Conditions: Advanced Malignancies
Keywords: Solid tumors Melanoma Non small cell lung cancer NSCLC Renal cell carcinoma RCC Phase I-Ib/II MBG453 PDR001 Checkpoint inhibitor PD-1 TIM-3
Allocation: NON_RANDOMIZED | Intervention model: PARALLEL
Enrollment: 252
Healthy volunteers: no

Brief summary:
The purpose of this first-in-human study of MBG453 was to characterize the safety, tolerability, pharmacokinetics, pharmacodynamics and anti-tumor activity of MBG453 administered i.v. as a single agent or in combination with PDR001 or decitabine in adult patients with advanced solid tumors

Detailed description:
This study was a first in human (FIH), open-label, Phase I-Ib/II, multi-center study which consisted of a Phase I dose escalation part of sabatolimab (MBG453) as single agent, and a Phase Ib dose escalation part of sabatolimab in combination with spartalizumab (PDR001) that commenced after two cohorts in the dose escalation with single agent were completed. Once the maximum tolerated dose (MTD)/recommended Phase II dose (RP2D) of sabatolimab as single agent and in combination with spartalizumab was achieved, a dose ranging part and a Phase II part started.

• Phase I dose escalation part (sabatolimab single agent): In the Phase I part of the study, cohorts of subjects were treated with sabatolimab as single agent either every 2 weeks (Q2W) or every 4 weeks (Q4W) until the MTD was reached or a lower RP2D was established.

The sabatolimab single agent dose escalation part in Japan ran separately in order to ensure that the safety and pharmacokinetics (PK) profiles of single-agent sabatolimab are adequately characterized in Japanese patients. If the recommended dose of single agent sabatolimab in Japanese patients was the same as in the rest of the world (ROW) patients, then patients enrolled in Japan were to be recruited into the other parts of the study.

• Phase Ib dose escalation part (sabatolimab in combination with spartalizumab): The combination Phase Ib part of the study was to be commenced after at least two cohorts of sabatolimab as single agent were completed, and safety data suggested acceptable toxicity for subjects to begin treatment in combination. Following identification of the MTD/RP2D for the combination of sabatolimab and spartalizumab with a Q2W dosing schedule, a further dose escalation was planned to identify the MTD/RP2D with a Q4W dosing schedule.

The sabatolimab in combination with decitabine treatment arm (Phase Ib) was not opened for enrollment.

* Dose ranging part: During the dose ranging part various dose levels of single agent sabatolimab were tested to better understand the safety, tolerability and PK.
* Phase II part (sabatolimab in combination with spartalizumab): Once the MTD and/or RP2D were declared for sabatolimab in combination with spartalizumab, additional subjects were enrolled in the Phase II part in the selected indications (melanoma and non-small cell lung carcinoma) in order to assess the preliminary anti-tumor activity.

The Phase II single agent sabatolimab treatment arm was not opened for enrollment.

Arms:
arm 1: Sabatolimab every 2 weeks (Q2W) in Phase I Dose Escalation Part in rest of the world (ROW) patients arm 2: Sabatolimab Q2W in Phase I Dose Escalation Part in Japanese patients arm 3: Sabatolimab every 4 weeks (Q4W) in Phase I Dose Escalation Part in ROW patients arm 4: Sabatolimab Q4W in Phase I Dose Escalation Part in Japanese patients arm 5: Sabatolimab Q2W in combination with spartalizumab Q2W in Phase Ib Dose Escalation Part arm 6: Sabatolimab Q4W in combination with spartalizumab Q4W in Phase Ib Dose Escalation Part arm 7: Sabatolimab in combination with decitabine in Phase Ib Dose Escalation Part. This arm was not opened for enrollment. arm 8: Sabatolimab Q4W in Dose Ranging Part arm 9: Sabatolimab Q4W in combination with spartalizumab Q4W in non-small cell lung carcinoma (NSCLC) and melanoma arm 10: Sabatolimab alone in Phase II. This arm was not opened for enrollment.

Interventions: intervention 1: MBG453 intervention 2: PDR001 intervention 3: Decitabine
Intervention descriptions: intervention 1: Anti human TIM-3 monoclonal antibody. MBG453 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W). intervention 2: Anti-human PD-1 monoclonal antibody. PDR001 administered via intravenous (i.v.) infusion either every 2 weeks (Q2W) or every 4 weeks (Q4W). intervention 3: commercially available chemotherapy

Protocol document:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of appendices................................................................................................................6
List of figures ......................................................................................................................7
List of tables ........................................................................................................................7
List of abbreviations............................................................................................................9
Glossary of terms...............................................................................................................12
Protocol Summary:............................................................................................................14
Amendment 06 (31-Aug-2020).........................................................................................17
Amendment 05 (04-Nov-2019).........................................................................................19
Amendment 04 (04-Sep-2018)..........................................................................................24
Amendment 03 (18-Jul-2016) ...........................................................................................25
Amendment 02 (06-Jun-2016) ..........................................................................................26
Amendment 01 (19-Oct-2015) ..........................................................................................31
1
Background........................................................................................................................32
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............33
1.1.1
TIM-3 overview ....................................................................................33
1.1.2
PD-1 overview ......................................................................................35
1.1.3
Hypomethylation overview...................................................................36
1.2
Introduction to investigational treatments .............................................................36
1.2.1
Overview of MBG453...........................................................................36
1.2.2
Overview of PDR001............................................................................38
1.2.3
Overview of decitabine .........................................................................39
1.2.4
Overview of MBG453, PDR001 and decitabine...................................40
2
Rationale............................................................................................................................42
2.1
Study rationale and purpose...................................................................................42
2.2
Rationale for the study design ...............................................................................44
2.3
Rationale for dose and regimen selection..............................................................46
3
Objectives and endpoints...................................................................................................48
4
Study design ......................................................................................................................51
4.1
Description of study design ...................................................................................51
4.2
Timing of interim analyses and design adaptations...............................................58
4.3
Definition of end of the study................................................................................58
4.4
Early study termination..........................................................................................59
5
Population..........................................................................................................................59
5.1
Patient population..................................................................................................59


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5.2
Inclusion criteria ....................................................................................................59
5.3
Exclusion criteria...................................................................................................60
6
Treatment...........................................................................................................................63
6.1
Study treatment......................................................................................................63
6.1.1
Dosing regimen.....................................................................................63
6.1.2
Ancillary treatments..............................................................................64
6.1.3
Treatment duration................................................................................65
6.2
Dose escalation guidelines.....................................................................................65
6.2.1
Starting dose rationale...........................................................................65
6.2.2
Provisional dose levels..........................................................................66
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D .......67
6.2.4
Definitions of dose limiting toxicities (DLTs) for MBG453 single 
agent and MBG453 in combination with PDR001 ...............................71
6.2.5
Definition of dose limiting toxicities (DLTs) for MBG453 in 
combination with decitabine .................................................................73
6.3
Dose modifications ................................................................................................74
6.3.1
Dose modifications and dose delay.......................................................74
6.3.2
Follow-up for toxicities.........................................................................75
6.3.3
Anticipated risks and safety concerns of the study drug.......................79
6.4
Concomitant medications ......................................................................................80
6.4.1
Permitted concomitant therapy .............................................................80
6.4.2
Permitted concomitant therapy requiring caution and/or action...........80
6.4.3
Prohibited concomitant therapy ............................................................81
6.5
Patient numbering, treatment assignment or randomization .................................81
6.5.1
Patient numbering .................................................................................81
6.5.2
Treatment assignment or randomization...............................................81
6.6
Study drug preparation and dispensation...............................................................82
6.6.1
Study drug packaging and labeling.......................................................83
6.6.2
Drug supply and storage........................................................................83
6.6.3
Study drug compliance and accountability ...........................................83
6.6.4
Disposal and destruction .......................................................................84
7
Visit schedule and assessments .........................................................................................84
7.1
Study flow and visit schedule................................................................................84
7.1.1
Screening/Baseline................................................................................93
7.1.2
Treatment period...................................................................................93
7.1.3
Discontinuation of Study Treatment .....................................................94
7.1.4
Withdrawal of Consent .........................................................................96


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7.1.5
Follow up period ...................................................................................97
7.1.6
Lost to follow-up...................................................................................97
7.2
Assessment types...................................................................................................97
7.2.1
Efficacy assessments.............................................................................97
7.2.2
Safety and tolerability assessments.......................................................98
7.2.3
Pharmacokinetics and immunogenicity assessments..........................102
7.2.4
Biomarkers..........................................................................................106
8
Safety monitoring and reporting......................................................................................109
8.1
Adverse events.....................................................................................................109
8.1.1
Definitions and reporting ....................................................................109
8.1.2
Laboratory test abnormalities..............................................................110
8.2
Serious adverse events.........................................................................................111
8.2.1
Definitions...........................................................................................111
8.2.2
Reporting.............................................................................................112
8.3
Pregnancies..........................................................................................................113
8.4
Warnings and precautions....................................................................................113
8.5
Data Monitoring Committee................................................................................113
8.6
Steering Committee .............................................................................................114
9
Data collection and management.....................................................................................114
9.1
Data confidentiality .............................................................................................114
9.2
Site monitoring ....................................................................................................115
9.3
Data collection.....................................................................................................115
9.4
Database management and quality control..........................................................116
10 Statistical methods and data analysis ..............................................................................116
10.1
Analysis sets ........................................................................................................117
10.1.1
Full Analysis Set .................................................................................117
10.1.2
Safety Set ............................................................................................117
10.1.3
Per-Protocol Set ..................................................................................118
10.1.4
Dose-determining analysis set.............................................................118
10.1.5
Pharmacokinetic analysis set...............................................................119
10.2
Patient demographics/other baseline characteristics ...........................................119
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................119
10.4
Primary objective.................................................................................................120
10.4.1
Variable...............................................................................................120
10.4.2
Statistical hypothesis, model, and method of analysis........................121
10.4.3
Handling of missing values/censoring/discontinuations.....................126




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14.1.4
Data handling and programming rules................................................165
14.1.5
References (available upon request) ...................................................169
14.2
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) .................................170
14.2.1
Introduction.........................................................................................170
14.2.2
New lesions and non-target lesions.....................................................170
14.2.3
Follow-up evaluation of target and non-target lesions........................170
14.2.4
Definitions of response categories and evaluation of overall lesion 
response...............................................................................................171
14.2.5
References (available upon request) ...................................................172
14.3
Appendix 3: Statistical details of Bayesian regression models, priors, design 
operating characteristics and hypothetical dose escalation scenarios..................173
14.3.1
Phase I part MBG453 single agent......................................................173
14.3.2
Phase I part MBG453 single agent with Japanese patients.................180
14.3.3
Phase Ib part MBG453 in combination with PDR001........................189
14.3.4
References (available upon request) ...................................................196
List of appendices
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, TTP, Progression-
Free Survival and Overall Survival (based on RECIST version 1.1)
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using one-dimensional 
measurements (simulating RECIST version 1.1)
Appendix 3: Statistical details of Bayesian regression models, priors, design operating 
characteristics and hypothetical dose escalation scenarios
Appendix 4: Recommended management algorithms for suspected toxicities


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List of figures
Figure 4-1
Study Design .........................................................................................53
Figure 4-2
Study flow.............................................................................................58
List of tables
Table 3-1
Objectives and related endpoints ..........................................................48
Table 6-1
Dose and treatment schedule.................................................................63
Table 6-2
Provisional dose levels (Phase I part – MBG453 single agent)............66
Table 6-3
Provisional dose levels (Phase Ib part – MBG453 in combination 
with PDR001)........................................................................................66
Table 6-4
Provisional dose levels (MBG453 in combination with decitabine) ....67
Table 6-5
Criteria for defining dose limiting toxicities (MBG453 single agent 
and MBG453 in combination with PDR001)........................................72
Table 6-6
Criteria for defining dose limiting toxicities (MBG453 in 
combination with decitabine)................................................................73
Table 6-7
Management of toxicities defined as study treatment-related only ......76
Table 7-1
Visit evaluation schedule (MBG453 single agent and MBG453 in 
combination with PDR001)...................................................................85
Table 7-2
Visit evaluation schedule (MBG453 in combination with 
decitabine).............................................................................................89
Table 7-3
Disease assessment collection plan.......................................................98
Table 7-4
ECOG performance status.....................................................................99
Table 7-5
Local/Central clinical laboratory parameters collection plan .............100
Table 7-6
12-lead ECG collection plan for MBG453 single agent and 
MBG453 in combination with PDR001..............................................102
Table 7-7
12-lead ECG collection plan for MBG453 in combination with 
decitabine ............................................................................................102
Table 7-8
Pharmacokinetic blood collection log for MBG453 single agent 
and MBG453 and PDR001 combination, for soluble TIM-3, RO 
and IG (all patients).............................................................................103
Table 7-9
Pharmacokinetic blood collection log for MBG453 in combination 
with decitabine, for soluble TIM-3 and IG (patients treated with 
MBG453 and decitabine) ....................................................................104
Table 7-10
Biomarker sample collection plan for MBG453 single agent and 
MBG453 in combination with PDR001 (tumor/blood samples) ........106
Table 7-11
Biomarker sample collection plan MBG453 in combination with 
decitabine (tumor/blood samples).......................................................107
Table 10-1
Noncompartmental pharmacokinetic parameters................................129


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Table 10-2
Probability to detect at least one special adverse event of interest .....134
Table 10-3
Operating characteristics of the design for ORR ................................135
Table 14-1
Response criteria for target lesions .....................................................153
Table 14-2
Response criteria for non-target lesions..............................................155
Table 14-3
Overall lesion response at each assessment ........................................156
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................163
Table 14-5
Options for event dates used in PFS, TTP, duration of response........164
Table 14-6
Overall response at each assessment...................................................171
Table 14-7
Prior specifications for model parameters...........................................175
Table 14-8
Data from CPDR001X2101 as of 18-Jun-2015 ..................................175
Table 14-9
Summary of prior distribution of DLT rates with CPDR001X2101 
data ** .................................................................................................176
Table 14-10
Hypothetical scenarios ........................................................................176
Table 14-11
True underlying probabilities of DLT for different scenarios ............178
Table 14-12
Simulation results................................................................................180
Table 14-13
Prior specifications for model parameters...........................................182
Table 14-14
Data from ROW patients CMBG453X2101 as of 07-Mar-2016........183
Table 14-15
Summary of prior distribution of DLT rates with ROW patient data 
**.........................................................................................................183
Table 14-16
Hypothetical scenarios ........................................................................184
Table 14-17
True underlying probabilities of DLT in Japanese patients stratum 
for different scenarios .........................................................................187
Table 14-18
Simulation results................................................................................188
Table 14-19
Prior distribution of model parameters ...............................................191
Table 14-20
Summary of prior distribution of DLT rates.......................................192
Table 14-21
Hypothetical scenarios ........................................................................192
Table 14-22
True underlying cumulative probabilities of DLT for different 
scenarios..............................................................................................194
Table 14-23
Simulation results................................................................................195


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List of abbreviations
Ab(s)
Antibody(ies)
AE
Adverse Event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
AUC
Area Under the Curve
BHLRM
Bayesian Hierarchical Logistic Regression Model
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CEACAM1
Carcinoembryonic Antigen-Related Cell Adhesion Molecule 1 
CI
CMO&PS
Confidence Interval
Chief Medical Office and Patient Safety
CNS
Central Nervous System
CR
Complete Response
CRO
CRS
Contract Research Organization
Cytokine Release Syndrome
CSF
Colony Stimulating Growth Factor
CSR
Clinical study report
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-lymphocyte-associated protein 4
DC
Dendritic Cell
DDS
Dose Determining Set
DLT
Dose Limiting Toxicity
DOR
Duration of Response
eCRF
Electronic Case Report/Record Form
ECG
Electrocardiogram
EDC
Electronic Data Capture
ELISA
Enzyme-Linked Immunosorbent Assay
EWOC
Escalation With Overdose Control
EOT
End of Treatment
FAS
Full Analysis Set
FDA
Food and Drug Administration
FIH
First In Human
GLP
Good Laboratory Practice
HBV
Hepatitis B Virus
HCV
Hepatitis C Virus
hCG
Human Chorionic Gonadotropin
HED
Human Equivalent Dose
HIV
Human Immunodeficiency Virus
HNSCC
Head and Neck Squamous Cell Carcinoma
HNSTD
IB
Highest Non-Severely Toxic Dose
Investigator brochure
IEC
Independent Ethics Committee
IFN-
Interferon-gamma
IG
Immunogenicity
IHC
Immunohistochemistry
IL
Interleukin


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INR
International Normalized Ratio
IRB
Institutional Review Board
irAE(s)
Immune-related Adverse Event(s)
irCR
Immune-related Complete Response
irPD
Immune-related Progressive Disease
irPFS
Immune-related Progression Free Survival
irPR
Immune-related Partial Response
irSD
Immune-related Stable Disease
irRC
Immune-related Response Criteria
i.v.
Intravenous(ly)
JP
Japan
LAG-3
Lymphocyte-activation gene-3
LLOQ
Lower Limit Of Quantitation
LMWH
Low Molecular Weight Heparin
mAb(s)
monoclonal Antibody(ies)
MDSCs
Myeloid-Derived Suppressor Cells
MTD
NCCN
Maximum Tolerated Dose
National Comprehensive Cancer Network
NSCLC
Non-Small Cell Lung Carcinoma
NK
Natural Killer
ORR
Overall Response Rate
PAS
Pharmacokinetic Analysis Set
PBMC(s)
Peripheral Blood Mononuclear cell(s)
PHI
Protected Health Information
PD
Progressive Disease
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
(m)PFS
(median) Progression Free Survival
PK
Pharmacokinetics
PPS
Per Protocol Set
PR
Partial Response
PtdSer
Phosphatidylserine
Q2W
Every 2 weeks
Q4W
Every 4 weeks
RAP
Report and Analysis Plan
RCC
Renal Cell Carcinoma
RECIST
Response Evaluation Criteria In Solid Tumors
RO
Receptor Occupancy
ROW
Rest of the World
RP2D(s)
Recommended phase II dose(s)
SAE(s)
SCLC
Serious Adverse Event(s)
Small Cell Lung Cancer
SEB
Staphylococcal enterotoxin B
SEC
SJS
Safety Event Categories
Steven Johnson Syndrome
SD
Stable Disease


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TADC(s)
TEN
Tumor-associated Dendritic cell(s)
Toxic Epidermal Necrosis
TIL(s)
Tumor Infiltrating Lymphocyte(s)
TIM-3
T-cell Immunoglobulin domain and Mucin domain-3
Th1
T helper 1
Tlast
Time to last measurable concentration
TLR
Toll-like Receptor
TNF-α
Tumor Necrosis Factor-alpha
TTP
Time to Progression
TTR
Time To Response
Tregs
Regulatory T cells
ULN
Upper Limit of Normal
UNK
Unknown


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


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Variable
Identifier used in the data analysis; derived directly or indirectly from data collected 
using specified assessments at specified timepoints
Withdrawal of Consent
Withdrawal of consent from the study occurs only when a patient does not want to 
participate in the study any longer, and does not allow any further collection of 
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Protocol Summary:
Protocol number
CMBG453X2101
Title
A phase I-Ib/II, open-label, multi-center study of the safety and efficacy of MBG453 
as single agent and in combination with PDR001 in adult patients with advanced 
malignancies
Brief title
Phase I-Ib/II study of MBG453 as single agent and in combination with PDR001 in 
patients with advanced malignancies.
Sponsor and Clinical 
Phase
Novartis Phase I-Ib/II
Investigation type
Drug
Study type
Interventional
Purpose and 
rationale
The purpose of this “first-in-human” study of MBG453 is to characterize the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics and antitumor activity of 
MBG453 administered i.v. as a single agent or in combination with PDR001 or 
decitabine in adult patients with advanced solid tumors.
In addition, the safety, tolerability, pharmacokinetics and pharmacodynamics of 
MBG453 as single-agent and in combination with PDR001 in Japanese adult patients 
will be evaluated.
Primary Objective(s) 
Phase I-Ib: To characterize the safety and tolerability of MBG453 as a single agent 
and in combination with PDR001 and to identify recommended doses for future 
studies.Phase I-Ib dose ranging: To further investigate the safety and tolerability of 
different doses of MBG453 as single agent or in combination with PDR001.
To characterize the safety and tolerability of MBG453 in combination with decitabine 
in anti-PD-1/PD-L1 therapy naïve small cell lung cancer (SCLC) patients
Phase II: 
To estimate the anti-tumor activity of MBG453 as single agent in patients with solid 
tumors, and in combination with PDR001or decitabine in selected disease 
indications (melanoma, non-small cell lung cancer (NSCLC), renal cell carcinoma 
(RCC) , small cell lung cancer (SCLC)).
Secondary 
Objectives

Evaluate the preliminary anti-tumor activity of MBG453 as single agent and in 
combination with PDR001 or decitabine.

Make an initial comparison of safety, PK and efficacy for MBG453 and PDR001 
administered in combination on a every 2 weeks (Q2W) and every 4 weeks 
(Q4W) dosing schedules. 

Characterize the pharmacokinetic profile of MBG453 as single agent and in 
combination with PDR001 or decitabine.

Assess emergence of anti-MBG453 and anti-PDR001 antibodies.

Assess potential predictors of efficacy of MBG453 as single agent and in 
combination with PDR001 or decitabine in tumor samples.

Assess the pharmacodynamic effect of MBG453 as single agent and in 
combination with PDR001 or decitabine in tumor samples.

Describe the survival distribution of patients treated with MBG453 as single 
agent and in combination with PDR001 or decitabine for each disease group.


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Study Design
This is a first-in-human (FIH), open label, phase I-Ib/II, multi-center study which 
consists of a phase I dose escalation part of MBG453 as single agent (including a 
separate Japanese single agent dose escalation part), and a phase Ib dose 
escalation part of MBG453 in combination with PDR001 that will commence after two 
cohorts in the dose escalation with single agent have been completed. Once the 
Maximum Tolerated Dose (MTD)/Recommended Phase 2 Dose (RP2D) of MBG453 
as single agent and/or in combination with PDR001 is achieved, a Phase I/Ib dose 
ranging part, and a phase II part in patients with solid tumors (MBG453 as single 
agent), and in selected indications (MBG453 in combination with PDR001) will 
commence. In addition, MBG453 in combination with decitabine in anti-PD-1/PD-L1 
therapy naïve SCLC patients will be explored in phase Ib followed by a phase II.
MBG453 and PDR001 will be administered i.v. Q2W or Q4W, decitabine will be 
administered on Days 1-5 Q4W until a patient experiences unacceptable toxicity, 
progressive disease (PD) as per irRC and/or treatment is discontinued at the 
discretion of the Investigator or the patient. Patients should not discontinue treatment 
based on progressive disease per Response Evaluation Criteria in Solid Tumors 
(RECIST) v1.1 unless clinical deterioration or increase in tumor markers is observed
Population

The phase I-Ib dose escalation and dose ranging parts of the study will be 
conducted in adult patients with advanced solid tumors.

The single agent phase II part of the study will be conducted in adult patients in 
indications showing preliminary signs of activity in the phase I dose escalation 
part.

The combination phase II part of the study will be conducted in adult patients 
enrolled in 3 distinct groups (melanoma, NSCLC and RCC).

The phase Ib-II of MBG453 in combination with decitabine will be conducted in
anti-PD-1/PD-L1 therapy naïve SCLC patients.
Inclusion criteria 
(selected)
1.
Histologically documented advanced or metastatic solid tumors.
2.
Phase I-Ib part (including dose ranging part): Patients with 
advanced/metastatic solid tumors, with measurable or non-measurable disease 
as determined by RECIST v1.1, who have progressed despite standard therapy 
or are intolerant of standard therapy, or for whom no standard therapy exists.        
3.
Phase II part (MBG453 single agent): Patients with advanced/metastatic solid 
tumors in the indication in which at least one confirmed PR or CR was seen 
during the dose escalation phase I part. Patients must have measurable disease 
as determined by RECIST v1.1, have progressed despite standard therapy or be 
intolerant to standard therapy.
4.
Phase II part (MBG453 in combination with PDR001): Patients with 
advanced/metastatic tumors in the below selected indications, with at least one 
measurable lesion as determined by RECIST v1.1, who have received standard 
therapy and are intolerant of standard therapy or have progressed following their 
last prior therapy:

Melanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)

NSCLC (anti-PD-1/PD-L1 therapy naïve or pre-treated)

RCC (anti-PD-1/PD-L1 therapy naïve or pre-treated)
5.
Must have a site of disease amenable to biopsy, and be a candidate for tumor 
biopsy according to the treating institution’s guidelines. Patient must be willing to 
undergo a new tumor biopsy at screening/baseline, and during therapy on the
study.
6.
Phase Ib-II part for MBG453 in combination with decitabine : anti-PD-1/PD-
L1 therapy naïve SCLC patients who have failed no more than two lines of 
standard chemotherapy, including topotecan.


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Exclusion criteria 
(selected)
1.
Presence of symptomatic central nervous system (CNS) metastases.
2.
History of severe hypersensitivity reactions to any ingredient of study drugs and 
other monoclonal antibodies (mAbs) and/or their excipients.
3.
Human Immunodeficiency Virus (HIV), Hepatitis B Virus (HBV) or Hepatitis C 
Virus (HCV) infection. 
4.
Active autoimmune disease or a documented history of autoimmune disease, 
including ulcerative colitis and Crohn’s disease or any condition that requires 
systemic steroids.
5.
Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day 
prednisone or equivalent).
6.
Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) 
within 4 weeks of initiation of study treatment.
7.
Pre-treatment with anti-CTLA4 antibodies (Abs) in combination with any other 
antibody or drug specifically targeting T-cell co-stimulation or checkpoint 
pathway.
8.
Participation in an interventional, investigational non-immunotherapy study within 
2 weeks of the first dose of study treatment.
9.
Prior participation in an interventional, investigational cancer vaccine or 
immunotherapy study except for an anti-PD-1/PD-L1 study.
Investigational and 
reference therapy
MBG453 ,PDR001 and decitabine
Efficacy 
assessments
Tumor assessment per RECIST v1.1 and per irRC.
Safety assessments
Incidence and severity of Adverse Events (AEs) and Serious Adverse Events 
(SAEs), including changes in laboratory values, vital signs and Electrocardiograms 
(ECGs).
Other assessments

Serum PK parameters, 
 and Immunogenicity 
(IG).
Data analysis
The study data will be analyzed and reported based on all patients’ data of the Phase 
I-Ib and Phase II parts up to the time when all patients have completed at least six 
cycles of treatment or discontinued the study.
Key words
Phase I-Ib/II, MBG453, PDR001, decitabine, checkpoint inhibitor, PD-1, TIM-3.






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Amendment 05 (04-Nov-2019) 
Amendment rationale
The main purpose of this amendment is to explore a new treatment arm of MBG453 in 
combination with decitabine with the option, at disease progression, to add PDR001 in anti-PD-
1/PD-L1 therapy naïve small cell lung cancer (SCLC) patients who have failed no more than 
two lines of standard chemotherapy including topotecan.
Recent data suggest that decitabine treatment in a mouse model of colon carcinoma enhanced 
both the activation of immune cells in the tumor and combined with anti-PD-1 therapy enhanced 
the anti-tumor immune response (Yu et al 2018). Decitabine enhanced the expression of type I 
interferon in murine cancer models (Stone et al 2017) and this has also been shown in in vitro
with the treatment of myeloid derived suppressor cells (unpublished data). Moreover clinical 
data from this study and from the study done by Harding with an anti-TIM-3 monoclonal 
antibody LY3321367 (Harding et al 2019) suggest that TIM-3 inhibitors have preliminary 
efficacy in SCLC. Moreover clinical data from this study and a competitor study suggest that 
TIM-3 inhibitors have preliminary efficacy in SCLC. Taken together, these data provide the 
rationale to combine decitabine with an anti TIM-3/antiPD-1 in SCLC.
Enrolment in this new arm is applicable to potential study sites in Italy, South Korea, 
Netherlands, Switzerland and United States.
In addition, in consideration of the rapidly evolving landscape for treatment options in 
melanoma, NSCLC, and RCC, Novartis made the decision to not open the Phase II of the 
following expansion groups as per the enrolment halt letter dated 22-May-2018:

MBG453 in combination with PDR001 in Melanoma, and NSCLC (naive to anti PD-
1/PD-L1 therapy) (Group 1 and Group 3) 

MBG453 in combination with PDR001 in RCC (both pretreated and naive to anti PD-
1/PD-L1 therapy) (Group 5 and Group 6) 
This amendment also includes the following changes 

To add that certain exceptions for steroid use can be allowed after discussion with Novartis.

To add that for patients ongoing after cycle 24, and after documented discussion with 
Novartis and the Investigator, a treatment break lasting up to 2 cycles may be granted.

The withdrawal of consent language was revised to differentiate sample use after a patient 
withdraws consent based on different regulations/laws around the world.

To align with the EMA standard term list, the PDR001 pharmaceutical form has been 
updated to “Powder for solution for infusion”.

Other minor corrections were made for consistency and/or clarifications.
Study status
As of 25-Jul-2019, a total of 252 patients have been treated with either MBG453 single agent 
or MBG453 in combination with PDR001. Of the 133 patients treated with MBG453 as a single 
agent, 132 have permanently discontinued study treatment. Of the 119 patients treated with 


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MBG453 in combination with PDR001, 111 have permanently discontinued study treatment.
As of the cut-off date, out of the 9 ongoing patients, 6 are on treatment for more than 2 years.
MBG453 single agent and MBG453 in combination with PDR001 are now closed for enrolment.
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.
Following sections throughout the protocol have been added or updated to introduce MBG453 
in combination with decitabine.

Protocol Summary

Section 1 Background

Section 1.1.1 TIM-3 overview

Section 1.1.3 Decitabine overview

Section 1.2.1.2 MBG453 clinical experience

Section 1.2.2.2 PDR001 Clinical experience

Section 1.2.3 Overview of decitabine

Section 1.2.3.1 Clinical experience with decitabine

Section 1.2.4 Overview of MBG453 , PDR001 and decitabine

Section 1.2.4.2 Clinical experience with the combination of MBG453 and PDR001

Section 1.2.4.3 Non clinical experience with MBG453 in combination with decitabine

Section 1.2.4.4 Clinical experience with MBG453 in combination with decitabine and 
MBG453 in combination with decitabine and PDR001

Section 1.2.4.5 Potential drug interaction

Section 2.1 Study rationale and purpose

Section 2.2 Rationale for the study design

Section 2.3 Rationale for dose and regimen selection 

Section 3 Objectives and endpoints

Section 4.1 Description of study design

Section 4.2 Timing of interim analyses and design adaptations

Section 5.1 Patient population 

Section 5.2 Inclusion criteria

Section 5.3 Exclusion criteria

Section 6.1 Study treatment 

Section 6.1.1 Dosing regimen

Section 6.1.2 Ancillary treatments

Section 6.1.3 Treatment duration

Section 6.2.2 Provisional dose levels

Section 6.2.3.1 MTD definition


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
Section 6.2.3.2 Dose cohort modification 

Section 6.2.4 Definitions of dose limiting toxicities (DLTs) for MBG453 single agent and 
MBG453 in combination with PDR001

Section 6.2.5 Definition of dose limiting toxicities (DLTs) for MBG453 in combination 
with decitabine

Section 6.3.1 Dose modification and dose delay

Section 6.3.2 Follow-up for toxicities

Section 6.3.3 Anticipated risks and safety concerns of the study drug

Section 6.4.2 Permitted concomitant therapy requiring caution and/or action

Section 6.5.2 Treatment assignment or randomization

Section 6.6 Study drug preparation and dispensation 

Section 6.6.2 Drug supply and storage

Section 7.1 Study flow and visit schedule

Section 7.1.2 Treatment period

Section 7.1.3.1 Replacement policy

Section 7.1.4 Withdrawal of consent

Section 7.2.2.6 Cardiac assessments

Section 7.2.3 Pharmacokinetics and immunogenicity assessments

Section 7.2.3.1 Bioanalytics

Section 7.2.3.2 PK, 
 and IG samples handling, labeling and shipping 
instructions

Section 7.2.4 Biomarkers

Section 7.2.4.1 Tumor collection 

Section 7.2.4.2 Blood sample collection 

Section 7.2.4.3 Additional biomarker assessments

Section 8.1.1 Definitions and reporting

Section 8.2 Serious adverse events

Section 10 Statistical methods and data analysis

Section 10.1.2 Safety Set

Section 10.1.3 Per-protocol Set

Section 10.1.4 Dose-determining analysis set

Section 10.3 Treatments (study treatment, concomitant therapies, compliance)

Section 10.4 Primary objective

Section 10.4.1 Variable

Section 10.4.2 Statistical hypothesis, model and method of analysis

Section 10.5.2 Other secondary efficacy objectives

Section 10.5.3 Safety objectives

Section 10.5.4 Pharmacokinetics


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
Section 10.7 Interim analysis

Section 10.8 Sample size calculation

Section 13 References
Additional changes

Glossary of terms has been updated to add the “Personal data” term and revise the 
“Withdrawal of consent” term.

Section 6.4.3 Prohibited concomitant therapy.

Added a statement that exceptions can be made for steroid use after discussion with 
Novartis.

Section 6.6 Study drug preparation and dispensation.

To align with the EMA standard term list, the PDR001 pharmaceutical form has been 
updated to “powder for solution for infusion”.

Section 6.6.1 Study drug packing and labeling.

The pharmaceutical form for PDR001 was changed to “powder for solution for infusion”.

Section 7.1.4 Withdrawal of Consent.

The withdrawal of consent language was revised to differentiate sample use after a 
patient withdraws consent based on different regulations/laws around the world.

Section 7.1.2 Treatment period.

To add that for patients ongoing after cycle 24, and after documented discussion with 
Novartis and the Investigator, a treatment break lasting up to 2 cycles may be granted.

Section 8.2.2 Reporting and Section 8.3 Pregnancies.

The name of the Novartis Drug Safety and Epidemiology department was updated to 
Chief Medical Office and Patient Safety. In addition, clarification was added in the 
pregnancy section to specify that the follow-up of the newborn will be 12 months.

Section 10.5.3.1 Analysis set and grouping for the analyses.

The on-treatment and post-treatment observation periods have been updated.

Section 10.6.1 Biomarkers.

The wording using blood and plasma samples has been removed.
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. 


