............................................................................57
5
Appendix ...........................................................................................................................57
5.1
Imputation rules.....................................................................................................57
5.1.1
Study drug.............................................................................................57
5.1.2
AE, ConMeds and safety assessment date imputation..........................58
5.2
AEs coding/grading ...............................................................................................61
5.3
Laboratory parameters derivations ........................................................................61
5.4
Statistical models...................................................................................................62
5.4.1
Primary analysis....................................................................................62
5.4.2
Key secondary analysis.........................................................................62
5.4.3
Audit-based BIRC assessment of PFS..................................................63
5.5
Rule of exclusion criteria of analysis sets..............................................................63
63
6
Reference...........................................................................................................................64
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List of abbreviations
ADA
Anti-Drug Antibodies
AE
Adverse event
AESI
Adverse Event of Special Interest
ALP
Alkaline Phosphatase
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
ATC
Anatomical Therapeutic Classification
BID
bis in diem/twice a day
BOR
Best Overall Response
CD8
Cluster of differentiation 8
CI
Confidence Interval
CRS
Case Retriveal Strategy
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dosage Administration Record
DCR
Disease Control Rate
DI
Dose Intensity
DoR
Duration of Response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
HLGT
High Level Group Terms
HLT
High Level Terms
IRT
Interactive Response Technology
i.v.
Intravenous
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NE
Not Evaluable
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NMQ
Novartis MedDRA queries
ORR
Overall Response Rate
OS
Overall Survival
PDI
Planned Dose Intensity
PD-1
Programmed Death 1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
pFBP
Proportion of subjects with a favorable biomarker profile
PFS
Progression-Free Survival
p.o.
Per os/by mouth/orally
PPS
Per-Protocol Set
PT
Preferred Term
Q4W
Every four weeks
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
s.c.
Subcutaneous
SOC
System Organ Class
SMQ
Standardized MedDRA queries
TBL
Total Bilirubin
TA
Tumor Assessment
TIL
Tumor Infiltrating T cells
ULN
Upper Limit of Normal
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the clinical study report(s)
(CSR) of study CPDR001J2201, a randomized, open-label, phase II open platform study 
evaluating and safety of novel spartalizumab (PDR001) combinations in previously treated 
unresectable or metastatic melanoma. 
The content of this SAP is based on protocol CPDR001J2201 version 01.  All decisions 
regarding final analysis, as defined in the SAP document, have been made prior to database 
lock and unblinding of the study data.
1.1
Study design
This is a randomized, open-label, multi-center, two-part, open platform phase II study to 
assess the efficacy and safety of the anti-PD-1 antibody spartalizumab in combination with
novel agents in previously treated unresectable or metastatic melanoma.
This study consists of two parts:

Part 1: Selection phase (refer to Section 1.1.1 for further details)

Part 2 : Expansion phase (refer to Section 1.1.2 for further details)
At any time during the study, subjects deemed eligible after the completion of screening 
procedures will be randomized into any of the combination arms open to enrolment (in either 
part 1 or part 2) for which the subject meets the eligibility criteria as described in Section 5 of 
the protocol using an Interactive Response Technology (IRT) system. Randomization will be 
stratified by baseline level of lactate dehydrogenase (LDH): baseline LDH ≤ULN (upper 
limit of normal) vs. baseline LDH > ULN.
Crossover or re-randomization of subjects to other combination arms, including better
performing arms, is not allowed.
Overall response rate (ORR), as assessed by local review of tumor response and using 
Response Evaluation Criteria in Solid Tumors (RECIST) 1.1 criteria, is the primary endpoint 
in this study. Duration of Response (DoR), as assessed by local review and using RECIST 
1.1 criteria is the key secondary endpoint.
The primary analysis will be performed after all patients randomized in the expansion arm 
have been followed for at least 9 months or have discontinued study.  Timing of the interim 
analyses is discussed further in Section 1.1.3.  
1.1.1
Study design: Part 1: Selection phase
The primary objective of part 1 is to evaluate the preliminary ORR of spartalizumab in 
combination with novel agents in patients with previously treated unresectable or metastatic 
melanoma. 
As dose regimens for additional new combinations with spartalizumab become established, new 
combination arms will be added under the same master protocol through protocol amendments. 
A maximum of 10 arms may be active (open to enrolment) at any given time under this master 
protocol, and any arms active in part 1 will continue to be randomized with equal probability. 


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At each interim analysis, it will be determined which arm(s) (1) is declared efficacious and will 
be expanded to part 2, (2) will continue enrolment in part 1 (up to a maximum of 45 subjects 
enrolled in a given arm) or (3) will be dropped for futility, taking into account all available 
efficacy, safety and biomarker data.  If a combination arm can be expanded to part 2, the exact 
sample size for part 2 will be determined at that time when the decision to expand this arm is 
taken (refer to Section 10.8 of the protocol for further details on sample size considerations).
The timing of interim analyses and the criteria used for decision-making at each interim analysis 
are detailed in Section 1.1.3 and Section 10 of the protocol.
Further discussion on the study design for part 1 can be found in Section 4.1 of the protocol.
1.1.2
Study design: Part 2: Expansion phase
The primary objective for part 2 is to further characterize ORR of spartalizumab in combination 
with novel agents with relevant preliminary activity, as determined in part 1, for patients with 
previously treated unresectable or metastatic melanoma. 
Only combinations arms that have met the pre-specified criteria defined in Section 1.1.3 and
Section 10 of the protocol will be opened to enrollment in part 2.
Exact randomization strategies in the situation when there is one (or more) arms open for 
enrollment in part 2 and there are still arms open for enrollment in part 1 will be determined at 
the time of the selection of the arm that will be expanded in part 2. Four factors will be 
considered at the time of opening an arm in part 2 to determine the exact randomization strategy 
and those are the following:
1) Number of subjects enrolled in part 1 for the arm that will graduate to part 2
2) Number of subjects that will need to be enrolled in part 2 to have sufficient predictive 
power and alpha control
3) Observed effect size for the arm that will graduate to part 2
4) Observed effect size of other arms which are open for enrolment in part 1
Further discussion on the study design for part 2 can be found in Section 4.1 of the protocol.
1.1.3
Timing of interim analyses and design adaptations
The first interim analysis will be conducted in part 1 after approximately 10 subjects have been 
enrolled in each of the first three arms and have completed the second post-baseline tumor 
assessment or have discontinued study prior to completing the second post-baseline tumor 
assessment. The requirement to have at least 10 subjects in each arm is based on simulations 
showing that 10 is the minimal number of subjects to be able to declare futility as per decision 
rules presented below and also in Section 10.4.2 of the protocol. If more combination arms are 
added to the study via future protocol amendments, those combination arms would also have 
their 1st interim analysis after approximately 10 subjects have been enrolled.  Timing of 
subsequent interim analyses for part 1 and statistical thresholds are further discussed in Section 
4.2 
of 
the 
protocol
and 
Section 
10.4.2 
of 
the 
protocol, 
respectively.
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Figure 1-1 presents pre-specified criteria for decision-making in the selection phase.
Figure 1-1
Pre-specified criteria for decision making at each decision point
(interim analysis) in part 1 to determine expansion in part 2 or drop of 
a combination arm
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.
Table 1-1
Objectives and related endpoints
Primary objective
Endpoint
To evaluate the efficacy of each 
combination arm, as measured by 
confirmed objective response rate 
(ORR)
Confirmed ORR using RECIST v1.1, per local 
assessment
Key secondary objective
Endpoint
To evaluate the efficacy of each 
combination arm in terms of duration of 
response (DoR) 
DoR using RECIST v1.1, per local assessment
Other secondary objectives
Endpoint
To evaluate the efficacy of each 
combination arm as measured by
progression-free survival (PFS) and 
disease control rate (DCR) 
PFS and DCR, assessed using RECIST v1.1, per local 
assessment
To evaluate the overall survival (OS) of 
each combination arm
Overall survival (OS)
To characterize the safety and
tolerability of each combination arm
Safety: Incidence and severity of adverse event (AE)
including changes in laboratory values, vital signs and
cardiac assessment. 
Tolerability: Dose interruptions, reductions, and 
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To characterize the prevalence and 
incidence of immunogenicity of 
spartalizumab,  LAG525 and 
canakinumab in each combination arm
Anti-drug antibodies (ADA) prevalence at baseline and 
ADA incidence on treatment
To evaluate changes in levels and 
phenotype of T cell populations in the 
tumor and tumor microenvironment after 
treatment with combination therapies
Proportion of subjects with a favorable biomarker 
profile (pFBP), as defined by changes in numbers of 
cells expressing the CD8+ T cell marker and/or T cell 
activation marker(s), T cell clonality and/or gene
expression in tumor biopsy samples collected at 
baseline (screening) and compared to on treatment (3-
4 weeks) samples
2
Statistical methods
2.1
Data analysis general information
All analysis will be performed by Novartis and/or a designated CRO.  SAS version 9.4 or later 
software will be used to perform all data analyses and to generate tables, figures and listings.  
Analysis using Rshiny apps might also be used as needed.
Data included in the analysis
The analysis cut-off date for the primary analysis of study data will be established after all 
randomized patients in the expansion arm have either completed nine months of follow-up or 
have discontinued study.  For the selection phase, interim analyses will be conducted once the 
1st 10 subjects have been enrolled in each of the 1st three arms and then conducted 
approximately every 20 weeks thereafter.  No formal interim analysis for efficacy will be 
conducted for combination arms in the expansion phase.
For each of the analyses, 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.
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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 cases, the end date will not be imputed and 
therefore will not appear in the listings.
The analysis cutoff date for the final analysis of study data will be established at the end of the 
study defined as the earliest occurrence of one of the following:

All subjects have died or discontinued from the study

Another clinical study (i.e. rollover study) becomes available that can continue to 
provide the appropriate combination treatment in this subject population and all subjects 
ongoing are eligible to be transferred to that clinical study

52 weeks after data-cut for primary CSR. For subjects still receiving study treatment at
the time of end of study, every effort will be made to continue provision of study 
treatment outside this study through an alternative setting (e.g. post-trial access 
programs) to subjects who in the opinion of the investigator are still deriving clinical 
benefit.
The timing of primary and final analyses will be updated, should new arms be added through 
protocol amendment or if more than one arm is expanded to the expansion phase.
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 patients enrolled at each centers, no center effect 
will be assessed.
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables; 
a missing category will be included as applicable. Percentages will be
calculated using the number of patients 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).
2.1.1
General definitions
Investigational drug and study treatment
Investigational drug can refer to either PDR001 or any of the novel agents.
Study treatment will refer to PDR001 in combination with any of the novel agents.
The term investigational treatment may also be referred to as study treatment which is used 
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Date of first administration of investigational drug
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug is administered and recorded on the Dosage Administration 
Record (DAR) Electronic Case Report Form (eCRF). The date of first administration of study 
drug will also be referred as start of investigational drug.
Date of last administration of investigational drug
The date of last administration of investigational drug is defined as the last date when a nonzero 
dose of investigational drug is administered and recorded on DAR eCRF. The date of last
administration of investigational drug will also be referred as end of investigational drug.
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 any component of study treatment was administered as per the Dosage Administration 
(e)CRF. (Example: if 1st dose of PDR001 is administered on 28-Jul-2018, and 1st dose of 
combination partner is administered on 26-Jul-2018, then the date of first administration of 
study treatment is on 26-Jul-2018). The date of first administration of study treatment will also 
be referred as start of study treatment.
Date of last administration of study treatment 
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 Dose Administration (e)CRF. 
(Example: if the last PDR001 dose is administered on 26-Jul-2019, and the last dose of a 
combination partner is administered on 28-Jul-2019, then the date of last administration of study 
treatment is on 28-Jul-2019).
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, 
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, and Eastern Cooperative Oncology Group [ECOG])
performance status 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.
P
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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. In 
the context of baseline definition, the efficacy evaluations also include performance status.  
For safety evaluations, the last available assessment is on or before the date of start of study 
treatment is taken or ‘‘baseline” assessment.
In case time of assessment and time of treatment start is captured (e.g. pre-dose ECG), the last 
available assessment before the treatment start date/time is used for baseline.
For safety parameters (e.g ECGs or vital signs), 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 last value should be considered as baseline.
If patients 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 patient’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.
Notes:

If data on clock time is available in the clinical database (e.g. for time of blood/urine 
sample taken, ECG performed, etc. and first study treatment administration), a more 
precise distinction between pre-treatment and on-treatment periods is encouraged to be 
used.

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.


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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 Serious Adverse Events (SAEs) and SAEs related to study treatment collected up to 150 
days after last administration of PDR001.
Note: If a patient starts a post-treatment antineoplastic therapy after the last administration of 
study treatment, only adverse events suspected to be related to study treatment will be collected 
up to 150 days after discontinuation of PDR001. All AEs/ all SAEs are planning to be reported 
up to 150 days after discontinuation of PDR001 acknowledging that complete collection of data 
may not be feasible for each patient.
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.
Windows for multiple assessments 
In order to summarize performance status (ECOG), 
laboratory, and 
vital signs collected over time (including unscheduled visits), the assessments will be time
slotted. The following general rule will be applied in creating the assessment windows: If more
than one assessment is done within the same time window, the assessment performed closest to
the target date will be used. If 2 assessments within a time window are equidistant from the 
target date, then the earlier of the 2 assessments will be used. If multiple assessments on the 
same date then the worst case will be used.  Data from all assessments (scheduled and 
unscheduled), including multiple assessments, will be listed.
Table 2-1
Time window for ECOG PS assessments
Assessment
Target day of assessment
Time Interval
Baseline
≤ Day 1
Cycle 2 Day 1
29
Day 15 to day 42
Cycle 3 Day 1
57
Day 43 to day 70
Cycle 4 Day 1
85
Day 71 to day 98
Cycle k Day 1 (k≥5)
d=(k-1)*28+1
Day d-14 to day d+13
End of Treatment
Assessment taken at the 
end of treatment visit
30-day safety follow-
up
Post treatment study day 30
Assessment taken at the 
30-day safety follow-up visit
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Table 2-2
Time window for Laboratory assessments
Assessment
Target day of assessment
Time Interval
Baseline
        
≤ Day 1 
Cycle 1 Day 15
15
Day 2 to day 21
Cycle 2 Day 1
29
Day 22 to day 42
Cycle 3 Day 1
57
Day 43 to day 63
Cycle 3 Day 15
71
Day 64 to day 77
Cycle 4 Day 1
85
Day 78 to day 98
Cycle k Day 1 (k≥5)
d=(k-1)*28+1
Day d-14 to day d+13
End of Treatment
Assessment taken at the 
end of treatment visit
30-day safety follow-
up
Post treatment study day 30
Assessment taken at the 
30-day safety follow-up visit
Last contact date 
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following:
Table 2-3
Last contact date data sources
Source data
Conditions
Date of Randomization 
No Condition
Last contact date/last date patient was known to 
be alive from Survival Follow-up page 
Patient 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 drug administration record 
Non-missing dose. Doses of 0 are allowed.
End of treatment date from end of treatment page
No condition.
Tumor (RECIST) assessment date. 
Evaluation is marked as ‘done’.
Verification for treatment beyond RECIST1.1 PD
At least one non missing parameter value
Laboratory
 collection dates
Sample collection marked as ‘done’. 
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 patient 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 is coming from ‘Survival information’ eCRF. 
The last contact date will be used for censoring of patients in the analysis of overall survival.
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2.2
Analysis sets
All below defined analysis sets will be used to analyze data from both the selection phase 
(part 1) and the expansion phase (part 2).
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 they have been assigned to during the randomization procedure regardless of 
whether or not treatment was administered.  This population will be the primary population for 
efficacy analysis.
Per protocol set (PPS) 
Not applicable.
Safety
The Safety Set includes all subjects who received at least one dose of study treatment. 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.
The actual treatment received corresponds to:
-
the randomized treatment if patients took at least one dose of that treatment.
-
the first treatment received if the randomized treatment was never received
Note: if a patient is assigned to a dose level for instance, PDR001 400 mg and just receives 
partial infusion of the treatment, the patient will still be analyzed under PDR001 400 mg 
treatment arm for safety analysis.
Biomarker analysis set
The biomarker analysis set, as it pertains to the secondary objective (Section 10.5.5 of the 
protocol), consists of all subjects in the safety set with an evaluable baseline tumor biopsy 
sample and at least one evaluable post-baseline tumor biopsy sample. 
 
 
 
 
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Immunogenicity (IG) analysis sets
The Immunogenicity prevalence set includes all subjects in the Full analysis set with a 
determinant baseline IG sample or at least one determinant post-baseline IG sample.
The Immunogenicity incidence set includes all subjects in the Immunogenicity prevalence set 
with a determinant baseline IG sample and at least one determinant post-baseline IG sample.   
See Section 2.10.1.1 for the definition of determinant.
Patient Classification: 
Patients 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 2-4
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 study medication 
Biomarker set
No written inform consent
No dose of study medication
and no evaluable post-
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baseline tumor biopsy 
sample
Immunogenicity Prevalence 
Set
No written informed consent
Not meeting the definition 
for inclusion in the 
Immunogenicity Prevalence 
set
Immunogenicity Incidence 
Set
No written informed consent
Not meeting the definition 
for inclusion in the 
Immunogenicity Incidence 
set
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 patient 
withdraws full consent is recorded in the eCRF. 
Death events may be used in the analysis if captured from public records (registers), local law 
and subject informed consent pending.
Additional data for which there is a separate informed consent, e.g. 
 biomarker 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.
2.2.1
Subgroup of interest
Efficacy
The primary efficacy endpoint will be summarized if there is sufficient number of patients in 
the following subgroups: 
!
Stratification factor (based on randomization data from IRT)
o
LDH (≤ ULN vs. > ULN)
!
BRAFV600 mutation status (wild-type vs.  mutant)
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In addition, if a combination arm is expanded, the following subgroup analysis may also be 
performed if there is sufficient number of patients using all patients randomized within that 
combination arm:

Age category (< 65 years, ≥ 65 years)

ECOG PS (0 vs ≥0)

PD-L1 expression (positive, negative) where a positive status is defined as having ≥ 1% 
expression and negative is defined as having <1% expression
No formal statistical test of hypotheses will be performed for the subgroups, only point estimate 
of the treatment effect and 95%-confidence intervals will be provided (see Section 2.5.2 and 
Section 5.4.1 for further analysis details). The objective of the efficacy subgroup analysis is to 
demonstrate homogeneity of treatment effect in the above subgroups, and to identify potential 
subgroups with differential efficacy. Summary tables will only be performed if at least 10% of 
patients or 10 patients are present in each subgroup.
Safety
Safety subgroup analyses will use the same method as for the analysis in the overall analysis 
set. Key safety analyses (e.g. deaths, SAEs, AESIs, AEs leading to discontinuation) will be 
repeated on safety set in the following subgroups:

Sex

Race 

Age category (< 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 patients, or safety issues that are more commonly 
observed in a subgroup of patients. Summary tables will only be performed if at least 10% of 
patients or 10 patients are present in each subgroup. 
2.3
Patient disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline (including disease characteristics) and 
demographic summaries and listings unless otherwise specified. Summaries will be reported by 
treatment arm and for all patients and listings will be reported by treatment arm to assess 
baseline comparability.  No inferential statistics will be provided.
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 and ≥ 65 years, race, ethnicity, 
etc...) will be summarized by frequency counts and percentages; the number and percentage of 
patients with missing data will be provided. Continuous data (e.g. age, weight, height, body 
mass index) will be summarized by descriptive statistics (N, mean, median, standard deviation, 


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minimum and maximum).  BMI (kg/m2) will be calculated as weight[kg] / (height[m]2) using 
weight at Screening.
Baseline stratification factors
The number (%) of patients in each stratum (LDH (≤ ULN vs. > ULN)) 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.
Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include
the
following:
primary site
of
cancer,
details of tumor 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, 
and number of tumor infiltrating T cells (TIL)).  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.
Medical history
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e) CRF 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.
Other
All data collected at baseline such as child bearing potential, 
 
 treatment beyond progression informed consent will be listed.
2.3.1
Patient disposition
Enrollment by country and center will be summarized for all screened patients and also by 
treatment arm using the FAS. The number (%) of randomized patients included in the FAS will 
be presented overall and by treatment group. The number (%) of screened and not-randomized 
patients and the reasons for screening failure will also be displayed. The number (%) of patients 
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 patients):
!
Number (%) of patients who were randomized (based on data from IRT system)
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
Number (%) of patients who were randomized but not treated (based on ‘DAR’ 
eCRF page not completed for any study treatment component)

Primary reason for not being treated (based on “End of Treatment Phase Completion” 
eCRF page)

Number (%) of patients who were treated (based on ‘DAR’ eCRF pages of each 
study treatment component completed with non-zero dose administered)

Number (%) of patients who are still on-treatment (based on the ‘End of Treatment 
Phase’ page not completed); 

Number (%) of patients who discontinued the study treatment phase (based on the 
‘End of Treatment Phase’ page) 

Primary reason for study treatment phase discontinuation (based on the ‘End of 
Treatment Phase’ page)

Number (%) of patients who have entered the post-treatment follow-up (based on 
the ‘End of Treatment Phase’ page);

Number (%) of patients who have discontinued from the post-treatment follow-up
(based on the End of Post-treatment follow-up  page);

Reasons for discontinuation from the post-treatment follow-up (based on End of 
Post-treatment follow-up page);

Number (%) of patients who have entered the survival follow-up (based on the 
‘End of Treatment Phase’ or ‘End of Post-treatment follow-up’ page).
Protocol deviations
The number (%) of patients 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 group
for the FAS. Major protocol deviations leading to exclusion from analysis sets will be tabulated 
separately overall and by treatment group. All protocol deviations will be listed.
Analysis sets
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized by
treatment group and stratum.
2.4
Treatments (study treatment, rescue medication, 
concomitant therapies, compliance)
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.


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2.4.1
Study treatment / compliance
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) will be summarized by combination arm, separately for each component of study 
treatment (PDR001 and appropriate novel agent).  The duration of treatment will also be 
presented for each combination arm. 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 or interruptions, and the 
reasons, will be summarized by combination 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 PDR001 and any novel agent partner for each combination arm:
Duration of exposure to study treatment (days) for each combination arm = (last date of 
exposure to study treatment) – (date of first administration of study treatment) + 1. 
The last date of exposure to study treatment for each combination arm is the latest of the last 
dates of exposure to PDR001 or any novel agent partner (see Table 2-5).
Summary of duration of exposure of study treatment in appropriate time units will include 
categorical summaries and continuous summaries (i.e. mean, standard deviation etc.) using 
appropriate units of time.
Duration of exposure to PDR001 and novel agent combination partner
Duration of exposure to PDR001 (days) = (last date of exposure to PDR001) – (date of first 
administration of PDR001) + 1.
Table 2-5
Definition of last date of exposure of study drug
Scenario
Definition of last date of exposure 
of study drug 
Example
PDR001
LAG525
ACZ885
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 patient 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. 
Example 1: If PDR001, LAG525, 
or ACZ885 is administered every 
four weeks, the last date of 
exposure 
is 
the 
date 
of 
administration in the last cycle + 
27 days.


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If the derived last date of exposure goes 
beyond the data cutoff date, it should be 
truncated to the date of data cutoff.
INC280
Date of last administration of a non -
zero dose of the study drug.
Example 2: A patient had a 
permanent discontinuation of the 
study drug 06Jan2013 after being 
put on a temporary interruption 
since 01Jan2013. In this case the 
last 
date
of 
exposure 
is-
31Dec2012. 
Scenario 
1: 
Novel 
agent with a cyclic 
administration other 
than Q4W
The planned end date of the last cycle 
in which the last non-zero dose of the 
investigational 
drug 
was 
last 
administered.
Note :  If the patient 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 cutoff date, it should be 
truncated to the date of data cutoff.
Example 1: In a once a week 
administration of an investiga-
tional drug, the last date of 
exposure 
is 
the 
date 
of 
administration in the last cycle + 6 
days.
Example 2: In a 21-day cycle with 
one or several infusions in the 
beginning of the cycle, the last 
date of exposure is the date of first 
infusion in the last cycle + 20 days.
As more novel agents are combined with PDR001, the above table will be updated, and the 
novel agents added to the appropriate rows in the above table.
Summary of duration of exposure of PDR001 will include categorical summaries based on 28 
day intervals and using descriptive statistics (mean, standard deviation etc).
The duration includes the periods of temporary interruption.
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 planned 
cumulative dose is not summarized or listed. It is used for relative dose intensity calculations.
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 Dose Administration eCRF.
For patients who did not take any drug the cumulative dose is by definition equal to zero.
For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the subject is assumed to have taken a non-zero dose during dosing periods. 


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Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows: 

For PDR001, LAG525, and Canakinumab (ACZ885):
o
DI (mg / week) = Actual Cumulative dose (mg) / Duration of exposure to study 
treatment (week).
o
If for example, the duration of exposure to PDR001 is 8 weeks and the patient 
receives two injections of PDR001 at 400 mg :
o
DI (mg/week) = Actual Cumulative dose (mg) / Duration of exposure (week)
= 800 (mg) / 8 (week) = 100 (mg/week)

For Capmatinib (INC280):
o
DI (mg/day)= Actual Cumulative dose (mg)/ Duration of exposure (in days)
For patients who did not take any drug the DI is by definition equal to zero.
Planned dose intensity (PDI) is defined as follows:

For PDR001, LAG525, and Canakinumab (ACZ885):
o
PDI (mg/week) = Planned Cumulative dose (mg) / Duration of exposure (week).

For Capmatinib (INC280):
o
PDI (mg/day)= Planned Cumulative dose (mg)/ Duration of exposure (in days).
Relative dose intensity (RDI) is defined as follows:

For PDR001, LAG525, and Canakinumab (ACZ885):
o
RDI = DI (mg /week)  / PDI (mg /week).

For Capmatinib (INC280):
o
RDI = DI (mg/day)  / PDI (mg /day).
For each PDR001 and novel agent combination, 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.
Dose reductions, interruptions or permanent discontinuations
The number of subjects who have dose reductions, dose escalations, permanent discontinuations,
administration stopped/paused during infusion or interruptions, and the reasons, will be 
summarized separately for each of the study treatment components.  Dose reductions and dose 
escalations are only allowed for Capmatinib (INC280) (see Table 2-6).
‘Dose changed’, “Was drug administration stopped or paused” and ‘Dose permanently 
discontinued’ fields from the Dosage Administration CRF pages (DAR) will be used to 
determine the dose reductions, dose escalations, dose interruptions, administration stopped 
/paused and permanent discontinuations, respectively.


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The corresponding fields ‘Reason for dose change/dose interrupted’, ‘Reason for administration 
stopped or paused’ and ‘Reason for permanent discontinuation’ will be used to summarize the 
reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
Note:  Dose interruptions are captured in the eCRF following the Oncology Data standard 
Reference manual and CRF Completions Guidelines. Depending on the dosing administration 
schedule (e.g. continuous dosing, interval dosing), data would be collected in different fashion. 
For instance, for continuous dosing, an interruption is defined as a dose of zero in a unit of time 
between two non-zero dosing records. In general, any rest period as part of the regimen/schedule 
is not considered as an interruption.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption are entered on consecutive days/dose administrations with different reasons,
separate interruptions will be counted. However, if the reason is the same in this mentioned 
multiple entries on consecutive days/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 or where the actual dose administered/total daily dose is lower than the calculated 
dose amount based on the prescribed dose. Therefore any dose change to correct a dosing error 
will not be considered a dose reduction.  Only dose change is collected in the CRF, number of 
reductions will be derived programmatically based on the change and the direction of the change.
Table 2-6
DAR record example for capmatinib (INC280)
DAR 
record 
number
Prescribed 
daily dose
Administered 
daily dose
Dose reduction 
Yes/No
Comment
1
800
800
No
2
800
1000
No
Dosing error
3
800
800
No
Correcting dosing error
4
800
600
Yes
Due to AE
5
600
400
Yes 
Dosing error
6
600
600
No
Correcting dosing error
7
400
600
Yes
Protocol-prescribed dose 
reduction (e.g. due to AE), 
dosing error
8
600
600
No
Dose increase
9
600
400
Yes
Dosing error


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10
400
400
Yes
Dose reduction due to lower 
prescribed dose, although 
actual dose is not lower than 
before.
Note: It is assumed that if dose reduction is yes, that dose change was checked.
Escalation: For capmatinib, if the dose has been reduced per the mandatory dose modification, 
escalation to the previous dose level is permitted if the following criteria are met.