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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 04 (04-Sep-2018) 
Amendment rationale 
The purpose of this amendment is to incorporate health authority-requested language requiring 
study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS)/ toxic 
epidermal necrolysis (TEN).
After the occurrence of a case of Steven Johnson Syndrome in a study with PDR001 in 
combination with another investigational agent, the dose modification guidelines for protocols 
using PDR001 were updated to mandate permanent discontinuation of study treatment for 
patients who experience SJS or Lyell syndrome/toxic epidermal necrolysis (TEN). This change 
has already been implemented as part of an urgent safety measure released on 15 June 2018. 
This protocol amendment is now finalizing these changes in the dose modification section and 
corresponding table describing the criteria for dose reduction/interruption and re-initiation of 
treatment for adverse drug reactions
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section 6.3.1: Dose modification and dose delay

Instruction for dose modification was updated and Table 6-5 updated accordingly. The list 
of abbreviations was updated to add SJS and TEN
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 15 June 2018. These changes are required for patient 
safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH GCP 3.3.8). 
Therefore they were required to have been implemented prior to IRB/IEC approval of this 
amendment. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 03 (18-Jul-2016)
Amendment rationale
Main purpose of the amendment:
The purpose of this amendment is to update the exclusion criterion 2 as requested by a 
regulatory authority. The exclusion criterion is modified to clarify that patients with a history 
of hypersensitivity to any ingredient of the study drugs are also excluded.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 5.3 Exclusion criteria

Update of the exclusion criterion 2.
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to
implementation. 


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Amendment 02 (06-Jun-2016)
Amendment rationale
Main purpose of the amendment:
The main purpose of this amendment is to include a Japanese dose escalation part for single-
agent MBG453 with the goal of informing subsequent clinical development opportunities in 
Japan.
The single agent dose escalation part of this study is already underway globally with the 
exception of Japan. At the time of this protocol amendment patients are being treated with 
single-agent MBG453 at 80mg Q2W and at 240mg Q2W and Q4W.
In order to ensure that the safety and pharmacokinetic profiles of single-agent MBG453 are 
adequately characterized in Japanese patients at more than one MBG453 dose, a Japanese-
specific MBG453 single agent dose escalation is being included in the protocol. The Japanese 
dose escalation will run separately from the ongoing dose escalation with a starting dose for 
single agent MBG453 in Japanese patients of 80mg Q2W. After the first cohort Japanese 
patients may be treated in two different dosing regimens (Q2W and Q4W). Dose escalation 
decisions will be guided by a BHLRM. 
If the recommended dose of single agent MBG453 in Japanese patients is the same as in patients 
from the rest of the world (ROW), then Japanese patients may be enrolled into the phase II 
single agent part of the study.
In addition, if the recommended dose of PDR001 for Japanese patients in the single agent study 
(PDR001X1101) currently ongoing in Japan is the same as that determined in the single agent 
ROW study (PDR001X2101), Japanese patients may also enter the combination parts of the 
current MBG453 study at whichever dose is being tested at that time. 
If any of the Japanese single agents (PDR001 and/or MBG453) RP2D and/or MTD is different 
than the ROW, a new clinical development plan will be required to investigate the combination 
treatment in Japanese patients.
Other objectives of the amendment:
To update eligibility criteria:
In addition to the inclusion of Japan within the study, below described eligibility criteria have 
been updated and a new exclusion criterion has been added.

The inclusion criterion 4 has been amended to allow inclusion in the phase I-Ib parts of 
patients who previously received therapy with PD-1/PD-L1 blocking agents, as it has been
recently shown that TIM-3 is significantly up-regulated in T-cells of patients previously 
exposed to PD-1 blocking agents (Koyama et al 2016).

As durable stable disease (SD) is also a characteristic of cancer immunotherapy, the 
inclusion criterion 5 has been amended to be less stringent and allow opening of the 
phase II MBG453 single agent in indications in which durable tumor shrinkages that may 
not qualify for PR have been observed. 


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
The exclusion criterion 5 (Excluding HIV, HBV or HCV positive patients at 
screening/baseline) has been amended to allow inclusion of patients who may be HBV and 
HCV infection positive without active disease. Considering the mechanism of action of 
TIM-3 and PD1 blockade, the risk of hepatitis reactivation further to study treatment is 
very low.

Given that pneumonitis is a reported adverse event of PD-1 blockade therapy, patients 
with a history of drug-induced pneumonitis or current pneumonitis are excluded.
To update other aspects of the protocol:

Based on latest information recently communicated on Nivolumab, the immune-related 
adverse events (irAEs) expected to be associated with all classes of checkpoint inhibitors 
including MBG453 have been updated to add “Encephalitis”.

In keeping with current medical procedures the possibility to allow limited-field palliative 
radiotherapy or surgery to non-target lesion(s) as concomitant therapy requiring caution 
and/or action has been introduced.

Due to its higher specificity, Free T4 substitutes Total T4 analysis.

Furthermore the baseline cytokine collection for safety assessment has been removed as it 
was a duplicate. Baseline cytokine levels can be assessed from the biomarker blood 
sample collected at pre-dose Cycle 1 day 1.

With the available PK data obtained from the single agent first-in-human study 
[CPDR001X2101], an exploratory population PK (PopPK) analysis showed that the T1/2 
of PDR001 in man is 20 [17, 23] days (mean [90% CI]). Therefore the protocol will be 
amended by increasing the duration of contraception and safety follow-up periods post 
PDR001 treatment from 90 days to 150 days. These changes are related to an Urgent 
Safety Measure communicated on 08-June-2016 to all investigators. 

Additional minor corrections/clarifications were also made. The details are provided in the 
below section “Changes to the protocol”.
Changes to the Protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 1.2.1.2 MBG453 Clinical experience

Encephalitis has been added as an irAE expected to be associated with all classes of 
checkpoint inhibitors.

Section 1.2.2.2 PDR001 Clinical Experience

Updated the summary of CPDR001X2101 study.

Section 2.2 Rationale for the study design: 

Added a statement to include a separate Japanese dose escalation with MBG453 
single agent. 

Added statements of recruitment of Japanese patients in the other phases of the study.

Language update on signs of anti-tumor activity.

Section 4.1 Description of study design


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
The description of the study design was updated in order to include a separate 
Japanese dose escalation with MBG453 single agent and to describe the participation 
of Japanese patients in the other phases of the study.

Updated to align with the new duration of contraception and safety follow-up periods 
post treatment from 90 days to 150 days.

Figure 4-1 was updated to include a separate Japanese dose escalation with MBG453 
single agent.

Figure 4-2 was updated to align with the new duration of contraception and safety 
follow-up periods post treatment from 90 days to150 days.

Section 5.2 Inclusion criteria

Updated for Japan only: written consent is necessary both from the patient and his/her 
legal representative if he/she is under the age of 20 years for Japanese patients.

Language update in order to allow for patients pre-treated with PD1/PD L1 to be 
enrolled in the phase I-Ib parts.

Language update on signs of anti-tumor activity.

Inclusion criterion 9: life expectancy > 12 weeks, has been removed.

Section 5.3 Exclusion criteria

Minor clarification on hypersensitivity reactions.

Update on HBV/HCV/HIV patients exclusion criteria. 

Minor clarification on post-menopausal criteria.

Addition of an exclusion criterion for patients with a history of drug-induced 
pneumonitis or current pneumonitis.

Clarification of indolent malignancies.

Updated to align with the new duration of contraception and safety follow-up periods 
post treatment from 90 days to 150 days.

Section 6.2.3.2 Dose cohort modification

Included dose escalation guidelines for Japanese patients. 

Minor clarification on RP2D/MTD identification conditions.

Table 6-5 Management of toxicities defined as study treatment-related only

Clarified language on management of Bilirubin, and AST or ALT toxicities.

Clarified language for discontinuation due to grade 3 and 4 CRS toxicity.

Minor clarification on any neurological disorder. 

Section 6.3.2 Follow-up for toxities

Updated to align with the new duration of contraception and safety follow-up periods 
post treatment from 90 days to 150 days.

Section 6.4.2 Permitted concomitant therapy requiring caution and/or action

Clarified that limited-field palliative radiotherapy to non-target lesion(s) may be 
allowed after documented discussion with Novartis.

Table 7-1 Visit evaluation schedule




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
Section 10: Statistical Methods and data analysis

Updated to include data analysis rules throughout the section; statistical hypothesis; 
model; and method of analysis for the Japanese-specific single agent MBG453 dose 
escalation.

Section 10.4.2 Phase II part: corrected values of observed ORR less than 10%.

Section 10.4.2 Listing of DLT: DLT summary table may be provided.

Section 10.5.3 Safety objectives

Updated to align with the new duration of contraception and safety follow-up periods 
post treatment from 90 days to 150 days.

Section 14: Appendices.

Added a new Section 14.3.2: “Phase I part MBG453 single agent with Japanese 
patients”.

Section 14.3.3: Operating characteristics: remove irrelevant text and correct typo.

Section 14.4 (Appendix 4): Recommended management algorithms for suspected 
toxicities: Corrected inconsistency in the algorithm tables for management of AEs.
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to
implementation. The changes herein affect the Informed Consent. Sites are required to update
and submit for approval a revised Informed Consent that takes into account the changes
described in this protocol amendment.


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Amendment 01 (19-Oct-2015)
Amendment rationale
This amendment addresses the following revisions requested by a regulatory authority:

Clarification in protocol to require discontinuation of study drug for Grade 3 treatment-
related cardiac adverse events and for grade 3 treatment-related neurological events. 

To include assessment of vital signs during infusion of study drug as well as after. In 
addition, include requirements to observe patients for 1-2 hours post infusion of study 
drug.

Clarification of wording in protocol to provide additional details concerning dose 
escalation decision and number of patients to include in the first cohort.

Additional minor corrections/clarifications were also made. The details are provided in the 
below section Changes to the protocol.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.

Section 6.1.1, Section 6.2.3.2 and Table 6-4: corrections as requested by regulatory 
authority. 

Section 6.5.1: minor correction in wording.

Table 7-1: changes in Vital signs as per requested by regulatory authority and correction 
of an extra sample not needed.

Section 7.2.2.2: corrections as requested by regulatory authority. 

Table 7-6: minor correction of a missing timepoint.

Section 8.1.1 and Section 8.2.2: new language added for electronic SAE process.

Section 8.3: clarification of follow up pregnancy for female of male participant.

Section 14.2.1: minor clarification.
IRB/IEC/HA Approval
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. The changes herein affect the Informed Consent. Sites are required to update 
and submit for approval a revised Informed Consent that takes into account the changes 
described in this protocol amendment.


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1
Background
The ultimate goal of cancer immunotherapy is to break tumor-induced immunosuppression and 
activate a powerful immune response against cancer. Since the approval of ipilimumab, an anti-
cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) antibody for patients with advanced 
melanoma, the blockade of immune checkpoints has been considered a promising approach to 
fight cancer. Immune checkpoints refer to a variety of inhibitory pathways that are crucial for 
maintaining self-tolerance and modulating the duration and amplitude of physiological immune 
responses in peripheral tissues in order to minimize collateral tissue damage 
(Shin and Ribas 2015).
During tumorigenesis, cancer cells from a wide range of tumor types exploit immune 
checkpoint pathways, such as the programmed death-1 (PD-1) / programmed death-ligand 1 
(PD-L1) pathway, to avoid detection by the adaptive immune system (Murphy 2011). Blockade 
of the PD-1 pathway leads to increased numbers of effector T cells through induction or 
expansion, and improved anti-tumor cytolytic activity. Additionally, PD-1 blockade is 
associated with accumulation of effector T cells and a reduced numbers of regulatory T cells 
(Tregs) at the tumor site (Wang 2009, Mangsbo 2010, Mkrtichyan 2011, Rosenblatt 2011). 
Blockade of the PD-1 pathway has demonstrated clinically relevant durable responses in 
melanoma (Robert 2015, Weber 2015), leading to the Food and Drug Administration (FDA)
approval of both pembrolizumab and nivolumab. The durable responses observed in lung cancer 
(Brahmer 2015, Garon 2015) led to the approval of nivolumab and a priority review for 
pembrolizumab in this indication.
In metastatic melanoma, the anti PD-1 antibody pembrolizumab induced durable responses in 
30–35% patients (Hamid 2013). In advanced NSCLC, data from the ongoing Phase Ib 
KEYNOTE-001 study showed an overall response rate (ORR) of 19.4% with the median 
duration of response (DOR) of 12.5 months in an unselected population (Garon 2015).
In March 2015, nivolumab was approved by the FDA for the treatment of metastatic squamous 
NSCLC that has failed chemotherapy, based on results of the pivotal phase III CheckMate-017 
trial (Brahmer 2015), which showed improved overall survival (OS) compared to docetaxel in 
NSCLC patients with squamous cell histology (9.2 vs 6.0 months; HR = 0.59; 95% CI, 0.44-
0.79; P = 0.00025). More recently, the phase III CheckMate -057 trial also met the primary 
endpoint of improved OS (Paz-Ares 2015).
Furthermore, durable responses have been observed among patients with Hodgkin’s disease 
(Ansell 2015), breast cancer (Homet Moreno and Ribas 2015), RCC (Michel Ortega and 
Drabkin 2015, Sunshine 2015), and bladder cancers (Powles 2014) treated with anti-PD-1 or 
anti-PD-L1 antibody monotherapy, representing a new and promising treatment approach for 
patients with advanced cancer.Recurrence in Small Cell Lung Cancer (SCLC) after second line 
treatment is inevitable. There are limited options at the time of progression including institution 
of best supportive care. In the subgroup of 109 SCLC patients enrolled in the CheckMate-032 
study in third or later-line treatment receiving nivolumab monotherapy, the ORR was 11.9% 
and the 6-month PFS rate was 17.2% (Ready et al 2018). It is, therefore, important to investigate 
new strategies that might improve the antitumor response in this disease after failure of standard 
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The blockade of other negative immune regulators, such as T-cell immunoglobulin domain and 
mucin domain-3 (TIM-3) and lymphocyte-activation gene-3 (LAG-3), has also shown 
promising preclinical activity alone and synergistic activity when combined with anti-PD-1/ 
PD-L1. Blockade of TIM-3 has shown anti-tumor efficacy (moderate effect alone, and 
additively or synergistically in combination with PD-1 pathway blockade) in several preclinical 
cancer models, including CT26 colon carcinoma (Sakuishi 2010) and WT3 sarcoma and 
TRAMP-C1 prostate carcinoma (Ngiow 2011). In all models tested, efficacy was improved 
relative to single agent treatment by combination of PD-1 and TIM-3 pathway blockade.
Despite the clinical results seen to date, the majority of patients still do not respond to anti- PD-
1/anti-PD-L1 blockade. It is therefore important to investigate new strategies and assess 
whether the concurrent blockade of other inhibitory pathways (such as TIM-3 and PD-1) might 
improve the objective response rate to single agent anti-PD-1 or anti-PD-L1 therapy, provide 
more durable responses than single agent checkpoint inhibition, or re-induce response in 
patients who progressed on or after anti-PD-1 or anti-PD-L1 monotherapy.
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
1.1.1
TIM-3 overview
The transmembrane immunoglobulin and mucin domain (TIM) family are characterized by an 
N-terminal Immunoglublin (Ig) domain of the V subset, followed by a mucin-like domain, 
single transmembrane domain and a cytoplasmic tail of variable length. The human genome 
contains three TIM genes, which encode the proteins TIM-1, TIM-3 and TIM-4.
Studies published thus far have indicated that TIM-3 has a widespread and complex role in 
immune system regulation. TIM-3 was initially described as a co-inhibitory protein expressed 
on activated T helper 1 (Th1) CD4+ and cytotoxic CD8+ T cells that secrete interferon-gamma 
(IFN-. TIM-3 protein is not expressed by naïve T cells, and little TIM-3 can be detected after 
several rounds of antigenic stimulation in the presence of interleukin (IL)-4. In contrast, 
repetitive in vitro re-stimulation of murine T cells in the presence of Th1-polarizing conditions 
(IL-12 and anti-IL-4) leads to an abundance of Th1 cells expressing TIM-3 (Monney 2002, 
Sánchez-Fueyo 2003). TIM-3 is largely co-expressed on PD-1+ exhausted T cells and co-
blockade of these pathways restores effector T cell function (IFN-secretion, proliferation) in 
several models as well as human PBMCs derived from metastatic melanoma patients and 
patients with HIV or HCV (Jones 2008, Golden-Mason 2009, Fourcade 2010).
TIM-3 is also enriched on FoxP3+ Tregs, which correlate with disease severity in NSCLC, 
hepatocellular and ovarian carcinomas (Gao 2012, Yan 2013). Intratumoral PD-1+ TIM-3+ 
FoxP3+ Tregs are highly suppressive, and in vivo co-blockade of TIM-3 and PD-1 pathways 
downregulates molecules associated with TIM-3+ Treg suppressor functions (Sakuishi 2013). 
Interestingly, TIM-3+ Tregs, unlike CTLA-4+ Tregs, are predominantly localized to the tumor 
microenvironment rather than peripheral circulation (Sakuishi 2013).
TIM-3 is also constitutively expressed on dendritic cells (DCs), monocytes/macrophages, and 
natural killer (NK) cells (Anderson 2007, Ndhlovu 2012), and blockade of TIM-3 has been 
shown to correlate with increased cytotoxicity in NK cells (da Silva 2014), increased secretion 


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of IL-12/tumor necrosis factor-alpha (TNF-α) by monocytes/macrophages (Zhang 2011) and 
increased nuclear factor 'kappa-light-chain-enhancer' of activated B-cells expression in DCs 
(Anderson 2007). High expression of TIM-3 has been detected in tumor-associated DCs 
(TADCs), in tumor-bearing mice as well as tumor samples from patients. Critically, tumor cells 
as well as tumor-derived immunoregulatory factors (such as IL-10 and vascular endothelial 
growth factor) promote TIM-3 expression on immature bone marrow-derived DCs, which 
suggests that immunosuppressive factors in the tumor microenvironment induce DCs to express 
TIM-3. TIM-3 has also been shown to contribute to expansion of myeloid-derived suppressor 
cells (MDSCs) through an unknown mechanism (Dardalhon 2010). Constitutive expression of 
TIM-3 on macrophages is associated with less IL-12 secretion, and downregulation of TIM-3 
post- Toll-like receptor (TLR) activation leads to enhanced IL-12 and subsequent effector T 
cell responses (Zhang 2011, Zhang 2012).Blockade of TIM-3 on antigen cross-presenting 
dendritic cells enhances activation and inflammatory cytokine/chemokine production 
(Chiba et al 2012, de Mingo Pulido et al 2018), potentially ultimately leading to enhanced 
effector T cell responses.
TIM-3 was found to be expressed on leukemic stem cells (CD34+CD38- LSCs) as well as CD34 
positive leukemic blasts in the majority of AML subtypes (M0-M2; M4-M7) (Kikushige et al 
2010). Upregulation of TIM-3 is also associated with leukemic transformation of pre-leukemic 
disease, include myelodysplastic syndromes (MDSs) and myeloproliferative neoplasms 
(MPNs), such as chronic myelogenous leukemia (CML) (Kikushige et al 2015, Asayama et al 
2017). Preclinical evidence in AML murine models also suggests that disease progression may 
be associated with increased PD-1 expression on CD8-positive T-cells, and treatment with anti-
PD-1 or anti-PD-L1 antibodies decreased AML burden and improved survival (Zhang et al 
2009). Dual blockade of PD-1 and TIM-3 significantly reduced AML burden and prolonged 
survival in mouse syngeneic model of AML (Zhou et al 2011).
TIM-3 ligand usage and intracellular signaling pathways remain unclear. There are four
proposed ligands for TIM-3: S-type lectin galectin-9 has been described in murine models to 
inhibit TIM-3-associated Th1 effector function and induce apoptosis on TIM-3-expressing T 
cells (Zhu 2005); phosphatidylserine (PtdSer), which binds a preserved cleft in all three human 
TIM family members (TIM-1, 3, 4), though functional effects of engagement of TIM-3 are 
unknown (DeKruyff 2010); DNA alarmin HMGB1, for which TIM-3 has been proposed to act 
as a ‘sink,’ preventing the HMGB1/RAGE interactions that stimulate innate immunity 
(Chiba 2012); and most recently, the carcinoembryonic antigen-related cell adhesion molecule 
1 (CEACAM1), proposed to interact with TIM-3 both in cis as a heterodimer on T cells and in 
trans as a ligand (Huang 2015). Co-blockade of TIM-3 and CEACAM1 in CT26 colon 
carcinoma showed similar efficacy to that seen for co-blockade of PD-L1 and TIM-3. The 
intracellular signaling pathways engaged downstream of TIM-3 remain largely unknown. 
TIM-3 has a critical role in tumor-induced immune suppression as it marks the most suppressed 
or dysfunctional populations of CD8+ T cells in animal models of solid and hematologic 
malignancies (Sakuishi 2010, Yang 2012, Zhou 2011). TIM-3 blockade in these animal models 
has successfully demonstrated similar anti-tumor activity compared to PD-1 pathway blockade 
(Ngiow 2011, Zhou 2011), with greater efficacy with the combined use of TIM-3 and PD-1 
blockade (Sakuishi 2010, Ngiow 2011). Increasing data support the relevance of TIM-3 
blockade in human cancer as TIM-3+ NY-ESO-1 specific CD8+ T cells in patients with 


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melanoma showed dysfunctional phenotypes. TIM-3 blockade restored IFN-γ and TNF-α 
production as well as the proliferation of these cells in response to antigenic stimulation 
(Fourcade 2010). 
TIM-3 has now emerged as an immune checkpoint receptor with its selective expression in 
tumor tissue as well as its critical role in multiple immune suppressive mechanisms, which 
strongly supports TIM-3 targeted immunotherapies as single or combined modalities.
1.1.2
PD-1 overview
PD-1 is a critical checkpoint receptor that is expressed by effector T cells upon activation 
(Okazaki et al 2013). It is also expressed by B cells, NKT cells, CD4+ Tregs, and some DC 
subsets upon activation (Francisco et al 2010). Its ligands, PD-L1 and programmed death-ligand 
2 (PD-L2) are expressed by DCs macrophages and monocytes, and can be induced on virus-
infected cells and many types of tumors (Keir et al 2008). Engagement of PD-1 with its ligands 
PD-L1 and PD-L2 negatively regulates effector T cell signaling and function and protects the 
tumor cells from the induction of apoptosis by effector T cells.
The PD-1/PD-L1 axis is exploited by many tumor types to avoid detection by the adaptive 
immune system (Murphy 2011). Blockade of the PD-1 pathway has been shown to lead to 
increased numbers of effector T cells through induction or expansion and improved cytolytic 
activity towards tumors. Additionally, PD-1 blockade is associated with accumulation of 
effector T cells and a reduced numbers of Tregs at the tumor site (Wang et al 2009, Mangsbo
et al 2010, Mkrtichyan et al 2011, Rosenblatt et al 2011). 
Both preclinical and clinical studies have demonstrated that anti-PD-1 blockade restores activity 
of “exhausted” effector T cells and results in robust anti-tumor response. Clinical data with 
other anti-PD-1 antibodies have demonstrated that PD-1 checkpoint inhibition results in 
clinically relevant anti-tumor activity in a variety of solid tumors, including melanoma, NSCLC, 
RCC, breast cancer, bladder cancer and head and neck squamous cell cancer (HNSCC) with an 
acceptable and manageable safety profile (Topalian 2012, Hamid 2013, Topalian 2014, Lyford-
Pike 2013, Powles 2014, Ansell 2015, Homet Moreno and Ribas 2015, Michel Ortega and 
Drabkin 2015, Sunshine 2015).


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1.1.3
Hypomethylation overview
The incorporation of the hypomethylating agent decitabine in place of 5-methylcytosine in 
DNA results in the inactivation of DNA methyltransferase 1 due to covalent bond formation 
between the 5-azacytosine ring of decitabine and this enzyme. The end result of this process is 
hypomethylation of DNA. Genes that are silenced by aberrant DNA methylation can be 
reactivated by treatment with decitabine. Both leukemic and tumor cells are very sensitive to 
the antineoplastic action of low concentrations of decitabine. In animal models of leukemia and 
cancer, decitabine shows curative potential (Momparler 2005). A pilot study on intense dose 
decitabine showed promising results in patients with metastatic NSCLC (Montparler et al 1997,
Montparler and Ayoub 2001). However, subsequent clinical studies using low dose decitabine 
were not very effective against NSCLC and interest in this therapy diminished. Recently, 
interesting responses were observed in a patient with NSCLC following treatment with a 
combination of the related inhibitor of DNA methylation, 5-azacytidine, and an inhibitor of 
histone deacetylation. This finding has generated a renewed interest in the epigenetic therapy 
of lung cancer (Schrump et al 2006, Lemaire et al 2008). The delayed and prolonged epigenetic 
action of the hypomethylating agent has been taken into consideration and decitabine is dosed
before MBG453.
1.2
Introduction to investigational treatments 
1.2.1
Overview of MBG453
MBG453 is a high-affinity, ligand-blocking, humanized anti-TIM-3 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of TIM-3 to PtdSer. MBG453 is cynomolgus monkey 
cross-reactive and shows functional activity.
1.2.1.1
MBG453 Non-clinical experience 
MBG453 binds specifically and with high affinity to human TIM-3. In Biacore assays, the KD
of MBG453 for human TIM-3 is 0.167±0.008 nM and in cell binding assays, MBG453 binds 
human TIM-3 expressing cells with an affinity of 0.5±0.1nM. MBG453 does not cross-react 
with rat or mouse TIM-3, and therefore cannot be evaluated in murine tumor models. It does 
cross-react with cynomolgus monkey TIM-3 (affinity of 0.9±0.1nM on cynomolgus TIM-3-
expressing cells), making cynomolgus monkey a relevant species and the only species for 
toxicology studies.
In order to assess potential off target binding of MBG453, a good laboratory practice (GLP)
tissue cross reactivity study using frozen human and cynomolgus monkey tissues was 
conducted. Due to the low level of staining in healthy monkey compared to human tissues, lung 
and colon tissue from a monkey in which several inflammatory foci were observed was also 
included to increase the population of (active) mononuclear cells. In human tissues, positive 
membranous/cytoplasmic staining with MBG453 was primarily observed in interstitial round 
and occasionally spindle cells; consistent with mononuclear inflammatory cells in most tissues; 
binding was also observed in tissues with resident monocyte-macrophage lineage cells and at 
low level in some renal tubular epithelial cells. In monkeys, staining was limited to placenta, 
cerebellum, pituitary gland and spinal cord and staining intensity was lower compared to human 
tissues staining. Stained cells were similar to cells described above in the human tissues 


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(mononuclear cells probably consistent with resident macrophages). Positive staining was not 
observed in the tissues (lung and colon that had mononuclear cell infiltrations) from the diseased 
monkey.
Safety was evaluated in a limited panel in a PK study that included single and repeat dose arms 
as well as a five week repeat dose GLP toxicology study, both in cynomolgus monkeys. In the 
PK study, animals were dosed either once at 10 mg/kg i.v. or twice at 100 mg/kg i.v. one week 
apart. Clinical observations, clinical chemistry, and hematology endpoints were evaluated as 
part of an in-life assessment of safety in this study. There was no toxicity related to MBG453 
administration and exposure to MBG453 was confirmed. The only effects noted were transient 
decreases in counts of CD4+ and CD8+ T cells, and monocytes with lowest levels observed 2 
days after the second dose of 100 mg/kg. The biological significance of this is unclear.
In the five week GLP toxicology study, MBG453 was administered to monkeys weekly i.v. at 
6, 25, and 100 mg/kg. There was no test article-related toxicity observed at any dose. In females 
only there were greater CD4+CD25+, CD8+CD25+ and CD8+CD25+FoxP3+T cell counts per 
gram weight at all MBG453 doses. Dose proportionality was observed for all three doses, with 
immunogenicity impacting all 6 mg/kg/week animals in week 5. The Highest Non-Severely 
Toxic Dose (HNSTD) was 100 mg/kg weekly i.v. MBG453 has a favorable safety profile in 
monkeys that supports the proposed human starting dose of 1 mg/kg.
For details please refer to [MBG453 Investigator’s Brochure].
1.2.1.2
MBG453 Clinical experience
This is the FIH study with MBG453. Based on the clinical experience with the PD-1 blocking 
mAbs pembrolizumab and nivolumab, all classes of checkpoint inhibitors including MBG453 
therapy are expected to be associated with immune-related adverse events (irAEs), including 
skin reactions, endocrinopathies (hypothyroidism, hyperthyroidism, diabetes, hypophysitis, and 
hypopituitarism), pneumonitis, colitis, hepatitis, encephalitis and nephritis (pembrolizumab US 
label, nivolumab US label).
As of 25-Jul-2019 in the current study, 133 patients have been treated with MBG453 single 
agent on a Q2W or Q4W regimen. No Dose Limiting Toxicities (DLTs) were reported for any 
patients treated with MBG453 as a single agent. The RP2D has been declared for MBG453 
single agent at 800mg Q4W.
Of the 133 patients treated with MBG453  single agent on a Q2W or Q4W regimen, 125 patients 
(94%) experienced AEs of any grade, regardless of relationship to study drug, with the most 
frequent AEs (>10%) being fatigue (39 patients, 29%), nausea (34 patients, 26%), anemia (29 
patients, 22%), constipation (26 patients, 20%), decreased appetite (23 patients, 17%), dyspnea 
(21 patients, 16%) abdominal pain (19 patients, 14%), vomiting (18 patients, 14%), diarrhea 
(17 patients, 13%) cough and pyrexia (16 patients each, 12%) and edema peripheral (14 patients, 
11%).
For further details, refer to the most recent edition of the [MBG453 IB].