A period of 4 weeks of treatment has passed since restarting dosing at the reduced dose 
level and there is no recurrence of the AE

Subject is deriving clinical benefit.
Note: A dose rechallenge i.e when a subject goes back to the previous prescribed dose after an 
interruption, is not considered as an increase.
Missing data: If dose is recorded but regimen is missing or entered as ‘none’, it is assumed that 
the investigational drug was taken as per-protocol.
Treatment beyond RECIST progression
The number of patients who continue treatment beyond RECIST1.1 progression according to 
local investigators assessment based on protocol specified criteria will be summarized. It 
includes all patients who received any study treatment (i.e. at least one dose of any component 
of the study treatment) after RECIST 1.1 progression assessed by local investigators. Those 
patients 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 CRF 
pages.
2.4.2
Prior, concomitant and post therapies
Prior anti-cancer therapy
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior checkpoint inhibitor therapy, prior anti-neoplastic radiotherapy prior anti-neoplastic 
surgery, or other therapies not defined by the previous categories, will be summarized by 
treatment arm. Prior anti-neoplastic medications will be summarized by therapy type (e.g. 
chemotherapy, hormonal therapy, immunotherapy etc.), setting (e.g. adjuvant, metastatic, etc.) 
and also by lowest Anatomical Therapeutic Classification (ATC) class, preferred term and 
treatment.  Summaries will include total number of regimens, time from last treatment to 
progression for the last therapy, and type of therapy received as last therapy for unresectable
and metastatic melanoma prior to enrollment (checkpoint inhibitor vs targeted therapy).  Also, 
the prior checkpoint inhibitor therapy will be summarized by type of checkpoint inhibitor 
therapy (Anti-PD-1, Anti-CTLA-4, and combination therapy of anti-CTLA-4 and anti-PD-1).
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 
immunotherapy will be classified as ‘immunotherapy’.  For radiotherapy, time since last 


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radiotherapy, locations and setting of last therapy will be summarized.  For prior surgery, time 
since last surgery and procedure 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); anti-neoplastic surgery will be coded using MedDRA. 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 summarized 
by ATC class, preferred term, overall and by treatment group by means of frequency counts 
and percentages using FAS.
The number and percentages who reported taking at least one anti-neoplastic therapy since 
discontinuation of study treatment by category (see Table 2-7) will be summarized by treatment 
group.
Table 2-7
Categories of anti-neoplastic therapies since discontinuation
Category
Sub-category
Immunotherapy
Anti-CTLA-4
Anti-PD-1/Anti-PD-L1
Combination Anti-CTLA-4 + Anti-PD-1/Anti-PD-L1
IL-2
Interferon
Other or investigational
Targeted therapy
Chemotherapy
Radiotherapy
Surgery
Other or investigational
Concomitant medications
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient 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. 
Concomitant medications will be coded using the World Health Organization (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 


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frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. Concomitant medications with 
immunosuppressive intent will be summarized by lowest ATC class and preferred term using 
frequency counts and percentages.  
All reported systemic steroids will be summarized by lowest ATC class and preferred term 
using frequency counts and percentages.  Reported cumulative dose and maximum cumulative 
dose, adjusted for relative anti-inflammatory potency [Schimmer and Parker 1996], will also be 
summarized along with route of administration.
Table 2-8
Systemic steroid anti-inflammatory potency relative to 
Hydrocortisone
Steroid Name
Anti-inflammatory potency, 
relative to Hydrocortisone
Hydrocortisone
1
Cortisone acetate
0.8
Prednisone
4
Prednisolone
4
Methylprednisolone
5
Dexamethasone
30
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 150 days after last dose of PDR001.
Note: If a patient starts a post-treatment antineoplastic therapy after the last administration of 
study treatment, only medications relative to the AEs/SAEs that are reported are collected up 
to 150 days after discontinuation of PDR001/placebo. Medications starting between 31 days 
after last dose of study treatment and 150 days after last dose of PDR001 will be summarized 
acknowledging that complete collection of data may not be feasible for each patient.
All reported concomitant therapies will be listed. Any concomitant therapies starting and
ending prior to the start of study treatment or starting more than 150 days after the last dose of
PDR001 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 demonstrate the antitumor activity of spartalizumab in combination 
with novel agents as measured by ORR in previously treated unresectable or metastatic 
melanoma patients.


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2.5.1
Primary endpoint
Confirmed ORR is defined as the proportion of patients with confirmed best overall response
(BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1 (see 
Appendix 2 of the protocol). For the primary analysis, ORR will be calculated based on the 
FAS using local investigators review of tumor assessment data. ORR will be summarized using 
descriptive statistics (N,%) along with 2-sided exact 95% confidence interval (CI) [Clopper and 
Pearson 1934]. 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. Limited-field palliative radiotherapy may be allowed after documented 
discussion with Novartis (see Section 6.4.4 of the protocol). For patients who receive limited-
field palliative therapy, this therapy should not be considered in determining anti-neoplastic
therapy usage.
2.5.2
Statistical hypothesis, model, and method of analysis
Part 1:  Selection Phase
No formal hypothesis testing will be conducted in part 1. The objective of this part of the study 
is to explore the anti-tumor activity of the combination of spartalizumab with novel agents as 
measured by ORR per RECIST v1.1, and to select an arm(s) with promising efficacy that will 
be advanced to the expansion phase.
To determine whether arms have the potential to demonstrate clinically meaningful response 
rates, arms will need to show that they cross a specific efficacy probability threshold during the 
selection phase to advance to the expansion phase. Conversely, arms can also be shown to cross 
a specific futility probability threshold and consequently will be declared as futile and 
enrollment in those arms will be terminated.  These thresholds and probabilities are highlighted 
in Table 2-9.
Table 2-9
Probabilities thresholds used to declare efficacy or futility for 
an arm
Decision rule
Action
P(ORR ≤15%) ≥ 70%
Drop arm for futility
P(ORR ≥20%) ≥ 70%
Efficacy declared; Advance arm to 
expansion phase (part 2) 
The futility decision rule was determined based on simulations such that arms with response 
rate that is not considered clinically meaningful (i.e. ORR < 10%) will be dropped with high 
probability (as illustrated in Table 10-7 of the protocol). Similarly, the decision criterion for 
advancement to the expansion phase was determined so that arms with clinically meaningful 
response rate that warrants further development (i.e. ORR>25%) will be advanced with high 
probability (‘power’) (see also Table 10-7 of the protocol).  
To calculate these probabilities, a beta-binomial posterior distribution will be used as shown 
below:
~ 	
( + 1,  − + 1)


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where  are the number of confirmed responses in a combination arm (i), and  are the
number of subjects enrolled in a combination arm (i). In calculation of the posterior distribution, 
the uniformed prior, Beta[1,1] will be taken into account for each arm.  The posterior probability 
will be calculated separately for each arm based on the observed ORR based on RECIST v1.1 
criteria at each decision point, i.e. at each interim analysis as described in Section 10.7 of the 
protocol.  
No formal comparisons will be made between the combination arms for ORR in this ‘selection’ 
phase; instead each of the arms will be evaluated against efficacy and futility thresholds as 
presented above.
The final decision on whether an arm will be selected for advancement to the expansion phase 
will primarily be based on the observed ORR using decision rule described above but other 
efficacy (in particular duration of response), safety, and biomarker data will be considered as 
well. Further considerations related to the design and execution of the selection phase will be
captured in the [SAP Technical Appendix].
Part 2:  Expansion Phase
For the arms which show promise for efficacy in part 1 (based on pre-defined criteria), these 
arms will be expanded.  After completion of the expansion phase and within each arm separately, 
the following statistical hypothesis will be tested based on objective response rate (ORR):  

The null hypothesis is that the response rate is not clinically meaningful (≤ 10%).  

The alternative hypothesis is that the response rate is clinically meaningful (>10%). The 
target response rate that  warrants further development is ≥ 25% 
The null hypothesis will be formally rejected if the lower bound of exact 95% CI for ORR is 
above 10%.  The primary analysis of ORR at the end of part 2 will be based on a combined 
pool of part 1 and part 2 data for any given arm.
For example, assuming 24 subjects enrolled in an arm of interest in part 1 (see Section 10.8 of 
the protocol for details), assuming this arm met criteria for expansion and finally assuming 50 
subjects are enrolled in the expansion phase, then combined among 74 subjects enrolled in this 
arm in total and followed sufficiently, 14 or more responses need to be observed to reject the
null hypothesis. With those 14 responders among 74 subjects, the point estimate for ORR will 
be 18.9% with an exact 95% confidence interval of (10.8%, 29.7%).  Since the lower bound of 
the exact 95% CI will be > 10%, this leads to rejection of null hypothesis. The exact 95% CIs 
for potential observed ORR in 74 subjects are shown in Table 2-10:
Table 2-10
Exact binomial 95% confidence intervals around potential observed 
ORR for N=74
Number of responders
Observed ORR (%)
95% exact CI (%)
10
13.5
6.7, 23.5
11
14.9
7.7, 25.0
12
16.2
8.7, 26.6
13
17.6
9.7, 28.2
14
18.9
10.8, 29.7


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Number of responders
Observed ORR (%)
95% exact CI (%)
15
20.3
11.8, 31.2
16
21.6
12.9, 32.7
17
23.0
14.0, 34.2
18
24.3
15.1, 35.7
19
25.7
16.2, 37.2
20
27.0
17.4, 38.6
21
28.4
18.5, 40.1
22
29.7
19.7, 41.5
23
31.1
20.8. 42.9
24
32.4
22.0, 44.3
Fifty subjects enrolled in the expansion phase considered in the example above also correspond 
to the number of subjects needed to ensure that the hypothesis to be tested after completion of 
part 2 has sufficient predictive power conditioned on the ORR observed in the selection phase 
(part 1) (see Section 10.8 of the protocol). 
Alpha Control Considerations
For each arm (treatment combination cohort) included in the study, the potential for alpha 
inflation arises from the adaptive nature of the design, and in particular, from the presence of a 
selection process based on probabilistic decision rules described in Table 2-9.
To assess whether alpha is controlled for each combination treatment separately, simulations 
were conducted.  Below in Table 2-11, simulation results for scenarios that include one or more 
arms with the true ORR of 0.10 corresponding to the null hypothesis threshold (see also 
Scenarios 1 and 2 in presented in Section 10.8 of the protocol), are presented.  Scenario 2 is 
investigated to assess a potential impact of shrinkage estimator on type I error inflation.  In 
simulations, the focus was on assessing type I error for each ‘null hypothesis’ arm separately 
defined as the proportion of significant results after completion of part 2 for given arm 
(successful arm).  The technical details for the simulations are summarized in the [SAP 
Technical Appendix].
As shown in Table 2-11, for each of the ‘null hypothesis’ arms with the true ORR = 0.10, the 
probability is less than 0.025 (ranging between 0.0093 and 0.0126) and therefore alpha is well-
controlled.  Even though there no explicit alpha control measure used, alpha within each arm is 
still well-controlled due to the use of the futility criterion in the selection phase, as well as the 
adaptive nature of the sample size of part 2, based on the shrinkage estimator. Further simulation 
results for alpha for other scenarios and under a wide variety of samples sizes for the expansion 
arm will be presented in the [SAP Technical Appendix]. 
Table 2-11
Type I error assessment: Probability of a successful result for 
scenario where the true ORR equals 0.10 for each arm and sample 
size of the expansion arm is 50 subjects
Scenario
Arm
True ORR
Probability of significant result
1
1
0.10
0.0093
1
2
0.10
0.0114


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1
3
0.10
0.0093
2
1
0.10
0.0126
2
2
0.25
NA*
2
3
0.25
NA*
* NA = not applicable in the context of type I error assessment; applicable only to 
the arms with true ORR = 0.10 corresponding to the null hypothesis.
2.5.3
Handling of missing values/censoring/discontinuations
Patients with unknown or missing best overall response (BOR) will be counted as failures, i.e. 
non-responders. Patients who were non-responders before initiation of subsequent anti-cancer 
therapy will still be non-responders.  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 patients will be included in the FAS and will be 
counted as ‘failures’.
2.5.4
Supportive analyses
As a supportive analysis, ORR based on RECIST v1.1 criteria as per blinded independent 
central review (BICR) will be analyzed with the same analysis conventions as the primary 
efficacy analysis, and the treatment effect will be summarized by the ORR with its 95% 
confidence interval using the Clopper-Pearson method.
Subgroup analyses for the primary endpoint
The primary endpoint of ORR will be summarized 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. For each of the subgroups, the proportion of patients with objective 
response will be analyzed.
 
 Forest plot (n, odds ratio, 95% CI) will be produced to 
graphically depict the treatment effect estimates in different subgroups. No inferential statistics 
(p-values) will be produced for the subgroups.
Concordance analysis of BOR
An assessment of the concordance between BIRC assessment and local assessment of the Best 
Overall Response for each subject will be provided by treatment arm. The calculation will be 
based on the percent agreement (the proportion of response outcomes that agree or match across 
both Independent Reviewer and Investigator Assessments):
	 	 =   
	ℎ   +   
	ℎ  −  
!	
"    #	 
    
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Reasons for “Unknown” BOR
Patients with ‘unknown’ BOR will be summarized by reason for having unknown status. The 
following reasons will be used:

No valid post-baseline assessment

All post-baseline assessments have overall lesion response UNK

New anti-neoplastic therapy started before first post-baseline assessment

SD or non-CR/non-PD too early  

PD too late 
Note 1: A SD or Non-CR/Non-PD is considered as “SD too early”’ if the SD or Non-CR/Non-
PD is documented within first 11 weeks (takes into account the 1 week window for post-
baseline assessments) after randomization date.
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 (takes into account the 1 week window for post-baseline 
assessments) with no qualifying CR, PR or SD or Non-CR/Non-PD 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 based on local and central 
assessment separately. These plots will display the best percentage change from baseline in
the sum of diameters of all target lesions for each patient. Only patients 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 patient 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. Patients without any valid assessments will 
be completely excluded from the graphs.
The total number of patients displayed in the graph will be shown and this number will be 
used as the denominator for calculating the percentages of patients with tumor shrinkage and 
tumor growth. Footnote will explain the reason for excluding some patients (due to absence of 
any valid assessment).
All possible assessment scenarios are described in Table 2-12.
Table 2-12
Inclusion/exclusion of assessments used in waterfall graph
Criteria for inclusion/exclusion
Possible sources
of contradictions


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case
Target
response
Overall
lesion
Include
in waterfall?
Non-
target
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
Percentage change from baseline in the sum of diameters of all target lesions over the time will 
be displayed for individual patients per combination arm.
2.6
Analysis of the key secondary objective
The key secondary objective of the study is to determine duration of response treatment with 
spartalizumab in combination with novel agents in patients with previously treated unresectable 
or metastatic melanoma.
2.6.1
Key secondary endpoint
The key secondary endpoint of the study is DoR, defined as the time from the date of first 
documented response of CR or PR (i.e., the start date of response, not the date when response 
was confirmed) to the date of the first documented progression or death due to underlying 
cancer.  For the key secondary efficacy analysis, DoR will be based on local investigators
review of tumor assessments and using RECIST 1.1 criteria (see Appendix 2 of the protocol). 
The key secondary analysis will be based on FAS and will include all data observed up-to the 
cut-off date.  As a supportive analysis, DoR will also be summarized based on the BIRC review 
of tumor data.
If a subject has not had an event before leaving study or initiation of subsequent anti-cancer 
therapy, progression-free survival is censored at the date of last adequate tumor assessment. 
Censoring of subjects who have not had an event before initiation of subsequent anti-cancer 
therapy corresponds to option F(2) presented in Table 14-9 of the protocol and is used in this 
study in order to obtain DoR estimates that are not confounded by subsequent therapies.
Discontinuation due to disease progression (collected on the ‘End of treatment’ and ‘End of 
post treatment follow up’ disposition pages) without supporting objective evidence satisfying
progression criteria per RECIST 1.1 will not be considered disease progression for DoR
derivation. Clinical deterioration will not be considered as a qualifying event for progression 
for the key secondary analysis.
2.6.2
Statistical hypothesis, model, and method of analysis
No formal hypothesis testing will be conducted for the DoR analysis. The key secondary 
efficacy variable, DoR will be analyzed at the interim analyses for the selection phase, and the 
primary analysis for the expansion phase, based on the data observed in the FAS up-to the cut-
off date, according to the treatment group and stratification assigned at randomization.  The
survival distribution of DoR will be estimated using the Kaplan-Meier method from a 


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combined pool of part 1 and part 2 data for any given arm.  The results will be plotted 
graphically by treatment arm. The median 25th and 75th percentiles of DoR along with 95%
confidence intervals will be presented by treatment group.  The survival probabilities at 4, 6, 8 
and 12 months, and the associated 95% confidence intervals will be summarized by treatment 
arm.
2.6.3
Handling of missing values/censoring/discontinuations
DoR will be censored at the date of the last adequate tumor assessment if no DoR 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 
are available (before an event or a censoring reason occurred) then the date of 
randomization/start date of treatment will be used.
In particular, DoR will be censored at the last adequate tumor assessment if one of the following 
occurs: absence of event; the event occurred after two or more missing tumor assessments; 
before the start of the new anti-cancer therapy. The term “missing adequate tumor assessment” 
is defined as a tumor assessment (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 2-13 for censoring and event date options and outcomes for DoR and PFS 
analysis (PFS analysis is further discussed in Section 2-7).
Table 2-13
Outcome and event/censor dates for DoR and PFS 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


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Situation
Date
Outcome
New anticancer therapy given 
prior to protocol defined 
progression (including patients 
who crossover from the control 
to the treatment arm.)
Date of last adequate 
assessment on or prior to 
starting new anti-cancer 
therapy (or crossover 
treatment)
Censored
Death before first PD 
assessment
Date of death
Progressed
2.7
Analysis of secondary 
 efficacy 
objective(s)
The other secondary
efficacy objectives are to: 
!
Evaluate the efficacy of each combination arm, as measured by progression-free 
survival (PFS)
!
Evaluate the efficacy of each combination arm, as measured by disease control rate 
(DCR)
!
Evaluate the overall survival (OS) of each combination arm
2.7.1
Secondary 
 efficacy endpoints
Progression-Free Survival (PFS)
PFS is defined as the time from the date of randomization to the date of the first documented 
progression or death due to any cause.  PFS will be based on both local investigator and central 
assessments of tumor assessments and using RECIST 1.1 criteria (see Appendix 2 of the 
protocol). The primary analysis will be based on FAS and will include all data observed up-to 
the cut-off 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 _Table_2-4_SubjectTable 2-13 and 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 ‘End of treatment’
and ‘End of post treatment follow up’ disposition 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.
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Disease Control Rate (DCR)
DCR is defined as the proportion of patients with a best overall response (BOR) of confirmed 
CR or PR, or SD lasting 12 weeks or longer, according to RECIST 1.1 criteria. A patient will 
be considered to have SD for 12 weeks or longer if a SD response is recorded at 11 weeks or 
later from randomization, allowing for the ±1 week visit window for tumor assessments. DCR
will be calculated using the FAS based on both the local investigator and central tumor 
assessments. 
Overall Survival (OS)
Overall Survival (OS) is defined as the time from date of randomization to date of death due to 
any cause. A cut-off date will be established for each analysis of OS. All deaths occurring on 
or before the cut-off date in the FAS will be used in the OS analysis. 
If a patient is not known to have died at the time of analysis cut-off, OS will be censored at the
date of last contact.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.7.2
Statistical hypothesis, model, and method of analysis
There will be no hypothesis testing for any of the endpoints listed below.
Progression-Free Survival
The secondary efficacy variable, PFS, will be analyzed at the interim looks, the primary analysis, 
and the final analysis based on the data observed in the FAS up-to the cut-off date, according 
to the treatment group and strata assigned at randomization. The survival distribution of PFS 
will be estimated using the Kaplan-Meier method. The results will be plotted graphically by 
treatment arm. The median 25th and 75th percentile of PFS along with 95% confidence intervals 
will be presented by treatment group. The survival probabilities at 4, 6, 8 and 12 months, and 
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the associated 95% confidence intervals will be summarized by treatment arm.  As a supportive 
analysis, PFS will also be summarized based on the BIRC review of tumor data.
Disease Control Rate
DCR will be summarized using descriptive statistics (N, %) by treatment arm along with two-
sided exact binomial 95% CIs [Clopper and Pearson 1934].  As a supportive analysis, DCR will 
also be summarized using descriptive statistics (N, %) based on the BIRC review of tumor data.
Overall Survival
The survival distribution of OS distribution will be estimated using the Kaplan-Meier method, 
and Kaplan-Meier curves, medians and 95% confidence intervals [Brookmeyer and Crowley
1982] of the medians intervals along with the proportion of patients alive at 4, 6, 8 and 12
months and the associated 95% confidence intervals will be presented for each treatment group.
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
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ECOG performance status
The ECOG PS scale (Table 2.14) will be used to assess physical health of patients, ranging from 
0 (most active) to 5 (least active):
Table 2-14
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 patients in each score category will be provided by 
treatment arm and time point based on the windows defined in Section 2.1.
2.7.3
Handling of missing values/censoring/discontinuations
Progression-Free Survival
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 
are available (before an event or a censoring reason occurred) then the date of 
randomization/start date of treatment will be used.
In particular, PFS 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 tumor assessment (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 2-13 for censoring and event date options and outcomes for PFS.
Overall Survival
If a patient 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 patient was alive, i.e., last contact date (see Section 2.4).


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2.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group.  In addition, pooled safety analysis based on all subjects will be produced.
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 dose of 
study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose of 
study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
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.
Safety will be assessed based on all treated subjects; toxicities will be defined by CTCAE v4.03. 
Incidence and severity of adverse events, causality attribution to drug, time to event onset, 
duration of the event, its resolution and concomitant medications administered will be recorded.  
Additional safety assessments will include laboratory safety assessment, vital signs, and cardiac 
assessment. 
2.8.1
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 PDR001. All AEs 
collected in the AE (e)CRF page will be listed along with the information collected on those 
AEs e.g. AE relationship to study 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 Common Terminology Criteria for 
Adverse Events (CTCAE) grades for the same preferred term will be summarized under the 
maximum CTCAE grade recorded for the event. AE with missing CTCAE grade will be 
included in the ‘All grades’ column of the summary tables.
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the total column.
The following adverse event summaries will be produced by treatment arm; overview of 
adverse events and deaths (number and % of subjects who died, with any AE, any SAE, any 
dose reductions/interruptions, leading to treatment discontinuation), AEs by SOC and PT,
summarized by relationship (all AEs and AEs related to study treatment), seriousness (SAEs 
and non-SAEs), leading to treatment discontinuation, leading to dose interruption/adjustment, 
requiring additional therapy, requiring immunosuppressive medication and leading to fatal 
outcome. In addition, a summary of serious adverse events with number of occurrences will be 


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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, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 
and equal to 5% and on 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 patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date 
of the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest (AESI) during the on-treatment period will be tabulated. The 
list of AESI will also include relevant events for spartalizumab, and the novel agents.
Data analysis of AESIs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound PDR001, the individual novel agents, as well as 
combination specific AESIs (PDR001 + novel agent). 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. All AESI terms for the individual compounds as well as for combination 
specific AESIs are captured in the case retrieval strategy (CRS).
For each specified AESI, number and percentage of patients with at least one event of the AESI 
occurring during on treatment period will be summarized.
Summaries of these AESIs will be provided by 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.


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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 PDR001.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. This listing should be included in section 16 of CSR.
2.8.2
Deaths
Separate summaries for on-treatment and all deaths 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 PDR001.
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.
Note: “Study indication” as primary reason of death should be coded using MedDRA terms 
based on the diagnosis eCRF field at start of study. If not coded accordingly in the database, it 
still must be included in the summary table. Coded reasons for deaths will then be summarized 
by category ‘Study indication’ and ‘Other’ (as selected by the investigator).
The death summaries cover subjects from the Safety Set. The count of deaths in safety analyses 
could be different from the number of deaths in the efficacy analyses.
2.8.3
Laboratory data
Grading of laboratory values will be assigned programmatically as per National Cancer Institute 
(NCI) Common Terminology Criteria for Adverse Events (CTCAE) v4.03. 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 v4.03, results will be categorized 
as low/normal/high based on laboratory normal ranges.
The following summaries will be generated separately for hematology, and biochemistry tests:

Listing of all laboratory data with values flagged to show the corresponding CTCAE 
v4.03 grades if applicable and the classifications relative to the laboratory normal ranges
For laboratory tests where grades are defined by CTCAE v4.03

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will 
be counted only once for the worst grade observed post-baseline.

Shift tables using CTCAE v4.03 grades to compare baseline to the worst on-treatment 
value
For laboratory tests where grades are not defined by CTCAE v4.03

Shift tables using the low/normal/high/ (low and high) classification to compare baseline 
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On analyzing laboratory, data from all sources (central and local laboratories (as applicable)) 
will be combined. The summaries will include all assessments available for the lab parameter 
collected no later than 30 days after the last study treatment administration date (see Section 
2.1.1).
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment):

Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject
will be counted only for the worst grade observed post-baseline.

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value

For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.

Trends of lab parameter values over time (baseline and selected on-treatment 
timepoints) should be displayed via boxplots based on time windows and 
corresponding tables displaying the statistics used for the box plots by the selected 
time points.
The following listings will be produced for the laboratory data:

Listings of all laboratory data, with CTCAE grades and classification relative to the 
laboratory normal range. Lab data collected during the post-treatment period will be 
flagged.  

Listing of all CTCAE grade 3 or 4 laboratory toxicities
Liver function parameters 
Liver function parameters of interest are total bilirubin (TBL), alanine aminotransferase 
(ALT), aspartate aminotransferase (AST) and alkaline phosphatase (ALP). The number (%) of 
patients 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


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
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 metastases, liver function at baseline etc.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Categorical Analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these subjects will be produced by treatment group.
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
12-lead ECG including PR, QRS, QT, QTcF, and RR intervals will be obtained for each subject 
during the study. ECG data will be read and interpreted centrally.
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. A separate listing of only the subjects with notable ECG values may also be produced.
In the listing, the assessments collected during the post-treatment period will be flagged.


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2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
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 2-15
below.
Table 2-15
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%
Body 
temperature
>= 39.1
-
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented by treatment arm.
A listing of all vital sign assessments will be produced by treatment arm and notable values will 
be flagged. A separate listing of only the subjects with notable vital sign values may also be 
produced. In the listing, the assessments collected outside of on-treatment period will be 
flagged. 
 
 
 
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2.10
PD and 
PD analyses
2.10.1
Immunogenicity
2.10.1.1 Sample ADA Status
Each IG sample is assessed in a three tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). Samples identified as 
positive in the confirmatory assay are considered ADA positive 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
! Presence of NAb (for positive samples, if NAb assay results are available): yes or no
! 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
!
Sample ADA status is determined based on the following definitions:
!
ADA-inconclusive sample: Sample where assay is ADA negative 
 
 at the time of IG sample collection is greater than or 
equal to the drug tolerance level or missing.  
!
Unevaluable sample: Sample where assay is not available.
!
Determinant sample: Sample that is neither ADA-inconclusive nor unevaluable.
The following definitions apply only to determinant samples:
!
ADA-negative sample: Determinant sample where assay is ADA negative 
 
 at the time of IG sample collection is less 
than the drug tolerance level.
!
ADA-positive sample: Determinant sample where assay is ADA positive.
!
ADA-positive NAb sample: Determinant sample where assay is ADA positive and 
presence of NAb = yes.
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. 
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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
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).
2.10.1.2 Subject ADA status
Any IG sample collected after 150 days of the last dose of PDR001, LAG525, or Canakinumab
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. 
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!
Treatment-induced ADA-positive subjects; denominator is the number of subjects with 
ADA-negative sample at baseline. 
!
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.
 
 
 
2.11
Patient-reported outcomes
Not applicable.
2.12
Biomarkers
2.12.1
Introduction
As a project standard, Novartis Oncology Biostatistics will analyze only biomarkers collected
in the clinical database. The biomarker analysis covered within the SAP pertains mainly to the 
secondary objective endpoint of determining the proportion of subjects with a favorable 
biomarker profile (pFBP, Table 1-1 and Table 2-18).
 
 
 
For example, there may be inadequate sample number, issues related to the 
quality of the sample or issues related to the assay that preclude analysis. Alternatively, there 
may be insufficient efficacy to allow for correlative analyses. Therefore, depending on the 
results obtained during the study, collection/analysis of some samples may be omitted.
 