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1.2.2
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody (stabilized 
hinge, S228P) which blocks the binding of PD-1 to PD-L1 and PD-L2. PDR001 is cynomolgus 
monkey cross-reactive and shows functional activity in vitro and in vivo. For further details, 
please refer to the most recent edition of the [PDR001 Investigator’s Brochure].
1.2.2.1
PDR001 Non-clinical experience
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the KD of 
PDR001 on human PD-1 is 0.83 nM. In ex vivo lymphocyte stimulation assays using human 
blood, PDR001 enhances IL-2 production by approximately 2-fold in response to super antigen 
stimulation with Staphylococcal enterotoxin B (SEB). PDR001 does not cross-react with rodent 
PD-1, and cannot be evaluated in murine tumor models. It does cross-react with cynomolgus 
monkey PD-1, and is functionally active, making cynomolgus monkey a relevant species for 
toxicology studies. A GLP tissue cross reactivity study using frozen human and cynomolgus 
monkey tissues was also done in support of the safety of PDR001. There was no unexpected 
binding observed.
The non-clinical toxicology of PDR001 was evaluated in a five week GLP toxicology study in 
cynomolgus monkeys with safety pharmacology endpoints and an eight week recovery. Repeat 
administration of PDR001 to monkeys was well tolerated at all doses tested in the GLP 
toxicology study. No test article-related in-life, mortality, organ weight changes, or 
macroscopic findings were noted. There were no PDR001-related effects seen in any of the 
safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 
100 mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given 25 mg/kg/week.
These PDR001-related microscopic changes were fully reversible after an eight week recovery.
The following changes were noted in main phase and recovery treated animals as well as control 
recovery animals. Mostly low grade changes were noted in several tissues in the form of 
mononuclear infiltrates in the vascular and perivascular space. In general, in most organs, 
vascular/perivascular changes were limited to one or a few blood vessels in each organ and 
sometimes involved a segment of a blood vessel with occasional vessel wall degeneration. 
No evidence of parenchymal damage was associated with the vascular/perivascular changes in 
any of the organs examined and the changes were not associated with any frank tissue injury. 
While these effects were not exclusive to treated animals, because of their nature and close 
association with the expected pharmacology of PD-1 blockade, a potential PDR001 related 
effect cannot be excluded and possibly explained by mild enhanced pharmacology of PDR001. 
There were no test article related effects seen in the cardiovascular assessments. All other 
microscopic findings were considered spontaneous or otherwise unrelated to PDR001 
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Dose-dependent exposure to PDR001 in each dose group was confirmed. A pharmacodynamic 
ex vivo superantigen stimulated whole blood assay measuring IL-2 release was performed. 
Blood from untreated control animals showed augmentation of IL-2 release when PDR001 was 
added ex vivo, whereas blood from treated animals at all doses did not show augmented IL-2 
release, indicating target engagement and inability to further dis-inhibit the SEB induced 
response with the further addition of PDR001. The HNSTD dose in this study was 100 mg/kg.
For further details, please refer to the most recent edition of the [PDR001 Investigator’s 
Brochure].
1.2.2.2
PDR001 Clinical experience
PDR001 is being tested in a FIH, multi-center, open-label study [CPDR001X2101] starting with 
a phase I dose escalation part, followed by a phase II part. The study has completed enrolment. 
The dose escalation part of the study evaluated dose levels of 1, 3 and 10 mg/kg Q2W and 3 
and 5 mg/kg Q4W. No subject experienced a dose limiting toxicity (DLT). The PK analysis of 
the dose escalation data using a population approach and the expected wide therapeutic index 
of PD-1 inhibitors support the use of flat dosing for PDR001 of 400 mg Q4W or 300 mg Q3W. 
The expected PDR001 Ctrough concentrations using either dosing regimen exceed the EC50 
for PD-1 blockade by approximately 75-fold in an ex vivo assay in peripheral blood 
mononuclear cells (PBMCs). Based on the available PK and safety data, the RP2D of PDR001 
has been declared as 400 mg i.v. Q4W or 300 mg i.v. Q3W for combination treatment regimens 
for which this may be more convenient. 
PDR001 is currently being studied alone or in combination with other agents in ongoing phase 
I/II clinical trials. The preliminary toxicity profile appears to be similar to that of marketed 
inhibitors of PD-1 including the type, severity and frequency of occurrence of immune-
mediated adverse events. As observed with other PD-1 inhibitors, immune-mediated toxicities 
observed with PDR001 are reversible in many cases. In some cases, they may require treatment 
with corticosteroids. Certain toxicities are expected to be lifelong and may require replacement 
therapy with hormones, for example in the case of hypothyroidism.
Based on the preliminary data, PDR001 was well tolerated with a safety profile similar to those 
of other marketed anti-PD-1 antibodies. For additional information, please refer to the [PDR001 
Investigator’s Brochure].
1.2.3
Overview of decitabine
Decitabine (5-aza-2’-deoxycytidine) is a cytidine deoxynucleoside analogue that selectively 
inhibits DNA methyltransferases at low doses, resulting in gene promoter hypomethylation that 
can result in reactivation of tumor suppressor genes, induction of cellular differentiation or 
cellular senescence followed by programmed cell death. Decitabine is commercially available 
and indicated for the treatment of adult patients aged 65 years and above with newly diagnosed 
de novo or secondary AML, according to the WHO classification, who are not candidates for 
standard induction chemotherapy. Decitabine is also indicated for treatment of patients with 
MDS including previously treated and untreated, de novo and secondary MDS of all French-
American-British subtypes and intermediate-1, intermediate-2, and high-risk iPSS groups in the 
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1.2.3.1
Clinical experience with decitabine
There is limited clinical experience with decitabine treatment in solid tumors.The use of 
decitabine (20 mg/m2 daily for 5 days) has been evaluated in several studies, including an open-
label, randomized, multicenter Phase III study (DACO- 016) in patients with newly diagnosed 
de novo or secondary AML according to the WHO classification. The most common adverse 
drug reactions reported during treatment with decitabine are neutropenia, thrombocytopenia
and anemia. Neutropenia of any grade occurred in 90% of decitabine-treated patients with grade 
3 or 4 occurring in 87% of patients. Thrombocytopenia of any grade occurred in 89% of patients 
with grade 3 or 4 occurring in 85% of patients. Grade 3 or 4 febrile neutropenia occurred in 23% 
of patients. Anemia of any grade occurred in 82% of patients (decitabine country-specific label). 
Other commonly occuring Grade 3/4 adverse drug reactions (≥20%) included pneumonia (21%),
(Kantarjian et al 2012).
Decitabine exhibits linear PK, and following intravenous infusion, steady-state concentrations 
are reached within 0.5 hour post-infusion. The systemic half life is short (20 minutes) and there 
was no accumulation observed with this dosing regimen. Plasma protein binding of decitabine 
is negligible (< 1%). 
For further details refer to the decitabine product insert and prescribing information.
1.2.4
Overview of MBG453, PDR001 and decitabine
1.2.4.1
Non-clinical experience with the combination of MBG453 and PDR001
The rationale for combining MBG453 with PDR001 is based on scientific evidence in 
preclinical models. Several reports have shown that the cancer-induced inhibitory modulation 
of T-cell activation is synergistically promoted by the concurrent blockade of TIM-3 and PD-1
(Sakuishi 2010, Ngiow 2011). Furthermore, blockade of TIM-3 not only restores T cell function, 
but also blocks inhibitory signals mediated by TIM-3+ FoxP3 regulatory T cells (Sakuishi 2013) 
and may also alleviate inhibitory signals from innate cells in the tumor microenvironment 
(Zhang 2011, Zhang 2012).
In preclinical models of colon carcinoma (CT26 and MC38) and the poorly immunogenic 
B16F10 melanoma model, TIM-3 blockade alone exhibits similar efficacy to PD-1 pathway 
blockade (Ngiow 2011). However, the combination of TIM-3 blockade with PD-1 pathway 
blockade is markedly more effective than either TIM-3 or PD-1 blockade alone (Anderson 2015, 
Ngiow 2011).
Internal data support the combination efficacy seen in the published models described above. 
Co-blockade of the PD-1/PD-L1 axis and TIM-3 in murine colon tumor models demonstrated 
partial anti-tumor activity. In the CT26 tumor model in BALB/cJ mice, co-blockade of PD-L1 
with 10F.9G2, a rat anti-mouse IgG2b and TIM-3, with either RMT3-23 (a rat anti-mouse 
IgG2a), 2C12 (a rat anti-mouse isotype, rat IgG1) or 5D12 (a mouse anti-mouse isotype, IgG1), 
resulted in partial tumor growth delay. In the related COLON26 model, co-blockade of PD-1,
with the rat anti-mouse IgG2a RMP1-14, and TIM-3, with either 5D12 or RMT3-23, resulted 
in partial tumor growth delay. Notably, 5 of 10 and 2 of 10 animals in each treatment group had 
durable complete regressions when treated with RMP1-14 and 5D12 or RMP1-14 and RMT3-
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Moreover, TIM-3/PD-1 pathway co-blockade also drives the downmodulation of several genes 
associated with potent suppressor function such as Tregs, MDSC and TADC (reviewed in 
Anderson 2014). Thus, TIM-3 /PD-1 co-blockade abrogates two major mechanisms of immune 
suppression in tumor tissue, restoring function to dysfunctional CD8+ T cells and 
deprogramming potent intratumoral Tregs, TADC and MDSC.
TIM-3 deficient mice do not develop overt autoimmunity, suggesting that TIM-3 plays a more 
subtle role in modulating T cell function than either CTLA-4 or PD-1 (Sánchez-Fueyo 2003,
Sabatos 2003).
1.2.4.2
Clinical experience with the combination of MBG453 and PDR001
As of 25-Jul-2019 in this FIH study, 119 patients have been treated with MBG453 in 
combination with PDR001 on a Q2W or Q4W regimen. One DLT (myasthenia gravis grade 4) 
was reported for a patient (metastatic thymoma) treated at 240mg MBG453 Q4W and 80mg 
PDR001 Q4W. The RP2D has been declared for MBG453 at 800mg Q4W in combination with 
PDR001 at 400mg Q4W
Of the 119 patients treated with MBG453 in combination with PDR001, 115 patients (97%) 
experienced AEs of any grade, regardless of relationship to study drug, with the most frequent 
AEs (>10%) being fatigue (33 patients, 28%), anemia (25 patients, 21%), cough (23 patients, 
19%), constipation, nausea (22 patients each, 19%), abdominal pain pyrexia, dyspnea (19 
patients each, 16%), diarrhea, back pain (18 patients each, 15%), decreased appetite (17 patients, 
14%), vomiting (15 patients, 13%), pruritus (13 patients, 11%) aspartate aminotransferase 
increased (12 patients, 10%).For further details refer to the most recent edition of the [MBG453 
IB]
1.2.4.3
Non-clinical experience with MBG453 in combination with decitabine
Decitabine has been shown to enhance the expression of type I interferon in murine cancer 
models (Stone et al 2017) and in a mouse model of colon carcinoma decitabine treatment 
enhanced both the activation status of immune cells at the tumor and combined with anti-PD-1 
therapy enhanced the anti-tumor immune response (Yu et al 2018). The combination of 
MBG453 and decitabine was tested in two AML patient-derived xenograft models in immune 
deficient hosts where it was well-tolerated as measured both by body weight change monitoring 
and visual inspection of health status. While decitabine demonstrated efficacy to varying 
degrees in the two models, the addition of MBG453 did not enhance activity, likely due to the 
lack of immune cells, including key TIM-3-expressing T cells, NK cells, and myeloid cells. As 
MBG453 is not rodent cross-reactive, studies will be undertaken with murine surrogate 
antibodies in an immuno-competent setting (or with a human TIM-3-overexpressing murine 
AML line) to evaluate the role of the immune system in potential anti-TIM-3 activity in AML 
models.
1.2.4.4
Clinical experience with MBG453 in combination with decitabine and 
MBG453 in combination with decitabine and PDR001 
MBG453 is being evaluated in CPDR001X2105, an ongoing phase Ib, multi-arm, open-label 
study of PDR001 and/or MBG453 in combination with/without decitabine in patients with acute 
myeloid leukemia (AML) or high risk myelodysplastic syndrome (MDS). 


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As of 26-Jul-2019, 157 patients with AML de novo, AML-Relapsed/Refractory or high risk 
MDS have been treated in the MBG453 single agent arm and in the combination arms
(MBG453 in combination with decitabine (n=85), MBG453 in combination with PDR001
(n=11), MBG453 in combination with decitabine and PDR001 (n=19) and MBG453 in 
combination with Azacitidine (n=16)).
Four patients experienced DLTs during the first 2 cycles which included Grade 3 hepatitis 
(MBG453 in combination with decitabine), Grade 3 tubulointerstitial nephritis (MBG453 in 
combination with decitabine and PDR001), Grade 3 encephalitis (MBG453 in combination with 
PDR001) and Grade 2 uveitis (MBG453 in combination with decitabine and PDR001).
For further details refer to the most recent edition of the [MBG453 IB]. 
1.2.4.5
Potential drug interaction
Immunomodulators, such as MBG453 and PDR001, may regulate CYP enzymes and may cause
DDI with small molecule drugs because of the potential to alter CYP mediated metabolism. 
However, Cytochrome P450 mediated degradation is minor for decitabine and DDI between 
PDR001, MBG453 and decitabine is not expected. When MBG453 was administered in 
combination with decitabine in Study CPDR001X2105, decitabine PK was similar to the 
decitabine country-specific label reported value.
For further details refer to the most recent edition of the [MBG453 IB].
2
Rationale
Any reference to MBG453 in combination with decitabine is not applicable in this study as the 
enrolment of SCLC patients in this treatment will not open.
2.1
Study rationale and purpose
Checkpoint inhibitors have been successfully introduced to clinical practice with the recent 
approval of the antagonist antibodies to the CTLA-4 (ipilimumab) and PD-1 (e.g nivolumab 
and pembrolizumab) checkpoints. A large proportion of patients, however, do not respond to 
checkpoint inhibitors as monotherapy, and these patients therefore represent a population with 
high unmet medical needs that might benefit from alternative approaches. Different checkpoint 
inhibitors, by signaling via distinct pathways, have demonstrated enhanced activity in 
combination. The combination of ipilimumab and nivolumab in melanoma has shown an 
increased objective response rate compared to the monotherapy of either agents (Postow 2015, 
Larkin 2015). 
TIM-3 is a distinct co-inhibitory receptor which cooperates with PD-1 to dampen immune 
responses. The remarkable synergy of TIM-3/PD-1 pathway co-blockade in controlling tumor 
growth in experimental models of cancer could reflect the combined effects on modulating not 
only the functional phenotype of dysfunctional CD8+ effector T cells, but also inhibiting the 
suppressive activity of Tregs and deprogramming of other suppressor cells such as MDSC and 
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Taken together, these data suggest that TIM-3 blockade or the combined inhibition of TIM-3 
and PD-1 in the clinic may have significant anti-tumor efficacy.
PD-1 blockade has proven clinical efficacy in various disease settings, such as melanoma, 
NSCLC and RCC. These indications also express high levels of TIM-3 and thus are ideally 
placed to test the anti-PD-1/anti-TIM-3 combination.
MBG453 in combination with decitabine
Hypomethylating agents have been shown to alter the immune microenvironment in both solid 
tumors and hematological malignancies. HMAs have been shown to: (1) increase the expression 
of killer-cell immunoglobulin-like receptors (KIR) and in some instances, the activity of NK 
cells, which may play a role in anti-tumor immunity; (2) increase the expression of major 
histocompatibility complex (MHC) class I on tumor cells; (3) increase expression of 
endogenous retroviral elements (ERVs); and (4) increase the expression of checkpoint proteins, 
including PD-1, PD-L1 and Cytotoxic T-Lymphocyte-Associated protein 4 (CTLA-4) 
(Sohlberg et al 2015, Yang et al 2014, Orskov et al 2015, Fazio et al 2018; reviewed in 
Lindblad et al 2017).
Decitabine can enhance the expression of type I interferon in murine cancer models 
(Stone et al 2017). Decitabine treatment in a mouse model of colon carcinoma enhanced both 
the activation of immune cells at the tumor and combined with anti-PD-1 therapy to enhance 
the anti-tumor immune response (Yu et al 2018). De novo DNA methylation promoted T-cell 
exhaustion and limited the efficacy of anti–PD-1 immunotherapy, whereas inhibition of 
methylation enhanced PD-1 blockade–mediated T-cell activity. (Ghoneim et al 2017, 
Pauken et al 2016).
In an open-label phase Ia/Ib study of LY3321367 a monoclonal antibody against TIM-3, 23 
patients with histologically confirmed advanced relapsed/refractory solid tumors were treated 
with LY3321367 single agent including 2 patients with SCLC. Both patients experienced > 20% 
tumor regression, one of which was later confirmed as a RECIST v1.1 partial response (PR)
(Harding et al 2019).
In this MBG453X2101 study, three SCLC patients were treated with MBG453 in combination 
with PDR001. One patient experienced stable disease (SD) and one patient experienced PR. Six 
SCLC patients were treated with MBG453 single agent, 2 patients experienced SD, including 
one ongoing for 2 years.
Taken together, these data suggest the combination of an immune modulatory agent that 
stimulates a cytotoxic immune response such as decitabine with the antiTIM-3 agent MBG453
is a rationale therapeutic approach to test in SCLC.


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2.2
Rationale for the study design
This is an open-label, phase I-Ib/II study of parallel cohorts with single agent MBG453 or the 
combination of MBG453 and PDR001. The study consists of the following parts: 

Phase I-Ib ROW:
A phase I dose escalation part with MBG453 as single agent in advanced solid tumors.
A phase Ib dose escalation part with MBG453 in combination with PDR001 in advanced 
solid tumors. This part of the study will start after at least two cohorts of MBG453 as 
single agent have been completed and dose is assessed safe and tolerable.

Phase II ROW:
Should signs of anti-tumor activity [defined as either complete response (CR), partial 
response (PR) or durable stable disease (SD) with tumor shrinkage that does not qualify for 
PR] be detected in the phase I dose escalation part, a phase II part will open to evaluate 
clinical efficacy of MG453 as single agent.

A phase II part to evaluate clinical efficacy of MBG453 in combination with PDR001 at 
the MTD or RP2D (if that is lower than MTD) in the selected study disease indications, as 
shown in Figure 4-1 will be opened. Dose ranging part (optional, ROW):
Should signs of anti-tumor activity (defined as either CR, PR or durable SD with tumor 
shrinkage that does not qualify for PR) be detected in the phase I-Ib dose escalation parts, 
a dose ranging part will be opened, in which different dose levels of MBG453 as single 
agent and/or in combination with PDR001 will be also be evaluated.

Phase I-Ib / II in Japanese patients:
This is a separate phase I dose escalation part with MBG453 as single agent in Japanese 
patients with advanced solid tumors. The purpose of the Japanese dose escalation is to 
ensure that the safety and pharmacokinetic profiles of single-agent MBG453 are adequately 
characterized in Japanese patients at more than one MBG453 dose.
If the recommended dose of single agent MBG453 is the same in Japanese patients and 
patients from the rest of the world, then Japanese patients may be enrolled in the Phase II 
single-agent part of the study.
In addition, if the recommended dose of PDR001 for Japanese patients in the single agent 
study ([PDR001X1101]) currently ongoing in Japan is the same as that determined in the 
single agent ROW study ([PDR001X2101]), Japanese patients may also enter the 
combination parts of the current MBG453 study at whichever dose is being tested at that 
time.
If any of the Japanese single agents (PDR001 and/or MBG453) RP2D and/or MTD is 
different than the ROW, a new clinical development plan will be required to investigate the 
combination treatment in Japanese patients.
Combination of MBG453 and decitabine
A safety run-in testing the combination of MBG453 with decitabine will be conducted in anti 
PD-1/PD-L1 therapy naïve SCLC patients.
Following the safety run-in, additional patients will be enrolled in a phase II part to further 
evaluate the clinical efficacy.


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Patients will be given the option to add PDR001 (i.v Q4W) to the MBG453 and decitabine
combination after confirmed disease progression per irRC. The first iv Q4W dose of PDR001 
may be given at the next scheduled cycle on day 8 of MBG453 administration, after documented 
discussion with the Novartis medical monitor.
Objectives and related endpoints apply to all patients enrolled and treated unless otherwise 
stated.
The objective for the phase I-Ib dose escalation parts will be to determine the MTD and/or 
RP2D of MBG453 as single agent and in combination with PDR001 or decitabine. 
The objectives for the phase I-Ib dose ranging part will be to further define safety and 
tolerability of MBG453 as single agent, or in combination with PDR001 or decitabine.
The objectives for the phase II part of the study, either with MBG453 as single agent or in 
combination with PDR001 will be:

To assess if MBG453 as single agent or in combination with PDR001 is efficacious in 
indications with high expression levels of both TIM-3 and PD-L1.

To compare with published data - assess if MBG453 as single agent or in combination 
with PDR001 is more efficacious than anti PD-1/PD-L1 alone in these indications.

To assess if MBG453 as single agent or in combination with PDR001 is efficacious in 
patients who progressed on or after anti-PD-1/PD-L1 as single-agent.

To make an initial comparison of safety, PK, and efficacy between Q2W and Q4W dosing 
schedules of MBG453 in combination with PDR001 in one tumor disease indication.
The MTDs/RP2Ds (as single agent and in combination) will be determined from the collective 
experience in the clinic considering the safety data, pharmacokinetic data, pharmacodynamic 
data and any early anti-tumor activity observed along with the statistical inference from the 
Bayesian Hierarchical Logistic Regression Model (BHLRM) in the phase I single agent dose 
escalation part, and from the Bayesian Logistic Regression Model (BLRM) in the combination 
dose escalation part. The BHLRM is a hierarchical adaptation of the BLRM.
This open-label dose escalation study design using a BLRM is a well-established method to 
estimate the MTD/RP2D in cancer patients. The adaptive BLRM will be guided by the EWOC 
principle to control the risk of DLT in future patients on study. The use of Bayesian response 
adaptive models for small datasets has been accepted by European Medicines Agency
(Guideline on clinical trials in small populations, 13-Feb-2007) and endorsed by numerous 
publications (Zacks 1998, Neuenschwander 2008, Neuenschwander 2010), and its development 
and appropriate use is one aspect of the FDA’s Critical Path Initiative.
In the Phase II part of the study, an estimation approach will be used for patients treated on the 
single agent and MBG453 in combination with PDR001 for patients in Group 1, 3 and 6 and 
MBG453 in combination with decitabine (Figure 4-1). A Bayesian design will be used in order 
to estimate the true ORR for MBG453 in combination with PDR001 for patients in Group 2, 4 
and 5, as well as for MBG453 in combination with decitabine. In one group, to be selected 
based on feasibility of enrollment, an initial comparison of the safety, PK, and efficacy of Q2W 
and Q4W dosing schedules will be made. Patients within these groups will have their activity 
monitored and in addition to continue evaluation of safety.


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Because TIM-3 plays a more subtle role in modulating T cell function than either CTLA-4 or 
PD-1 (Sánchez-Fueyo 2003, Sabatos 2003), it is not expected that MBG453 would have a 
relevant anti-tumor activity as single agent in the clinic. Therefore, a group of patients will be 
treated with MBG453, if evidence of anti-tumor activity is detected in the dose escalation Phase 
I part.
2.3
Rationale for dose and regimen selection
The starting dose of MBG453 in the clinical setting was determined from toxicology studies as 
well as observed toxicity and efficacy from agents in the clinic with the similar mechanism of
action of checkpoint inhibition (e.g. CTLA-4 and PD-1 inhibitors). The HNSTD dose from the 
cynomolgus monkey for MBG453 was 100 mg/kg. As MBG453 will be administered i.v., and 
it is generally accepted that antibody therapeutics allometrically scale according to body weight, 
the human equivalent dose (HED) of the HNSTD is 100 mg/kg. Based on the ICH S9 guidance, 
a factor of six can be used to determine the maximum allowable starting dose, with an estimated 
maximum starting dose of 17 mg/kg administered weekly. MBG453 has a KD for human at 
approximately 0.5, while cyno KD is 0.9. There is a 44% difference in affinity between cyno 
and human, and so therefore the starting dose based on S9 guidance and the additional affinity 
difference was used to calculate a starting dose of 7.6 mg/kg. MBG453 will be administered via 
intravenous (i.v) infusion every 2 weeks, consistent with a schedule commonly used for 
humanized monoclonal antibodies with an expected half-life of approximately 10-20 days. 
Based on the pharmacologically active doses of 2-10 mg/kg in the clinic with agents having a 
similar mechanism of action (checkpoint inhibitors, CTLA-4 and PD-1 inhibitors, 
(Topalian 2014, Wolchok 2013, Robert 2014) and with the intent to fully characterize the safety, 
pharmacokinetics, pharmacodynamics and preliminary efficacy at multiple dose levels, the 
starting dose of MBG453 is planned 1 mg/kg (80 mg) every 2 weeks. Starting with flat dose of 
80 mg that equals approximately 1 mg/kg is not expected to overdose patients above the 
exposure observed in monkeys at the achieved HNSTD dose of 100 mg/kg or the estimated 
maximum starting dose of 7.6 mg/kg (600 mg).
For the dose escalation in combination part, the starting dose of PDR001 will be one dose level 
below the RP2D determined in the [CPDR001X2101] study, and the starting dose for MBG453 
will be at a dose level below the last dose tested in the single agent dose escalation and shown
to satisfy the EWOC criterion. Planned starting dose is provisionally (20 mg for MBG453 and 
80 mg for PDR001, with both drugs administered i.v. once every 2 weeks. The starting doses 
of MBG453 and PDR001 in the combination will be at least 3 fold lower than the doses that at 
time of start of the combination part of the study have been tested for either of the molecules as 
single agents. In addition, the doses will be more than 10-fold lower than the suggested starting 
dose level by the highest non severely toxic dose level.Decitabine has been explored in 
combination with MBG453 (up to 400mg Q2W and 800mg Q4W respectively) or MBG453 (up 
to 400mg Q2W) with PDR001 (400mg Q4W) in the CPDR001X2105 study (Section 1.2.4.4
and MBG453 IB). For the phase Ib safety run-in part of this study, decitabine will be 
administered at a dose of 20mg/m2 by i.v. infusion over a period of 1hr on days 1-5 Q4W, as 
per the decitabine country-specific label.


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In conclusion, patients will receive decitabine as per country-specific approved label (20mg/m2
daily for 5 days), followed by MBG453 at the RP2D (800 mg Q4W) on day 8, until confirmed  
disease progression per irRC or patient experiences unacceptable toxicity, and/or treatment is 
discontinued at the discretion of the Investigator or the patient. At the time of disease 
progression, patients may continue with the combination therapy with the addition of PDR001 
at the RP2D (400 mg Q4W) on day 8 of the next cycle (Section 6.2.2) 


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below and apply to all patients enrolled and treated unless otherwise stated.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
Phase I-Ib parts:
To characterize the safety and tolerability of MBG453 as a 
single agent in ROW and Japanese patients separately and 
in combination with PDR001 and to identify recommended 
doses for future studies.
To characterize safety and tolerability of MBG453 in 
combination with decitabine and identify recommended dose 
for future studies.

Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory parameters, vital signs and ECGs

Tolerability: Dose interruptions, reductions and dose intensity

The incidence of DLTs during the first cycle of treatment with single 
agent MBG453

The incidence of DLTs during the first and second cycle of treatment 
with MBG453 in combination with PDR001

The incidence of DLTs during the first cycle of treatment with MBG453 
in combination with decitabine
Phase I-Ib dose ranging part:
To further investigate the safety and tolerability of different 
doses of MBG453 as single agent or in combination with 
PDR001

Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory parameters, vital signs and ECGs

Tolerability: Dose interruptions, reductions and dose intensity
Phase II part:
To estimate the anti-tumor activity of MBG453 as single 
agent and in combination with PDR001 or in combination with 
decitabine
Overall response rate (ORR) per RECIST v1.1


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Objective
Endpoint
Analysis
Secondary
Refer to Section 10.5
Phase I-Ib/II parts: 
To evaluate the preliminary anti-tumor activity of MBG453 as 
single agent,in combination with PDR001 or in combination 
with decitabine
Best Overall Response (BOR), Progressive Free Survival (PFS) and 
Duration of Response (DOR) per RECIST v1.1; ORR and PFS per irRC
Phase II part (combination):
To make an initial comparison for MBG453 and PDR001 
administered in combination on a Q2W and Q4W dosing 
schedules.

Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory parameters, vital signs and ECGs

Tolerability: Dose interruptions, reductions and dose intensity

Serum PK parameters (e.g., AUC, Cmax, Tmax, half-life); Serum 
concentration vs. time profiles

ORR, BOR, PFS and DOR per RECIST v1.1; ORR and PFS per irRC
Phase I-Ib/II parts: 
To characterize the pharmacokinetic profile of MBG453 as 
single agent, in combination with PDR001 or in combination 
with decitabine
Serum PK parameters (e.g., AUC, Cmax, Tmax, half-life); Serum 
concentration vs. time profiles
Phase I-Ib/II parts: 
To assess emergence of anti-MBG453 and anti-PDR001 
antibodies following one or more i.v. infusions of MBG453 
single agent, in combination with PDR001 or in combination 
with decitabine
Presence and/or concentration of anti-MBG453 and anti-PDR001 
antibodies
Phase I-Ib/II parts:
To assess potential predictors of efficacy of MBG453 as 
single agent, in combination with PDR001 or in combination 
with decitabine in tumor samples
Assess potential associations between expression of PD-L1 and other 
immunological markers such as, but not restricted to TIM-3, CD8, FoxP3  
and anti-tumor activity
Phase I-Ib/II parts: 
To assess the pharmacodynamic effect of MBG453 as single 
agent, in combination with PDR001 or in combination with 
decitabine in tumor samples
Tumor Infiltrating Lymphocytes (TIL) counts 
Phase I-Ib/II parts: 
To describe the survival distribution of patients treated with 
MBG453 as single agent, in combination with PDR001 or in 
combination with decitabine for each disease group
Overall survival (OS)


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4
Study design
4.1
Description of study design
This study is a FIH, open-label, phase I-Ib/II, multi-center study which consists of a phase I 
dose escalation part of MBG453 as single agent, and a phase Ib dose escalation part of MBG453 
in combination with PDR001 that will commence after two cohorts in the dose escalation with 
single agent have been completed. Once the MTD/RP2D of MBG453 as single agent and/or in 
combination with PDR001 is achieved, a dose ranging part and a phase II part will commence.
MBG453 and PDR001 will be administered i.v. Q2W or Q4Wuntil a patient experiences 
unacceptable toxicity, progressive disease as per irRC and/or treatment is discontinued at the 
discretion of the Investigator or the patient. Patients should not discontinue treatment based on 
progressive disease per RECIST v1.1 unless clinical deterioration or increase in tumor markers 
is observed. The study design is summarized in Figure 4-1.
MBG453 in combination with decitabine (this study arm is applicable potentially
to Italy, South Korea, Netherlands, Switzerland and United States)*
A phase Ib safety run- in /phase II part will be conducted in approximately 15 anti-PD-1/PD-
L1 therapy naïve SCLC patients treated with MBG453 in combination with decitabine. 
The phase Ib safety run-in part will be conducted in 6 evaluable patients for the Dose 
Determining analysis Set (Section 10.1.4) to evaluate DLTs, AEs and available PK, PD, and 
preliminary efficacy. In the event that the administered dose levels are considered toxic
(≥2 DLTs out of 6 patients (Section 6.2.3.2)), an additional 6 evaluable patients will be accrued
to a lower dose level of decitabine for the Dose Determining analysis Set. The data from the 
safety run-in will be reviewed by Novartis study personnel and Investigators and approximately 
9 additional patients may be recruited in the phase II part of the study.
The combination of MBG453 and decitabine will be administered until a patient experiences 
unacceptable toxicity, progressive disease as per irRC and/or treatment is discontinued at the 
discretion of the Investigator or the patient.
Patients will be given the option to add PDR001 to the combination of MBG453 and decitabine 
after confirmed disease progression per irRC. The first i.v Q4W dose of PDR001 may be given 
at the next scheduled cycle on day 8 of MBG453 administration after documented discussion
with Novartis medical monitor.Treatment will be as follows:

Decitabine will be administered i.v. on days 1-5 of each Q4W cycle at the dose of 
20mg/m2 each day.

MBG453 will be administered i.v on day 8 of each Q4W cycle at the dose of 800mg. 

PDR001 may be administered i.v on day 8 of each Q4W cycle at the dose of 400mg after 
confirmed disease progression per irRC.
* Note: as of Protocol Amendment 6, this part will not open.


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Japanese specific study design:
A separate dose escalation will be performed in Japan in order to ensure that the safety and 
pharmacokinetic profiles of single-agent MBG453 are adequately characterized in Japanese 
patients. The proposed starting dose for single-agent MBG453 in Japanese patients is 80mg
Q2W. Dose escalation decisions will be guided by a BHLRM. After the first cohort Japanese 
patients may be treated in parallel with two different dosing regimens (Q2W and Q4W). 
Dose escalation decisions will be guided by a BHLRM. If the recommended dose of single 
agent MBG453 in Japanese patients is the same as in ROW patients, then patients enrolled in 
Japan may be recruited into the Phase II single-agent part of the study. 
In addition, if the recommended dose of PDR001 for Japanese patients in the single agent study 
([PDR001X1101]) currently ongoing in Japan is the same as that determined in the single agent 
ROW study ([PDR001X2101]), Japanese patients may also enter the combination parts of the 
current MBG453 study at whichever dose is being tested at that time. 
If any of the Japanese single agents (PDR001 and/or MBG453) RP2D and/or MTD is different 
than the ROW a new clinical development plan will be required to investigate the combination 
treatment in Japanese patients.
If Japanese patients have enrolled in the combination part and if during review of safety data
(either in a Dose Escalation Meeting for Phase Ib or during a regular safety review for Phase II) 
Novartis and the enrolling Investigators consider the safety profile of Japanese patients treated 
in the current combination dose to be potentially worse than that of patients treated in the ROW, 
an additional 3 to 6 Japanese patients may be recruited in the Phase Ib part to a lower dose 
combination (previously studied in dose escalation) to further characterize the safety and 
tolerability of the combination in patients enrolled in Japan. 
If after review of the safety data at the lower dose level, Novartis and the enrolling Investigators
consider that re-escalation to a higher combination dose level is acceptable, Japanese patients 
may be treated at the same dose as ROW patients. If re-escalation is not acceptable, any 
additional Japanese patients recruited to the combination dose escalation will be treated at the 
lower dose. The combination dose escalation in the ROW may continue as planned.


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Figure 4-1
Study Design
*This part will only be opened in relevant indications in the event that signs of anti-tumor activity (defined as either 
CR, PR or durable SD with tumor shrinkage that does not qualify for PR) to be observed in the phase I dose 
escalation part with MBG453 as single agent,
**Dose ranging part: Should signs of anti-tumor activity (defined as either CR, PR or durable SD with tumor 
shrinkage that does not qualify for PR) be observed in the phase I-Ib dose escalation parts, MBG453 as single 
agent or in combination with PDR001 will be tested at different doses levels.
***Additional patients will be enrolled to test Q2W versus Q4W dosing schedule. The selection of the group will be 
based on enrollment feasibility.
§The number of patients enrolled per group could be reduced depending on enrollment feasibility, and they will be 
increased to 25 if 3 or more confirmed PRs or CRs are observed.