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2.12.2
Secondary biomarker objectives
Changes in phenotype and/or activation of T cell populations in the tumor and tumor 
microenvironment will be analyzed on an on-going basis as part of the secondary objectives 
(Table 1-1 and Table 2-18).  Every effort will be made to make this data available for internal 
decision making purposes. Such analyses may include, but are not limited to number of CD8+
T cell infiltration, T cell activation level by IHC, gene expression analysis, and T cell 
repertoire/clonality by TCR-sequencing (Table 2-18). 
Table 2-18
Parameter definitions for categorization of biomarker outcome at 
subject level
Biomarker parameter
Analysis
Criteria for 
favorable 
biomarker result
Number of tumor infiltrating 
T cells (TILs)
Changes of CD8+ T cell numbers as 
assessed by IHC in tumor/ tumor 
microenvironment with treatment
Increase
Activation level of TILs
Change of T cell activation marker level(s) as 
assessed by IHC in tumor/tumor 
microenvironment with treatment
Increase
TIL repertoire/specificity of T 
cell response to tumor
TCR clonality changes as assessed by TCR-
sequencing in tumor/tumor microenvironment 
with treatment
Increase
Changes in immune 
response gene expression 
signatures
Changes in expression of genes and/or gene
signatures as assessed by mRNA analysis in 
tumor/tumor microenvironment with treatment
Defined per 
gene/gene signature
2.12.3
Biomarker data 
As a project standard, Novartis Oncology Biostatistics will analyze only biomarkers collected
in the clinical database. The biomarker analysis covered within the SAP pertains mainly to the 
secondary objective endpoint of determining the proportion of subjects with a favorable 
biomarker profile (pFBP, Table 1-1 and Table 2-18).
 
The biomarker analysis set, as it pertains to the secondary objectives (Table 1-1) as well as the 
analysis of the change in LAG-3 expression levels, consists of all subjects in the safety set with 
an evaluable baseline tumor biopsy sample and at least one evaluable post-baseline tumor 
biopsy sample. 
Table 2-19 summarizes the biomarker collection schedules and sample types which are in scope 
with this SAP.  
Table 2-19
Sample biomarker summary table
Biomarker 
parameter
Biomarker analysis 
measurement
Time point
Sample
Method
Dataset
Number of TILs
Percent of tumoral 
CD8+ cells 
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
IHC
B1
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Biomarker 
parameter
Biomarker analysis 
measurement
Time point
Sample
Method
Dataset
Activation level of 
TILs
Percent of tumoral 
GzmB+ within 
CD8+cells
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
FIHC/AQUA
B1
Activation level of 
TILs
Percent of tumoral 
CD8+ within Ki67+ 
cells
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
FIHC/AQUA
B1
TIL repertoire/
specificity of T cell 
response to tumor
TCR clonality
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
TCR 
sequencing
B1
Changes in 
immune response 
gene expression 
signatures
Gene signature 
expression levels
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
Nanostring
B1
2.12.4
General data handling and preprocessing
The mean of all pre dose assessments (i.e. screening and Cycle 1 Day 1 assessments) will be
used as the baseline value. The on-treatment assessment will be the result from the tumor biopsy 
taken between C1D21 and C2D1.
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
2.12.5
Secondary biomarker objectives
The secondary objective biomarker data will be listed for each subject for all time points 
(baseline and on treatment) and ordered by the treatment arm. Absolute and relative change 
(percent change) from baseline of each biomarker parameter will be calculated for each patient 
and summarized for each treatment arm. Graphical presentations of the change and percentage 
change from baseline will be produced via spaghetti plots and boxplots and ordered by the 
treatment arm.
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2.12.5.1
IHC for quantifying tumor infiltrating T cells (TILs)
The number of TILs at each timepoint will be assessed by measuring % CD8+ cells within the 
invasive margin, tumor and stroma area (as defined by Melamask staining), using the following 
variables provided in the raw data:

Intraepithelial tumor (IE) CD8+ density (% of cells containing CD8)

Intrastroma (IST) CD8+ density 

IST CD8+ density 0 to 10 µm (% of CD8+ IST cells within the 0 to 10 µm region of the 
IE-IST border)

IST CD8+ density >10 to 20 µm 

IST CD8+ density >20 to 30 µm 

IST CD8+ density >30 to 40 µm 

IST CD8+ density >40 to 50 µm  
For all CD8 parameters above, the baseline value, on-treatment (C1D21-C2D1) value, and the 
difference from baseline to on-treatment will be listed for each individual patient by treatment 
arm. The mean, standard deviation, %CV, median, minimum, maximum, inter-quartile range 
and number for all patients (regardless of treatment arms) will be reported for baseline and 
change from baseline to on-treatment by combination arm.   Inter-quartile range is the number 
of data points between the 25th and 75th percentile.
The proportion of GzmB+ T cells and Ki67+ T cells will be assessed using FIHC and AQUA
at each timepoint. The % of GzmB+CD8+ and Ki67+CD8+ cells within the invasive margin, 
tumor and stroma area (as defined by Melamask staining) will be calculated using the following 
variables provided in the raw data:

IE CD8+Ki67+ density (% of CD8+cells containing Ki67)

IST CD8+Ki67+ density 

IE CD8+GzmB+ density (% of CD8+cells containing GzmB)

IST CD8+GzmB+ density 
The GzmB+ density is expected to be low but unique to T cells. In instances where the density 
is <10%, the following raw data variables may be employed in lieu of the one above for all 
samples within a particular analysis:

IE GzmB+ density (% of cells containing GzmB)

IST GzmB+ density (% of cells containing GzmB)
For all parameters above, the baseline value, on-treatment value, and the difference from 
baseline to 3-4 weeks will be listed for each individual patient by treatment arm. The mean, 
standard deviation, %CV, median, minimum, maximum, inter-quartile range and number for 
all patients (regardless of treatment arms) will be reported for baseline and change from baseline 
to on-treatment (C1D21-C2D1) by combination arm.   Inter-quartile range is the number of data 
points between the 25th and 75th percentile.
2.12.5.2 TCR sequencing for quantifying T cell clonality 
T cell clonality is calculated as follows:


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1 −(
"$% &ℎ
 	)
Using the following variable provided in the raw data:

Normalized Shannon entropy.
2.12.5.3 Nanostring for quantifying gene expression signatures
Gene expression data will be calculated using the following variables provided in the raw data:

raw gene expression 

housekeeper-gene normalized gene expression
The gene signatures that will be scored for expression are defined in Table 2-20.  The score of 
each gene signature will be calculated using the simple average of log expression values for all 
genes. The aggregate score for the three gene signatures, calculated as average of the score of 
each gene signature will be used as one of the criteria for favorable biomarker result. Additional 
genes may be considered for gene expression analyses pertaining to biomarker outcomes.
Table 2-20
Immune response gene expression signatures
Signature 
Gene names
T-cell inflamed
[Ayers, 2017]
CD3D
IDO1
CIITA
CD3E
CCL5
GZMK
CD2
HLA-DRA CXCL13 IL2RG 
NKG7
HLA-E CXCR6
LAG3
TAGAP
CXCL10 STAT1
GZMB
CD8 T-cell
CCL5
CTSW
FASLG
CD8B
ZNF683
GZMA
XCL2
CD7
KLRC1
CD8A 
XCL1
TRDC NKG7
KLRK1
GNLY
PRF1
GZMB
GZMH
LAG3
KLRD1
IFN-gamma 
IFNG
CXCL9
CXCL10 CXCL11 GBP1
For all parameters above, the baseline value, on-treatment (C1D21-C2D1) value, and the 
difference from baseline to 3-4 weeks will be listed for each individual patient by treatment arm. 
The mean, standard deviation, %CV, median, minimum, maximum, inter-quartile range and 
number for all patients (regardless of treatment arms) will be reported for baseline and change 
from baseline to on-treatment by combination arm.   Inter-quartile range is the number of data 
points between the 25th and 75th percentile.  Calculation of proportion of patients with favorable 
biomarker profile 
The biomarkers listed in Table 2-20 will be used to calculate the proportion of subjects with a 
favorable biomarker profile (pFBP). 

As for the parameter of number of tumor infiltrating T cells (TIL), an increase from baseline 
to on-treatment (C1D21-C2D1) in the IE CD8+ density is considered a favorable change. 
Whether such increases are accompanied by a decrease in IST CD8+ density may be taken 
into consideration as a signal for CD8+ T cell migration into the tumor. Furthermore 
increases in CD8+ density in IST areas closer to the IE-IST border (e.g. an increase in 0-10 
µm and >10-20 µm regions compared to more distal regions, >30 µm) may be taken into 
consideration as another signal for CD8+ T cell migration into the tumor

As for the activation level of TIL, an increase from baseline to on-treatment in percentage 
of GzmB+ T cells is considered favorable. In the presence or absence of an increase in 
GzmB+ T cells, an increase in percentage of Ki67+ T cells is also considered favorable. If 
decreases in both GzmB + T cells and Ki67+ T cell are observed, this parameter would not 
be considered favorable.


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!
As for the TIL repertoire/specificity of T cell response to tumor, an increase from baseline 
to on-treatment in TCR clonality is considered favorable. 
!
An increase from baseline to on-treatment in the aggregate gene signature score would be 
considered favorable.
For each biomarker involved in the evaluation of pFBP as stated above, the baseline, 3-4 weeks
biomarker values, and the difference from baseline to 3-4 weeks will be listed for each 
individual patient by combination arm. The mean, standard deviation, %CV, median, minimum, 
maximum, inter-quartile range and number for all patients (regardless of treatment arms) will 
be reported for baseline and change from baseline to 3-4 weeks by combination arm.   Inter-
quartile range is the number of data points between the 25th and 75th percentile.
If an individual subject has two or more favorable biomarker parameters from Table 2-16 then 
that subject will be considered to have a favorable biomarker profile. 
For each combination arm, the proportion of subjects with a favorable biomarker profile (pFBP) 
are then defined as the number of subjects with favorable biomarker profiles divided by the 
number of subjects enrolled into the arm which are included in the biomarker analysis set for 
that particular interim analysis and will be summarized. 
 
 
 
 
 
 
 
 
 
 
 
 
 
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2.14
Interim analysis
Primary endpoint: Objective Response Rate (ORR)
Part 1: Selection phase
The 1st interim analysis is planned once at least ten patients have been randomized into each 
of the three initial treatment combination arms, and have completed at least 20 weeks of 
treatment (corresponding to two post-baseline assessments) or discontinued the study. It is 
possible to terminate one or more combination arms at the 1st interim analyses for lack of 
adequate efficacy, i.e. futility. It is also possible for advance one or more combination arms at 
the 1st interim analysis to the expansion phase if those arms cross a specific efficacy 
probability threshold. 
Assessment of futility and efficacy will be based on the calculated Bayesian predictive 
probabilities of occurrence, using the following criteria highlighted in Table 2-9.
The (posterior) predictive distribution of future responders conditioned on the observed data 
at the interim is a beta-binomial distribution.  More details on the (posterior) predictive 
distribution used for this study are highlighted in Section 2.5.2.
Enrollment and assessment at subsequent interim analyses for each treatment group will 
continue at an assessment period as defined in Section 4.2 of the protocol, or 45 subjects have 
been randomized into a treatment group rules presented in Section 2.5.2.  
Note:  If new combination arms are added to the study, those combination arms will have 
their interim analyses at the same time-points as the first three combination arms on this study 
(after 10 patients have been randomized and have sufficient data for analysis, and then if 
needed, at an assessment period as defined in Section 4.2 of the protocol, or 45 patients have 
been randomized into each arm).
Part 2: Expansion phase
No formal interim analysis is planned for this part of the trial. The primary analysis will be 
performed once the expanded arm has fully enrolled and also after all patients randomized in 
the expansion phase had at least 9 months of follow-up. This timing would allow for a 
potential minimum duration of response of 6 months for all subjects randomized. Formal 
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hypothesis testing of the primary endpoint (as described in Section 2.5.2) will be performed at 
the primary analysis.  The final analysis will be performed at the end of the study as described 
in Section 2.5.1.
3
Sample size calculation
In this section, sample size will be presented based on specific potential scenarios for true ORR.  
In particular, for selection phase (part 1), since one can consider a wide variety of potential true 
ORR scenarios, the sample size will not be based on an exact calculation leading to one fixed 
number, but will instead be characterized by simulation based on average number of subjects 
enrolled into these arms under each individual scenario for true ORR. It is important to 
emphasize that the true underlying efficacy activity (in terms of ORR) of the three initial arms 
will have a substantial bearing on the total sample size needed in part 1. Subsequently, and 
given the adaptive nature of the study design, the sample size needed in expansion phase (part 
2) to ensure sufficient power will depend on the ORR observed in part 1 and in particular on 
the rate observed in the arm that qualifies for expansion to part 2.
The sample size calculation for parts 1 and 2 were performed using SAS 9.4 software, based on 
the probabilities of first determining a efficacious treatment and a futile (non-efficacious) 
treatment in the selection phase (part 1), and then determining the number of subjects needed 
to reject the null hypothesis (part 2). Assumptions and sample size calculations for both the 
selection and expansion phases are summarized in Section 10.8 of the protocol.  Additional 
simulation results for both the selection and expansion phases will be summarized in the [SAP 
Technical Appendix].
4
Change to protocol specified analyses
The only changes to protocol specified analysis in the SAP is the inclusion of an IG analysis set 
for immunogenicity analysis, as well as specific sub-group analyses for efficacy and safety 
analysis.
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 patient is considered as on-going:
The patient should be treated as on-going and the cut-off date should be used as the dose end
date.
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR


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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.
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
Patients 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


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Missing 
Element
Rule
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  


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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* 
day, month

If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period * 
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*
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. 
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications.
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.