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be escalated in order to achieve similar exposure to that observed at the MTD/RP2D for the 
Q2W dosing schedule. In this dose escalation, patient’s safety will continue to be monitored by 
the BHLRM following the EWOC principal, and will follow the same process as the Q2W 
dosing schedule at dose escalation.
Determination of MTD(s)/RP2D(s) for Phase I dose escalation part
MTDs/RP2Ds may be determined for the Q2W dosing schedule, the Q4W dosing schedule, or 
for both schedules. A minimum of 21 patients, treated on either Q2W or Q4W dosing schedules, 
are required during the single agent MBG453 dose escalation to define the MTD(s); however, 
fewer than 21 patients may be treated if the RP2D(s) is determined prior to reaching the MTD(s) 
(for further details see Section 6.2.3). A minimum of 12 patients are required during the single 
agent MBG453 dose escalation with Japanese patients to define the MTD(s) and/or RP2D(s).
Phase Ib dose escalation part (MBG453 in combination with PDR001)
The combination phase Ib part of the study will commence after at least two cohorts of MBG453 
as single agent have been completed, and safety data suggests acceptable toxicity for patients 
to begin treatment in combination. The combination dose escalation will follow a Q2W dosing
schedule. Treatment in combination will continue until the MTD is reached or a lower RP2D is 
established based on safety and PK data. The dose escalation will also be guided by an adaptive 
Bayesian logistic regression model (BLRM) following the EWOC principle. 
Determination of MTD/RP2D for Phase Ib dose escalation part (MBG453 in 
combination with PDR001)
A minimum of 15 patients (including Japanese patients) are required during dose escalation in 
combination to define the MTD; however, fewer than 15 patients may be treated if the RP2D is 
determined prior to reaching the MTD (for further details see Section 6.2.3).
Optional: additional dose escalation using Q4W dosing schedule during Phase 
Ib dose escalation part (MBG453 in combination with PDR001)
Following identification of the MTD/RP2D for MBG453 and PDR001 in combination 
following a Q2W dosing schedule, a further dose escalation may open to identify the 
MTD/RP2D following a Q4W dosing schedule. This will be guided by a newly derived BLRM 
that will incorporate data from the Q2W dosing schedule dose escalation into an informative 
prior. The starting dose for the Q4W dosing schedule dose escalation will be no higher than the 
highest dose tested on the Q2W dosing schedule and demonstrated to satisfy the EWOC 
criterion. The dose for the Q4W dosing schedule may subsequently be escalated in order to 
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Phase II part (MBG453 in combination with PDR001)
Once the MTD and/or RP2D have been declared for MBG453 in combination with PDR001, 
additional patients will be enrolled in the Phase II part in the selected indications (melanoma, 
NSCLC and RCC) in order to assess the preliminary anti-tumor activity. Japanese patients may 
enter the Phase II combination part only if each of their respective single agents’ RP2D/MTD 
are identical to the RP2D and/or MTD in the ROW (MBG453 in the current study and PDR001 
in PDR001X2101). Initially the phase II part will enroll approximately 15 patients to each of 
the defined patient groups (see Figure 4-1). Should enrollment for any of these groups not be 
feasible, then enrollment to that group may be closed before the 15 patients target is met. Based 
on current understanding of enrollment feasibility it is expected that full enrollment may be met 
for the benchmark diseases (melanoma and NSCLC) in pre-treated patients, since anti-PD-1 
has been approved for these indications. For RCC, an indication for which anti-PD-1 has not 
been approved; it is expected to meet full enrollment in naïve patients.
If at least 3 patients out of the first 15 treated in any group have confirmed objective response 
(PR or CR) per RECIST v1.1 or irRC, then enrollment to that group may be extended to 
approximately 25 patients in order to better characterize efficacy.
A Bayesian design will be used in order to estimate ORR within each disease group. Details of 
the sample size calculations leading to the patient numbers are provided in Section 10.8.
Optional: testing of Q2W versus Q4W dosing schedule during Phase II part 
(MBG453 in combination with PDR001)
After a preliminary assessment of the Q4W dosing schedule in the phase I/Ib dose escalations, 
a decision may be made to further investigate the Q4W dosing schedule during the phase II 
combination part to further assess efficacy and safety. This comparison will take place within 
only one of the 6 identified patient groups included in the combination phase II, with the group 
to be used chosen based on enrollment feasibility.
The dose used for the Q4W dosing schedule will be either that recommended following the 
Q4W combination escalation, or in the event that Q4W dosing is not evaluated in the 
combination dose escalation, the dose for Q4W will be chosen so that it is no higher than the 
highest dose with which at least 6 patients were treated in the Q2W combination dose escalation 
that was demonstrated to satisfy the EWOC criterion.
To facilitate comparison between Q2W and Q4W dosing schedules in the chosen indication, 
patients will be randomized between the two dosing schedules.
In the event that the Q2W and Q4W dosing schedules are compared, then the two arms will be 
extended from 15 to 25 patients, if 3 or more objective confirmed responses are observed in 
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Optional: MBG453 single agent Phase II part
Should signs of anti-tumor activity (defined as either CR, PR or durable SD with tumor 
shrinkage that does not qualify for PR) be seen in the phase I dose escalation with MBG453 as 
single agent, a phase II part will open in order to further explore single agent efficacy at the 
recommended dose and schedule. Patients with tumor types that have been shown to respond 
to single agent MBG453 (maximum of two indications) will be enrolled. Up to 15 patients may 
be enrolled in each indication depending on feasibility. If the recommended dose of single agent 
MBG453 is the same in Japanese patients and ROW patients, then Japanese patients may be 
enrolled into the Phase II single agent part of the study.
Optional: dose ranging part
Following declaration of the MTDs/RP2Ds for single agent and combination, and only if 
efficacy has already been observed in the dose escalation parts (defined as either CR, PR or 
durable SD with tumor shrinkage that does not qualify for PR) an optional dose ranging part of 
the study may be opened. The dose ranging part will only enroll patients not eligible for the 
Phase II parts of the study. Japanese patients may also be enrolled in the dose ranging part.
The dose ranging part may include the testing of different dose levels to better understand the 
safety, tolerability and PK of MBG453 as single agent and in combination with PDR001.
Further enrollment to achieve a target of approximately 15 patients per dose group will be based 
on the number of Grade 3 or Grade 4 treatment-related adverse events observed within the first 
8 weeks of study treatment. All the Adverse event data (and any other data considered 
significant by Novartis or requested by the Investigators) will be reviewed by the Investigators 
and Novartis, prior to additional enrollment to the respective dose levels.
Because data from several PD-1 and PDL-1 inhibitors have demonstrated that PD-1 blockade
at any dose above 0.3 mg/kg can result in tumor response across a broad range of solid tumors 
(Topalian et al 2012, Hamid and Carvajal 2013b, Seiwert et al 2014, Segal et al 2014, 
Powles et al 2014, Herbst et al 2014), doses below that recommended for the phase II part of 
the study may be explored in order to further understand safety, tolerability, and clinical efficacy.
The dose ranging part of the study will only use doses that have already been explored in the 
phase I and Ib dose escalation parts of the study, and demonstrated to be safe by satisfying the 
EWOC criterion under the relevant BLRM.
The assignment of a patient into a particular dose level will be coordinated by Novartis and will 
be based on the dose levels available at the time the patient consents the participation in the 
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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 patient should be seen as soon as possible for End of Treatment (EOT) visit and the 
assessments for EOT should be performed as described in Section 7.1.3 and Section 7.1.4 for a 
discontinued or withdrawn patient. The investigator may be informed of additional procedures 
to be followed in order to ensure that adequate consideration is given to the protection of the 
patient’s interests. The investigator will be responsible for informing Institutional Review 
Boards (IRBs) and/or independent ethics committees (IECs) of the early termination of the trial.
5
Population
5.1
Patient population
The phase I-Ib and dose ranging parts of the study will be conducted in adult patients with 
advanced solid tumors. 
The phase II part of the study in combination with PDR001 will be conducted in adult patients 
with melanoma, NSCLC, RCC, either anti-PD-1/PD-L1 therapy naïve or pre-treated as outlined 
in Figure 4-1
In addition, the phase II part for single agent MBG453 will be conducted in adult patients with 
advanced solid tumors.
The Phase Ib safety run-in and Phase II part of the study of MBG453 in combination with 
decitabine  will be conducted in anti-PD-1/PD-L1 therapy naïve SCLC patients.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any procedures.
For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.
2. Age ≥18 years.
3. Histologically documented advanced or metastatic solid tumors.
4. Phase I-Ib parts (including dose ranging part): Patients with advanced/metastatic solid 
tumors, with measurable or non-measurable disease as determined by RECIST v1.1 (refer 
to Appendix 1), who have progressed despite standard therapy or are intolerant of standard 
therapy, or for whom no standard therapy exists, and who did not receive prior anti-PD-
1/PD-L1 treatment. 
Prior therapy with PD-1/PDL-1 inhibitors is allowed provided any toxicity attributed to 
priorPD-1 or PD-L1-directed therapy did not lead to discontinuation of therapy and after 
discussion between the Investigator and Novartis study medical representative.
5. Phase II part (MBG453 single agent): Patients with advanced/metastatic solid tumors in 
the indication in which  signs of anti-tumor activity (CR, PR or durable SD with tumor 


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shrinkage that does not qualify for PR) were seen during the dose escalation study of 
MBG453 as single agent. Patients must have measurable disease as determined by 
RECIST v1.1 (refer to Appendix 1), have progressed despite standard therapy or be 
intolerant to standard therapy.
6. Phase II part (MBG453 in combination with PDR001): Patients with 
advanced/metastatic tumors in the below selected indications, with at least one measurable 
lesion as determined by RECIST v1.1 (refer to Appendix 1), who have received standard 
therapy or are intolerant to standard therapy, have progressed following their last prior 
therapy:

Melanoma (anti-PD-1/PD-L1 therapy naïve or pre-treated)

NSCLC (anti-PD-1/PD-L1 therapy naïve or pre-treated)

RCC (anti-PD-1/PD-L1 therapy naïve or pre-treated )
7. ECOG Performance Status ≤ 2.
8. Must have a site of disease amenable to biopsy and be a candidate for tumor biopsy 
according to the treating institution’s guidelines. Patient must be willing to undergo a new 
tumor biopsy at screening/baseline, and during therapy on the study.
9. For MBG453 in combination with decitabine (phase Ib/II): anti-PD-1/PD-L1 therapy 
naïve SCLC patients who have failed no more than two lines of standard chemotherapy 
including topotecan.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Presence of symptomatic CNS metastases, or CNS metastases that require local CNS-
directed therapy (such as radiotherapy or surgery), or increasing doses of corticosteroids 
within the prior 2 weeks. Patients with treated brain metastases should be neurologically
stable (for 4 weeks post-treatment and prior to study enrollment) and off of steroids for at 
least 2 weeks before administration of any study drug.
2. History of severe hypersensitivity reactions to any ingredient of study drugs and other 
mAbs and/or their excipients.
3. Having out of range laboratory values defined as:

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) < 40
mL/min

Total bilirubin > 1.5 x Upper Limit of Normal (ULN), except for patients with 
Gilbert’s syndrome who are excluded if total bilirubin > 3.0 x ULN or direct 
bilirubin > 1.5 x ULN

Alanine aminotransferase (ALT) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if ALT > 5 x ULN

Aspartate aminotransferase (AST) > 3 x ULN, except for patients that have tumor 
involvement of the liver, who are excluded if AST > 5 x ULN

Absolute neutrophil count (ANC) < 1.0 x 109/L

Platelet count < 75 x 109/L

Hemoglobin < 9 g/dL


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4. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following:

Clinically significant and/or uncontrolled heart disease such as congestive heart 
failure requiring treatment (NYHA grade ≥ 2), uncontrolled hypertension or clinically 
significant arrhythmia

QTcF >470 msec on screening/baseline ECG or congenital long QT syndrome

Acute myocardial infarction or unstable angina pectoris < 3 months prior to study 
entry
5.
HBV or HCV positive patients, with active disease or whose hepatitis is not controlled by 
therapy are excluded. HIV positive patients are excluded.
6. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers and completely resected carcinoma in situ of any type.
7. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results.
8. Active autoimmune disease or a documented history of autoimmune disease, including 
ulcerative colitis and Crohn’s disease or any condition that requires systemic steroids,
except vitiligo or resolved asthma/atopy that is treated with broncho-dilators (e.g. 
albuterol). Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately 
treated for skin rash or with replacement therapy for endocrinopathies should not be 
excluded.
9. Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or 
equivalent). Topical, inhaled, nasal and ophthalmic steroids are not prohibited.
10. Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 
weeks of initiation of study treatment.
11. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. For 
cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 
weeks is indicated as washout period.
12. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not 
considered major surgery).
13. Pre-treatment with anti-CTLA4 antibodies in combination with any other antibody or drug 
specifically targeting T-cell co-stimulation or checkpoint pathway.
14. Participation in an interventional, investigational non-immunotherapy study within 2 
weeks of the first dose of study treatment.
15. Prior participation in an interventional, investigational cancer vaccine or immunotherapy 
study except for an anti-PD-1/PD-L1 study (please refer to Section 5.2 Inclusion 
criterion 6).
16. Presence of ≥ Common Terminology Criteria for Adverse Events (CTCAE) grade 2 
toxicity (except alopecia, peripheral neuropathy and ototoxicity, which are excluded if 
≥CTCAE grade 3) due to prior cancer therapy.


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17. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) 
≤2 weeks prior to start of study drug. An erythroid stimulating agent is allowed as long as 
it was initiated at least 2 weeks prior to the first dose of study treatment and the patient is 
on a stable dose.
18. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass. To allow evaluation for response to treatment, patients enrolled in the phase 
II part must have remaining measurable disease that has not been irradiated.
19. Pregnant or lactating women, where pregnancy is defined as the state of a female after 
conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test. In rare cases of an endocrine-secreting 
tumor, hCG levels may be above normal limits but with no pregnancy in the patient. In 
these cases, there should be a repeat serum beta-hCG test (with a non-rising result) and a 
vaginal/pelvic ultrasound to rule out pregnancy. Upon confirmation of results and 
discussion with the Novartis Medical representative, these patients may enter the study.
20. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception 
during study treatment and for 150 days after the last dose of MBG453 as single agent or 
in combination with decitabine and/or PDR001 or 3 months after the last dose of 
decitabine or per decitabine country specific label, whichever is the longest. Highly 
effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
patient. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or tubal ligation at least 6 weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening/baseline). For female patients 
on the study the vasectomized male partner should be the sole partner for that patient.

Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device (IUD) or intrauterine
system (IUS) or other forms of hormonal contraception that have comparable efficacy 
(failure rate <1%), for example hormone vaginal ring or transdermal hormone 
contraception.
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment.
Women are considered post-menopausal and not of child bearing potential if they have had over 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (e.g. age 
appropriate [generally age from 40 to 59 years], history of vasomotor symptoms [e.g. hot flush])
in the absence of other medical justification or have had surgical bilateral oophorectomy (with 
or without hysterectomy) or tubal ligation at least 6 weeks ago. In the case of oophorectomy 


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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. 
21. Sexually active males unless they use a condom during intercourse while taking drug and 
for 150 days after stopping study treatment period or 3 months after the last dose of 
decitabine or per decitabine country specific label, whichever is the longest. A condom is 
required to be used also by vasectomized men in order to prevent delivery of the drug via 
seminal fluid.
22. Patients with a history of drug-induced pneumonitis or current pneumonitis.
23. For MBG453 in combination with decitabine (phase Ib/II): Hypersensitivity to 
decitabine or to any of the excipients, listed in decitabine country specific label.
6
Treatment
6.1
Study treatment
For this study, the investigational drugs are MBG453, PDR001 and decitabine. The study 
treatment is defined as MBG543 as single agent, MBG453 in combination with PDR001, or 
MBG543 in combination with decitabine with or without PDR001. All dosages prescribed and 
dispensed to patients and all dose changes during the study must be recorded on the Dosage 
Administration Record eCRF.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study treatments
Pharmaceutical form and 
route of administration
Starting Dose 
Frequency and/or Regimen
PDR001
Lyophilisate in vial for
i.v. infusion
80 mg 
Every 2 weeks 
(every 4 weeks if testing of a 
new dosing schedule)
On day 8 (every 4 weeks)
when in combination with 
MBG453 and decitabine
MBG453
Liquid in vial for i.v. 
infusion
80 mg (as single agent)
20 mg (when in 
combination with PDR001)
Every 2 weeks 
(every 4 weeks if testing of a 
new dosing schedule)
On day 8 (every 4 weeks)
when in combination with 
decitabine 
Decitabine 
i.v infusion
20mg/m2
Day1 to day5 (every 4 
weeks)
MBG453 and PDR001 will be administered via i.v. infusion over 30 minutes (up to 2 hours, if 
clinically indicated) once every 2 weeks. When given in combination, both study drugs are to 
be administered on the same day, separate infusion bags and filters must be used for each 
infusion. MBG453 is to be administered first and promptly followed by a dextrose solution 
flush as described in the pharmacy manual for approximately 1 hour before starting the PDR001 
infusion. There should be a period of at least one hour after the infusion where by the patient 
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Decitabine is commercially available. For details on preparation refer to the country-specific 
label instructions and/or decitabine package insert. Decitabine should be administered 
according to standard clinical practice. A standard dose of decitabine (20mg/m2) will be given 
intravenously every day for five consecutive days (days 1-5) every 4 weeks (refer to local 
decitabine package insert), followed by MBG453 or MBG453 in combination with PDR001 on 
day 8.  In order to maximize the potential immune priming effect and minimize the risk of 
toxicity with concomitant administration of decitabine, MBG453 infusions will be administered 
on day 8 every 4 weeks. If PDR001 is added as per Section 4.1, it will be administered after 
MBG453 administration on day 8.
Further instructions for the preparation and dispensation of MBG453 and PDR001 are described 
in the Pharmacy Manuals.
Next dose (as single agent or in combination) may be delayed by up to 7 days to recover from 
previous AEs. If the next dose (as single agent or in combination) cannot be administered within 
the above mentioned 7-days delay, then the dose should be skipped. Dosing will resume at the 
scheduled dose and assessment schedule will be shifted accordingly. Dose modifications should 
follow Section 6.3.1.
For MBG453 in combination with decitabine, if there are toxicities that prevent the patient from 
starting decitabine on day 1 of the next cycle, then the cycle should be resumed when the AE 
has resolved. For AEs occurring during a cycle that prevent the administration on day 8 of 
MBG453 (with or without PDR001), the dose may be delayed by up to 7 days to recover from 
the AEs.
6.1.2
Ancillary treatments
Patients should not receive pre-medication to prevent infusion reaction before the first infusion 
of MBG453 single agent or in combination with PDR001, in order to determine if pre-
medication is necessary. If a patient experiences an infusion reaction, he/she may receive pre-
medication on subsequent dosing days. Consider antiemetic premedication for nausea due to 
decitabine as specified in each decitabine country-specific label. The pre-medication should be 
chosen per institutional standard of care, at the discretion of the treating physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient will be discontinued from the study.
Patients should be treated in a facility equipped for cardiopulmonary resuscitation. Appropriate 
resuscitation equipment should be available at the bedside and a physician readily available.
Guidelines on management of MBG453 and PDR001 infusion reactions are provided in
Table 6-7.
The CTCAE category of “Infusion related reaction” should be used to describe MBG453 and 
PDR001 infusion reactions, unless the investigator considers another category, such as 
“Allergic reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a 
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6.1.3
Treatment duration
All patients treated with either MBG453 single agent or in combination with PDR001 will begin 
study treatment on Cycle 1 Day 1. Each cycle will consist of 28 days.
Patients treated with MBG453 in combination with decitabine will receive decitabine from day
1 to day 5 and MBG453 will be administered on day 8. Each cycle will consist of 4 weeks.
A patient may continue treatment with MBG453 single agent or in combination with PDR001
or decitabine until the patient experiences unacceptable toxicity, confirmed disease progression 
per irRC and/or treatment is discontinued at the discretion of the investigator or the patient. 
Patients will not be withdrawn from the study due to progressive disease per RECIST v1.1. 
Refer to Section 7.1.3.
Patients will be given the option to add PDR001 to the combination of MBG453 and decitabine 
after confirmed disease progression per irRC
If more than 2 consecutive doses of MBG453 as single agent or in combination with PDR001
or 1 cycle of MBG453 in combination with decitabine have to be skipped due to study 
treatment-related toxicities, then the default position is that study drugs should be permanently 
discontinued. However, if a patient who misses more than 2 consecutive doses due to a study 
treatment-related toxicity is experiencing clinical benefit, and in the opinion of the investigator 
it is in the patient’s best interest to remain on study, then the patient may continue treatment 
after discussion with Novartis.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
MBG453 cross reacts with monkey but not rodent TIM-3; therefore, the starting dose selected 
for this study is based on 5-week GLP toxicology studies performed in cynomolgus monkeys. 
MBG453 is a naked monoclonal antibody that does not have agonist activity, and will be 
administered to patients with advanced malignancies; therefore the starting dose is based on the 
ICH S9 guidance. The HNSTD was 100 mg/kg, administered i.v., once weekly. As MBG453 
will be administered i.v. and it is generally accepted that antibody therapeutics allometrically 
scale according to body weight, the HED of the HNSTD is 100 mg/kg. Based on the ICH S9 
guidance, a factor of six can be used to determine the maximum allowable starting dose, with 
an estimated maximum starting dose of 17 mg/kg administered weekly. MBG453 has a KD for 
human at approximately 0.5, while cyno KD is 0.9. There is a 44% difference in affinity between 
cyno and human, and so therefore the starting dose based on S9 guidance and the additional 
affinity difference was used to calculate a starting dose of 7.6 mg/kg. In order to evaluate the 
safety, PK and anti-tumor activity of MBG453 across a range of doses, the recommended 
starting dose as a single agent is 80 mg, i.v., every 2 weeks. Starting with flat dose of 80 mg 
that equals approximately 1 mg/kg is not expected to overdose patients above the exposure 
observed in monkeys at the achieved HNSTD dose of 100 mg/kg or the estimated maximum 
starting dose of 7.6 mg/kg (600 mg). The recommended starting dose of MBG453 in 
combination with PDR001 is 20 mg, i.v., every 2 weeks, which is well below the maximum 
permitted starting dose. The phase Ib combination part of the protocol will not begin until single 
agent safety for both MBG453 (up to 240 mg) and PDR001 (up to 800 mg) is established.


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6.2.2
Provisional dose levels
Table 6-2, Table 6-3 and Table 6-4 describe the starting dose for Phase I and Phase Ib parts, 
and the dose levels that may be evaluated during this trial.
Table 6-2
Provisional dose levels (Phase I part – MBG453 single agent)
Dose level
MBG453 Proposed dose*
Increment from previous dose
-1** 
20 mg
-70%
1 (starting dose)
80 mg
Starting dose
2
240 mg***
300%
3
800 mg
333%
*It is possible for additional and/or intermediate dose levels to be added during the course of the study Cohorts
may be added at any dose level below the MTD in order to better understand safety, PK or PD. Multiple dose 
levels below the MTD may be evaluated simultaneously in order to obtain PK and PD data across a range of 
doses.
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.
***The escalation of Q4W dosing schedule will open at same dose as the current cohort of Q2W. Subsequent 
cohorts will have dose adjusted based on observed PK exposure.
Table 6-3
Provisional dose levels (Phase Ib part – MBG453 in combination with 
PDR001)
Dose level
MBG453 Proposed dose*
PDR001 Proposed dose*
-1**
20 mg
20 mg
1 (starting dose)
20 mg
80 mg
2
80 mg
80 mg
3
240 mg
80 mg
3a
80 mg
240 mg
4***
800 mg
80 mg
5***
240 mg
240 mg****
*It is possible for additional and/or intermediate dose levels to be added during the course of the study Cohorts 
may be added at any dose level below the MTD in order to better understand safety, PK or PD. Multiple dose 
levels below the MTD may be evaluated simultaneously in order to obtain PK and PD data across a range of 
doses.
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.
***Cohorts to be opened simultaneously.
****If Q4W dosing schedule is investigated, it will open at same dose as the current cohort of Q2W. 
Subsequent cohorts will have dose adjusted based on observed PK exposure.


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Table 6-4
Provisional dose levels (MBG453 in combination with decitabine)
Dose level
Decitabine proposed 
dose
MBG453 dose
PDR001 dose **
-1*
10 mg/ m2
800 mg
400mg
1 (starting dose)
20 mg/ m2
800 mg
400mg
* If there are 2 or more DLTs within those 6 evaluable patients, 6 additional patients may be accrued to the -1 
dose level. No dose reduction below dose level -1 is permitted for this study.
** for patients adding PDR001 to MBG453 in combination with decitabine
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D
6.2.3.1
MTD definition
The MTD will be defined as follows in each of the phase I parts (as single agent or in 
combination):

MBG453 single agent: the MTD is defined as the highest drug dosage not expected to 
cause DLT in 33% or more of the treated patients in the first cycle (28 days) of MBG453 
treatment during the escalation part of the study. 

MBG453 in combination with PDR001: the MTD is defined as the highest combination 
drug doses not expected to cause DLT in 33% or more of the treated patients in the first 
two cycles (56 days) of treatment during the escalation part of the study. Co-blockade of 
CTLA4 and PD-1 has shown enhanced anti-tumor efficacy matched by an increased 
incidence of irAE, often with delayed onset (Wolchok et al 2013, Larkin et al 2015). For 
this reason the DLT safety profile will be followed for 2 cycles instead of one.
For MBG453 in combination with PDR001, since several possibilities may correspond to this 
definition, more than one MTD may be identified with different doses of the study drugs. One 
(or more) of these MTD(s) or a suitable lower dose combination will then be selected as the 
RP2D(s).
The applied adaptive Bayesian methodology provides an estimate of the single-agent MBG453 
and the combinations of MBG453 and PDR001 not exceeding the MTD. Typically the MTD is 
a tested combination with maximum probability of targeted toxicity (DLT rate between 16% 
and < 33%). The use of the EWOC principle limits the risk that a potential next dose will exceed 
the MTD (Section 10.4.2). Adverse events and laboratory abnormalities considered to be DLTs 
are defined in Table 6-5 and Table 6-6.

MBG453 in combination with decitabine: the MTD is defined as the highest drug dosage 
not expected to cause DLT in 33% or more of the treated patients who are evaluable for the 
dose determining set in the first cycle (28 days) of treatment (Section 6.2.4 and
Section 10.1.4).


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6.2.3.2
Dose cohort modification
For the purposes of dose escalation decisions (both Phase I and Phase Ib for MBG453 alone or
in combination with PDR001), each cohort will consist of 3 to 6 newly enrolled patients who 
will be treated at the specified dose level. Should only two of these patients in the first cohort
recruited to the study be considered evaluable (i.e., meet the criteria described below for a 
patient to be considered evaluable) and neither patient has experienced a treatment-related 
toxicity > CTCAE grade 1, then a dose escalation decision may be made following a dose 
escalation meeting between Novartis and Investigators. If however one, or both of these patients 
experiences a treatment-related toxicity > CTCAE grade 1, or if Novartis and Investigators 
decide additional information is required before making a dose escalation decision, then 
additional patients will be enrolled to this cohort to reach the minimum of 3 evaluable patients.
Subsequent cohorts will have at least 3 evaluable patients. The first cohort will be treated with 
the starting dose of 80 mg of MBG453 as single agent and provisionally 20 mg of MBG453 
and one dose level below RP2D for PDR001 for the combination.
The dose escalation will proceed as follows:

MBG453 single agent (ROW patients): The first cohort enrolled in the study will be 
treated with the starting dose as specified in Table 6-2. Once this cohort is complete and 
the dose escalation decision has been determined collectively between Novartis and the 
participating Investigators to escalate, the second cohort for the single agent will open. 
After all ongoing patients completed 1 cycle for the first two cohorts, combination dosing 
will begin at the planned starting dose in parallel to proceeding doses of the single agent 
cohorts. 

MBG453 in combination with PDR001: The combination dose escalation will proceed 
provided that the starting doses of the combination do not exceed the MTD of the single 
agents and the starting doses of the combination satisfy the EWOC criterion. Provisionally, 
the first cohort enrolled in the study will be treated with the starting dose for MBG453 at 
20 mg in combination with PDR001 (a lower dose may be considered for starting the 
combination if emerging data support this, but will not be higher than 20 mg for MBG453 
and 80 mg for PDR001; Section 6.2.1). Since the combination starting dose for MBG453 is 
anticipated to be below the efficacious range, and to be well tolerated, an initial assessment 
of DLT data in the first cohort may be made after all ongoing patients in the first cohort 
have completed a minimum of 1 cycle of treatment. Based on all existing data and after the 
dose escalation decisions with the Investigators and Novartis, a new cohort may be initiated 
at a higher dose satisfying the EWOC criteria. Once all patients in cohort 1 have completed 
cycle 2, the safety of the cohort 2 dose will be re-evaluated based on all available data at the 
confirmation decision with the Investigators and Novartis. Since cohort 2 can only open 
once all patients in cohort 1 have entered cycle 2, the confirmation of cohort 2 dose safety 
will be made before cohort 2 patients enter cycle 2. Should this dose no longer satisfy the 
EWOC criteria, then the dose for cohort 2 may be reduced before going into cycle 2. 
Subsequent cohorts will open in a similar fashion, with dose selected based on a minimum 
of one cycle’s safety data from the previous cohort, and complete (2 cycle) data from earlier 
cohorts. In each case, where a cohort is opened based on incomplete data from the previous 
cohort, safety will be reconfirmed before patients begin the second cycle of treatment.


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
MBG453 single agent in Japanese patients: For the purposes of dose escalation decisions, 
each cohort will consist of 1 to 6 newly enrolled patients who will be treated at the specified 
dose level. The first cohort of patients enrolled in the Japanese sub-population will be 
treated with the starting dose of 80 mg MBG453 Q2W as a single agent. When two patients 
(who may be in different cohorts) have experienced a toxicity of CTCAE grade 2 for which 
relationship to study drug cannot be ruled out; or when any single patient experiences a 
DLT or AE of CTCAE grade 3 or greater during Cycle 1, the minimum cohort size will be 
3 evaluable patients for the current and subsequent cohorts. Once this cohort is complete 
and the dose escalation decision has been determined collectively between Novartis and the 
participating Investigators to escalate, the second cohort will open in a dose that satisfies 
the EWOC criterion. After the first cohort Japanese patients may be treated in two different 
dosing regimens (Q2W and Q4W). The dose escalation will then proceed until the 
MTD/RP2D is determined. The dose escalation in Japanese patients will run separately from 
the ROW. Dose escalation decisions will be guided by the BHLRM to estimate the 
MTD/RP2D in Japanese patients in the context of available safety and PK information. 

MBG453 in combination with decitabine: Provisionally, the first cohort of 6 patients 
enrolled in Phase Ib safety run-in of this treatment arm will be treated with the starting dose 
for MBG453 at 800 mg in combination with decitabine at 20 mg/m2. Since the starting dose 
of the specific combination is anticipated to be well tolerated, the assessment of DLT data 
will be made after all six patients evaluable for the dose determining analysis set 
(Section 10.1.4) have completed one cycle of treatment, unless they have experienced a 
DLT before. The safety of the combination will be evaluated based on all available data at 
the dose confirmation decision with the Investigators and Novartis. If there are 2 or more 
DLTs within those 6 evaluable patients, 6 additional evaluable patients will be accrued to 
the -1 dose level (Table 6-4). In case there are 2 or more DLTs within the 6 evaluable 
patients for the dose determining analysis set in the -1 dose level, then further enrolment 
will be halted in this treatment arm  due to excessive toxicity.
For the purpose of dose escalation decisions, patients can be considered evaluable after having 
met the following criteria: 

MBG453 single agent: Patients must complete a minimum of 1 cycle of treatment with 
the minimum safety evaluation and drug exposure (all planned doses of MBG453) or have 
had a DLT within the first cycle of treatment to be considered evaluable for dose 
escalation decisions (Section 10.1.4). 

MBG453 in combination with PDR001:

Cycle 1 risk set: For initial assessment of DLT data, patients must complete a 
minimum of 1 cycle of treatment with the minimum safety evaluation and drug 
exposure (all planned doses of study drugs) or have had a DLT within the first cycle 
of treatment to be considered evaluable for dose escalation decisions. 

Cycle 2 risk set: For confirmation of DLT data, patients from the Cycle 1 risk set 
must receive at least one of their planned cycle 2 doses, and have completed 
minimum safety evaluation, or have had a DLT within cycle 2 to be considered 
evaluable for dose escalation decisions.

Dose escalation decisions will occur when the cohort of patients has met these criteria. If 
only 2 patients in a cohort are evaluable and neither patient has experienced a treatment-


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related toxicity > CTCAE grade 1, dose escalation decisions may be considered Dose 
escalation decisions will be made by Investigators and Novartis study personnel. Decisions 
will be based on a synthesis of all relevant data available from all dose levels evaluated in 
the ongoing study including safety information, DLTs, all CTCAE Grade ≥ 2 toxicity data 
during Cycle 1 (single agent) and Cycle 1 and 2 (combination), available PK, and PD data 
from evaluable patients. For the single agent dose escalation, the recommended dose for the 
next cohort of patients will be guided by the three separate BHLRMs (one for ROW patients 
and two for Japanese patients with Q2W and Q4W schedules) with EWOC principle 
evaluating the probability of DLT. For the combination dose escalation, the recommended 
dose for the next cohort of patients will be guided by the BLRM with EWOC principle 
evaluating the probability of DLT (Section 10.4.2).

MBG453 in combination with decitabine: Patients must complete a minimum of 1 cycle 
of treatment with the minimum safety evaluation and drug exposure (all planned doses of 
study drugs) or have had a DLT within the first cycle of treatment to be considered evaluable 
for dose escalation decisions. 
Bayesian logistic regression model of DLT rate (MBG453 single agent and 
MBG453 in combination with PDR001)
The adaptive Bayesian methodology provides an estimate of DLT rate for all dose levels of 
MBG453 as single agent and in combination with PDR001 that do not exceed the MTD and 
incorporates all accumulated DLT information from all dose cohorts for this estimation. 
The next dose will always satisfy the EWOC principle (less than 25% probability that the DLT 
rate is ≥ 33%) and will not exceed a 334% (1/2 log) increase from the previous dose 
(a standardly used escalation factor for mAb and immuno-oncology treatments). 
Smaller increases in dose may be recommended by the Investigators and Novartis upon 
consideration of all of the available clinical data. Any dose escalation decisions made by 
investigators and Novartis personnel will not exceed the dose level permissible under by the 
BLRM using the EWOC principle. If needed to better define the dose-toxicity relationship 
additional patients may be enrolled to the current dose level, to a preceding dose level, or to an 
intermediate dose level before proceeding with further dose escalation.
If 2 patients in a previously untested dose level experience a DLT, enrollment to that cohort 
will stop, the BHLRMs/BLRM will be updated and the next cohort will open at the next lower 
dose level or an intermediate dose level (see Table 6-2, Table 6-3 and Appendix 3) that satisfies 
the EWOC criteria. However, if 2 patients in a new cohort at a previously tested dose level 
experience a DLT (e.g., a total of 8 patients are treated on this dose level with 2 DLT observed), 
further enrollment to that cohort will stop, the BLRM will be updated with this new information 
and re-evaluation of the available safety, PK, and PD data will occur. By incorporating 
information gained at the preceding dose cohorts, additional patients may be enrolled into the 
current dose cohort only if the combination still meets the EWOC criteria and as agreed by 
Investigators and Novartis personnel. Alternatively, if recruitment to the same cohort may not 
resume, a new cohort of patients may be recruited to a lower dose combination as agreed by 
Investigators and Novartis personnel and if the BLRM predicts that the risk for this lower dose 
combination to exceed the MTD remains below 25% (EWOC). Re-escalation may then occur 


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if data in subsequent cohorts supports this (EWOC criteria are satisfied) and Investigators and 
Novartis personnel agree.
Dose escalation will continue until identification of the RP2D, which for single agent MBG453 
is expected to occur before the MTD is reached.
The MTD and/or RP2D is identified when the following 3 conditions are met:
1. at least 6 patients have been treated at this dose or combination
2. this dose or combination satisfy one of the following conditions: 
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or
b. minimum of 21 patients for the single agent in ROW or minimum of 15 patients for 
the combination or minimum of 12 patients for the single agent in Japanese patients
have already been treated to identify the MTD. Recommendation of RP2D may be 
made with fewer patients, prior to identification of MTD, or
c. significant activity is seen early in the phase I or Ib part, in which case a 
recommended dose for expansion may be identified and the phase II groups may be 
initiated without determination of the MTD.
3. it is the maximum dose recommended for patients, either per the model or by review of all 
clinical data by Novartis and Investigators in a dose-escalation teleconference see 
Section 6.2.3.3.
6.2.3.3
Implementation of Dose Escalation/Confirmation Decisions
To implement dose escalation/confirmation decisions, the available toxicity information 
(including AEs and laboratory abnormalities that are not DLTs), the recommendations from the 
BLRM, and the available PK and pharmacodynamics information will all be evaluated by the 
Investigators and Novartis study personnel (including the study physician and statistician) 
during a dose decision meeting by teleconference. Drug administration at the next higher dose 
level may not proceed until the Investigator receives written confirmation from Novartis 
indicating that the results of the previous dose level were evaluated and that it is permissible to 
proceed to a higher dose level.
6.2.4
Definitions of dose limiting toxicities (DLTs) for MBG453 single agent 
and MBG453 in combination with PDR001
A DLT is defined as an AE or abnormal laboratory value of CTCAE grade ≥ 3 assessed as 
unrelated to disease, disease progression, inter-current illness or concomitant medications, 
which occurs within the first cycle of treatment with MBG453 as single agent or in the first two 
cycles of treatment when MBG453 is given in combination with PDR001 during the dose 
escalation part of the study, with the exceptions described in Table 6-5.