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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 4.03.
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 4.03. 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 4.03 at the time of analysis will be used. The Novartis 
internal CTC grading document should be added as appendix to the SAP and to Section 16.1.9 
of the CSR.  For laboratory tests where grades are not defined by CTCAE version 4.03, results 
will be graded by the low/normal/high (or other project-specific ranges, if more suitable)
classifications based on laboratory normal ranges.
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 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.
Imputation Rules  
Common Toxicity Criteria (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 an xxx differential
''' 	 = (()* 	) ∗,''' % .
"
100
0
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:


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*	 *
"$ 1
2 3 = *
"$ 1
" 3 −0.8 6"$ 1 
23 −48
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
Please refer to Section 10 of the protocol, Section 2.5.2, and the [SAP Technical Appendix] for 
extended details on the modeling and SAS procedures used for both the selection and expansion 
phases of the trial.  Other details for the primary analysis are shown below
Analysis of Binary Data
Single arm study
For the selection phase, the following statistical hypothesis will be tested:
H0: ORR ≤10 % will be tested vs H1: ORR > 10 % 
using a one-sided test with α=0.025 based on the exact binomial distribution.
Responses will be summarized in terms of percentage rates with 95% CIs. An exact binomial 
confidence interval (implemented using SAS procedure FREQ with EXACT statement for one-
way tables) will be calculated [Clopper and Pearson 1934]
SAS procedure FREQ will be used to estimate the proportion of responders (binary outcome = 
1 or “Yes”), along with the associated 95% (=100 × (1 – two-sided alpha level)) two-sided 
Pearson-Clopper CI and exact one-sided p-value for the hypothesis test of the null proportion
(0.10). 
Confidence interval for response rate
Responses will be summarized in terms of percentage rates with 100(1 −α)% confidence 
interval using exact binomial confidence interval (implemented using SAS procedure FREQ
with EXACT statement for one-way table [Clopper and Pearson 1934].
5.4.2
Key secondary analysis
Kaplan-Meier estimates
For Duration of Response, 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 


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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 ties = EFRON statement in LIFETEST procedure will be used to analyze time to event data 
with ties.
5.4.3
Audit-based BIRC assessment of PFS
Not applicable.
5.5
Rule of exclusion criteria of analysis sets 
Not applicable.
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6
Reference
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http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/on
cologicdrugsadvisorycommittee/ucm311141.pdf
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10. Fleming TR, Harrington DP and O’Brien PC (1984). Designs for group sequential tests. 
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167-174.


Clinical Development
Spartalizumab (PDR001), LAG525
CPDR001J22011&7
A randomized, open-label, phase II open platform study 
evaluating the efficacy and safety of novel spartalizumab
(PDR001) combinations in previously treated unresectable 
or metastatic melanoma
Statistical Analysis Plan (SAP)for non-randomized section 
(single-arm1A)
Author:
Trial Statistician, 
Document type:
SAP Documentation
Document status:
Final
Release date:
12-Nov-2020
Number of pages:
26
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
PPD


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for update
Outcome for update
Section and title impacted 
(Current)
12-
Nov-
2020
Prior to
FPFV of 
Arm 1A
Initial version
N/A - First version
NA


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical methods...............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General definitions..................................................................................7
2.2
Analysis sets ............................................................................................................8
2.2.1
Subgroup of interest ................................................................................9
2.3
Subject disposition, demographics and other baseline characteristics ....................9
2.3.1
Subject disposition ................................................................................10
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................11
2.4.1
Study treatment / compliance................................................................11
2.4.2
Prior, concomitant and post therapies...................................................12
2.5
Analysis of the primary objective..........................................................................13
2.5.1
Primary endpoint...................................................................................14
2.5.2
Statistical hypothesis, model, and method of analysis..........................14
2.5.3
Handling of missing values/censoring/discontinuations.......................15
2.5.4
Supportive analyses...............................................................................15
2.6
Analysis of the key secondary objective ...............................................................16
2.6.1
Key secondary endpoint........................................................................16
2.6.2
Statistical hypothesis, model, and method of analysis..........................16
2.6.3
Handling of missing values/censoring/discontinuations.......................16
2.6.4
Duration of follow-up ...........................................................................16
2.7
Analysis of secondary 
 efficacy objective(s)................................17
2.7.1
Secondary 
 efficacy endpoints .....................................17
2.7.2
Statistical hypothesis, model, and method of analysis..........................17
2.8
Safety analyses.......................................................................................................18
2.8.1
Adverse events (AEs)............................................................................18
2.8.2
Deaths....................................................................................................18
2.8.3
Laboratory data .....................................................................................18
2.8.4
Other safety data ...................................................................................20
20
2.10
PD and
PD analyses.........................................................................................20
2.11
Subject-reported outcomes ....................................................................................21
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2.12
Biomarkers.............................................................................................................21
2.12.1
Introduction...........................................................................................21
2.12.2
Secondary biomarker objectives ...........................................................21
2.12.3
Biomarker data......................................................................................22
2.12.4
General data handling and preprocessing .............................................22
2.12.5
Secondary biomarker objectives ...........................................................22
2.13
Other Exploratory analyses....................................................................................24
2.14
Interim analysis......................................................................................................24
3
Sample size calculation .....................................................................................................25
4
Change to protocol specified analyses ..............................................................................25
5
Appendix ...........................................................................................................................25
5.1
Imputation rules.....................................................................................................25
5.1.1
Study drug.............................................................................................25
5.1.2
AE date imputation ...............................................................................25
5.1.3
Concomitant medication date imputation .............................................25
5.2
AEs coding/grading ...............................................................................................25
5.3
Laboratory parameters derivations ........................................................................26
5.4
Statistical models...................................................................................................26
5.4.1
Primary analysis....................................................................................26
5.4.2
Key secondary analysis.........................................................................26
5.4.3
Audit-based BIRC assessment of PFS..................................................26
5.5
Rule of exclusion criteria of analysis sets..............................................................26
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List of abbreviations
AE
Adverse event
AESI
Adverse Event of Special Interest
ALT
Alanine aminotransferase
AST
Aspartate aminotransferase
BIRC
Blinded Independent Central Review
BOR
Best Overall Response
CI
Confidence Interval
CR
Complete Response
CSR
Clinical Study report
CTCAE
Common Terminology Criteria for Adverse Events
DCR
Disease Control Rate
DoR
Duration of Response
ECOG
Eastern Cooperative Oncology Group
eCRF
Electronic Case Report Form
FAS
Full Analysis Set
IA
Interim Analyses
IHC
Immunohistochemistry
LDH
Lactate Dehydrogenase
MedDRA
Medical Dictionary for Regulatory Activities
NCI
National Cancer Institute
NMQ
Novartis MedDRA queries
ORR
Overall Response Rate
OS
Overall Survival
PD-1
Programmed Death 1
PD-L1
Programmed Death-Ligand 1
pFBP
Proportion of subjects with a favorable biomarker profile
PFS
Progression-Free Survival
PR
Partial Response
PT
Preferred Term
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SD
Stable Disease
SMQ
Standardized MedDRA queries
TIL
Tumor Infiltrating T cells
ULN
Upper Limit of Normal
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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1
Introduction
This statistical analysis plan (SAP) describes all planned analyses for the non-randomized 
section of the clinical study report (CSR), including the non-randomized single-arm 1A of
CPDR001J2201. CPDR001J2201 is a randomized, open-label, phase II open platform study 
evaluating efficacy and safety of novel spartalizumab (PDR001) combinations in previously 
treated unresectable or metastatic melanoma. All planned analyses for the randomized section 
of the study are described in a separate analysis plan, referred as “main SAP for the randomized 
part of the study” in this document.
The content of this SAP is based on CPDR001J2201 protocol amendment version 05.  All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock of the study data.
1.1
Study design
This is a randomized, open-label, multi-center, two-part, open platform phase II study to assess 
the efficacy and safety of the anti-PD-1 antibody spartalizumab in combination with novel 
agents in previously treated unresectable or metastatic melanoma.
A non-randomized single-arm (Arm 1A) has been added with protocol amendment 5 to assess 
the efficacy and safety of spartalizumab in combination with LAG525 in subjects with 
previously treated unresectable or metastatic LAG-3 positive melanoma, based on encouraging 
results from arm 1 following interim analysis 2 of the randomized section of the study. 
This study consists of two parts, applicable for both randomized and non-randomized sections 
of the study : 

Part 1 : Selection phase

Part 2 : Expansion phase
For more details on the design of the randomized part, refer to protocol or corresponding 
statistical analysis plan.
In the non-randomized section, arm 1A will enroll up to approximately 100 subjects in total 
with LAG-3 positive melanoma: 20 subjects in part 1 and up to approximately 80 subjects in 
part 2. 
Study treatment in Arm 1A will be: LAG525 600 mg i.v. Q4W and spartalizumab 400 mg i.v. 
Q4W.
Two interim analyses for efficacy and futility will be conducted for arm1A: based on data from 
20 subjects treated in Part 1 and from 20 additional subjects treated in part 2 (i.e. 40 subjects in 
total combined with part 1 subjects). The primary analysis will occur after all 100 subjects have 
been enrolled (combining part 1 and part 2) and followed for at least 9 months. The final 
analysis will be performed at the end of study (as defined in the protocol). 
1.2
Study objectives and endpoints
The same objectives than for the randomized section of the study have been defined for the non-
randomized section of the study. Refer to the main SAP for the randomized part of the study 


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for more details. 
 
2
Statistical methods
2.1
Data analysis general information
All analysis will be performed by Novartis. SAS version 9.4 or later software will be used to 
perform all data analyses and to generate tables, figures and listings.  
Data included in the analysis
For each of the analyses, 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.
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 cases, the end date will not be imputed and 
therefore will not appear in the listings.
For Part 1, the interim analysis will be conducted once 20 patients enrolled in arm 1A have 
either completed two post-baseline tumor assessments or have discontinued the study treatment. 
For Part 2, if the arm 1A is expanded after interim analysis in part 1, the 2nd interim analysis 
will be performed once 40 patients (e.g. 20 in part 1 and 20 in part 2) have either completed 
two post-baseline tumor assessments or have discontinued the study treatment.
The cut-off date of the primary analysis of this non-randomized section will be determined once 
all patients from Part 2 are enrolled and followed for at least 9 months or have discontinued the 
study. The analysis cut-off for the final analysis will be established at the end of the study as 
defined in the protocol. 
General analysis conventions
For information on general analysis conventions, see the main SAP for the randomized part of 
the study.
2.1.1
General definitions
For information on general definitions, see the main SAP for the randomized part of the study 
except for the ones below.
Study day
For arm 1A, the reference start date for non-safety assessments is the date of start of study 
treatment. 
Baseline
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For arm 1A, for efficacy evaluations, the last non-missing assessment, including unscheduled 
assessments on or before the start of study treatment is taken as “baseline” value or “baseline” 
assessment. In the context of baseline definition, the efficacy evaluations also include 
performance status. 
Extended follow-up 
Additional summaries will be displayed to report deaths, all AEs, AEs related to study treatment,
all serious adverse events (SAEs), SAEs related to study treatment and AESI collected up to 
150 days after last administration of PDR001/LAG525. 
2.2
Analysis sets
All below defined analysis sets will be used to analyze data from both the selection (Part 1) and
expansion (Part 2) phases. Note, the immunogenicity (IG) analysis sets are outside the scope of 
the interim analyses (IA).
Full Analysis Set
The Full Analysis Set (FAS) comprises all subjects who received at least one dose of study 
treatment. This population will be the primary population for efficacy analysis.
Safety
The Safety Set is identical to the FAS. 
Note: Even if the subject receives partial infusion of the treatment or only one component of 
the treatment, the subject will still be analyzed under PDR001+LAG525 treatment arm.
Biomarker analysis set
The biomarker analysis set, as it pertains to the secondary objective (Section 10.5.5 of the 
protocol), consists of all subjects in the safety set with an evaluable baseline tumor biopsy 
sample and at least one evaluable post-baseline tumor biopsy sample. 
Evaluability for the analysis of the secondary objective will consist of the following:
!
Having both tumor biopsy samples as stated above,
!
Having quantifiable results for at least two assays to calculate the secondary endpoint 
as described in Section 2.12.2.
 
 
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Immunogenicity (IG) analysis sets
The immunogenicity prevalence set includes all subjects in the Full analysis set with a
determinant baseline IG sample or at least one determinant post-baseline IG sample.
The immunogenicity incidence set includes all subjects in the Immunogenicity prevalence set
with a determinant baseline IG sample and at least one determinant post-baseline IG sample.
See Section 2.10.1.1 of the main SAP for the randomized part of the study for the definition of 
determinant.
For more information on the additional analyses sets as well as subject classification and 
withdrawal of informed consent information, see the main SAP for the randomized part of the 
study.
2.2.1
Subgroup of interest
Subgroup analysis as described in the main SAP for the randomized part of the study may be 
only performed at the primary analysis (e.g. once all patients from part 2 have been enrolled 
and followed for at least 9 months) but not at interim analyses. Of note, LDH subgroup defined 
in the main SAP for the randomized part of the study as a stratification factor is not a 
stratification factor for this non-randomized section of the study. In addition, subgroup linked 
to ECOG performance status will be defined as 0 versus 1.
2.3
Subject disposition, demographics and other baseline 
characteristics
The Full Analysis Set (FAS) will be used for all baseline (including disease characteristics) and 
demographic summaries unless otherwise specified. Summaries will be reported for all subjects
to assess baseline comparability. No inferential statistics will be provided.
Basic demographic and background data
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data (e.g. gender, age groups: < 65 and ≥ 65 years, race, ethnicity, ECOG 
performance status, etc...) 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, body mass index) 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 weight at Screening.
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Diagnosis and extent of cancer 
Summary statistics will be tabulated for diagnosis and extent of cancer. This analysis will 
include the following: primary site of cancer at initial diagnosis, diagnosis of disease, BRAF 
mutation status, details of tumor histology/cytology, stage at study entry per AJCC Edition 8, 
time since initial diagnosis, time from initial diagnosis to first recurrence/progression (in 
months),
time since most recent relapse/progression to randomization (in months), 
presence/absence of target and non-target lesions, sum of lesion diameter for target lesions at 
baseline, number and type of metastatic sites involved, and number of metastatic sites.  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.  Tumor (T) stage at study entry, lymph nodes (N) stage at study entry, and metastases (M) 
at study entry will be further listed in the Subject disease history listing.
Medical history
Medical history and ongoing conditions will be presented identically to the content in the main 
SAP for the randomized part of the study.
2.3.1
Subject disposition
The number (%) of enrolled Arm 1A subjects included in the FAS will be presented overall. 
The number (%) of screened and not-treated 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.
The remaining summaries for subject disposition are identical to those in the main SAP for the 
randomized part of the study.
The following summaries will be provided (with % based on the total number of FAS patients):

Number (%) of patients who completed the screening phase but not treated,

Primary reason for not being treated,

Number (%) of patients who were treated,

Number (%) of patients who are still on-treatment,

Number (%) of patients who discontinued the study treatment phase,

Primary reason for study treatment phase discontinuation,

Number (%) of patients who have entered the post-treatment follow-up,

Number (%) of patients who have discontinued from the post-treatment follow-up,

Reasons for discontinuation from the post-treatment follow-up,

Number (%) of patients who have entered the survival follow-up.
Protocol deviations
Summaries and listing for protocol deviations are identical to those in the main SAP for the 
randomized part of the study.
Analysis sets
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2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
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.
2.4.1
Study treatment / compliance
Study treatment and compliance information will be presented identically for the IAs, the 
primary analysis and the final analysis. Therefore, more details on study treatment and 
compliance information can be found in the main SAP for the randomized part of the study.
For PDR001 and LAG525, for the calculation of the dose intensity, planned dose intensity and 
relative dose intensity, the full theoretical treatment cycle duration (e.g. 28 days) for the last 
cycle will be considered : the modified duration of exposure will use the last date of exposure 
of study drug as defined in the main SAP for the randomized part of the study, but without 
cutting at the date of death, last contact date or cut-off date in case the patient died, was lost to 
follow-up, before the end of the cycle or the last exposure date is going beyond the cut-off date, 
respectively. Table 2-1 below reflects the definition of the last date of exposure of study drug
to be used for the modified duration of exposure in the dose intensity calculation.
Duration of exposure to study treatment, dose intensity and planned dose 
intensity
Duration of exposure to study treatment (days) = (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 PDR001
and to LAG525 (see Table 2-1 below).
Table 2-1
Definition of last date of exposure of study drug
Scenario
Definition of last date of exposure of 
study drug 
Example
PDR001
LAG525
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))
The note below will not be applicable for 
dose intensity calculation : 
Note : If the patient 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
Example 1: If PDR001 or LAG525, 
is administered every four weeks, 
the last date of exposure is the 
date of administration in the last 
cycle + 27 days.