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National Cancer Institute Common Terminology Criteria for Adverse events version 4.03 will 
be used for all grading. For the purpose of dose-escalation decisions, DLTs will be considered 
and included in the BLRM. Adverse events meeting the criteria of DLT (please refer to 
Table 6-5) will be also collected in cycle 2 of MBG453 single agent, and will be used to derive 
prior distributions for the combination BLRM.
The Investigator must notify Novartis immediately of any unexpected CTCAE grade ≥ 3 AEs 
or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE grade 
≥ 2 AEs will be reviewed for all patients at the current dose level.
Table 6-5
Criteria for defining dose limiting toxicities (MBG453 single agent and 
MBG453 in combination with PDR001)
For the purpose of dose escalation and cohort expansion, DLT will be adjudicated as follows :
Any Grade 4 AEs will be adjudicated DLTs with the exception of:
Neutropenia lasting <48 hours that is not associated with fever or other clinical symptoms.
Lymphopenia.
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected with 
appropriate management or supplementation within 72 hours of the onset.
Any Grade 3 AEs will be adjudicated as DLTs with the exception of:
Infusion reaction that resolves to ≤ grade 1 within 6 hours.
Nausea and vomiting persisting for < 2 days after optimal anti-emetic therapy.
Thrombocytopenia without significant bleeding.
Diarrhea persisting for < 2 days after optimal anti-diarrhea treatment.
Hypertension persisting < 7 days after treatment. 
Infection or fever in the absence of neutropenia persisting < 5 days. 
Rash or photosensitivity persisting < 7 days after treatment.
Fatigue lasting < 7 days.
Immune-related adverse events persisting < 7 days after treatment with corticosteroids.
The following Grade 2 AEs will be adjudicated as DLTs:
Total bilirubin with ≥ CTCAE grade 2 ALT.
Pneumonitis persisting > 7 days despite treatment with corticosteroids. 
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not
improve to grade 1 severity within 2 weeks of the initiation of topical therapy OR requires 
systemic treatment.
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event that lead to a dosing delay of > 7 days in cycle 1.


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6.2.5
Definition of dose limiting toxicities (DLTs) for MBG453 in combination 
with decitabine
A DLT is defined as an AE or abnormal laboratory value of CTCAE grade ≥ 3 assessed as 
unrelated to disease, disease progression, inter-current illness or concomitant medications, 
which occurs within the first cycle of treatment with MBG453 when is given in combination 
with decitabine during the safety run in part of the study, with the exceptions described in 
Table 6-6.
Myelosuppression is an expected toxicity for patients treated with decitabine and is managed 
with treatment interruption, dose reduction, growth factor support and anti-infective therapies 
as needed. AEs of myelosuppression are the most frequently reported with decitabine single 
agent (neutropenia of any grade in 90% of decitabine-treated patients with grade 3 or 4 
occurring in 87% of patients; thrombocytopenia of any grade in 89% of patients with grade 3 
or 4 in 85% of patients; grade 3 or 4 febrile neutropenia in 23% of patients; anemia of any grade 
in 82% of patients). Patients will be closely monitored for grade 3-4 hematological AEs as 
defined in the DLT criteria (Table 6-6).  The dose -1 level of decitabine at 10 mg/m2 (days 1 to 
5) might be considered after discussion and agreement between Novartis and the Investigators.
National Cancer Institute Common Terminology Criteria for Adverse events version 4.03 will 
be used for all grading. For the purpose of dose-escalation decisions, DLTs will be considered 
and included in the BLRM. Adverse events meeting the criteria of DLT (please refer to 
Table 6-6) will be also collected, and will be used to derive prior distributions for the 
combination BLRM.
The Investigator must notify Novartis immediately of any unexpected CTCAE grade ≥ 3 AEs 
or laboratory abnormalities. Prior to enrolling patients into a higher dose level, CTCAE grade 
≥ 2 AEs will be reviewed for all patients at the current dose level.
Table 6-6
Criteria for defining dose limiting toxicities (MBG453 in combination 
with decitabine)
Any Grade 3 and 4 Hematological AEs will be adjudicated DLTs with the exception of:
Grade 3 or 4 Neutropenia lasting < 7 consecutive days that is not associated with fever or 
other clinical symptoms
Grade 3 thrombocytopenia without clinically significant bleeding
Grade 4 thrombocytopenia lasting < 7 consecutive days and without clinically significant 
bleeding
Grade 3 anemia
Grade 4 anemia lasting for < 7 consecutive days
Lymphopenia


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Any Grade 4 AEs will be adjudicated DLTs with the exception of:
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected with 
appropriate management or supplementation within 72 hours of the onset.
Any Grade 3 AEs will be adjudicated as DLTs with the exception of:
Infusion reaction that resolves to ≤ grade 1 within 6 hours.
Nausea and vomiting persisting for < 2 days after optimal anti-emetic therapy.
Diarrhea persisting for < 2 days after optimal anti-diarrhea treatment.
Hypertension persisting < 7 days after treatment. 
Infection or fever in the absence of neutropenia persisting < 5 days. 
Rash or photosensitivity persisting < 7 days after treatment.
Fatigue lasting < 7 days.
Immune-related adverse events persisting < 7 days after treatment with corticosteroids.
The following Grade 2 AEs will be adjudicated as DLTs:
Total bilirubin with ≥ CTCAE grade 2 ALT.
Pneumonitis persisting > 7 days despite treatment with corticosteroids. 
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not 
improve to grade 1 severity within 2 weeks of the initiation of topical therapy OR requires 
systemic treatment.
Other clinically significant toxicities, including a single event or multiple occurrences of the 
same event that lead to a dosing delay of > 14 days in cycle 1.
6.3
Dose modifications
6.3.1
Dose modifications and dose delay
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments are 
permitted in order to allow the patient to continue the study treatment. The following guidelines 
need to be applied:

If a patient experiences an AE meeting the criteria for DLT as outlined in Section 6.2.4
(including events occurring after cycle 1), treatment should be withheld. Dose modifications 
for toxicities related to MBG453 and PRD001 are summarized in Table 6-7. If decitabine 
treatment is deemed by the investigator to possibly have contributed to an observed adverse 
event, the dose or duration of decitabine treatment may be modified according to the 
country-specific label guiding decitabine use. Following resolution of the toxicity to grade 
1 or to the patient’s baseline value, the patient may resume study treatment at a lower dose 
level assessed to be safe (on the same dosing schedule), if there is no evidence of disease 
progression as per irRC. For patients in the dose escalation part receiving MBG453 in 
combination with PDR001, MBG453 dose level will be lowered except for the first two 
cohorts where PDR001 will be lowered instead. 

A decision to resume treatment with MBG453 as single agent or in combination with 
PDR001 or decitabine following the occurrence of a DLT is at the discretion of the 
Investigator. If the Investigator considers it to be in the patient’s best interest to resume 
therapy before the toxicity has resolved to grade 1, or to resume without dose reduction, this 
may be permitted on a case by case basis, following discussion with Novartis.


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
Dose reductions to doses below 20 mg are not permitted for MBG453 or PDR001. If more 
than 2 consecutive doses have to be skipped due to study treatment-related toxicities, then 
the patient must be discontinued from the study. If a patient who misses more than 2 
consecutive doses due to study treatment-related toxicity is experiencing clinical benefit,
and in the opinion of the investigator it is in the patient’s best interest to remain on study, 
then the patient may continue treatment after discussion with Novartis.

Patients who discontinue the study treatment for a study related AE or a study-related 
abnormal laboratory value must be followed as described in Section 6.3.2.
All interruptions or change to study drug administration must be recorded on the Dose 
Administration Record eCRF.
6.3.2
Follow-up for toxicities
The emergence of Immune-Related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators.
An irAE is a clinically important AE of unknown etiology associated with the study drug 
exposure. irAEs are typically low grade and self-limited, often occurring after multiple doses, 
and most frequently involving the GI tract (diarrhea/colitis), skin (rashes), liver (hepatitis), and 
endocrine systems (a variety of endocrinopathies). 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 exclude the neoplastic, infectious or metabolic 
origin of the AE. For clinical management of suspected immune-related events, reference to 
consensus management guidelines is recommended such as those provided in the National 
Comprehensive Cancer Network (NCCN) Guidelines for the Management of Immunotherapy-
Related 
Toxicities 
(available 
at: 
[https://www.nccn.org/professionals/physician_gls/default.aspx#immunotherapy], the ASCO
clinical practice guideline for Management of Immune-Related Adverse Events in Patients 
Treated With Immune Checkpoint Inhibitor Therapy (Brahmer et al 2018) or the ESMO 
Clinical Practice Guidelines for Management of Toxicities from Immunotherapy 
(Haanen et al 2017)Patients 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 4 weeks, 
and subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor, 
anti-DNA Ab, etc.) should be performed. In case of a toxicity suspected to be a cytokine release 
syndrome, the assessments outlined in Section 7.2.2.5.6 must be performed. All patients must 
be followed up for irAEs, AEs and SAEs for 150 days following the last dose of MBG453 
single agent or in combination with PDR001. 
Table 6-7 outlines the follow-up evaluation recommended for selected toxicities. For any
irAEs/AEs Grade 1 and/or Grade 2, treatment with MBG453 and/or PDR001 should be 
maintained at the determined dose and schedule, unless otherwise specified in Table 6-6.
Decitabine treatment may be modified according to the country-specific label guiding 
decitabine use.


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Table 6-7
Management of toxicities defined as study treatment-related only
Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specified)
Recommended dose interruption, delay and discontinuation for study treatment
During a cycle of therapy
Infusion/Hypersensitivity reactions
Grade 1

Decrease MBG453 or PDR001 infusion rate until recovery of the symptoms
Grade 2

Stop MBG453 or PDR001 infusions immediately, and keep line open. Provide 
supplemental oxygen and fluids, as needed

Monitor vital signs (e.g. blood pressure, pulse, respiration, and temperature) every 
15 ± 5 minutes until resolution

Administer medications for symptomatic relief as needed:

Urticaria: Diphenhydramine (25 to 100 mg i.v.) as needed every 4 to 6 hours, 
or alternative as appropriate

Fever: Acetaminophen/paracetamol (650-1000 mg by mouth) as needed 
every 4 to 6 hours, or alternative as appropriate

Rigors: Meperidine 25 mg i.v. as needed every 6 hours or alternative as 
appropriate. Corticosteroids or bronchodilators may be administered, as 
needed 

Resume MBG453 or PDR001 infusions once infusion reaction resolves (within 8 
hours of initial start of infusion). Maintain dose level(s) 

Administer oral pre-medication (e.g.1000 mg of acetaminophen/paracetamol, 50-
100 mg diphenhydramine hydrochloride or alternative antihistamine), within 60 
minutes of restarting the MBG453 or PDR001 infusion. 

Restart MBG453 or PDR001 infusion at 50% of previous rate under continuous 
observation. Ensure that there is a minimum observation period of 1 hour prior to 
restarting the infusion(s)

If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then discontinue patient from study
Grade 3 or Grade 4

Discontinue MBG453 or PDR001 infusion immediately, and discontinue patient 
from study

Provide supplemental oxygen, fluids, and other resuscitative measures and/or 
measures for symptomatic relief (see under Grade 2, above) as needed. Monitor 
vital signs (e.g. blood pressure, pulse, respiration, and temperature) every 15 ± 5 
minutes until resolution
Hematology
Neutropenia (ANC)
Grade 3 (ANC < 
1000 - 500/mm3)

Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1
Grade 4 (ANC < 
500/mm3)

Discontinue for study treatment-related Grade 4 > 7 days duration
Thrombocytopenia
Grade 3 (PLT < 
50,000 -
25,000/mm3)

Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1

Discontinue for study treatment-related Grade 3 > 7 days or associated with 
bleeding
Grade 4 (PLT < 
25,000/mm3)

Discontinue for study treatment-related Grade 4


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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specified)
Recommended dose interruption, delay and discontinuation for study treatment
During a cycle of therapy
Febrile neutropenia
(ANC < 1.0 x 109/L, 
fever ≥ 38.5°C)

Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1

Discontinue for study treatment-related Grade 4
Lymphopenia
Grade 3 (<0.5-0.2 x 
109/L)

Maintain dose level for study treatment-related ≤ Grade 3
Grade 4 (<0.2 x 
109/L)

Dose delay for study treatment-related Grade 4 until resolved to ≤Grade 3

Study treatment-related Grade 4 lymphopenia or leukopenia does not require 
discontinuation
Renal
Serum creatinine
Grade 2 (> 1.5 - 3.0 
x ULN) 
Grade 3 (> 3.0 - 6.0 
x ULN)

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1
Grade 4 (> 6.0 x 
ULN)

Discontinue for study treatment-related Grade 4
Hepatic
Bilirubin*
Grade 2 (> 1.5 - 3.0 
x ULN)

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1

Baseline Grade 1 AST/ALT or Total bilirubin requiring dose delays for reasons 
other than a  shift of 2 grades in AST/ALT or Total bilirubin may resume treatment 
in the presence of Grade 2 AST/ALT OR Total bilirubin
Grade 3 (> 3.0 - 10.0 
x ULN)
Grade 4 (> 10.0 x 
ULN)

Discontinue for study treatment-related ≥ Grade 3 

Combined Grade 2 AST/ALT AND Total bilirubin values meeting discontinuation 
parameters (AST or ALT > 8 x ULN, Total bilirubin > 5 x ULN, concurrent AST or 
ALT > 3 x ULN and total bilirubin > 2 x ULN) should permanently discontinue 
treatment

If baseline total bilirubin is within normal limits, delay dosing for study treatment-
related Grade ≥2 toxicity
AST or ALT
Grade 2 (> 3.0 -  5.0 
x ULN)

If baseline total bilirubin is within the Grade 1 toxicity range, delay dosing for study 
treatment -related Grade ≥3 toxicity

Discontinue for:

Concurrent AST or ALT > 3x ULN and total bilirubin > 2x ULN
Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1

Baseline Grade 1 AST/ALT or Total bilirubin requiring dose delays for reasons 
other than a shift of 2 grades in AST/ALT or Total bilirubin may resume 
treatment in the presence of Grade 2 AST/ALT OR Total bilirubin
Grade 3 (> 5.0 - 20.0 
x ULN)
Grade 4 (> 20.0 x 
ULN)

Discontinue for study treatment-related ≥ Grade 3 Combined Grade 2 AST/ALT 
AND Total bilirubin values meeting discontinuation parameters (AST or ALT > 8 x 
ULN, Total bilirubin > 5 x ULN, concurrent AST or ALT > 3 x ULN and total 
bilirubin > 2 x ULN) should permanently discontinued treatment


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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specified)
Recommended dose interruption, delay and discontinuation for study treatment
During a cycle of therapy
Asymptomatic 
amylase and/or 
lipase elevation**
Grade 3 (> 2.0 - 5.0 
x ULN) 
Grade 4 (> 5.0 x 
ULN)

Any study treatment-related Grade ≥ 3 isolated amylase or lipase abnormality that 
is not associated with symptoms or clinical manifestations of pancreatitis does not 
require dose delay or discontinuation. The Novartis Medical representative should 
be consulted for such amylase or lipase abnormalities.
Cardiac General
Grade 2 

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1
Grade 3 or Grade 4

Discontinue for study treatment-related Grade 3 or Grade 4
Endocrinopathy
Grade 2 or Grade 3

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1

Grade 3 study treatment-related endocrinopathies adequately controlled with only 
physiologic hormone replacement do not necessarily require discontinuation
Grade 4

Grade 4 study treatment-related endocrinopathy adverse events, such as adrenal 
insufficiency, ACTH deficiency, hyper- or hypothyroidism, or glucose intolerance, 
which resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, respectively, 
may  require delays or discontinuation. Therapy can only be continued after 
discussion with and approval from the Novartis Medical representative.
Skin
Grade 2

In presence of study treatment-related Grade 2 skin toxicity, treatment may be 
resumed (even if patient experience before a study treatment -related Grade 3 
toxicity)
Grade 3 or Grade 4

Dose delay for study treatment-related ≥ Grade 3 until resolved to ≤  Grade 1

Discontinue for study treatment-related ≥ Grade 3 lasting > 7 days or Grade 4
Stevens-Johnson 
syndrome (SJS), or 
Lyell syndrome/toxic 
epidermal necrolysis 
(TEN)

Permanently discontinue study treatment.
Gastrointestinal
Diarrhea ***
Grade 2

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1. 
Resume treatment when resolved to baseline value.
Grade 3 or Grade 4

Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Fatigue/Asthenia
Grade 3 or Grade 4

Dose delay for study treatment-related Grade 3 until resolved to ≤Grade 1

Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Any neurological disorder
Grade 2

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1
Grade 3 or Grade 4

Discontinue for study treatment-related Grade 3 or Grade 4


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Worst toxicity 
CTCAE v4.03 
Grade (unless 
otherwise 
specified)
Recommended dose interruption, delay and discontinuation for study treatment
During a cycle of therapy
Ocular (uveitis, eye pain, blurred vision)
Grade 2 

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1

Discontinue for any study treatment-related Grade 2 uveitis, eye pain or blurred 
vision that does not respond to topical therapy and does not improve to Grade 1 
severity within the re-treatment period OR requires systemic treatment
Grade 3 or Grade 4

Discontinue for study treatment-related Grade 3 uveitis of any duration

Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Pulmonary (pneumonitis, bronchospasm)
Grade 1

Patients with persistent Grade 1 pneumonitis after completion of a steroid taper 
over at least 1 month may be eligible for retreatment if discussed with and 
approved by Novartis Medical representative
Grade 2 

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1
Grade 3 or Grade 4

Discontinue for any study treatment-related Grade 3 pneumonitis of any duration 

Discontinue for any study treatment-related Grade 3 lasting > 7 days or Grade 4
Cytokine release syndrome (CRS)
Grade 2

If CRS is suspected (very high fever and precipitous drops in blood pressure, 
myalgia, change in mental status) treat with corticosteroids. 

Take blood for cytokine measurements immediately after the occurrence of the AE 
and during treatment. If very high levels of IL-6 can be confirmed, a more specific 
treatment may be used.
Grade 3 or Grade 4

Discontinue for study treatment-related ≥Grade 3
Other non-laboratory adverse events
Grade 2 

Dose delay for study treatment-related ≥ Grade 2 until resolved to ≤Grade 1
Grade 3 or Grade 4

Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Any other laboratory adverse events
Grade 3 or Grade 4

Dose delay for study treatment-related ≥ Grade 3 until resolved to ≤Grade 1
*Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then ↓1 dose level and continue treatment at the discretion of the 
investigator.
**Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within 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, patients will be discontinued permanently 
from study treatment.
***Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt 
diarrhea.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Recommended guidelines for 
prophylactic or supportive treatment for expected toxicities, including management of study-
drug induced AEs, i.e. hematologic toxicity, infusion reaction, pneumonitis and other immune 
related toxicities, are provided in Section 6.3.2 and in the decitabine country-specific label.


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Refer to preclinical toxicity data provided in the [PDR001 Investigator’s Brochure] and 
[MBG453 Investigator’s Brochure] respectively.
6.4
Concomitant medications
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 patient are allowed.
The patient must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. 
All medications (other than study treatment) and significant non-drug therapies (including 
physical therapy, herbal/natural medications and blood transfusions) administered during the 
study must be listed on the Prior/Concomitant Medications or the Surgical and Medical 
Procedures eCRFs.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) may not be taken during the study (with exception of the MBG453 in combination with 
decitabine arm). If a patient is using erythropoiesis stimulating agents (ESAs) prior to 
enrollment (at least 2 weeks before start of study treatment), he/she may continue at the same 
dose.
Anticoagulation therapy is permitted if the patients are already at stable doses of warfarin or 
stable doses of low molecular weight heparin (LMWH) 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-hypertensive therapy is allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with MBG453 
and/or PDR001.
A brief (< 24 hours) course of steroids for prophylaxis against contrast dye allergy is permitted 
for patients undergoing tumor assessments with exposure to the allergen.
Limited-field palliative radiotherapy or surgery to non-target lesion(s) may be allowed as 
concomitant therapy after documented discussion with Novartis. For the purpose of assessing 
response, a lesion treated with local therapy will be considered to have unequivocal progression 
of disease. Such local therapies administered during the study treatment must be listed on the 
Surgical and Medical Procedures eCRF.


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6.4.3
Prohibited concomitant therapy
During the course of the study, patients may not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune responses. Additionally, no other therapeutic monoclonal antibodies and no 
immunosuppressive medication may be administered while on this study.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed, with 
the only exclusion of steroids for the treatment infusion reaction, irAEs or replacement-dose 
steroids in the setting of adrenal insufficiency (providing this is ≤10mg/day prednisone or 
equivalent) Additional exceptions may be discussed with Novartis. Systemic corticosteroids 
required for the control of infusion reactions or irAEs must be tapered and be at non-
immunosuppressive doses (≤10 mg/day of prednisone or equivalent) before the next study 
drug administration. If more than 10 mg/day prednisone is used, study treatment should be 
suspended.
Topical, inhaled, nasal and ophthalmic steroids are not prohibited. The use of live vaccines is 
not allowed through the whole duration of the study. Other vaccines are excluded, except 
inactivated seasonal influenza vaccines.
6.5
Patient numbering, treatment assignment or randomization
6.5.1
Patient numbering
Each patient is identified in the study by a Patient Number (Patient No.),that is assigned when 
the patient is enrolled for screening/baseline. The Patient No. is retained as the primary 
identifier for the patient throughout his/her entire participation in the trial. The Patient No. 
consists of the Center Number (Center No.) (as assigned by Novartis to the investigative site) 
with a sequential patient number suffixed to it, so that each patient is numbered uniquely across 
the entire database. Upon signing the informed consent form, the patient is assigned to the next 
sequential Patient No. available to the investigator through the Oracle Clinical RDC interface. 
Once assigned, the Patient No. must not be reused for any other patient and the Patient No. for 
that individual must not be changed, even if the patient is re-screened. If the patient fails to start 
treatment for any reason, the reason will be entered into the Screening Disposition eCRF page.
6.5.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort during Phase I-Ib parts will be coordinated by 
Novartis. 
The assignment of a patient into testing one of the two dosing schedules during phase II part, 
and of a patient included for additional safety monitoring at different dose levels (dose ranging 
group), will be coordinated by Novartis and will be based on the dose levels available at the 
time the patient consents the participation in the study.
Randomization for Q2W versus Q4W comparison (Phase II part in combination 
only)
The investigator or designated staff will contact the Novartis Representative and provide the 
requested identifying information for the patient to register them. Once assigned, the Patient


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No. must not be reused for any other Patient and the Patient No. for that individual must not be 
changed. If the patient is randomized but fails to start treatment for any reason, the reason will 
be entered into the End of Treatment phase Disposition eCRF and Novartis Representative must 
be notified within 2 days that the patient was not randomized.
The randomization numbers will be generated using the following procedure to ensure that 
treatment assignment is unbiased from patients and investigator staff. A patient randomization 
list will be produced by the Novartis Representative using a validated system that automates 
the random assignment of patient 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 Global Clinical Supply using a validated system that automates the 
random assignment of medication numbers to medication packs containing each of the study 
treatments.
Prior to dosing, all patients who fulfill all inclusion/exclusion criteria will be randomized via 
Novartis Representative to one of the treatment arms (Section 4.1 and Section 6.1) in a ratio of 
1:1. Randomization will not be stratified. The investigator or his/her delegate will call Novartis 
Representative and confirm that the patient fulfills all the inclusion/exclusion criteria. The 
Novartis Representative will assign a randomization number to the patient, which will be used 
to link the patient to a treatment arm and will specify a unique medication number for the first 
package of study treatment to be administered to the patient. The randomization number will 
not be communicated to the caller.
6.6
Study drug preparation and dispensation
MBG453
MBG453 (100 mg liquid in vial) will be administered i.v. Further instructions for the 
preparation and dispensation of MBG453 are described in the Pharmacy Manual.
All dosages for MBG453 prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
PDR001
PDR001 (100 mg powder for solution for infusion) will be administered i.v. Further instructions 
for the preparation and dispensation of PDR001 are described in the Pharmacy Manual.
All dosages for PDR001 prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.


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Decitabine
Decitabine is commercially available. For details on preparation refer to decitabine country-
specific label instructions and/or decitabine package insert.
6.6.1
Study drug packaging and labeling
MBG453 100 mg liquid in vial and PDR001 100 mg powder for solution for infusion, will be 
supplied by Novartis to Investigator as open label bulk medication.
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but will not supply information about 
the patient.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, MBG453 and PDR001 should be stored according to 
the instructions specified on the drug labels.
Decitabine will be sourced as local commercial supply (in the locally approved formulation and 
packaging configuration) and labeled in the country according to local practice and regulation.
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 patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
Study treatment will be administered to the patient by the study site staff. 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 according to local institutional drug
accountability processes. 
Drug accountability will be noted by the field monitor during site visits and at the completion 
of the study.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.


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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.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all the assessments and indicates with an “X”, the visits when they are performed. 
All data obtained from these assessments must be supported in the patient’s source 
documentation. The table (“Category” column) indicates which assessments produce data to be 
entered into the clinical database (D) or remain in source documents only (S).
No eCRF will be used as a source document.
Screening/Baseline evaluations must be performed ≤ 28 days of Cycle 1 Day 1 (except for the 
pregnancy test which has to be performed within 72 hours before first dose). Assessments 
performed as part of the screening/baseline evaluations and within 3 days prior to the first dose 
of study treatment, are not required to be repeated on Cycle 1 Day 1. Laboratory and 
radiological assessments performed as part of standard of care prior to signing informed consent 
may be used if performed within the screening/baseline time window.
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of +/- 7 days is allowed. In case the infusion of MBG453 as single 
agent or in combination with PDR001 or decitabine cannot be administered at the scheduled 
visit, it has to be administered as soon as possible. If the delay is between 1 and 7 days the 
procedures at the original schedule visit should be performed. If the delay is longer than 7 days, 
the procedure of the following visit should be performed and subsequent visits will take place 
every 2 weeks. On PK collection days the windows are provided in Section 7.2.3.


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Table 7-1
Visit evaluation schedule (MBG453 single agent and MBG453 in combination with PDR001)
Screening/Baseline
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/Baseline
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles6
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
15
Obtain Informed 
Consent
D
7.1.1
X
Obtain additional 
biomarkers/biological 
sample informed 
consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and extent 
of cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, surgery 
and medical 
procedures
D
7.1.1.2
X
Continuous
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X


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Screening/Baseline
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/Baseline
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles6
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
15
ECOG status
D
7.2.2.4
X
X
X
X
X
X
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
Coagulation
D
7.2.2.5
X
X
X
X
X
X
Urinalysis
D
7.2.2.5
X
If clinically indicated
X
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
HIV, HBV and HCV
D
7.2.2.5
X
Pregnancy test
D
7.2.2.5
X1
X
X
X
X
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation as 
per RECIST v1.1 
and as per irRC
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and 
then every 3 cycles until progression of disease as per irRC or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until 
progression of disease per irRC or lost to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
12-Lead ECG
D
7.2.2.6
X
X
X
X2
X
Adverse events
D
8 
X
Continuous


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Screening/Baseline
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/Baseline
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles6
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
15
Collection of new 
tumor sample
D
7.2.4
X
Any time during C3D1 and End of 
Treatment
PDR001 infusion 
(only in 
combination)
D
6.1.1
i.v. every 2 weeks (every 4 weeks if testing of a new dosing schedule)
MBG453 infusion
D
6.1.1
i.v. every 2 weeks (every 4 weeks if testing of a new dosing schedule)
Blood sample for PK
analysis4
D
7.2.3
X
X
X
X
X
X
X
X
X
X
X
X3
X
Blood sample for 
soluble TIM-3 
analysis4
D
7.2.3
X
X
X
X
X
X
X
X
X
X3
X
Blood sample for IG 
analysis4
D
7.2.3
X
X
X
X3
X
Blood sample for RO 
analysis
D
7.2.3
X
X
X
X
X
X
X
X
X
X3
X
Blood sample for 
immunomonitoring
D
7.2.4
X
X
X
X
Blood sample for 
cytokine analysis5
D
7.2.4
X
X
X
X
Cytokines for safety
(IFN-γ; IL-6, IL-
1,TNF-α)5
D
7.2.2.5
Anytime for a suspected cytokine release syndrome, immediately after the 
AE, and one week after occurrence of the AE


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Screening/Baseline
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/Baseline
Cycle 1
Cycle 
2
Cycle 3
Subsequent 
cycles6
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
1
15
1
2
8
11
15
1
15
Survival contact 
(every 3 months)
D
7.1.5
X
1To be performed within 72 hours before first dose. 
2Cycle 6 Day 1 only. 
3Cycles 4, 5 and 6 only. 
4 For PK, IG and soluble TIM-3 analysis, a single blood sample will be collected and then aliquoted into different tubes for each analyte and backups. For Japan only: 
Japanese patients enrolled in the dose escalation are required to be hospitalized during Cycle 1.
5 The Cycle1 Day1 pre-dose biomarker cytokine sample will also be used as baseline for cytokine safety.
6After Cycle 24, in patients who are not experiencing grade 3 and 4 related toxicities, only visit at day1 of each cycle is required for patients at Q4W regimen.


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Table 7-2
Visit evaluation schedule (MBG453 in combination with decitabine)
Screening/
Baseline 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/
Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles  
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
22
1
8
15
1
2
8
11
15
22
1
8
15
Obtain Informed 
Consent
D
7.1.1
X
Obtain additional 
biomarkers/biological 
sample informed 
consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and extent 
of cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, surgery 
and medical 
procedures
D
7.1.1.2
X
Continuous
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
X
X
X
X
X
X
X
X
X
X
X
Height 
D
7.2.2.3
X
Weight
D
7.2.2.3
X
X
X
X
X
X


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Screening/
Baseline 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/
Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles  
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
22
1
8
15
1
2
8
11
15
22
1
8
15
ECOG status
D
7.2.2.4
X
X
X
X
X
X
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
Coagulation
D
7.2.2.5
X
X
X
X
X
X
Urinalysis
D
7.2.2.5
X
If clinically indicated
X
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
HIV, HBV and HCV
D
7.2.2.5
X
Pregnancy test
D
7.2.2.5
X1
X
X
X
X
X 5
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation as 
per RECIST v1.1 and 
as per irRC
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and then 
every 3 cycles until progression of disease as per irRC or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until 
progression of disease per irRC or lost to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
12-Lead ECG
D
7.2.2.6
X
X
X 
X
Adverse events
D
8 
X
Continuous


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Screening/
Baseline 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/
Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles  
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
22
1
8
15
1
2
8
11
15
22
1
8
15
Collection of new 
tumor sample
D
7.2.4
X
X
Decitabine infusion 
D
6.1.1
on days 1-5 of every cycle (Q4W)
MBG453 infusion
D
6.1.1
X
X
X
X
PDR001 infusion   
(only if in 
combination with 
Decitabine and 
MBG453)
D
6.1.1
X6
Blood sample for PK
analysis4
D
7.2.3
X
X
X
X
X 
X
X
X
X
X3
X
Blood sample for 
soluble TIM-3 
analysis4
D
7.2.3
X
X
X
X
X 
X
X
X
Blood sample for IG 
analysis4
D
7.2.3
X
X 
X 
X3
X
Blood sample for 
immunomonitoring
D
7.2.4
X
X
X
X
Blood sample for 
cytokine analysis
D
7.2.4
X
X
X
X
Survival contact 
(every 3 months)
D
7.1.5
X
1To be performed within 72 hours before first dose. 
2Cycle 3 Day 1 and Day 8 only. 


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Screening/
Baseline 
Phase
Treatment Phase
Follow-up
Visit name
Category
Protocol 
Section
Screening/
Baseline
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles  
EOT
150-Days 
Safety
Disease 
Progression
Survival 
Day of cycle
-28 to -1
1
2
8
11
15
22
1
8
15
1
2
8
11
15
22
1
8
15
3Cycles 4, 5 and 6 only. 
4 For PK, IG and soluble TIM-3 analysis, a single blood sample will be collected and then aliquoted into different tubes for each analyte and backups. 
5A urine pregnancy test should be performed every month during safety follow-up period
6After confirmed disease progression per irRC on MBG453 in combination with decitabine


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7.1.1
Screening/Baseline
The study IRC/IEC informed consent form must be signed and dated before any 
screening/baseline procedures are performed, except for evaluations performed as part of 
standard of care.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1 or Table 7-2. Screening/Baseline assessments 
must be repeated if performed outside of the specified screening window. The screening failure 
reason will be entered on the Screening Phase Disposition eCRF. 
Submission of a newly obtained tumor sample (formalin fixed, in ethanol) is requested from all 
patients at screening/baseline. For details refer to Section 7.2.4.
7.1.1.1
Information to be collected on screening failures
A patient who signed an Informed Consent Form but failed to be started on-treatment for any 
reason will be considered a screen failure. The screening failure reason will be entered on the 
Screening Phase Disposition eCRF.
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 
for patients who are screen failures, unless the patient experienced a SAE during 
screening/baseline (see Section 8 for SAE reporting details) or died (Death eCRF should be 
completed) or withdrew consent (Withdrawal of consent eCRF should be completed).
7.1.1.2
Patient demographics and other screening/baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic
treatments, prior medication, procedures, significant non-drug therapies and any other 
assessments that are done for the purpose of determining eligibility for inclusion in the study.
7.1.2
Treatment period
For the purpose of scheduling and evaluations, a treatment cycle will consist of 28 days for 
patients treated with MBG453 as single agent or in combination with PDR001 or decitabine
For Japan only; patients enrolled in dose escalation are required to be hospitalized during cycle 
1.
Patients who meet the following criteria will continue treatment in additional cycles:

Patients with SD/irSD, PR/irPR, unconfirmed CR/irCR, and unconfirmed PD/irPD.
Patients who meet the following criteria may continue treatment in additional cycles:

Patients with confirmed PD/irPD, if the Investigator considers it to be in the patient’s best 
interest to remain on the study, and after discussion with Novartis.


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Patients who meet the following criteria will NOT continue treatment in additional cycles:

Patients who experience unacceptable toxicity.

Patients with confirmed PD/irPD. These patients will then enter the Safety follow-up 
period.  

Patients with an unconfirmed PD/irPD who show signs of clinical deterioration or toxicity.
These patients will enter the Safety follow-up period, and will continue to be followed up 
until confirmed irPD or initiation of a new treatment. 