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If the derived last date of exposure goes 
beyond the data cutoff date, it should be 
truncated to the date of data cutoff.
Dose intensity and planned dose intensity
For drugs administered every 4 weeks (PDR001 and LAG525), the dose intensity and planned 
dose intensity will be reported in mg/cycle, defined as follows :

DI (mg / cycle) = (Actual Cumulative dose (mg) / modified duration of exposure to 
study treatment (days)) * 28, where modified duration of exposure (days) = last date of 
exposure of study drug (as defined in Table 2-1 above) - (date of first administration of 
study drug) + 1.
If for example, the duration of exposure to PDR001 is 6 days because patient died 6 
days after first day of dosing, the modified duration of exposure to PDR001 used in dose 
intensity calculation will be 28 days.

PDI (mg/cycle) is 400 mg/cycle and 600 mg/cycle, for PDR001 and LAG525, 
respectively.
Dose interruptions or permanent discontinuations
The number of subjects who have dose permanent discontinuations, dose interruptions, and the 
reasons, will be summarized separately for each study drug, as described in the main SAP for 
the randomized part of the study. 
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 any component 
of the study treatment) after RECIST 1.1 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 CRF 
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 checkpoint inhibitor therapy, prior anti-neoplastic radiotherapy, prior anti-neoplastic 
surgery, or other therapies not defined by the previous categories, will be summarized. Prior 
anti-neoplastic medications will be summarized by therapy type (e.g. chemotherapy, hormonal 
therapy, immunotherapy etc.) and by setting (e.g. adjuvant, metastatic, etc.).  Summaries will 
include total number of regimens, time from last treatment to progression for the last therapy, 
type of therapy received at any time or as last systemic therapy for unresectable and metastatic 
melanoma prior to enrollment (checkpoint inhibitor vs targeted therapy vs Other) excluding 


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radiotherapy and surgery, best response to last systemic therapy, to anti Anti-PD-1/Anti-PD-L1 
therapy and best response to any immunotherapy, based on RECIST v1.1.
For radiotherapy, time since last radiotherapy, locations and setting of last therapy will be 
summarized.  For prior surgery, time since last surgery and procedure will be summarized.
The prior checkpoint inhibitor therapy will be further summarized by type of checkpoint 
inhibitor therapy (Anti-PD-1, Anti-CTLA-4, and combination therapy of anti-CTLA-4 and anti-
PD-1). The prior targeted therapy will be further summarized by type of targeted therapy 
(BRAF Inhibitor and MEK Inhibitor). The medication therapy type of any combination therapy 
will be classified based on the types of treatment taken at each regimen. For example, a 
combination therapy of targeted therapy and immunotherapy will be classified in both 
categories with appropriate sub-types.
Swimmer plot will be performed to present the subject’s response according treatment duration. 
The different type of checkpoint inhibitor therapy (Anti-PD-1, Anti-CTLA-4, and combination 
therapy of anti-CTLA-4 and anti-PD-1, …) received by the patient will be presented in parallel 
on the same graph, with the duration of the different prior therapy and best response to prior 
therapy. This plot will be produced at time of interim analyses, if number of patients is 
appropriate to keep the plot readable, for patients who responded (BOR in (CR,PR)) or with a 
BOR as SD.
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); anti-neoplastic surgery will be coded using MedDRA. 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 summarized 
by ATC class, preferred term, by means of frequency count and percentages using FAS at 
primary and final analysis. The number and percentage of patients who reported  at least one 
anti-neoplastic therapy since discontinuation of study treatment by category (see main SAP for 
the randomized part of the study Table 2-7) will be reported.
Concomitant medications
Summaries and listings as described in the main SAP for the randomized part of the study will 
be provided at primary and final analysis.
2.5
Analysis of the primary objective
The primary objective is to demonstrate the antitumor activity of spartalizumab in combination 
with LAG525 as measured by overall response rate (ORR) in previously treated unresectable 
or metastatic melanoma LAG-3 positive subjects. In particular, for the IAs, the primary 
objective will be to determine if investigator assessed ORR is sufficient to allow for the non-
randomized arm 1A to be expanded or not.


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2.5.1
Primary endpoint
Confirmed ORR is defined as the proportion of subjects with confirmed best overall response 
(BOR) of complete response (CR) or partial response (PR) according to RECIST 1.1. 
Of note, BOR of SD will be assigned if at least one SD assessment (or better) occurred > 11 
weeks after randomization (and not qualifying for CR or PR).
Tumor assessments performed after the start of any further antineoplastic therapy (i.e. any 
additional secondary antineoplastic therapy, radiotherapy or surgery, including limited-field 
palliative radiotherapy) will not be considered in the assessment of BOR. Further antineoplastic 
therapies will be identified via protocol deviations and from the data collected on 
“antineoplastic therapies since discontinuation of study treatment” (e)CRF pages. Of note, 
“biopsy” will not be considered as a new antineoplastic surgery. 
For additional information on the primary endpoint, see the main SAP for the randomized part 
of the study.
2.5.2
Statistical hypothesis, model, and method of analysis
Part 1: Selection Phase
No formal hypothesis testing will be conducted in part 1. The objective of this part of the study 
is to explore the anti-tumor activity of the combination of spartalizumab with LAG525 agent in 
subjects with LAG-3 positive melanoma as measured by ORR per RECIST v1.1, and to expand 
this new arm if it shows promising efficacy.
To determine whether the arm has the potential to demonstrate clinically meaningful response 
rate, a specific efficacy probabilistic threshold should be met during the selection phase to 
advance to the expansion phase. If not, the arm will be declared as futile and won’t be expanded.
These thresholds and probabilities are highlighted in Table 2-2.
Table 2-2
Probabilities thresholds used to declare efficacy or futility for arm 1A
Decision rule
Action
P(ORR ≥20%) ≤70%
Drop arm for futility
P(ORR ≥20%) > 70%
Efficacy signal - Consider advancing arm to expansion phase (part 2) 
To calculate the posterior probabilities, a beta-binomial posterior distribution will be used as 
shown below:
 ~ 	( + 1,  − + 1)
Where  is the number of confirmed responses in arm 1A and  is the number of subjects 
treated. In calculation of the posterior distribution, uninformed prior Beta[1,1] will be taken 
into account. The posterior probability will be calculated based on the observed ORR using 
RECIST v1.1 criteria at interim analysis.
The final decision on whether the arm will be selected for advancement to the expansion phase 
will primarily be based on the observed ORR using decision rule described above but other 
efficacy (in particular duration of response), safety, and biomarker data will be considered as 
well. Novartis may decide to not expand the arm despite the efficacy probability threshold 
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With 20 treated patients, 5 or more responders need to be observed to meet the efficacy 
probabilistic threshold. 
Part 2: Expansion Phase
If the pre-defined efficacy probabilistic threshold is met after the selection part, the arm 1A 
might be expanded.
A second interim analysis will be conducted including 20 additional patients treated in the 
expansion phase, i.e. based on the total of 40 patients. The objective of this second interim 
analysis is to support and inform decision-making on whether arm 1A will be: (1) further 
explored (2) stopped for futility . To determine whether arm 1A has the potential to demonstrate 
clinically meaningful ORR, an efficacy probabilistic threshold same as in part 1 will need to be 
crossed (see Table 2-2). If not, the arm 1A will be declared futile and further 
exploration/enrollment will be stopped in this combination. With 40 subjects at time of 2nd
interim analysis treated in arm 1A (combining part 1 and part 2), 9 responders will have to be 
observed to cross the efficacy probabilistic threshold.
If efficacy probabilistic threshold is met at the 2nd interim analysis enrollment may continue in 
expansion up to approximately 80 subjects (i.e. 100 subjects in total adding the subjects in part 
1). 
After completion of the expansion phase, the following statistical hypothesis will be tested 
based on objective response rate (ORR) at time of primary analysis: 

H0: ORR ≤ 15%

H1: ORR >15%
The null hypothesis will be formally rejected if the lower bound of exact 95% CI for ORR is 
above 15%. The primary analysis of ORR at the end of part 2 will be based on a combined pool 
of part 1 and part 2 data.
23 or more responses need to be observed among the 100 subjects to reject the null hypothesis. 
With those 23 responders among 100 subjects, the point estimate for ORR will be 23% with an 
exact 95% confidence interval of (15.2, 32.5). 
2.5.3
Handling of missing values/censoring/discontinuations
For information on the handling of missing values/censoring/discontinuations, see the main 
SAP for the randomized part of the study.
2.5.4
Supportive analyses
Same supportive analysis on ORR using BIRC than the one described in the main SAP for the 
randomized part of the study will be performed for Arm 1A at 2nd interim analysis and primary 
analysis.
Concordance analysis of BOR
Refer to the main SAP for the randomized part of the study for details on the concordance 
analysis between BIRC assessment and local assessment. 


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Reasons for “Unknown” BOR
Reasons for “Unknown” BOR will be presented identically for the IAs and primary analysis.  
Therefore, more details on reasons for “Unknown” BOR can be found in the main SAP for the 
randomized part of the study.
Waterfall plot to depict anti-tumor activity
Waterfall plot to depict anti-tumor activity will be presented identically for the IAs and primary  
analysis.  Therefore, more details on reasons for “Unknown” BOR can be found in the main 
SAP for the randomized part of the study.
Subgroup analyses
At primary analysis, data from part 2 will be combined with part 1 to assess ORR in the 
following subgroups : 
-
LDH (≤ ULN vs. > ULN),
-
ECOG PS (0 vs. 1).
2.6
Analysis of the key secondary objective
The key secondary objective of the study is to determine duration of response (DoR) treatment 
with spartalizumab in combination with LAG525 in subjects with previously treated 
unresectable or metastatic LAG3-positive melanoma. It will be analyzed at time of IAs, primary 
and final analysis.
When the main SAP for the randomized part of the study referred to the date of randomization 
for endpoints definition, the date of first study treatment dose is rather used for this arm 1A 
analysis. 
2.6.1
Key secondary endpoint
For information on the key secondary endpoint, see the main SAP for the randomized part of 
the study. Note, due to small sample size at 1st interim analysis, only listings will be generated 
for DoR.
2.6.2
Statistical hypothesis, model, and method of analysis
For information on the statistical hypothesis, model, and method of analysis for the key 
secondary endpoint, see the main SAP for the randomized part of the study.
2.6.3
Handling of missing values/censoring/discontinuations
For information on the handling of the missing values/censoring/discontinuations for the key 
secondary endpoint, see the main SAP for the randomized part of the study.
2.6.4
Duration of follow-up
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!
Duration between the date of first dose of study treatment in arm 1A and data cut-off 
date = (Cut-off date – Date of first dose of study treatment in arm 1A+ 1) / 30.4375 
(months),
!
Duration between the date of first dose of study treatment in arm 1A and the last contact 
date = (Date of last contact/death date (equivalent to the date used for OS time) – Date 
of first dose of study treatment in arm 1A+ 1) /30.4375 (months). 
2.7
Analysis of secondary 
 efficacy objective(s)
The other secondary objectives are the following:
!
Evaluate the efficacy of arm 1A, as measured by progression-free survival (PFS)
!
Evaluate the efficacy of arm 1A, as measured by disease control rate (DCR)
!
Evaluate the overall survival (OS) of arm 1A
 
 
 
 
 
 
2.7.1
Secondary 
 efficacy endpoints
For secondary endpoints definition, see the main SAP for the randomized part of the study. 
Note, due to small sample size at 1st interim analysis, only listings for the following secondary 
endpoints PFS and OS will be provided. Full analyses using Kaplan Meier method will be 
performed at 2nd interim analysis, primary and final analyses.  
 
 
2.7.2
Statistical hypothesis, model, and method of analysis
There will be no hypothesis testing for any of the endpoints listed above.
For the method of analysis of secondary 
 endpoints, refer to the main SAP for 
the randomized part of the study. 
2.7.3
Handling of missing values/censoring/discontinuations
For handling of missing values/censoring/discontinuations for PFS and OS endpoints, please 
see the main SAP for the randomized part of the study.
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2.8
Safety analyses
For all safety analyses, the safety set will be used. All listings and tables will include only arm 
1A.  
The overall obervation period, incomplete dates, and safety assessments will be treated 
similarly in the IA analyses, the primary analysis and the final analysis.  More details on these 
components of the safety analyses can be found in the main SAP for the randomized part of the 
study.
2.8.1
Adverse events (AEs)
Adverse event summaries and details will be presented identically for the IAs, the primary and 
the final analysis.  Therefore, more details on AEs can be found in the main SAP for the 
randomized part of the study. Of note, the additional summaries to report all AEs, AEs related 
to study treatment, all SAEs, and SAEs related to study treatment as described in the main SAP 
for the randomized part of the study as “collected up to 150 days after last administration of 
PDR001/LAG525” will rather use the extended follow-up period definition (section 2.1.1). 
2.8.1.1
Adverse events of special interest / grouping of AEs
Adverse events of special interest (AESI) during the on-treatment period will be tabulated. The 
list of AESI will also include relevant events for spartalizumab, and LAG525 agent.
Refer to the main SAP for the randomized part of the study for details on the analysis of AESIs. 
Of note, the additional summaries to report all AESIs as described in the main SAP for the 
randomized part of the study as “collected up to 150 days after last administration of 
PDR001/LAG525” will rather use the extended follow-up period definition (section 2.1.1). In 
addition, analysis of time to first occurrence summaries will not be generated.
2.8.2
Deaths
Deaths will be presented identically for the IAs, the primary and the final analysis.  Therefore, 
more details on deaths can be found in the main SAP for the randomized part of the study. The 
additional summary reported all deaths “up to 150 days after last administration of 
PDR001/LAG525”, as described in the main SAP for the randomized part of the study, will 
rather used the extended follow-up definition (section 2.1.1).
2.8.3
Laboratory data
Grading of laboratory will be assigned programmatically as per National Cancer Institute (NCI)
Common Terminology Criteria for Adverse Events (CTCAE) v5.0. 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 v5.0, results will be categorized 
as low/normal/high based on laboratory normal ranges.