Patients who discontinued treatment at the discretion of the investigator or the patient as 
described in Section 7.1.3 and Section 4.3.
For MBG453 in combination with decitabine: patients will continue treatment until 
confirmed disease progression per irRC, or unacceptable toxicity and/or treatment is 
discontinued at the discretion of the Investigator or the patient. Only in the event of confirmed 
disease progression per irRC, the patient will have the option to add PDR001 to MBG453 in 
combination with decitabine based on investigator judgment and following a documented 
discussion with Novartis. 
The patient will continue treatment until confirmed disease 
progression per RECIST v1.1, or unacceptable toxicity and/or treatment is discontinued at the 
discretion of the Investigator or the patient.
Accumulating evidence indicates that objective responses to immunotherapy follows delayed 
kinetics of weeks or months, and can be preceded by initial apparent radiological progression 
or appearance of new lesions or some enlarging lesions while other target lesions are regressing 
(“mixed response”) (Wolchock 2009). It is therefore reasonable to allow for these possibilities 
and continue to treat the patient until progression is confirmed and found to be advancing at the 
next imaging assessment as per immune-related Response Criteria (irRC). An outline of the 
irRC is provided in Appendix 2. 
These considerations should be balanced by clinical judgment as to whether the patient is 
clinically deteriorating and unlikely to receive any benefit from continued treatment.
Such deterioration will be assessed to have occurred after a clinical event that, in the
Investigator’s opinion, is attributable to disease progression, is unlikely to reverse with 
continued study treatment and therefore indicates that the patient is not benefiting from study 
treatment and cannot be managed by the addition of supportive care. 
The decision to continue or stop treatment should be discussed with the Novartis Medical 
Responsible and will be documented in the study files.
Optimal duration of immune therapy has not been established. There are some reports that 
indicate the durable response for the patients who have interrupted immunotherapy because of 
toxicity (Weber et al 2017). To improve patients’ life who have been on therapy for more than 
24 cycles and after documented discussion with Novartis and the Investigator, a treatment break 
lasting up to 2 cycles may be granted. 
7.1.3
Discontinuation of Study Treatment
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a
patient decides to discontinue from the study treatment, the investigator must make every effort
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this


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information in the patient’s chart and on the appropriate eCRF. They may be considered 
discontinued if they state an intention to withdraw or fail to return for visits.
The Investigator should discontinue study treatment for a given patient if, on balance, he/she
believes that continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued under the following circumstances:

Adverse event

Lost to follow-up

Physician’s decision

Progressive disease as per confirmed irRC (not as per RECIST v1.1)

Confirmed Complete response (as per RECIST v1.1)

Study terminated by Novartis

Patient/guardian decision

Protocol deviation

Technical problems
Patients must be discontinued if any of the following occur:

Death

Pregnancy
Patients who discontinue study treatment should not be considered discontinued from the study. 
They should return for the EOT assessments as soon as possible and within 14 days of the last 
dose of study treatment or within 14 days of the decision to discontinue study treatment, and 
then enter the follow-up period as indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone calls, e-mail, letter) should be 
made to contact them as specified in Section 7.1.6. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments.
If the decision to discontinue the patient occurs at a regular scheduled visit, that visit may 
become the EOT visit rather than having the patient return for an additional visit. An End of
Treatment Phase Disposition eCRF should be completed, giving the reason for stopping the 
study treatment. End of treatment/Premature withdrawal visit is not considered as the end of the 
study.
Patients who transfer into another study or an alternative treatment option to continue provision 
of study treatment will perform the end of treatment procedures.
7.1.3.1
Replacement policy
Phase I-Ib dose escalation parts:
Patients will not be replaced on study. However, if a patient is considered to be non-evaluable 
for the Dose Determining Set (DDS), enrollment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrollment of new 
patients may be considered until at least the minimum number or at most the maximum number 


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of evaluable patients is achieved within the cohort. Minimum and maximum numbers of 
evaluable patients per cohort are defined in Section 6.2.3.
For MBG453 in combination with decitabine: if a patient is considered to be non-evaluable 
for the Dose Determining Set (DDS), enrollment of a new patient to the current cohort will be 
considered if there are less than 6 evaluable patients treated at this dose level, unless more than 
2 DLTs are experienced in the specific dose level.
Phase II part:
During the phase II part no replacements will be needed.
7.1.4
Withdrawal of Consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a patient does not want to participate in the study
anymore, and does not allow further collection of personal data. 
In this situation, the investigator should make a reasonable effort (e.g. telephone calls, e-mail, 
letter) to understand the primary reason for the patient’s decision to withdraw his/her consent 
and record this information.
Study treatment must be discontinued and no further assessments conducted and the data that 
would have been collected at subsequent visits will be considered missing
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s 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 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.


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7.1.5
Follow up period
All patients must have safety evaluations 150 days after the last dose of study treatment. 
Data collected should be added to the Adverse Events eCRF and the Concomitant Medications 
CRF.Patients who discontinue study treatment for any reason other than death, disease 
progression per confirmed irRC, clinical deterioration, lost to follow-up, consent withdrawal or 
study termination, also should return for tumor evaluation assessments and should not be 
considered withdrawn from the study until at least 80% of the patients enrolled had completed 
the survival follow-up period (minimum 18 months after the first dose of treatment) or 
discontinued the study for any reason. 
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine if the patient had disease 
progression.
Upon completion of the 150 days safety follow up or disease progression follow up, patients 
will be followed for survival every 3 months (can be done by telephone call) until death or until 
the end of the study is reached, unless they withdraw consent or are lost to follow-up.
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period in the appropriate eCRF page.
For patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment, as described in Section 4.3, the follow-up for safety, disease 
progression and survival will not be performed.
7.1.6
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient (e.g. dates of telephone calls, e-mail, 
letters). A patient should not be considered lost to follow-up until due diligence has been 
completed. Patients lost to follow up should be recorded as such on the appropriate Disposition 
eCRF.
7.2
Assessment types
7.2.1
Efficacy assessments
Tumor response will be determined locally according to two sets of criteria:

RECIST v1.1 (Appendix 1)

irRC (Appendix 2)
The local investigator’s assessment will be used for the analysis of response according to both 
RECIST 1.1 and irRC, and for treatment decision making (study discontinuation due to PD as 
per irRC). During the course of the study, Novartis may decide to have a central review of the 
radiological assessments performed. In such case, the investigator’s staff will be instructed on 
how to send data from these radiological assessments to a Contract Research Organization 
(CRO) for central review when needed.


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At screening/baseline, all patients will undergo CT with i.v. contrast of the brain, chest, 
abdomen and pelvis. If there is clinical evidence of disease in the neck, a CT with i.v. contrast 
of the neck will also be performed. MRI should only be used to evaluate sites of disease that 
are not adequately imaged by CT. If a patient is intolerant of iodine-based contrast agents, CTs 
may be performed without contrast. MRI may be used to evaluate sites of disease where a CT 
without i.v. contrast is not adequate. Visible skin lesions and easily palpable subcutaneous 
tumors may be measured by physical examination using a ruler or calipers. Ultrasound should 
not be used to measure sites of disease.
Tumor assessments will be performed at the time points as described in Table 7-3. PR or CR, 
per both RECIST v1.1 and irRC, will be confirmed by a new assessment after at least 4 weeks. 
Also PD, as per irRC, will be confirmed after at least 4 weeks. Disease progression follow-up 
should be performed as described in Section 7.1.5.
Table 7-3
Disease assessment collection plan
Procedure
Screening/
Baseline
During Treatment/Follow-up
CT or MRI
with contrast enhancement
(Chest, Abdomen, Pelvis)
Mandated
During treatment: starting on Cycle 3 Day 1, every 
2 cycles until Cycle 11 Day 1, and then every 3 
cycles until progression of disease as per irRC or 
patient withdrawal.
Follow-up for progression: every 8 weeks until 
week 40, then every 12 weeks until progression of 
disease per irRC or lost to follow-up.
EOT: if a scan was not conducted within 30 days 
prior to end of study treatment.
Brain CT or MRI with contrast
Mandated
If disease was detected at baseline, or if clinically 
indicated
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, thyroid function, pregnancy, ECG, as 
well as collecting of the AEs at every visit. For details on AE collection and reporting, refer to
Section 8.
7.2.2.1
Physical examination
Physical examination will be performed according to Table 7-1 or Table 7-2.
At screening/baseline and Cycle 1 Day 1, before infusion, a complete physical examination will 
be performed and will include the examination of general appearance, skin, neck (including 
thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities and 
neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed.
After Cycle 1 Day 1 and onwards, a short physical examination will be performed. A short 
physical exam will include the examination of general appearance, vital signs (blood pressure 
and pulse) and body sites as directed by symptoms.


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Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History eCRF. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event eCRF.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before and during
infusion at the visits indicated in Table 7-1 or Table 7-2. Vital signs should be assessed in the 
same position through the study.
There should be a period of at least one hour after the infusion where by the patient requires 
close observation.
More frequent examinations may be performed any time during the study at the discretion of 
the Investigator if medically indicated, and will be recorded as unscheduled assessment.
7.2.2.3
Height and weight
Height and body weight will be measured as indicated in Table 7-1 or Table 7-2 as per 
institutional standards.
7.2.2.4
Performance status
ECOG performance status will be assessed according to Table 7-4 and as indicated in
Table 7-1 or Table 7-2.
Table 7-4
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
Note: Grade 5 (death) was removed from this table. This information will be collected on a separate eCRF.
7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally (except 
cytokines and serology examinations that will be evaluated centrally). Refer to Table 7-5 for a 
summary of the parameters to be evaluated.
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges for that laboratory.


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Table 7-5
Local/Central clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Amylase, Lipase, Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), 
Bicarbonate, Calcium, Chloride, Sodium, Potassium, Creatinine, Glucose, Magnesium, 
Inorganic Phosphate, Total Bilirubin (also measure direct and indirect bilirubin if total 
bilirubin is > grade 1), Blood Urea Nitrogen (BUN) or Urea
Coagulation
Prothrombin time (PT) or INR, Activated partial thromboplastin time (APTT)
Urinalysis
Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific Gravity, White Blood Cells
Thyroid
Free T4, TSH (Thyroid Stimulation Hormone)
Serology exam*
Anti-DNA antibodies (Abs), Anti-nuclear abs, Anti-phospholipid abs, Anti-mitochondrial 
abs, c-Reactive protein (CRP), Rheumatoid factor (RF)
Cytokines*
IFN-γ, IL-6, IL-1,TNF-α
Virology
HIV, HBV, HCV
Pregnancy
Serum samples only for women of childbearing potential
* To be performed by a Central laboratory. Details will be provided in the [CMBG453X2101 Laboratory 
Manual].
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 or Table 7-2.
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-5 will be performed as per the assessment schedule 
in Table 7-1 or Table 7-2.
It should be noted in the patient’s eCRF if the patient was fasting at the time of blood sampling.
7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 or Table 7-2.
7.2.2.5.4 Urinalysis
Abnormal findings will be followed up with a microscopic evaluation and/or additional 
assessments as clinically indicated. A microscopic evaluation (WBC/HPF, RBC/HPF, and any 
other evaluations depending on macroscopic findings) need only to be performed if the 
urinalysis result is significantly abnormal.
Urinalysis will be performed at screening/baseline and EOT visit.
7.2.2.5.5 Thyroid function and Serology exam
Thyroid and Serology panels outlined in Table 7-5 will be performed as per the assessment 
schedule in Table 7-1 or Table 7-2.


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7.2.2.5.6 Cytokine analysis
Samples for the cytokine panel outlined in Table 7-5 will be collected at the following time 
points:

Cytokine baseline level for safety purpose can be assessed from the biomarker blood 
sample (plasma) collected at pre-dose Cycle 1 day 1.

On an ad-hoc basis in case a patient has an adverse event suspected to be a cytokine 
release syndrome (Table 7-1 or Table 7-2). In such case, this assessment should be 
performed at the following time points:
a. within 5 hours (or as soon as possible) after the occurrence of the adverse event,
b. one week after the occurrence of the adverse event. 
7.2.2.5.7 Virology
Virology panel outlined in Table 7-5 will be performed as per the assessment schedule in 
Table 7-1 or Table 7-2.
7.2.2.5.8 Pregnancy and assessments of fertility
All females of childbearing potential will have a serum pregnancy test at screening/baseline 
and/or within ≤72 hours before first dose of study treatment. During the study, a serum 
pregnancy test should be done at day 1 of each cycle, and at EOT visit.
A positive pregnancy test requires immediate discontinuation of study treatment and 
discontinuation from study. See Section 8.3 for pregnancy reporting.
A urine pregnancy test should be performed every month during and at the end of the safety 
follow-up period. If the patient is not coming to the clinic during the safety follow-up, it can be 
performed at home or at a local doctor’s office, and the results will be communicated to the site 
staff. These follow-up pregnancy tests will be recorded only in the source documentation, not 
in the CRF.
7.2.2.6
Cardiac assessments
7.2.2.6.1 Electrocardiogram (ECG)
A standard 12-lead ECG will be performed as per the assessment schedule in Table 7-1 (or 
Table 7-2) and Table 7-6 (or Table 7-7). Blood samples scheduled at the same time point should 
be taken after the ECGs are completed. The ECGs on Day 1 of Cycles 1, 3 and 6 must be 
performed in triplicate.
The post-infusion ECGs in the Phase Ib combination part will be collected after the completion 
of the last infusion.


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Table 7-6
12-lead ECG collection plan for MBG453 single agent and MBG453 in 
combination with PDR001
Cycle
Day
Time
Screening/Baseline
-28 to -1
Anytime 
1
1
*Pre-infusion
1
1
*1hour (±5 min)  post-infusion
3
1
*Pre-infusion
3
1
*1hour (±5 min) post-infusion
6
1
*Pre-infusion
6
1
*1hour (±5 min) post-infusion
EOT
-
Anytime
Unscheduled**
-
Anytime
*ECGs performed in triplicate.
**A PK sample should be collected just after an ECG performed due to an unexpected cardiac signal.
Table 7-7
12-lead ECG collection plan for MBG453 in combination with 
decitabine 
Cycle
Day
Time
Screening
-28 to -1
Anytime 
1
1
*Pre-decitabine infusion
1
1
*Right after completion of decitabine infusion
1
8
*Pre-MBG453 infusion
1
8
*1hour (±5 min) after completion of  MBG453 infusion
EOT
-
Anytime during the EOT visit
Unscheduled**
-
Anytime if clinically indicated
*ECGs performed in triplicate
**A PK sample should be collected just after an ECG performed due to an unexpected cardiac signal.
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the ECG Manual.
Clinically significant abnormalities present at screening/baseline should be reported on the 
Medical History eCRF. New or worsened clinically significant findings occurring after 
informed consent must be recorded on the Adverse Events eCRF. All eligibility and patient 
management decisions should be made based on the local reading of the ECG.
7.2.3
Pharmacokinetics and immunogenicity assessments
The following PK parameters will be determined for MBG453 as single agent, MBG453 in 
combination with PDR001 and PDR001 in combination with MBG453 using non-
compartmental methods: Cmax, Tmax, AUC0-tlast (Cycle 1 Day 1 and Cycle 3 Day 1), time to 
last measurable concentration (Tlast), t1/2, and the accumulation ratio of MBG453 and PDR001.




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Cycle
Day
Scheduled Time Point (h)b, c
Analytesa
3
8
168h post-infusion (± 8h)
mAb, soluble TIM-3, ROd
3
11
240h post-infusion (± 24h)
mAb
3
15
Pre-infusion of next dose/336h post-infusion (±24h)
mAb, soluble TIM-3, ROd
4
1
Pre-infusion of cycle 4/ 336h or 672h post infusion 
(±24h)
mAb, soluble TIM-3, RO and IG
5
1
Pre-infusion of Cycle 5
mAb, soluble TIM-3, RO and IG
5
1
1h post-infusion (± 5 min)b
mAb
6
1
Pre-infusion of Cycle 6
mAb, soluable TIM-3, RO and 
IG
6
1
1h post-infusion (± 5 min)b
mAb
EOT
Anytime
mAb, soluble TIM-3, RO and IG
Unscheduled
Anytime
mAb, soluble TIM-3, IG and RO
a.
IG samples associated with MBG453 and PDR001 are to be collected together with PK samples.
b.
After completion of the infusion (during combination treatment, after completion of the last infusion)
c.
PK samples will be collected from the arm opposite of infusion site. Alternatively, infusion site will need to be 
flushed with 10 mL of saline.
d.
Applicable only for patients in the phase I-Ib dose escalation part.
Table 7-9
Pharmacokinetic blood collection log for MBG453 in combination with 
decitabine, for soluble TIM-3 and IG (patients treated with MBG453 
and decitabine)
Cycle
Day
Scheduled Time Point (h)2
Analytes1
1
1
Pre-decitabine infusion3
Decitabine and soluble TIM-3
1
1
Right after completion of decitabine infusion
Decitabine
1
1
1h (± 5 min) after completion of decitabine infusion
Decitabine
1
8
Pre-MBG453 infusion3
MBG453, IG and soluble TIM-3
1
8
1h (± 5 min) after completion of MBG453 infusion
MBG453 and soluble TIM-3
1
15
168h (±2h) after completion of MBG453 infusion
MBG453 and soluble TIM-3
1
22
336h (±8h) after completion of MBG453 infusion
MBG453 and soluble TIM-3
2
8
Pre-MBG453 infusion3
MBG453, IG and soluble TIM-3
3
1
Pre-decitabine infusion3
Decitabine, 
3
1
Right after completion of decitabine infusion
Decitabine
3
1
1h (± 5 min) after completion of decitabine infusion
Decitabine
3
8
Pre-MBG453 infusion3
MBG453, IG, soluble Tim-3
3
8
1h (± 5 min) after completion of MBG453 infusion
MBG453 and soluble TIM-3
3
15
168h (±2h) after completion of MBG453 infusion
MBG453 and soluble TIM-3
3
22
336h (±8h) after completion of MBG453 infusion 
MBG453 and soluble TIM-3
4
8
Pre- MBG453 infusion3
MBG453 and IG


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Cycle
Day
Scheduled Time Point (h)2
Analytes1
5
8
Pre- MBG453 infusion3
MBG453 (and PDR001 if 
applicable)4 and IG
6
8
Pre-MBG453 infusion3
MBG453 (and PDR001 if 
applicable)4 and IG
EOT
Anytime
MBG453 (and PDR001 if 
applicable)4 and IG
Unscheduled
Anytime
PDR0014, MBG453, decitabine 
and IG
1IG samples are to be collected together with PK samples. PDR001 PK, MBG453 PK and anti-PDR001 and anti-
MBG453 antibodies
2Blood samples are to be collected from the arm opposite from the infusion site. 
3Pre-infusion: blood samples should be collected prior to the start of the current infusion. 
4if PDR001 is given to MBG453 in combination with decitabine
7.2.3.1
Bioanalytics
Bioanalysis for pharmacokinetic studies will employ 2 validated assays:

The assay to quantify MBG453 and PDR001 will be a validated LC-MS. The details of 
the assay will be documented in the [CMBG453X2101 Laboratory Manual].

The assay to quantify and assess the IG against MBG453 and PDR001 will be using a 
validated homogeneous ELISA. The details of the assay will be documented in the 
[CMBG453X2101 Laboratory Manual].

Quantification of decitabine will be determined with a validated liquid chromatography-
tandem mass spectrometry (LC-MS/MS) assay.  The details of the assay will be 
documented in the [CMBG453X2101 Laboratory Manual].

Bioanalysis for soluble TIM-3 will employ a validated ELISA. The details of the assay 
will be documented in the [CMBG453X2101 Laboratory Manual].

Bioanalysis for RO will employ a validated assay. The details of the assay will be 
documented in the [CMBG453X2101 Laboratory Manual].
7.2.3.2
PK, Soluble TIM-3, RO and IG samples handling, labeling, and 
shipping instructions
Blood samples should be collected from the arm opposite from the investigational drug(s)
infusion(s), or from another site. A total of 5 mL of blood will be collected at each time point. 
For time points when MBG453, decitabine and/or PDR001 (mAb) PK and IG are to be 
measured, a single blood sample will be collected for IG, soluble TIM-3, MBG453,decitabine
and /or PDR001 PK. After clotting and centrifugation, the resulting serum will be separated in 
aliquots and will be stored frozen until analysis. 
Samples for RO for MBG453 will be assessed using frozen PBMCs that will be generated from 
7 mL of whole blood (separate blood collection).
Please see the [CMBG453X2101 Laboratory Manual] for detailed instructions about collection, 
handling and shipment of samples.
The actual collection date and time of each sample will be entered on the 
Pharmacokinetics/Immunogenicity/Soluble TIM-3/Receptor Occupancy Blood Collection 
eCRF pages.










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The occurrence of adverse events should be sought by non-directive questioning of the patient 
during the screening process after signing informed consent and at each visit during the study. 
Adverse events also may be detected when they are volunteered by the patient during the 
screening process or between visits, or through physical examination, laboratory test, or other 
assessments. As far as possible, each adverse event should be evaluated to determine:

The severity grade (CTCAE Grade 1-4)

Its duration (Start and end dates)

Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)

Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1.
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC or as per RECIST), should not be reported as a serious adverse 
event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 AE (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent

Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition

Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event.
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST or 
irRC. Hospitalization due solely to the progression of underlying malignancy should NOT be 
reported as a serious adverse event.
Clinical symptoms of progression may be reported as adverse events if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does not fit 
the expected pattern of progression for the disease under study.
Symptomatic deterioration may occur in some patients. In this situation, progression is evident 
in the patient’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made 
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If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE.
8.2.2
Reporting
SAE collection will start upon signing the informed consent whether the patient is a screen 
failure or not. SAEs will only be reported if the event is suspected to be causally related to a 
study procedure as assessed by the investigator (e.g. an invasive procedure such as biopsy). 
SAEs will be followed until resolution or until clinically relevant improvement or stabilization.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 150 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence.
Any SAEs experienced after this 150 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 
occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English [For Japan: sites participating in FIH studies must complete the SAE report 
form in English], and submit the completed form within 24 hours Novartis. 
Detailed instructions regarding the submission process and requirements for signatures are to 
be found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. 
Each re-occurrence, complication, or progression of the original event should be reported as a 
follow-up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.
If the SAE is not previously documented in the [PDR001 Investigator’s Brochures] or 
[MBG453 Investigator’s Brochures] or Package Insert (new occurrence) and is thought to be 
related to the Novartis study treatment, a Chief Medical Office and Patient Safety department 
associate may urgently require further information from the investigator for Health Authority 
reporting. Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been reported. 
Suspected Unexpected Serious Adverse Reactions (SUSARs) will be collected and reported to 
the competent authorities and relevant ethics committees in accordance with Directive 
2001/20/EC or as per national regulatory requirements in participating countries.


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8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment or 
for the female partners of male participants in the study, must be reported to Novartis within 24 
hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. After 
the mother has provided consent, the newborn will be followed-up for 12  months.
Pregnancy outcomes should be collected for the female partners of any males who took study
treatment in this study and the newborn will be followed up to 12 months after delivery date. 
Consent to report information regarding these pregnancy outcomes should be obtained from the 
mother.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to 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 investigational treatment and any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.5
Data Monitoring Committee
A formal data monitoring board will not be used for this study. This is an open-label, 
Phase I-Ib/II study in which patients will receive MBG453 as single agent or in combination 
with PDR001. Novartis will have access to the Safety Data on a regular basis. Novartis will 
host investigator teleconferences on a regular basis during the study. Further, during the phase 
I part of the study Novartis and the investigators will meet at the end of each treatment cohort 
to discuss and evaluate all of the gathered safety data. At the dose escalation teleconference the 
clinical course (safety information including both DLTs and all CTCAE Grade 2 or higher 
toxicity data during the first cycle of treatment, and PK data) for each patient in the current dose 
cohort will be described in detail. Updated safety data on other ongoing patients, including data 
in later cycles, will be discussed as well.
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the BLRM with EWOC and a medical review of relevant clinical, PK and 
laboratory data. Novartis and the investigator parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or recruit an 
additional cohort of patients at the current dose level (Section 10.4.2). 


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During the phase II part of the study individual patient data will be reviewed on an ongoing 
basis and aggregate safety data and the primary endpoint will be monitored quarterly by the 
study team across the duration of the trial. The data review and analysis will be based on the 
available investigator reported data in the clinical database at that time (Section 10.7).
8.6
Steering Committee
A Steering Committee constituted of members of the Translational Clinical Oncology 
Leadership Team will be formed for this study. If the monitoring of the study data requires a 
decision to be taken on the continuation of the study, then the relevant data (e.g., safety data or 
primary analysis and predictive probability of success) will be communicated to the Steering 
Committee for decision making purposes.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed patient authorization informing the 
patient of the following:

What protected health information (PHI) will be collected from patients in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research patient to revoke their authorization for use of their PHI.
In the event that a patient revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of patient 
authorization. For patients 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 patient 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Patient Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Patient Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the patient satisfies protocol age requirements and 
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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. During the study, the field monitor will visit the site regularly to check the 
completeness of patient 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, administered, and accounted for according to specifications. 
Key study personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form 
(a signed copy is given to the patient).
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the eCRF entries. Novartis monitoring standards require full verification for 
the presence of informed consent, adherence to the inclusion/exclusion criteria and 
documentation of SAEs. Additional checks of the consistency of the source data with the eCRFs 
are performed according to the study-specific monitoring plan.
9.3
Data collection
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
allow modification or verification of the entered data by the investigator staff.
The Principal Investigator is responsible for assuring that the data entered into eCRF is complete, 
accurate, and that entry and updates are performed in a timely manner.
PK and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories, or local laboratories. ECG data collected during the 
study will be reviewed and processed centrally by a specialist CRO. During the course of the 
study, Novartis may decide to have a central review of the radiological assessments performed. 
In such case, the investigator’s staff will be instructed on how to send data from these 
radiological assessments to a Contract Research Organization (CRO) for central review when 
needed. Designated investigational site staff will enter the information required by the protocol 
into the appropriate eCRF and/or designated laboratory requisition forms. Field monitors will 
review the eCRFs and laboratory paper requisition forms for accuracy and completeness and 
instruct site personnel to make any required corrections or additions. One copy of the requisition 
form will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
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9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff is 
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).
For EDC studies, after database lock, the investigator will receive copies of the patient data for 
archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized using 
descriptive statistics (continuous data) and/or contingency table (categorical data) for 
demographic and screening/baseline characteristics, efficacy measurements, safety 
measurements and all relevant PK and PD measurements. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, median, minimum, 
and maximum will be presented.
The study data will be analyzed and reported based on all patients’ data of the dose escalation 
and Phase II parts up to the time when all patients have potentially completed at least six cycles 
of treatment or discontinued the study. Any additional data for patients continuing to receive 
study treatment past the data cutoff date for the primary Clinical Study Report (CSR), as 
allowed by the protocol, will be reported at completion of the study as defined in Section 4.3.
An interim CSR may also be prepared, if considered appropriate by the study team.
The following rules will be followed for reporting results unless stated otherwise:

For the phase I part, cohorts and patient groups treated with the same dose (dose levels 
and schedules) will be pooled into a single treatment group. Japanese patients and ROW 
patients will be separated into each of their respective single treatment group. All 
summaries, listings, figures and analyses will be performed by treatment group.

For the phase Ib part (including optional dose ranging part), cohorts and patient groups 
treated with the same dose or dose combination (dose levels and schedules) will be pooled 
into a single treatment group. All summaries, listings, figures and analyses will be
performed by treatment group. The additional phase Ib part referring to the SCLC patients
(run-in part) will be analyzed separately.

For the phase II part, all summaries, listings, figures for primary efficacy analysis and 
safety analyses will be presented by patient group. Patients from the phase II part will be 


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classified according to the patient group to which they were assigned at baseline based on 
the disease type. The additional phase II part referring to the SCLC patients (including the 
safety run-in part) will be analyzed separately.
Single agent phase I:

Up to two indications for which response has been observed in the phase I dose 
escalation may be explored
Combination phase II (MBG453 in combination with PDR001):

Group 1: Melanoma (naïve to anti-PD-1/PD-L1)

Group 2: Melanoma (pre-treated with anti-PD-1/PD-L1)

Group 3: NSCLC (naïve to anti-PD-1/PD-L1)

Group 4: NSCLC (pre-treated with anti-PD-1/PD-L1)

Group 5: RCC (naïve to anti-PD-1/PD-L1)

Group 6: RCC (pre-treated with anti-PD-1/PD-L1)
Note that for one of the combination phase II groups an exploration of Q2W versus Q4W 
dosing may be conducted. The group to be used for this comparison will be chosen based 
on feasibility. Data from the two dosing schedules will be summarized separately.
Note: patients from the Phase I-Ib dose escalation parts and the Phase II part will not be pooled 
in any analyses unless otherwise specified. In addition, Japanese patients will not be pooled 
with ROW patients in any analyses unless otherwise specified in the RAP.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.
Any reference to MBG453 in combination with decitabine is not applicable in this study as the 
enrolment of SCLC patients in this treatment will not open.
10.1
Analysis sets
10.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of assigned 
single agent MBG453, or at least one full or partial dose of assigned combination of study drugs. 
Patients will be analyzed according to the planned treatment. The FAS will be used for all 
listings of raw data. Unless otherwise specified, the FAS will be the default analysis set used 
for all analyses. 
10.1.2
Safety Set
The Safety Set includes all patients from the FAS who have received at least one dose of 
MBG453 or PDR001 or decitabine. Patients will be classified according to treatment received, 
where treatment received is defined as:

The treatment assigned if it was received at least once, or

The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.


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The safety set will be used for the safety summary of the study.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of FAS patients in the phase II part who meet 
the following criteria:

Presence of at least one measurable lesion according to RECIST v1.1 as per Appendix 1;

At least 2 post-baseline tumor assessments (unless disease progression is observed before 
that time);

For Group 1, 3 and 5, as well as for the group treated with MBG453 in combination with 
decitabine, patients have not been previously treated with PD-1 or PD-L1 directed 
therapy. For Group 2, 4 and 6 patients must have previously received a PD-1 or PD-L1 
directed therapy.
All major protocol deviations leading to exclusion from the PPS will be detailed in the RAP. 
Patients will be classified according to planned treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint Section 10.4. If the PPS and the FAS are 
identical, then analyses described by the PPS below will not be performed.
10.1.4
Dose-determining analysis set
Phase I part (MBG453 single agent) 
The DDS analysis consists of all patients from the safety set in the dose escalation part who 
either meet the minimum exposure criterion and have sufficient safety evaluations, or have 
experienced a DLT during Cycle 1. This constitutes an evaluable patient for the determination 
of MTD. 
A patient is considered to have met the minimum exposure criterion if having received all 
planned doses of MBG453 during Cycle 1. Patients who do not experience a DLT during the 
first cycle are considered to have sufficient safety evaluations if they have been observed for ≥ 
28 days following the first dose, and are considered by both Novartis and the Investigators to 
have enough safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be 
regarded as ineligible for the DDS and additional patients may be enrolled if required to meet 
the minimum cohort size for decision making, as described in Section 6.2.3.
Phase Ib part (MBG453 in combination with PDR001 or decitabine)
Cycle 1 risk set
The Cycle 1 risk set consists of all patients from the safety set in the dose escalation part who 
either meet the minimum exposure criterion for cycle 1 and have sufficient safety evaluations, 
or have experienced a DLT during Cycle 1. 
A patient is considered to have met the minimum exposure criterion for Cycle 1 if they have 
received all planned dose of MBG453 with PDR001 or decitabine during Cycle 1. 


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For the cycle 1 risk set, patients who do not experience a DLT during the first cycle are 
considered to have sufficient safety evaluations if they have been observed for ≥ 28 days 
following the first dose, and are considered by both Novartis and the Investigators to have 
enough safety data to conclude that a DLT did not occur.
Cycle 2 risk set (for MBG453 single agent and MBG453 in combination with PDR001)
The Cycle 2 risk set consists of all patients in the cycle 1 risk set who (a) did not experience a 
DLT in Cycle 1, and (b) satisfy the minimum exposure criterion for Cycle 2 and have sufficient 
safety evaluations, or have experienced a DLT during Cycle 2.
A patient is considered to have met the minimum exposure criterion for Cycle 2 if they have 
received at least one planned dose of both MBG453 and PDR001 (at the same level as 
administered in Cycle 1) during Cycle 2. 
For the Cycle 2 risk set, patients who do not experience a DLT during the second cycle are 
considered to have sufficient safety evaluations if they have been observed for ≥ 28 days 
following the first dose of Cycle 2, and are considered by both Novartis and the Investigators 
to have enough safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be 
excluded from the relevant risk set(s) and additional patients may be enrolled if required to meet 
the minimum cohort size for decision making, as described in Section 6.2.3.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable PK data. The PAS will be used for all PK analyses.
Note: Patients may be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples. These patients will be identified at 
the time of analysis.
10.2
Patient demographics/other baseline characteristics
Demographic and other screening/baseline data (including disease characteristics) will be listed 
in detail. 
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
For each of MBG453, PDR001 and decitabine, the actual dose and duration in days of treatment 
as well as the dose intensity (actual dose received/actual duration) and relative dose intensity 
(the ratio of dose intensity to planned dose/planned duration) will be listed and summarized by 
means of descriptive statistics by treatment group. Categories for relative dose intensity of 
MBG453, PDR001 or decitabine will be specified as < 0.5, ≥0.5 - < 0.75, ≥0.75 - < 0.9, ≥ 0.9 
- < 1.1 and ≥ 1.1. The number and proportion of patients within each category will be presented 
by treatment group.
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient and summarized by ATC term and treatment group. 


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The reason for discontinuation from treatment will be summarized and listed, along with dates 
of first and last doses of MBG453, PDR001 and decitabine (whatever is applicable), duration 
of exposure to MBG453, PDR001 and decitabine (whatever is applicable) and date of 
discontinuation for each patient.
Compliance with the protocol will be assessed by the number and proportion of patients with 
protocol deviations. Protocol deviations will be identified prior to database lock and will be 
listed and summarized.
10.4
Primary objective
Phase I-Ib parts
To characterize the safety and tolerability of MBG453 as a single agent and in combination 
with PDR001 or decitabine and to identify recommended doses for future studies.
Phase I-Ib dose ranging part (optional)
To further investigate the safety and tolerability of different doses of the MBG453 as single 
agent or in combination with PDR001. 
Phase II part
To assess the anti-tumor activity of MBG453 as single agent or in combination with PDR001
or decitabine.
10.4.1
Variable
Phase I-Ib parts

Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs

Tolerability: dose interruptions, reductions and dose intensity.
See Section 10.5.3 for details of analysis.
For MBG453 single agent, the primary variable is the incidence of DLTs in the first cycle of
treatment. 
For MBG453 in combination with PDR001, the primary variable is the incidence of DLTs in 
the first two cycles of treatment. 
For MBG453 in combination with decitabine, the primary variable is the incidence of DLTs in 
the first cycle of treatment
Estimation of the MTD(s)/RP2D(s) will be based upon the estimation by the BHLRM (phase I) 
or BLRM (phase Ib) of the probability of a DLT in the DLT window for patients in the 
applicable analysis set.
For the SCLC group of patients, the MTD/RP2D will be based upon the rule defined in 
Section 10.4.2.