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Laboratory data summaries and listings will be presented identically for the IAs, the primary 
and the final analysis.  More details on laboratory data summaries and listings can be found in 
the main SAP for the randomized part of the study.   
For laboratory figures, only the eDish plot examining the relationship between peak total 
bilirubin (measured as the maximum post-baseline total bilirubin and maximum post-baseline 
alanine aminotransferase (ALT) (both in reference to the ULN) or maximum post-baseline 
aspartate aminotransferase (AST) will be produced at IAs, primary and final analysis.
Liver function parameters 
The following liver function parameters are of interest : total bilirubin (TBL), alanine 
aminotransferase (ALT), aspartate aminotransferase (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 on peak post-baseline values will be produced:

ALT >3xULN, ALT>5x ULN, ALT>10xULN, ALT>20xULN

AST >3xULN, AST>5xULN, AST>10xULN, AST>20xULN

ALT or AST > 3xULN, ALT or AST > 5xULN, ALT or AST > 8xULN, ALT or 
AST > 10xULN, ALT or AST > 20xULN

TBL > 2xULN, TBL > 3xULN
For patients with AST and ALT ≤ULN at baseline:
-
ALT or AST > 3xULN & TBL > 2xULN
-
ALT or AST > 3xULN & TBL > 2xULN & (ALP < 2xULN or ALP ≥2xULN)
      For patients with ALT or AST > ULN at baseline
-
Elevated ALT or AST (>3xULN if ≤ULN at baseline, or (>3xBsl or 8xULN) 
if >ULN at baseline) 
o
and TBIL (>2xBsl and 2xULN)
o
and TBIL (>2xBsl and 2xULN) and ALP ≥2xULN
o
and TBIL (>2xBsl and 2xULN) and ALP < 2xULN
Potential Hy’s Law events are defined as occurrence of AST or ALT > 3xULN and TBL > 
2xULN, or occurrence of (ALT or AST >3xbaseline) OR (ALT or AST > 8.0xULN), whichever 
is lower, combined with (TBIL>2xbaseline AND >2.0xULN), for patients with abnormal ALT 
or AST baseline values; where combined elevations post-baseline are based on the peak values 
at any post-baseline time for a subject. 
Further medical review has to be conducted to assess potential confounding factor such as, liver 
metastases, liver function at baseline etc.   


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2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Categorical analysis of QT/QTc interval data based on the number of subjects meeting or 
exceeding predefined limits in terms of absolute QT/QTc intervals or changes from baseline 
will be presented. In addition, a listing of these subjects will be produced.
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
Data analysis for ECG and cardiac imaging data will be presented identically for the IAs, the 
primary and the final analysis.  More details on the data analysis of ECG and cardiac imaging 
data can be found in the main SAP for the randomized part of the study. Only notable ECG 
values will be listed.   
2.8.4.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).
Data handling
Vital signs collected on treatment will be summarized at primary and final analyses (but not for 
IAs purpose). Values measured outside of the on-treatment period will be flagged in the listings. 
 
  
2.10
PD and
PD analyses
Same analyses than in the main SAP for the randomized part of the study will be performed for 
immunogenicity. 
 
 
 
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2.11
Subject-reported outcomes
Not applicable
2.12
Biomarkers
2.12.1
Introduction
As a project standard, Novartis Oncology Biostatistics will analyze only biomarkers collected
in the clinical database. The biomarker analysis covered within the SAP pertains mainly to the 
secondary objective endpoint of determining the proportion of subjects with a favorable 
biomarker profile (pFBP).  More details on the pFBP can be found in the main SAP for the 
randomized part of the study.
 
2.12.2
Secondary biomarker objectives
Changes in phenotype and/or activation of T cell populations in the tumor and tumor 
microenvironment will be analyzed on an on-going basis as part of the secondary objective.  
Every effort will be made to make this data available for internal decision making purposes. 
Such analyses may include, but are not limited to number of CD8+ T cell infiltration, T cell 
activation level by IHC and gene expression analysis. T cell repertoire/clonality by TCR-
sequencing is excluded from all interim analyses as well as beyond due to low assay success. 
Further discussions of the parameter definitions to support the biomarker objectives can be 
found in Table 2-3 below.
Table 2-3
Parameter definitions for categorization of biomarker outcome at 
subject level
Biomarker parameter
Analysis
Criteria for 
favorable 
biomarker result
Number of tumor infiltrating 
T cells (TILs)
Changes of CD8+ T cell numbers as 
assessed by IHC in tumor/ tumor 
microenvironment with treatment
Increase
Activation level of TILs*
Change of T cell activation marker level(s) as 
assessed by IHC in tumor/tumor 
microenvironment with treatment
Increase
Changes in immune 
response gene expression 
signatures
Changes in expression of genes and/or gene 
signatures as assessed by mRNA analysis in 
tumor/tumor microenvironment with treatment
Defined per 
gene/gene signature
*Of note, the activation level of TILs by IHC (AQUA analysis) initially reported in the protocol 
may be excluded due to sample limitation associations with arm 1A, created by the need to 
retain tissue for potential further LAG3 test validation in support of future diagnostic 
development.
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2.12.3
Biomarker data 
As a project standard, Novartis Oncology Biostatistics will analyze only biomarkers collected
in the clinical database. The biomarker analysis covered within the SAP pertains mainly to the 
secondary objective endpoint of determining the proportion of subjects with a favorable 
biomarker profile (pFBP).
The biomarker analysis set, as it pertains to the secondary objectives consists of all subjects in 
the safety set with an evaluable baseline tumor biopsy sample.  When evaluating the pFBP, the 
analysis set should include all subjects in the safety set with an evaluable baseline tumor biopsy 
sample and at least one post-baseline tumor biopsy sample with evaluable results for 2 or more 
biomarker parameters listed in Table 2-3 (paired biomarker analysis set). 
Table 2-4 summarizes the biomarker collection schedules and sample types.  
Table 2-4
Sample biomarker summary table
Biomarker 
parameter
Biomarker analysis 
measurement
Time point
Sample
Method
Dataset
Number of TILs
Percent of tumoral 
CD8+ cells 
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
IHC
B1
Changes gene 
expression 
signatures
T-cell Inflammed 
Signature (TIS)
levels
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
Nanostring
B1
Baseline LAG-3 
expression 
(LAG525 
treatment arm 
only) 
Percent of tumoral 
LAG-3+ cells
Screening
Btw, C1D1 
and C2D1*
Newly 
obtained 
tumor 
biopsy
IHC
B1
2.12.4
General data handling and preprocessing
The mean of all pre dose assessments (i.e. screening and Cycle 1 Day 1 assessments) will be
used as the baseline value. The on-treatment assessment will be the result from the tumor biopsy 
taken between C1D21 and C2D1.
When more than one biomarker data value are available for a subject at any time point, the 
mean of the replicate values will be used for all statistical analyses.
2.12.5
Secondary biomarker objectives
The secondary objective biomarker data will be listed for each subject for all time points 
(baseline and on treatment). Absolute and relative change (percent change or fold change, 
depending on biomarker) from baseline of each biomarker parameter will be calculated for each 
subject and summarized for arm 1A.
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2.12.5.1 IHC for quantifying tumor infiltrating T cells (TILs)
The number of TILs at each timepoint will be assessed by measuring % CD8+ cells within the 
invasive margin, tumor and stroma area (as defined by Melamask staining).
For all CD8 parameters above, the baseline value, on-treatment (C1D21-C2D1) value, and the
absolute difference from baseline to on-treatment will be listed for each individual subject for 
arm 1A. The mean, standard deviation, %CV, median, minimum, maximum, inter-quartile 
range and number for all subjects (regardless of treatment arms) will be reported for baseline 
and change from baseline to on-treatment by combination arm. Inter-quartile range is the 
number of data points between the 25th and 75th percentile.
The summary statistics : mean, standard deviation, %CV, median, minimum, maximum, inter-
quartile range for baseline %CD8+ cells will be summarized for patients with best overall 
response of CR or PR (e.g. responders) versus others.  
For all parameters above, the baseline value, on-treatment value, and the absolute difference 
from baseline to 3-4 weeks will be listed for each individual subject. The mean, standard 
deviation, %CV, median, minimum, maximum, inter-quartile range and number for all subjects 
(regardless of treatment arms) will be reported for baseline and change from baseline to on-
treatment (C1D21-C2D1).   Inter-quartile range is the number of data points between the 25th
and 75th percentile.
2.12.5.2 Nanostring for quantifying gene expression signatures
The Tcell inflamed signature will be assess by the T-cell Inflammed Signature (TIS) score for 
Nanostring data.
For TIS score, the baseline value, on-treatment (C1D21-C2D1) value, and the fold change (on-
treatment / baseline) will be listed for each individual subject. The mean, standard 
deviation, %CV, median, minimum, maximum, inter-quartile range and number for all subjects 
(regardless of treatment arms) will be reported for baseline and fold change (on-treatment / 
baseline) .   Inter-quartile range is the number of data points between the 25th and 75th percentile.  
The summary statistics : mean, standard deviation, %CV, median, minimum, maximum, inter-
quartile range for baseline TIS score will be summarized for patients with best overall 
response of CR or PR (e.g. responders) versus others.  
2.12.5.3 Calculation of pFBP
The biomarkers listed in Table 2-3 will be used to calculate the proportion of subjects with a 
favorable biomarker profile (pFBP). 
For each biomarker involved in the evaluation of pFBP as stated above, the baseline, 3-4 weeks 
biomarker values, and the absolute difference from baseline to 3-4 weeks will be listed for each 
individual subject by combination arm. The mean, standard deviation, %CV, median, minimum, 
maximum, inter-quartile range and number for all subjects (regardless of treatment arms) will 
be reported for baseline and change from baseline to 3-4 weeks by combination arm.   Inter-
quartile range is the number of data points between the 25th and 75th percentile. 


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If an individual subject has two favorable biomarker parameters from Table 2-3 then that subject 
will be considered to have a favorable biomarker profile. A favorable biomarker will be defined 
as follows:
Number of tumor infiltrating T cells (TIL) as measured by CD8 IHC:
!
An increase from baseline to on-treatment (C1D21-C2D1) in the IE CD8+ density is 
considered a favorable change as follows:
!
IE CD8 increase which is ≥1% in magnitude (i.e. [on-treatment C1D21-C2D1 %IE 
value] – [baseline IE value = ≥1%])
And
!
Percent fold change in IE is ≥30% (i.e. ([on-treatment C1D21-C2D1 %IE value] –
[baseline IE value])/[ baseline IE value ] = ≥30%])
Changes in immune response gene expression signature as measured by Nanostring:
!
For baseline to on-treatment changes in the TIS score, the following would be considered 
favorable:
!
≥1.5 fold change (i.e. on-treatment aggregate gene signature score]/[baseline aggregate 
gene signature score])
For each combination arm, the proportion of subjects with a favorable biomarker profile (pFBP) 
are then defined as the number of subjects with favorable biomarker profiles divided by the 
number of subjects enrolled into the arm which are included in the paired biomarker analysis 
set for that particular interim analysis and will be summarized.  
 
 
 
 
 
  
 
 
2.13
Other Exploratory analyses
Not applicable
2.14
Interim analysis
Part 1 : Selection phase 
As described in protocol amendment v05 Section 4.2.2, there will be one interim analysis 
planned for ORR once all patients treated in arm 1A have either completed two post-baseline 
tumor assessments or have discontinued study treatment. 
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Part 2: Expansion phase
A 2nd interim analysis will be conducted once 40 patients have been treated within selection and 
expansion phases and have either completed two post-baseline tumor assessments or have 
discontinued study treatment.The primary analysis of this non-randomized section of the study 
will be performed once all patients treated in arm 1A had at least 9 months of follow-up. This 
timing would allow for a potential minimum duration of response of 6 months for all subjects 
enrolled. Formal hypothesis testing of the primary endpoint (as described in Section 2.6.2) will 
be performed at this primary analysis. The final analysis will be performed at the end of the 
study as described in protocol Section 4.3.
3
Sample size calculation
Further discussion on sample size calculations can be found in Section 10.8.2 of the protocol.
4
Change to protocol specified analyses
Not applicable.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Imputation rules for study drugs are identical for the IAs,the primary analysis and the final 
analysis.  Therefore, more details concerning the imputation rules for study drug can be found 
in the main SAP for the randomized part of the study.  
5.1.2
AE date imputation
Imputation rules for AE date are identical for all analyses.  Therefore, more details concerning 
the imputation rules for AE date imputation can be found in the main SAP for the randomized 
part of the study.  
5.1.3
Concomitant medication date imputation
Imputation rules for concomitant medication date are identical for all analyses.  Therefore, more 
details concerning the imputation rules for concomitant medication date imputation can be 
found in the main SAP for the randomized part of the study.  
5.2
AEs coding/grading
AEs coding/grading are identical for all analyses.  Therefore, more details concerning AEs 
coding/grading can be found in the main SAP for the randomized part of the study.  


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5.3
Laboratory parameters derivations
Laboratory parameter definitons are identical for all analyses.  Therefore, more details 
concerning laboratory parameter definitions can be found in the main SAP for the randomized 
part of the study.  
5.4
Statistical models
5.4.1
Primary analysis
Please refer to Section 10 of the protocol, Section 2.5.2 of the current SAP for extended details 
on the modeling and SAS procedures used.  
5.4.2
Key secondary analysis
Kaplan-Meier estimates
For information on the Kaplan-Meier estimates and dealing with ties, see the main SAP for the 
randomized part of the study.
5.4.3
Audit-based BIRC assessment of PFS
Not applicable.
5.5
Rule of exclusion criteria of analysis sets
Not applicable.