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Phase I-Ib dose ranging part (optional)

Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs

Tolerability: dose interruptions, reductions and dose intensity.
See Section 10.5.3 for details of analysis.
Phase II part
The primary variable is the Overall Response Rate (ORR), defined as the proportion of patients 
with a best overall response of CR or PR based on local Investigator assessment, as defined in 
RECIST v1.1 (Appendix 1). 
Estimation of the true ORR in this part of the study will be based upon the observed ORR for 
patients in FAS, using a Bayesian analysis.
10.4.2
Statistical hypothesis, model, and method of analysis
Phase I part single agent MBG453 dose escalation
A Bayesian hierarchical logistical regression model (BHLRM) will be applied to estimate the 
relationship between dose and the probability of a patient experiencing a DLT for patients 
treated Q2W (stratum 1) and patients treated Q4W (stratum 2).
The standard Bayesian hierarchical model assumes full exchangeability of strata parameters; 
for the methodology and an application to binary data (Thall 2003, Chugh 2009). Here, we 
extend the standard Bayesian hierarchical model to dose-toxicity data, and exchangeable as well 
as non-exchangeable strata parameters. 
In order to facilitate the inclusion of prior data in the model, a third stratum is added to the 
model. This additional stratum incorporated dose/DLT data from the dose escalation of PDR001, 
another checkpoint inhibitor expected to have a similar dose/toxicity profile to MBG453. By 
incorporating the prior data in this way the exchangeability (or otherwise) of the prior data with 
the on-study data will be assessed in an ongoing fashion, and if necessary the model will be 
able to compensate for differences between the prior data and data seen in the dose escalation 
of MBG453. 
For the three patient strata, the probability of experiencing a DLT is modeled as follows:
logit	

 = log	 +
	 log( 240
⁄
)
logit	

 = log	 + 	 log( 240
⁄
)
logit

 = log() +  log( 240
⁄
)


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where  denotes dose; 240 is a fixed reference dose for each respective strata; 	

	

, and 


, are the probability of a patient experiencing a DLT at dose  on the Q2W and Q4W 
dosing schedules, and in the [CPDR001X2101] study respectively; and the parameters 	 =
(	), (	)
, 
	 = (	), (	)
, 
and 
 =
((), ()), describe the relationship between dose and toxicity for the three strata.
We further allow the parameters 	, 	, and , to be either exchangeable or non-
exchangeable, with probability  	, 1 − 	,
 	, 1 − 	, and ( , 1 −
 ) respectively.
1. Under exchangeability, the parameters 	, 	, and  are assumed to follow a 
bivariate normal distribution:
	, 	,  ~ $%&('()*+, S()*+)
Prior distributions for the parameters '()*+ and S()*+ of the exchangeability distribution 
complete the model specifications for the exchangeability component of the model: 
'()*+ ~ -., S()*+~ /0
The prior distributions for '()*+ will be normal and the prior distributions for the standard 
deviations and the correlation in S()*+ will be log-normal and uniform, respectively.
1. Under non-exchangeability, the parameters 	 and 	, and  are assumed to have 
a weakly informative bivariate normal prior distribution.
	, 	,  ~ $%&('1, S1)
All prior distributions will be defined before first patient first dose, and will be defined based 
on all available data at that time. The prior distributions will be fully described in the RAP.
Phase I part single agent MBG453 dose escalation with Japanese patients
Further, two BHLRM guided by EWOC principle will be used to make dose recommendations 
and estimate the MTD(s)/RP2D(s) during the dose escalation of the Japanese patients for both 
Q2W and Q4W schedules. Currently, available information about the dose-DLT relationships 
of single agent MBG453 in ROW patients will be used to inform the dose-DLT relationship of 
Japanese patients by taking into consideration of heterogeneity between Japanese patients 
(stratum 1) and ROW patients (stratum 2). For further details on the statistical model including 
the prior specification for the model parameters refer to Section 14.3 (Appendix 3). Data from 
the ROW patients will be updated in the model on an ongoing basis during the course of the 
study.
Phase Ib part combination of MBG453 and PDR001 dose escalation
For the combination phase Cycle 1 and Cycle 2, a 5-parameter model is used:
logit234,5

 = log234,5 + 234,5 log234,5
6.8
2406.8
⁄

logit,5

 = log,5 + ,5 log,5
6.8
2406.8
⁄



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where i = 1 and 2 for Cycle 1 and 2, respectively; logit(.

) = log[ .

/{1- .

 }]; 240 is the 
reference dose of both MBG453 and PDR001.
Under independence, the odds of a DLT during cycle i at a given combination is 
234,5

+ ,5

−234,5

,5

(1 −234,5

)(1 −,5

)
The possibility of synergism or antagonism between the safety profiles of the two drugs is then 
captured in modifying the odds by a dose-dependent factor:
9234:,5

=
234:,5
1 −234:,5
= ;< => 234,5
6.8
2406.8
?
,5
6.8
2406.8
?
@ 234,5

+ ,5

−234,5

,5

(1 −234,5

)(1 −,5

)
Here,

234,5 and ,5 are the odds of a DLT at the reference doses;

234,5 and ,5 are the increase in the log-odds of a DLT by a unit increase in the log of 
the square root of dose;

> is the interaction term. 
The model is fitted to data from those patients eligible for the Cycle 1 and Cycle 2 risk sets (see 
Section 10.1.4), and provides estimates of the cumulative risk of DLT (A234:) up to the 
end of cycle 2 given doses 234,5 and ,5 for i = 1,2. This cumulative risk is calculated as 
follows:
A234: = 234:,B + 1 −234:,B × 234:,
No combination that exceeds the EWOC criteria (Section 6.2.3.1) will be considered for the 
next combination doses. A dose will not be tested in the Cycle 2 before having being studied 
successfully in Cycle 1. Any dose in Cycle 2 is always equal to or lower than the dose used in 
Cycle 1.
Optional: additional dose escalation using Q4W dosing schedule during Phase 
Ib dose escalation part
Should the optional dose escalation for MBG453 in combination with PDR001 following a 
Q4W dosing schedule take place, then a new model will be constructed. This model will follow 
the same functional form as that described above. Data from the Q2W dose escalation will be 
used to construct an informative prior distribution, which will be derived prior to first patient 
first treatment on the new dosing schedule. The priors will be fully documented in the RAP.
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels (or combinations) are obtained. Dose recommendation will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories:


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
[0,16%) under-dosing

[16%,33%) targeted toxicity

[33%,100%] excessive toxicity
For the single agent MBG453 and combination of MBG453 and PDR001 dose recommendation 
will also be guided by the EWOC principle, which mandates the dose for the next cohort and 
the full 2 cycle period for the combination to have less than 25% chance of excessive toxicity. 
The final estimate of the MTD(s)/ RP2D(s) will also satisfy this condition.
Phase Ib part (run-in) combination of MBG453 and decitabine
A rule-based model is used for the group of the SCLC patients treated with MBG453 in 
combination with decitabine. Since the starting dose of the specific combination is anticipated 
to be well tolerated, the assessment of DLT data will be made after all six patients evaluable for 
the dose determining analysis set (Section 10.1.4) have completed one cycle of treatment, unless 
they have experienced a DLT before. The safety of the combination will be evaluated based on 
all available data at the confirmation decision with the Investigators and Novartis. If there are 
2 or more DLTs within those 6 patients, 6 additional patients will be accrued to the -1 dose level 
(Table 6-4). In case there are 2 or more DLTs within the 6 evaluable for the dose determining 
analysis set patients in the -1 dose level, then this combination will stop due to excessive toxicity.
The dose level in which the two predefined rules are satisfied (less than 2 patients experiencing 
DLTs among the 6 patients evaluable for the dose determining analysis set) will be considered 
the final estimate of the MTD and will be used as the recommended dose for the phase II part 
of the study for the group of SCLC patients.
Listing of DLTs
DLTs will be listed and their incidence may be summarized by primary system organ class, 
worst grade based on the CTCAE version 4.03 and type of AE. The DDS will be used for these 
summaries. 
Phase II part
A Bayesian design will be used in order to estimate ORR for each of the following patient 
groups. The primary analysis will be on ORR as defined under RECIST 1.1, with a secondary 
analysis on ORR as defined under irRC.
MBG453 single agent

Up to two indications for which response has been observed in the phase I dose escalation
MBG453 in combination with PDR001

Group 1: Melanoma (naïve to anti-PD-1/PD-L1)

Group 2: Melanoma (pre-treated with anti-PD-1/PD-L1)

Group 3: NSCLC (naïve to anti-PD-1/PD-L1)

Group 4: NSCLC (pre-treated with anti-PD-1/PD-L1)


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
Group 5: RCC (naïve to anti-PD-1/PD-L1)

Group 6: RCC (pre-treated with anti-PD-1/PD-L1)
Note that for one of the combination phase II groups an exploration of Q2W versus Q4W dosing 
may be conducted. Data from the two dosing schedules will be summarized separately.
MBG453 in combination with decitabine

SCLC (naïve to anti-PD-1/PD-L1 therapy)
Initially, approximately 15 patients will be enrolled to each of the above defined patient groups. 
Should enrollment for any of these groups not be feasible, then enrollment to that group may 
be closed before the 15 patient target is met. Should 3 or more responses be observed in any 
patient group, then enrollment to that group may be extended to 25 patients.
For the SCLC group of patients treated with MBG453 in combination with decitabine a total of 
approximately 15 patients will be enrolled at the MTD/RP2D (including the 6 patients treated 
at the same dose level in the Phase Ib part of the study).
For all patient groups, a minimally informative unimodal beta prior distribution of the true ORR 
is derived as follows. A priori it is assumed that the true mean of the ORR equals 20%. A true 
ORR of 20% is the midpoint between limited and moderate efficacy and serves as a compromise 
between a skeptical view assuming the treatment has only limited efficacy and an optimistic 
view assuming the treatment has moderate efficacy. The parameter of the minimally 
informative beta prior distribution of the ORR are then derived as a = 1/4 and b = 1.
At completion of the study, this prior distribution will be updated with all of the data available. 
Once updated, the estimate of ORR and probabilities that the true ORR lies in the following 
categories will be reported:

[0, 10%) unacceptable efficacy

[10%, 20%) limited efficacy

[20%, 50%) moderate efficacy

[50%, 100%] clinically relevant efficacy
For patient groups with a minimum of 15 patients, if the observed ORR is equal to or greater 
than 20%, then this will be considered as preliminary evidence of at least moderate efficacy in 
the respective patient group. 
For n = 15, if the observed ORR is less than 10% (i.e. 1 CR or PR), then unacceptable efficacy 
will be concluded. If the observed ORR is greater than or equal to 20% (i.e. ≥ 3 CR or PR), then 
the true ORR has a posterior probability of 85.4% of at least limited efficacy.
For n = 25, if the observed ORR is less than 10% (i.e. < 3 CR or PR), then unacceptable efficacy 
will be concluded. If the observed ORR is greater than or equal to 20% (i.e. ≥ 5 CR or PR), then 
the true ORR has a posterior probability of 92.1% of at least limited efficacy.
See Table 10-3 for operating characteristics of the design.


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10.4.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the
primary analysis, although their data will be used for all remaining analyses.
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST v1.1 (Appendix 1).
Other missing data will simply be noted as missing on appropriate tables/listings.
10.4.4
Supportive analyses
For the phase II part, the primary analysis on ORR may be repeated using the PPS. Additional 
supportive or exploratory analyses will be conducted to support the primary objective, if 
appropriate, and the details of these analyses will be defined in the RAP.
10.5
Secondary objectives
Please refer to Table 3-1 for the secondary objectives. The following subsections describe the 
analyses of related secondary objectives.
10.5.1
Key secondary objective(s)
Not applicable.
10.5.2
Other secondary efficacy objectives
Phase I-Ib parts
To assess the preliminary anti-tumor activity of MBG453 single agent or in combination with 
PDR001 or decitabine. The evaluations of tumor responses will be based on local investigator 
assessment according to RECIST v1.1 and irRC.
For all efficacy analysis in phase I-Ib parts, data will be listed, and may be summarized or 
analyzed by treatment group where applicable. 
Phase II part
To assess the anti-tumor activity of MBG453 single agent or in combination with PDR001 or 
decitabine. The evaluations of tumor responses will be based on local investigator assessment 
according to RECIST v1.1 and irRC.
For all efficacy analysis in phase II part, data will be listed, summarized or analyzed by patient 
group (as defined in Section 10.4.2) for patients treated at the MTD(s)/RP2D(s).
The following endpoints and analyses will be used to assess the efficacy for phase I-Ib and 
phase II parts:

BOR is defined as the best response recorded from the start of the treatment until disease 
progression/recurrence as defined for RECIST v1.1 and irRC. Complete and partial 
responses must be confirmed by repeat assessments that should be performed not less than 


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4 weeks after the criteria for response are first met. Additionally, for irRC, progressive 
disease should be confirmed in a similar manner. 

ORR, defined as the proportion of patients with best overall response of CR or PR.

PFS:

For RECIST v1.1, PFS is defined as the time from the date of start of treatment to the 
date of the first documented progression or death due to any cause. 

For irRC PFS is defined as the time from the date of start of treatment to the date of the 
first documented and confirmed progression, or death due to any cause. Progressive 
disease should be confirmed by a repeat assessment that should be performed not less 
than 4 weeks after the criteria for progression are first met. The date of progression will 
then be the date of the first of these two assessments. For patients without a 
confirmation assessment, and with no subsequent assessments of SD, or better, a single 
assessment will be used as date of progression. If a patient has not had an event, PFS 
will be censored at the date of the last adequate tumor evaluation. 

OS, defined as the time from date of start of treatment to date of death due to any cause. If a 
patient is not known to have died, survival will be censored at the date of last known date
patient alive.

DOR, defined for responder as the time between the date of first documented response (CR 
or PR) and the date of first documented progression or death due to underlying cancer. If 
progression or death due to underlying cancer has not occurred, then the patient is censored 
at the date of last adequate tumor assessment.
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. Best overall response (BOR) will be listed and tabulated. 
The primary analysis of ORR will be as described in Section 10.4.2. Additionally ORR will be 
summarized as point estimate and corresponding 90% exact confidence interval (CI) according 
to Clopper-Pearson method (Clopper and Pearson 1934).
BOR will be summarized as observed proportion in each category, and corresponding 90% 
exact CI.
PFS will be analyzed using Kaplan-Meier estimates (Kaplan and Meier 1958) (including 
graphical representation) with CIs of median survival for each treatment group/patient group. 
In addition, median PFS and related 95% CI will be presented for each treatment group/patient 
group. 
OS data will be listed for all patients enrolled in the Phase I-Ib and Phase II parts. Descriptive 
statistics for OS endpoint (e.g., median OS and 90% CI of the Kaplan-Meier estimates) will be 
provided as appropriate by treatment group and furthermore by disease group (melanoma, 
NSCLC and RCC) for patients treated at the MTD(s)/RP2D(s).
DOR and time to response (TTR) will be listed for all patients who achieved a response of CR 
or PR. If there are a large number of patients achieving response, the Kaplan-Meier plots for 
DOR will also be produced and the median DOR will be estimated.
Any additional analyses of efficacy endpoints will be described in the RAP.


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10.5.3
Safety objectives
Another secondary objective is to characterize the safety and tolerability of MBG453 single 
agent and in combination with PDR001 or decitabine.
Incidence and severity of AEs and SAEs, changes in laboratory values, electrocardiograms and 
vital signs will be used to assess the safety of MBG453 single agent and combination with 
PDR001 or decitabine. 
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.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication
3. post-treatment period: starting at day 31 after last dose of study medication.
10.5.3.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and treatment group.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s). SEC will be specified in a case 
retrieval sheet (CRS) or in the RAP and finalized prior to database lock. 
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.
10.5.3.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.


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The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

Frequency table for newly occurring on-treatment grades 3 or 4 (see below for details).

Shift tables using CTCAE grades to compare baseline to the worst on-treatment value.

Listing of all clinically relevant laboratory data with values flagged to show the 
corresponding CTCAE grades and the classifications relative to the laboratory normal 
ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP.
10.5.3.4 Other safety data
ECG

Shift table baseline to worst on-treatment result for overall assessments.

Listing of ECG evaluations for all patients with at least one abnormality.
Vital signs
Definitions of notably abnormal results will be specified in the RAP.

Shift table baseline to worst on-treatment result.
10.5.3.5 Supportive analyses for secondary objectives
Not applicable.
10.5.3.6 Tolerability
The tolerability of the study treatment will be assessed by summarizing the number of dose 
interruptions or changes. The reason for dose interruption and dose reduction and dose change 
will be listed by patient and summarized. 
10.5.4
Pharmacokinetics
The pharmacokinetic parameters that will be assessed are presented in Table 10-1.
Table 10-1
Noncompartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x 
volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives






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10.7
Interim analysis
No formal interim analyses are planned. 
Phase I-Ib dose escalation part
The dose-escalation design foresees that decisions based on the current data are taken before 
the end of the study. More precisely, after each cohort in the dose escalation part, the next dose 
of MBG453 as single agent or in combination with PDR001 has to be chosen depending on the 
observed data. Similar procedure will be followed after each dose level tested in the run-in part 
of the SCLC patients treated with MBG453 in combination with decitabine Details of this 
procedure and the process for communication with Investigators are provided in Section 6.2.3.
Phase II part
Data from patients will be reviewed on an ongoing basis to monitor the safety and tolerability 
of the RP2D part of the study. The sample size in any of the 6 groups may be extended to 
approximately 25 patients, if at least 3 patients have a response (PR or CR) per RECIST v1.1 
or irRC (this is not applicable to the SCLC group of patient treated with MBG453 in 
combination with decitabine). The Investigators and Novartis study personnel will make the 
decision based on a synthesis of all relevant data available including safety, PK and PD 
information. 
10.8
Sample size calculation
Any reference to MBG453 in combination with decitabine is not applicable in this study as the 
enrolment of SCLC patients in this treatment will not open.
Phase I-Ib dose escalation parts
ROW patients: Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part 
including at least six patients at the MTD(s)/RP2D(s) level, as described in Section 6.2.3. 
Multiple cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 
to 6 patients may be enrolled at any dose level below the estimated MTD(s)/RP2D(s) for further 
elaboration of safety and pharmacokinetic parameters as required. At least 21 patients are 
expected to be treated in the single agent and 15 patients are expected to be treated in the 


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combination of in the dose escalation part, for the model to have reasonable operating 
characteristics relating to its MTD recommendation.
Japanese patients: Initially, cohorts of 1 to 6 evaluable patients will be enrolled in the single 
agent dose-escalation part with Japanese patients. Upon observation of specific toxicities 
(see Section 6.2.3 for details), minimum cohorts size of 3 evaluable patients will be enrolled 
including at least 6 patients at the MTD/RP2D level, as described in Section 6.2.3. Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients 
may be enrolled at any dose level below the estimated MTD/RP2D for further elaboration of 
safety and pharmacokinetic parameters as required. At least 12 patients are expected to be 
treated in the single agent dose-escalation part with Japanese patients, for the model to have 
reasonable operating characteristics relating to its MTD recommendation. 
Phase Ib run-in part for the SCLC patients
A cohort of 6 evaluable patients for the Dose Determining analysis Set (or twelve in total if the 
suggested dose level is considered toxic) will be enrolled in the run-in part including thus at 
least six patients at the MTD/RP2D level, as described in Section 6.2.3.
Phase I-Ib dose ranging part (optional)
A sample size of approximately 30-50 patients with advanced solid tumors will be treated at 
different dose levels of MBG453 as single agent or in combination with PDR001. The aim is to 
gain more information about the overall safety and tolerability, and to provide additional PK 
and PD data to guide the selection of dosing for future studies with the combination and identify 
anti-tumor activity. A minimum of 30 patients will result in 95.8% probability of detecting at 
least one special adverse event of interest with a true rate of 10%. This probability rises as the 
true adverse event rate increases. 
There is no statistical hypothesis being tested for efficacy within this group. Patients within this 
group will have their activity monitored to assess if there is any indication of potential impact 
on tumor lesions, and the data will be used for internal decision making on the future 
development of the combination in alternative indications and dose levels. 
Table 10-2
Probability to detect at least one special adverse event of interest
Special AE of interest 
incidence rate
Number of patients
10
20
30
50
10%
0.651
0.878
0.958
0.995
15%
0.803
0.961
0.992
1.000
20%
0.893
0.988
0.999
1.000
Phase II part
Approximately 15 patients will be initially enrolled to each of the patient groups. However, 
should enrollment for any of these groups not be feasible, then enrollment to that group may be 
closed before the 15 patient target is met. Any of the groups may be extended to approximately 
25 patients in the event that 3 or more responses are observed. This extension is not applicable 


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to the SCLC group of patient treated with MBG453 in combination with decitabine.The 
operating characteristics of the design is shown in Table 10-3, including the probability of 
stopping the enrollment at 15 patients (fewer than 3 responses in the first 15 patients) and 
posterior probability of true ORR of at least limited efficacy. It was assessed how likely it is to 
wrongly declare activity as defined by observing at least “moderate efficacy” (i.e. seeing ≥ 5 
responses out of 25 patients) given the true ORR = 10%, and how likely it is to correctly declare 
activity given the true ORR = 30% when 25 patients are evaluated.

If the true ORR = 10%, the probability to wrongly declare activity is 9.8%.

If the true ORR = 30%, the probability to correctly declare activity is 91.0%.
Table 10-3
Operating characteristics of the design for ORR
Pr(observe < 20% responses in N patients)
N / True ORR
0.1
0.15
0.2
0.25
0.3
0.4
10
73.6
54.4
37.6
24.4
14.9
4.6
15
81.6
60.4
39.8
23.6
12.7
2.7
20
86.7
64.8
41.1
22.5
10.7
1.6
25
90.2
68.2
42.1
21.4
9.0
0.9
Posterior probability of a true ORR corresponding to at least limited efficacy (i.e. ≥10%)
N / True ORR
0.1
0.15
0.2
0.25
0.3
0.4
10
44.7
64.5
79.5
89.3
94.9
99.1
15
45.5
69.2
85.4
94.1
98.0
99.8
20
46.0
72.8
89.4
96.7
99.2
100
25
46.4
75.8
92.1
98.1
99.6
100
Testing of Q2W versus Q4W dosing scheduling during the Phase II
combination part of MBG453 in combination with PDR001
To facilitate comparison between Q2W and Q4W dosing in the chosen indication, patients will 
be randomized between the two dosing schedules. Initially 15 patients will be enrolled to each 
arm, should 3 or more responses be observed in either arm, then enrollment for both arms will 
be extended to 25 patients. 
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.


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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, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent or, if incapable of 
doing so, after such consent has been provided by a legally acceptable representative of the 
patient. In cases where the patient’s representative gives consent, the patient should be informed 
about the study to the extent possible given his/her understanding. If the patient is capable of 
doing so, he/she should indicate assent by personally signing and dating the written informed 
consent document or a separate assent form.
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a patient’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.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
Additional consent form
Sub-studies 
 will have a separate 
consent form covering those studies. This form will be adapted for each Study based on a 
standard template used globally for all Studies. These informed consent forms will be submitted 
for ethical approval together with the Study Protocol and the main informed consent form of 
the Study. If a patient opts not to participate in the optional assessments, this in no way affects 
the patient’s ability to participate in the main research study.


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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 assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results.
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 patients. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of Novartis 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, patients’ 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 patient 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 electronic study case report form (eCRF) 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 eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the 
source documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. Any change or correction to a paper 
eCRF should be dated, initialed, and explained (if necessary) and should not obscure the original 
entry. For electronic eCRFs an audit trail will be maintained by the system. The investigator 
should retain records of the changes and corrections to paper eCRFs.
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.


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


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 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 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.


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14.1.2.1 Definitions
14.1.2.1.1
Disease measurability
In order to evaluate tumors throughout a study, definitions of measurability are required in order 
to classify lesions appropriately at baseline. In defining measurability, a distinction also needs 
to be made between nodal lesions (pathological lymph nodes) and non-nodal lesions.

Measurable disease - the presence of at least one measurable nodal or non-nodal lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology.
For patients without measurable disease see Section 14.1.3.2.8
Measurable lesions (both nodal and non-nodal)

Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non-nodal 
target lesion at baseline should be no less than double the slice thickness or 10mm 
whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI with 5mm cuts 
will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 mm.

Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue components, 
that can be evaluated by CT/MRI, can be considered as measurable lesions, if the soft 
tissue component meets the definition of measurability.

Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes 15 mm in short axis can be 
considered for selection as target lesions. Lymph nodes measuring 10 mm and <15 mm 
are considered non-measurable. Lymph nodes smaller than 10 mm in short axis at 
baseline, regardless of the slice thickness, are normal and not considered indicative of 
disease.

Cystic lesions: 

Lesions that meet the criteria for radiographically defined simple cysts (i.e., spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
definition, simple cysts.

‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions.

Non-measurable lesions - all other lesions are considered non-measurable, including small 
lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph nodes with 
10 to < 15 mm short axis), as well as truly non-measurable lesions e.g., blastic bone 
lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, inflammatory breast 
disease, lymphangitis cutis/pulmonis, abdominal masses/abdominal organomegaly
identified by physical exam that is not measurable by reproducible imaging techniques.


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14.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.1.3.2.8.
14.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to 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 patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.


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
If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression occurring at 
that Site (if so, the date of PD will be the date of the initial abnormal CT scan).

If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on CT 
that is not progressing on the basis of the anatomic images, this is not PD.

Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they are 
clearly defined and surrounded by aerated lung. However, CT is preferable.

Ultrasound: When the primary endpoint of the study is objective response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a possible 
alternative to clinical measurements of superficial palpable lymph nodes, subcutaneous 
lesions and thyroid nodules. US might also be useful to confirm the complete 
disappearance of superficial lesions usually assessed by clinical examination.

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 tumor 
samples are obtained.

Tumor markers: Tumor markers alone cannot be used to assess response. However, some 
disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, PSA 
for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be integrated 
as non-target disease. If markers are initially above the upper normal limit they must 
normalize for a patient to be considered in complete clinical response when all lesions 
have disappeared.

Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.


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14.1.2.3 Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest 
diameter) and their suitability for accurate repeated measurements (either by imaging 
techniques or clinically). Each target lesion must be uniquely and sequentially numbered
on the eCRF (even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least
10 mm in longest diameter. See Section 14.1.2.1.1.

Nodal target: See Section 14.1.2.1.1.
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.
14.1.2.4 Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first separately 
for the target (Table 14-1) and non-target lesions (Table 14-2) identified at baseline. 
These evaluations are then used to calculate the overall lesion response considering both the target 
and non-target lesions together (Table 14-3) as well as the presence or absence of new lesions.
14.1.2.4.1
Follow-up and recording of lesions
At each visit and for each lesion the actual date of the scan or procedure which was used for the 
evaluation of each specific lesion should be recorded. This applies to target and non-target
lesions as well as new lesions that are detected. At the assessment visit all of the separate lesion 
evaluation data are examined by the investigator in order to derive the overall visit response. 
Therefore all such data applicable to a particular visit should be associated with the same 
assessment number.


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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.
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.


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14.1.2.4.2
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response 
(CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes 
assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters.
Progressive Disease 
(PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
1 SOD for CR may not be zero when nodal lesions are part of target lesions
2 Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3 Methodology change See Section 14.1.2.2.
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 three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This applies 
to patients who have not achieved target response of CR. For patients who have achieved 
CR, please refer to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.


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Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

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. 


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14.1.2.4.3
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-
target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have not 
been assessed or have been assessed using a different method than baseline.
1 Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF.

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 
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
If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5).

A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to 10 mm for the first time in the study plus 5 
mm absolute increase.
FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). See Section 14.1.2.2.
14.1.2.5 Evaluation of overall lesion response
The evaluation of overall lesion response at each assessment is a composite of the target lesion 
response, non-target lesion response and presence of new lesions as shown below in 
Table 14-3.
Table 14-3
Overall lesion response at each assessment
Target lesions
Non-target lesions
New Lesions
Overall
lesion response
CR
CR
No
CR1
CR
Non-CR/Non-PD3
No
PR
CR, PR, SD
UNK
No
UNK
PR
Non-PD and not UNK
No
PR1
SD
Non-PD and not UNK
No
SD1, 2
UNK
Non-PD or UNK
No
UNK1
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
1 This overall lesion response also applies when there are no non-target lesions identified at baseline.
2 Once confirmed PR was achieved, all these assessments are considered PR.
3 As defined in Section 14.1.2.4.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.3
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.3.2.8 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.


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14.1.3.1 Best overall response
The best overall response is the best response recorded from the start of the treatment until 
disease progression/recurrence (taking as reference for PD the smallest measurements recorded 
since the treatment started). In general, the patient's best response assignment will depend on 
the achievement of both measurement and confirmation criteria.
The best overall response will usually be determined from response assessments undertaken 
while on treatment. However, if any assessments occur after treatment withdrawal the protocol 
should specifically describe if these will be included in the determination of best overall 
response and/or whether these additional assessments will be required for sensitivity or 
supportive analyses. As a default, any assessments taken more than 30 days after the last dose 
of study treatment will not be included in the best overall response derivation. If any alternative 
cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

For non-randomized trials where response is the primary endpoint, confirmation is needed.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)


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Overall lesion responses of CR must stay the same until progression sets in, with the exception 
of a UNK status. A patient who had a CR cannot subsequently have a lower status other than a 
PD, e.g. PR or SD, as this would imply a progression based on one or more lesions reappearing, 
in which case the status would become a PD.
Once an overall lesion response of PR is observed (which may have to be a confirmed PR 
depending on the study) this assignment must stay the same or improve over time until 
progression sets in, with the exception of an UNK status. However, in studies where 
confirmation of response is required, if a patient has a single PR (30% reduction of tumor 
burden compared to baseline) at one assessment, followed by a <30% reduction from baseline 
at the next assessment (but not 20% increase from previous smallest sum), the objective status 
at that assessment should be SD. Once a confirmed PR was seen, the overall lesion response 
should be considered PR (or UNK) until progression is documented or the lesions totally 
disappear in which case a CR assignment is applicable. In studies where confirmation of 
response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

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 patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD.


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Another approach is to summarize the progression rate at a certain time point after baseline. In 
this case, the following definition is used:
Early progression rate (EPR) is the proportion of patients with progressive disease within 
8 weeks of the start of treatment.
The protocol should define populations for which these will be calculated. The timepoint for 
EPR is study specific. EPR is used for the multinomial designs of Dent and Zee (2001) and 
counts all patients who at the specified assessment (in this example the assessment would be at 
8 weeks ± window) do not have an overall lesion response of SD, PR or CR. Patients with an 
unknown (UNK) assessment at that time point and no PD before, will not be counted as early 
progressors in the analysis but may be included in the denominator of the EPR rate, depending 
on the analysis population used. Similarly when examining overall response and disease control, 
patients with a best overall response assessment of unknown (UNK) will not be regarded as 
“responders” but may be included in the denominator for ORR and DCR calculation depending 
on the analysis population (e.g. populations based on an ITT approach).
14.1.3.2 Time to event variables
14.1.3.2.1
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.3.2.2
Overall survival
All patients should be followed until death or until patient has had adequate follow-up time as 
specified in the protocol whichever comes first. The follow-up data should contain the date the 
patient was last seen alive / last known date patient alive, the date of death and the reason of 
death (“Study indication” or “Other”).
Overall survival (OS) is defined as the time from date of randomization/start of treatment to 
date of death due to any cause. If a patient is not known to have died, survival will be censored 
at the date of last known date patient alive.


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14.1.3.2.3
Time to progression
Some studies might consider only death related to underlying cancer as an event which indicates 
progression. In this case the variable “Time to progression” might be used. TTP is defined as 
PFS except for death unrelated to underlying cancer.
Time to progression (TTP) is the time from date of randomization/start of treatment to the 
date of event defined as the first documented progression or death due to underlying cancer. If a 
patient has not had an event, time to progression is censored at the date of last adequate tumor 
assessment.
14.1.3.2.4
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 discontinuation due 
to reasons other than ‘Protocol violation’ or ‘Administrative problems’. The time to treatment 
failure for patients who did not experience treatment failure will be censored at last adequate 
tumor assessment.
14.1.3.2.5
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 patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by
Morgan (1988).
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis, et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.


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For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.1.3.2.6
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.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.


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14.1.3.2.7
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.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8).
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of discontinuation is the date of the end of treatment visit.

Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date.


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
Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery.
14.1.3.2.8
Handling of patients with non-measurable disease only at baseline
It is possible that patients with only non-measurable disease present at baseline are entered into 
the study, either because of a protocol violation or by design (e.g. in Phase III studies with PFS 
as the primary endpoint). In such cases the handling of the response data requires special 
consideration with respect to inclusion in any analysis of endpoints based on the overall 
response evaluations.
It is recommended that any patients with only non-measurable disease at baseline should be 
included in the main (ITT) analysis of each of these endpoints.
Although the text of the definitions described in the previous sections primarily relates to 
patients with measurable disease at baseline, patients without measurable disease should also 
be incorporated in an appropriate manner. The overall response for patients with measurable 
disease is derived slightly differently according to Table 14-4.
Table 14-4
Overall lesion response at each assessment: patients with non-target 
disease only
Non-target lesions
New Lesions
Overall lesion response
CR
No
CR
Non-CR/Non-PD1
No
Non-CR/non-PD
UNK
No
UNK
PD
Yes or No
PD
Any
Yes
PD
1 As defined in Section 14.1.2.4.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.


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14.1.3.2.9
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 patient being lost to follow-up? It is important that the protocol and RAP specify the 
primary analysis in detail with respect to the definition of event and censoring dates and also 
include a description of one or more sensitivity analyses to be performed.
Based on definitions outlined in Section 14.1.3.2.7, 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 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one 
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more 
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than deterioration 
of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1=Definitions can be found in Section 14.1.3.2.7.
2=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in 
Section 14.1.3.2.7.
3=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F.


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Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.4
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).


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14.1.4.1 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).
14.1.4.2 End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 14 days of the last 
study treatment. 
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Patient/guardian decision

Death

Progressive disease per irRC (not per RECIST)

Study terminated by Novartis
14.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Patient/guardian decision

Death

New therapy for study indication


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
Progressive disease

Study terminated by Novartis
14.1.4.4 Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the investigator or central reader’s response 
assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.4.5 Programming rules
The following should be used for programming of efficacy results:
14.1.4.5.1
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.
14.1.4.5.2
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 14.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.


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If the month is not completed, for any of the investigations, the respective assessment will be 
considered to be at the date which is exactly between previous and following assessment. If a 
previous and following assessment is not available, this assessment will not be used for any 
calculation.
14.1.4.5.3
Incomplete dates for last known date patient alive or death
All dates must be completed with day, month and year. If the day is missing, the 15th of the 
month will be used for incomplete death dates or dates of last contact.
14.1.4.5.4
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)’.
14.1.4.5.5
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.
14.1.4.5.6
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 (option

Death due al, see Table 14-5) to reason other than underlying cancer (only used for TTP 
and duration of response)

Initiation of new anti-cancer therapy 


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*Adequate assessment is defined in Section 14.1.3.2.7. 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=“Novartis decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.1.5
References (available upon request)
Dent S, et al (2001) application of a new multinomial phase II stopping rule using response
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer; Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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14.2
Appendix 2: Guidelines for immune-related Response Criteria 
(irRC) using one-dimensional measurements (simulating RECIST 
1.1)
14.2.1
Introduction
The currently used immune-related response criteria (irRC) uses unidimensional measurements 
to assess tumor response and it is an adaptation of the original irRC published by Wolchok 
(Wolchok et al 2009, Nishino 2013).
The purpose of this document is to summarize the irRC guidelines in details focusing on 
differences in tumor response assessments between irRC and RECIST v1.1. 
The primary difference between irRC and RECIST 1.1 is the definition of progressive disease. 
The definitions of baseline target/non target lesions, number of lesions selected at baseline, the 
criteria for lesion measurement method of evaluation of response and definition of response are 
the same for irRC and RECIST 1.1 and are available in the RECIST 1.1 guidelines 
(Appendix 1). 
14.2.2
New lesions and non-target lesions
In irRC a new lesion does not automatically indicate progressive disease. 
New measurable lesions are added to the sum of diameters of the previously existing target 
lesions, and the sum of diameters is followed at each subsequent tumor assessment.
New measureable lesions are defined using the same criteria as for baseline target lesions in 
RECIST v1.1. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions up to 10 lesions in total.
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 
at baseline and any new non-measurable lesions that have appeared during the study). If after 
worsening a non-target lesion becomes measurable, it should still be followed as a non-target 
lesion. Worsening of non-target lesions and new non-measurable lesions only indicate disease 
progression 
if 
there 
is 
unequivocal 
evidence 
of 
disease 
progression 
(Table 14-6). 
14.2.3
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of  diameters for all target lesions is calculated (at baseline 
and throughout the study). The diameters of any new measurable lesions are included in the 
sum of diameters at each assessment to provide the total tumor burden. At each assessment, 
percent change in the sum of  diameters is calculated and compared to baseline or to nadir in 
order to evaluate the target lesion response (including new measurable lesions) 
(Section 14.2.4). This evaluation combined with the status of non-target lesions (baseline and 
new non-measurable lesions) is then used to determinate the overall lesion response 
(Table 14-6). The thresholds for irPR and irPD assessment are the same as for RECIST v1.1.


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


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If the evaluation of any non-target lesions is not made, and all target lesions disappeared, irCR 
cannot be determined and overall response must be “irPR”.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the irCR.
14.2.5
References (available upon request)
Wolchok JD, Hoos A, O'Day S, et al (2009) Guidelines for the Evaluation of Immune 
Therapy Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res; 
15:7412-20.
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013) Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-Related Response Criteria Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-43.


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14.3
Appendix 3: Statistical details of Bayesian regression models, 
priors, design operating characteristics and hypothetical dose 
escalation scenarios
14.3.1
Phase I part MBG453 single agent
A Bayesian hierarchical logistic regression model (BHLRM) guided by the escalation with 
overdose control (EWOC) principle will be used in the MBG453 single agent phase I part to 
establish the maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D) of 
MBG453 in patients with solid tumors. This section provides details of the statistical model, 
the derivation of prior distributions for the model parameters, and the properties of the adaptive 
design (dose recommendations for hypothetical data scenarios).
14.3.1.1 Statistical model and prior distributions
Section 10.4.2 outlined the model description for the BHLRM, here the derivation of the priors 
for that model is described as follows:

Prior distributions for the exchangeability and non-exchangeability model components are 
derived.

For each stratum (Q2W, Q4W, PDR001), the weight of the exchangeable and non-
exchangeable mixture components are defined.

Prior summaries for DLT rates at different dose levels are shown.
Prior for the non-exchangeable case
Under non-exchangeability, the parameter vectors 	, 	, and  are assumed to have 
a weakly informative bivariate normal prior distribution,
	, 	,  ~ $%&(D1, E1)
where D1 = ('1B, '1) and E1 = =
F1B

GF1BF1
GF1BF1
F1

@ are the mean vector and 
covariance matrix. 
For the purposes of setting the prior for the BLRM model, the median DLT rate at 80 mg Q2W 
is assumed to be at 5%, and the median DLT rate at 800 mg Q2W is assumed to be 10%. For 
the remaining doses, median DLT rates a priori are assumed linear in the logit-scale as a 
function of log-dose.
Based on the above specified medians for the DLT rate and wide prior confidence intervals, the 
optimal parameters of the bivariate normal distribution can be obtained following the procedure 
described by Neuenschwander 2008. This leads to the BVN distribution defined by D1 = (-
2.692, -1.26), F1B = 2.484, F1 = 0.745 and G = −0.765.
To provide a simple, flexible prior, the same mean is retained, but the correlation is set to zero, 
and the standard deviations for log() and log() approximated by 2 and 1, respectively, the 
prior 
for 
the 
non-exchangeable 
case 
is 
set 
to
D1 =
(-2.692, 
-1.26), 
E1 = O2
0
0
1P.


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Prior for the exchangeable case
Under exchangeability, the parameters 	, 	, and  are assumed to follow a bivariate 
normal distribution:
	, 	,  ~ $%&(Q()*+, E()*+),
where Q()*+ = (R(B, R() and E()*+ = =
F(B

SF(BF(
SF(BF(
F(

@ are the mean vector and 
covariance matrix.
Prior specifications are as follows: 
1. R(B and R( are given prior normal distributions. Assume that prior means of R(B and R(  
are the same as prior means for non-exchangeable case, '1B and '1, respectively.
2. F(B and F( are given log-normal distributions with F(B~T&(log(0.5) , (log(2) /1.96))
and F(~T&(log(0.25) , (log(2) /1.96)) . This allows for substantial between-strata 
standard deviations for the logistic parameters, log() and log(), respectively.
3. Assume that the marginal (total) variance of parameter θ follows normal distribution with 
the prior mean of R~ N('Y, 9Y
) and the prior standard deviation of F~ LN('[, 9[
).
Under these assumptions, the marginal (total) variance of θ, V(θ), is calculated by
V(θ) = E[V(θ|R, F)] + V[E(θ|R, F)] = E(F) + V(R)
= {exp(9[
) −1} exp(2'[ + 9[
) + {exp('[ + 9[
 2
⁄ )} + 9Y

= exp(2'[ + 29[
) + 9Y
.
As a result, 
9Y
 = V() −exp(2'[ + 29[
)
(1)
In this study, assume that the marginal (total) variances of parameters log(α) and log(β)
are the same as those for non-exchangeable case, F1B

and F1
 . Since step 1 and step 2 
above and by applying (1), the prior variance of R(B and R(, V(RB) and V(R), are 
calculated by
V(RB) = F1B
 −exp{2 ∙log(0.5) + 2 ∙(log(2) 1.96
⁄
)}
V(R) = F1
 −exp{2 ∙log(0.25) + 2 ∙(log(2) 1.96
⁄
)}.
4. The correlation S is uniformly distributed between -1 and 1.
Prior probability of exchangeability
Let  	 = 1,  	 = 0.5 and   = 0.1, hence Stratum 2 (Q4W) has 50% prior probability
to be exchangeable with Stratum 1 (Q2W). Stratum 3 (PDR) has 10% prior probability to be 
exchangeable with Stratum 1 (Q2W).
Summary of priors
The prior specifications are summarized in Table 14-7. Table 14-9 summarizes the associated 
prior distribution of the DLT rates at different dose levels for the three strata. 


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Table 14-7
Prior specifications for model parameters
Non-exchangeable case
Model parameter
Bivariate normal prior distribution 
D1
(−2.692 −1.26)
E1
O2
0
0
1P
Exchangeable case
Model parameter
Prior distribution
R(B
N(−2.692, 1.918)
R(
N(−1.26, 0.959)
F(B
LN(log(0.5) , (log(2) 1.96
⁄
))
F(
LN(log(0.25) , (log(2) 1.96
⁄
))
S
U(−1, 1)
Probability of membership of exchangeable 
component for Q2W  	
1
Probability of exchangeability for Q4W  	
0.5
Probability of exchangeability for PDR001  
0.1
The following data was included in stratum 3 of the model.
Table 14-8
Data from CPDR001X2101 as of 18-Jun-2015
Cohort 
Dose level
(mg/kg) / mg 
No. of evaluable 
patients
No. of DLTs in cycle 1
1
1 / 80
6
0


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14.3.1.1.1
Summary of priors
Table 14-9
Summary of prior distribution of DLT rates with CPDR001X2101 data **
Dose 
level 
(mg)
Prior probabilities that P(DLT) 
is in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33, 1]
2.5%
50%
97.5%
Q2W
20
0.827
0.091
0.082
0.091
0.158
0
0.024
0.61
80*
0.774
0.112
0.115
0.119
0.181
0.001
0.039
0.695
240
0.704
0.136
0.159
0.153
0.206
0.001
0.061
0.775
800
0.608
0.153
0.239
0.211
0.251
0.002
0.098
0.887
Q4W
20
0.827
0.091
0.082
0.092
0.159
0
0.024
0.618
80
0.771
0.115
0.113
0.119
0.181
0.001
0.04
0.695
240
0.701
0.14
0.159
0.154
0.206
0.001
0.063
0.775
800
0.601
0.158
0.241
0.213
0.252
0.002
0.101
0.891
PDR001
20
0.978
0.02
0.002
0.026
0.043
0
0.01
0.151
80
0.956
0.039
0.005
0.039
0.056
0
0.018
0.203
240
0.899
0.079
0.022
0.062
0.086
0.001
0.03
0.313
800
0.784
0.128
0.088
0.116
0.173
0.001
0.051
0.687
* Starting dose level
** as in Table 14-8
14.3.1.2 Hypothetical on-study data scenarios
Table 14-10
Hypothetical scenarios
Scenario
Cohort
Dose level 
(mg) 
stratum
Ntox 
/ 
Npat
Next dose level 
(NDL) (mg) 
stratum
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
1
1
80 Q2W
0/3
240 Q2W
240 Q4W 
0.088
0.118
0.037
0.105
0.030
0.043
2
1
80 Q2W
1/3
80 Q2W 
0.288
0.210
0.159
3
1
80 Q2W
2/3
STOP
4
1
2
2
80 Q2W
240 Q2W
240 Q4W
0/3
0/3
0/3
800 Q2W
800 Q4W
0.090
0.108
0.052
0.063
0.033
0.039
5
1
2
2
80 Q2W
240 Q2W
240 Q4W
0/3
0/3
1/3
800 Q2W
240 Q4W
0.147
0.278
0.073
0.192
0.060
0.147
6
1
2
2
80 Q2W
240 Q2W
240 Q4W
0/3
1/3
1/4
240 Q2W
240 Q4W
0.296
0.330
0.099
0.146
0.129
0.153
7
1
80 Q2W
0/3
80 Q2W
0.373
0.182
0.179


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Scenario
Cohort
Dose level 
(mg) 
stratum
Ntox 
/ 
Npat
Next dose level 
(NDL) (mg) 
stratum
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
2
2
240 Q2W
240 Q4W
2/3
1/3
80 Q4W
0.316
0.177
0.158
8
1
2
2
80 Q2W
240 Q2W
240 Q4W
0/3
1/3
2/4
240 Q2W
20 Q4W
0.380
0.280
0.185
0.165
0.184
0.138
9
1
2
2
80 Q2W
240 Q2W
240 Q4W
0/3
2/3
2/4
80 Q2W 
20 Q4W 
0.383
0.293
0.222
0.188
0.201
0.152
10
1
2
80 Q2W
80 Q2W
1/3
0/4
240 Q2W 
240 Q4W
0.282
0.190
0.124
0.153
0.128
0.092
11
1
2
80 Q2W
80 Q2W
1/3
1/4
80 Q2W 
0.406
0.206
0.198
12
1
2
2
3
80 Q2W
240 Q2W
240 Q4W
800 Q2W
0/3
0/3
0/3
0/5
800 Q2W
800 Q4W
0.036
0.086
0.002
0.042
0.021
0.030
13
1
2
2
3
80 Q2W
240 Q2W
240 Q4W
800 Q2W
0/3
0/3
0/3
1/5
800 Q2W
0.177
0.030
0.081
14
1
2
2
3
3
80 Q2W
240 Q2W
240 Q4W
240 Q2W
240 Q4W
0/3
1/3
1/4
0/6
0/6
800 Q2W 
0.235
0.109
0.113
15
1
2
2
3
3
80 Q2W
240 Q2W
240 Q4W
240 Q2W
240 Q4W 
0/3
1/3
1/4
2/6
0/6
240 Q2W 
800 Q4W
0.503
0.342
0.145
0.186
0.199
0.169
Overall, the model is showing appropriate behaviors, in agreement with clinical sense and 
decision making process. The dose levels investigate correspond to the provisional dose levels 
specified in Section 6.2.2.




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Dose escalation continued until MTD was identified, that is, the following conditions were met:

At least 6 patients have been treated at the dose, and

The dose satisfies one of the following conditions:

The posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or

A minimum of 21 patients have already been treated on the trial.
Otherwise, a trial could stop before MTD declaration if all dose levels did not satisfy the EWOC 
criterion or the maximum number of patients defined below had been treated. 
The number of patients to treat in each stratum was defined as:

Minimum cohort size a fixed number of 3 patients in Q2W and Q4W

Minimum number of patients treated: 15 in Q2W and 6 in Q4W

Maximum number of patients treated: 40 in Q2W and 40 in Q4W
14.3.1.3.3
Simulation results
Metrics to assess operating characteristics
Operating characteristics are reviewed based on the simulation results under the three scenarios. 
The metrics reviewed are:
1. Average number of patients receiving a target dose on study (I).
2. Average number of patients receiving a dose with true P(DLT) ≥ 33% on study (II).
3. Average number of patients receiving a dose with true P(DLT) < 16% on study (III).
4. Probability of recommending a target dose as the MTD (correct final decision) (IV).
5. Probability of recommending a dose with true P(DLT) ≥ 33% as the MTD (patient risk) 
(V).
6. Probability of recommending a dose with true P(DLT) < 16% as the MTD (VI).
7. Probability of stopping a trial before declaring MTD because all doses levels are too toxic
(Stopped).


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Operating characteristics
Table 14-12 below summarizes the operating characteristics of the design under the four
scenarios. 
Table 14-12
Simulation results
Scenario
Stratum
% 
start 
Q4W
cohort
Metrics
I
II
III
IV
(Target 
MTD)
V
(Overdose 
MTD)
VI (Under-
dose MTD)
V
Stopped
(all too 
toxic)
1
Q2W
-
4.0
0
9.1
54.6
0
37.8
7.6
Q4W
81.5
6.0
0
6.3
62.6
0
31.0
6.4
2
Q2W
-
8.9
2.0
1.5
43.3
18.5
20.9
17.3
Q4W
65.0
5.4
0
7.1
53.8
0
39.4
6.8
3
Q2W
-
9.2
1.9
1.6
44.5
15.9
22.6
17.0
Q4W
65.0
8.0
2.4
1.2
51.7
12.5
15.1
20.8
4
Q2W
-
7.1
0
8.3
79.5
0
20.2
0.3
Q4W
96.5
5.0
0
4.5
77.0
0
20.6
2.4
Metric IV, indicates that the model is typically identifying an appropriate MTD with high 
probability. Scenario 1 (Q2W and Q4W), and Scenario 4 (Q4W) have a high probability of 
identifying an MTD with toxicity below the target range, however this is accounted for by the 
inclusion in these scenarios of a dose with P(DLT)=0.154, marginally below the lower limit of 
the target range, 0.16. Similarly, for Scenario 2 (Q2W) and Scenario 3 (Q2W and Q4W) there 
is an appreciable probability of identifying a dose with P(DLT) lying above 0.33, this is 
accounted for by the inclusion in these scenarios of a dose with a probability of DLT of 0.366, 
marginally above the target range.
The simulation results show that the BHLRM performs reasonably well under the investigated 
hypothetical scenarios.
14.3.2
Phase I part MBG453 single agent with Japanese patients
Similarly, the BHLRM guided by the EWOC principle (Section 14.3.1) will be used in Japanese 
patients for MBG453 single agent phase I part to make dose recommendations and estimate the 
MTD and/or identify the RP2D. This section provides details of the statistical model, the 
derivation of prior distributions for the model parameters, and the properties of the adaptive 
design (dose recommendations for hypothetical data scenarios).


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14.3.2.1 Statistical model and prior distributions
Section 10.4.2 outlined the model description for the BHLRM, here the derivation of the priors 
for that model is described as follows:

Prior distributions for the exchangeability and non-exchangeability model components are 
derived.

For each stratum (Japanese patients and ROW patients), the weight of the exchangeable 
and non-exchangeable mixture components are defined.

Prior summaries for DLT rates at different dose levels are shown.
Prior for the non-exchangeable case
Under non-exchangeability, the parameter vectors jk (Japanese patients) and lk (ROW 
patients) are assumed to have a weakly informative bivariate normal prior distribution,
jk, lk ~ $%&(D1, E1)
where D1 = ('1B, '1) and E1 = =
F1B

GF1BF1
GF1BF1
F1

@ are the mean vector and 
covariance matrix. 
For the purposes of setting the prior for the BLRM model, the median DLT rate at 80 mg Q2W 
is assumed to be at 5%, and the median DLT rate at 800 mg Q2W is assumed to be 10%. For 
the remaining doses, median DLT rates a priori are assumed linear in the logit-scale as a 
function of log-dose.
Based on the above specified medians for the DLT rate and wide prior confidence intervals, the 
optimal parameters of the bivariate normal distribution can be obtained following the procedure 
described by Neuenschwander et al 2008. This leads to the BVN distribution defined by D1 =
(-2.692, -1.26), F1B = 2.484, F1 = 0.745 and G = −0.765.
To provide a simple, flexible prior, the same mean is retained, but the correlation is set to zero, 
and the standard deviations for log() and log() approximated by 2 and 1, respectively, the 
prior 
for 
the 
non-exchangeable 
case 
is 
set 
to
D1 =
(-2.692, 
-1.26), 
E1 = O2
0
0
1P.
Prior for the exchangeable case
Under exchangeability, the parameters jk and lk are assumed to follow a bivariate normal 
distribution:
jk, lk, ~ $%&(Q()*+, E()*+),
where Q()*+ = (R(B, R() and E()*+ = =
F(B

SF(BF(
SF(BF(
F(

@ are the mean vector and 
covariance matrix.
Prior specifications are as follows: 


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1. R(B and R( are given prior normal distributions. Assume that prior means of R(B and R(  
are the same as prior means for non-exchangeable case, '1B and '1, respectively.
2. F(B and F( are given log-normal distributions with F(B~T&(log(0.5) , (log(2) /1.96))
and F(~T&(log(0.25) , (log(2) /1.96)) . This allows for substantial between-strata 
standard deviations for the logistic parameters, log() and log(), respectively.
3. Assume that the marginal (total) variance of parameter θ follows normal distribution with 
the prior mean of R~ N('Y, 9Y
) and the prior standard deviation of F~ LN('[, 9[
).
Under these assumptions, the marginal (total) variance of θ, V(θ), is calculated by
V(θ) = E[V(θ|R, F)] + V[E(θ|R, F)] = E(F) + V(R)
= {exp(9[
) −1} exp(2'[ + 9[
) + {exp('[ + 9[
 2
⁄ )} + 9Y

= exp(2'[ + 29[
) + 9Y
.
As a result, 
9Y
 = V() −exp(2'[ + 29[
)
(1)
In this study, assume that the marginal (total) variances of parameters log(α) and log(β)
are the same as those for non-exchangeable case, F1B

and F1
 . Since step 1 and step 2 
above and by applying (1), the prior variance of R(B and R(, V(RB) and V(R), are 
calculated by
V(RB) = F1B
 −exp{2 ∙log(0.5) + 2 ∙(log(2) 1.96
⁄
)}
V(R) = F1
 −exp{2 ∙log(0.25) + 2 ∙(log(2) 1.96
⁄
)}.
4. The correlation S is uniformly distributed between -1 and 1.
Prior probability of exchangeability
Let  jk = 1,  lk = 0.5, hence Stratum 2 (ROW patients) has 50% prior probability to be 
exchangeable with Stratum 1 (Japanese patients).
Summary of priors
The prior specifications are summarized in Table 14-13. Table 14-15 summarizes the associated 
prior distribution of the DLT rates at different dose levels for the two strata. 
Table 14-13
Prior specifications for model parameters
Non-exchangeable case
Model parameter
Bivariate normal prior distribution 
D1
(−2.692 −1.26)
E1
O2
0
0
1P
Exchangeable case
Model parameter
Prior distribution
R(B
N(−2.692, 1.918)
R(
N(−1.26, 0.959)
F(B
LN(log(0.5) , (log(2) 1.96
⁄
))
F(
LN(log(0.25) , (log(2) 1.96
⁄
))


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S
U(−1, 1)
Probability of membership of exchangeable 
component for Japanese patients  jk
1
Probability of exchangeability for ROW patients 
 lk
0.5
The following data was included in stratum 2 of the model.
Table 14-14
Data from ROW patients CMBG453X2101 as of 07-Mar-2016
Cohort 
Dose level mg 
Schedule
No. of evaluable 
patients
No. of DLTs in 
cycle 1
1
80
Q2W
4
0
Testing of Q4W dosing schedule
Similarly, the BHLRM of the same functional form and same prior specification as described 
above was used to set up the dose escalation for Q4W of dose-escalation with Japanese patients. 
However, since no data is currently available for the Q4W global population, no data was 
included in stratum 2 of the model for this schedule. Table 14-15 summarizes the associated 
prior distribution of the DLT rates at different dose levels for the two strata. 
14.3.2.1.1
Summary of priors
Table 14-15
Summary of prior distribution of DLT rates with ROW patient data **
Dose 
level 
(mg)
Prior probabilities that P(DLT) is in 
interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33, 1]
2.5%
50%
97.5%
Japanese patients (Q2W)
20
0.887
0.064
0.049
0.066
0.130
0
0.016
0.493
80*
0.841
0.090
0.069
0.088
0.150
0.001
0.028
0.587
240
0.773
0.123
0.104
0.119
0.175
0.001
0.047
0.688
800
0.658
0.155
0.187
0.180
0.228
0.002
0.081
0.860
ROW patients (Q2W)
20
0.963
0.032
0.005
0.032
0.055
0
0.011
0.194
80
0.931
0.057
0.012
0.047
0.070
0
0.020
0.252
240
0.866
0.100
0.034
0.073
0.100
0.001
0.034
0.374
800
0.746
0.140
0.114
0.131
0.182
0.002
0.058
0.714
Japanese patients (Q4W)
20
0.829
0.090
0.081
0.091
0.159
0
0.024
0.625
80
0.773
0.114
0.112
0.119
0.181
0.001
0.040
0.702
240
0.700
0.142
0.158
0.154
0.206
0.001
0.063
0.778
800
0.598
0.160
0.242
0.214
0.252
0.002
0.102
0.895
ROW patients (Q4W)
20
0.829
0.089
0.081
0.092
0.160
0
0.024
0.633
80
0.773
0.114
0.113
0.119
0.182
0.001
0.040
0.709
240
0.699
0.142
0.159
0.155
0.207
0.001
0.063
0.779
800
0.598
0.159
0.242
0.215
0.253
0.002
0.102
0.894


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Dose 
level 
(mg)
Prior probabilities that P(DLT) is in 
interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33, 1]
2.5%
50%
97.5%
* Starting dose level
** as in Table 14-14
14.3.2.2 Hypothetical on-study data scenarios
Table 14-16
Hypothetical scenarios
Scenario
Cohort
Dose level 
(mg) 
Ntox / 
Npat
Next dose level 
(NDL) (mg) 
P(target) 
at NDL
P(over) 
at NDL
Median at 
NDL
Q2W
1
1
80 ROW
80 JP
0/4
0/2
240 JP
0.106
0.038
0.035
2
1
80 ROW
80 JP
0/4
0/3
240 JP
0.107
0.042
0.035
3
1
80 ROW
80 JP
0/4
1/3
80 JP
0.251
0.160
0.126
4
1
80 ROW
80 JP
0/4
2/3
STOP
5
1
80 ROW
80 JP
0/4
1/6
240 JP
0.272
0.114
0.119
6
1
2
80 ROW
80 JP
240 ROW
240 JP
0/4
0/2
0/6
0/3
800 JP
0.096
0.053
0.033
7
1
2
80 ROW
80 JP
240 ROW
240 JP
0/4
0/2
0/6
1/3
800 ROW
240 JP
0.125
0.264
0.062
0.117
0.053
0.188
8
1
2
80 ROW
80 JP
240 ROW
240 JP
0/4
0/2
0/6
2/3
800 ROW
80 JP
0.128
0.323
0.075
0.232
0.049
0.182
9
1
2
80 ROW
80 JP
240 ROW
240 JP
0/4
0/2
1/6
1/3
800 ROW
240 JP
0.307
0.293
0.182
0.106
0.156
0.130
10
1
2
80 ROW
80 JP
240 ROW
240 JP
0/4
0/2
1/6
1/6
800 ROW
800 JP
0.290
0.297
0.181
0.205
0.150
0.161
11
1
2
80 ROW
80 JP
240 ROW
240 JP
800 ROW
0/4
0/2
1/6
1/6
0/3
800 ROW
800 JP
0.195
0.192
0.024
0.017
0.090
0.088


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Scenario
Cohort
Dose level 
(mg) 
Ntox / 
Npat
Next dose level 
(NDL) (mg) 
P(target) 
at NDL
P(over) 
at NDL
Median at 
NDL
3
800 JP
0/4
12
1
2
3
80 ROW
80 JP
240 ROW
240 JP
800 ROW
800 JP
0/4
0/2
1/6
1/6
0/3
2/4
800 ROW
240 JP
0.319
0.415
0.080
0.080
0.130
0.159


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Scenario
Cohort
Dose level 
(mg) 
Ntox / 
Npat
Next dose level 
(NDL) (mg) 
P(target) 
at NDL
P(over) 
at NDL
Median at 
NDL
Q4W
1
1
240 ROW
240 JP
0/5
0/4
800 ROW
800 JP
0.092
0.100
0.046
0.053
0.035
0.035
2
1
240 ROW
240 JP
0/5
1/4
800 ROW
240 JP
0.165
0.260
0.084
0.125
0.068
0.121
3
1
240 ROW
240 JP 
0/5
2/4
STOP
4
1
240 ROW
240 JP
0/5
1/6
800 ROW
800 JP
0.160
0.273
0.070
0.165
0.066
0.137
5
1
2
240 ROW
240 JP
800 ROW
800 JP
0/5
0/4
0/3
0/3
800 ROW
800 JP
0.046
0.046
0.006
0.006
0.023
0.023
6
1
2
240 ROW
240 JP
800 ROW
800 JP
0/5
0/4
0/3
1/3
800 ROW
800 JP
0.092
0.216
0.011
0.082
0.042
0.095
7
1
2
240 ROW
240 JP
800 ROW
800 JP
0/5
0/4
0/3
2/3
800 ROW
240 JP
0.135
0.285
0.032
0.081
0.052
0.121




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
Maximum number of patients treated: 20 in Japanese patients and 4 in ROW patients
14.3.2.3.3
Simulation results
Metrics to assess operating characteristics for Japanese strata
Operating characteristics are reviewed based on the simulation results under the four scenarios. 
The metrics reviewed are:
I.
Average number of patients receiving a target dose on study (I).
II.
Average number of patients receiving a dose with true P(DLT) ≥ 33% on study (II).
III.
Average number of patients receiving a dose with true P(DLT) < 16% on study (III).
IV.
Probability of recommending a target dose as the MTD (correct final decision) (IV).
V.
Probability of recommending a dose with true P(DLT) ≥ 33% as the MTD (patient 
risk) (V).
VI.
Probability of recommending a dose with true P(DLT) < 16% as the MTD (VI).
VII.
Probability of stopping a trial before declaring MTD because all doses levels are too 
toxic (Stopped).
Operating characteristics
Table 14-18 below summarizes the operating characteristics of the design under the four
scenarios. 
Table 14-18
Simulation results
Scenario
Metrics
I
II
III
IV
(Target 
MTD)
V
(Overdose 
MTD)
VI
(Under-dose 
MTD)
V
Stopped (all 
too toxic)
1
7.9
0
7.5
74.3
0
19.1
1.7
2
14.7
0
4.8
69.1
0
0
21.5
3
0
0
14.7
0
0
97.5
0.5
4
0
10.3
0
0
18.4
0
77.2
Scenario 4 displays the results of the simulation of extremely high toxicity at all dose levels. 
Results of the simulation should be interpreted with caution as this simulation does not allow 
for dose escalation decisions taken outside of the model based rules for dose selection which 
dooesn’t reflect dose selection in practice following clinical review of all available data. In 
particular, if 2 patients experience a DLT at a previously untested dose, recruitment to that 
cohort will cease and either the next cohort will be enrolled at a lower dose, or the dose 
escalation will end if no dose is identified as safe by the BHLRM along with EWOC. For this 
reason, the scenario is considered liable to overestimate the proportion of trial in which a dose 
in excessive target interval is wrongly declared as MTD.  Even with this limitation, it is notable 
that the average proportion of patients expected to be treated on trial is low (10), and the model 
correctly identifies in a high proportion of cases (77.2%) that the dose escalation should be 
stopped.


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Overall, the simulation results show that the BHLRM performs reasonably well under the 
investigated hypothetical scenarios.
14.3.3
Phase Ib part MBG453 in combination with PDR001
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will guide the dose-escalation of the MBG453 in 
combination with PDR001 to its MTD(s) and/or recommended phase 2 dose (RP2D) of 
MBG453 in patients with solid tumors. This section provides details of the statistical model, 
the derivation of prior distributions for the model parameters, and the properties of the adaptive 
design (dose recommendations for hypothetical data scenarios).
14.3.3.1 Statistical model and prior distributions
Section 10.4.2 outlined the model description for the BLRM, here the derivation of the priors 
for that model is described as follows:

The single-agent prior distribution for PDR001 is derived.

The single-agent prior distribution for MBG453 is derived.

The prior distribution for the interaction parameter is derived.

Numerical values and summary statistic at different dose levels are shown.
Prior for PDR001 parameters
A weakly informative bivariate normal prior for the model parameters 
log,5 , log,5 for cycle m = 1,2 is obtained as follows:

The prior mean given by mean(log() , log(
′
)) = (−2.692, −0.567). This is 
given the fact that, the corresponding slope in square-rooted scale is given by log() +
 log( 240
⁄
) = log() + 
r
log(6.8 2406.8
⁄
). Therefore, 
r
= 2, i.e. 
log(
r
) = log2 × exp(−1.26).
The prior standard deviation was set to sd(log() , log()) = (2,1), which allows 
for considerably prior uncertainty for the dose-toxicity profile. The correlation was set to, 
corr(log() , log()) = 0.

Data from 6 patients eligible for the dose determining set of the ongoing study 
[CPDR001X2101] were used to update the dose-toxicity profile (refer to Table 14-8).

Heterogeneity between the historical and current study was incorporated by between-trial 
standard deviations and FB and F for log() and log(). Both FB and F were set 
to follow a log-normal distribution. Mean log(0.25) and standard deviation log(2)/1.96 
was chosen for FB and mean log(0.125) and standard deviation log(2)/1.96 was chosen for 
F, which correspond to moderate between-trial variability.

The corresponding predicted distribution is given by a mixture of two components as 
detailed in Table 14-19.
Since risk over cycle is assumed to be constant for PDR001. Therefore, the mixture of two 
components with equal weight was used for both cycles.


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Prior for MBG453 parameters
A weakly informative bivariate normal prior for the model parameters 
log234,5 , log234,5 for cycle m = 1,2 is obtained as follows:

A prior distribution is derived considering the possible similarities in toxicity from 
PDR001. The prior mean given by mean(log(234) , log(234
r
)) = (−2.692, −0.567).
This is given the fact that, the corresponding slope in square-rooted scale is given by 
log(234) + 234 log( 240
⁄
) = log(234) + 234
r
log(6.8 2406.8
⁄
). Therefore, 
234
r
= 2234, i.e. log(234
r
) = log2 × exp(−1.26). 
The prior standard deviation was set to sd(log(234) , log(234)) = (2,1), which allows 
for considerably prior uncertainty for the dose-toxicity profile. The correlation was set to, 
corr(log(234) , log(234)) = 0.

After all ongoing patients completed 1 cycle for the first two cohorts of the single agent 
MBG453 dose escalation; combination dosing will begin at the planned starting dose. For 
the purposes of illustration, it is assumed here that in the single agent dose escalation there 
are 3 evaluable patients in each of the first two cohorts (doses 80mg and 240mg) and 0 
DLTs are observed. Note, the prior specification of the model will be updated based on 
actual data prior to first patient enrolling onto the combination part.

Heterogeneity between the historical and current study was incorporated by between-trial 
standard deviations and FB and F for log() and log(). Both FB and F were set 
to follow a log-normal distribution. Mean log(0.25) and standard deviation log(2)/1.96 
was chosen for FB and mean log(0.125) and standard deviation log(2)/1.96 was chosen for 
F, which correspond to moderate between-trial variability.

The corresponding predicted distribution is given by a mixture of two components as 
detailed in Table 14-19.

In order to increase robustness to the model, a further component was added to the 
mixture prior to represent the risk of increased toxicity for MBG453 in combination. The 
mean(log(234) , log(234)) = (log(0.5) , 0), i.e. the median DLT rate at the reference 
dose was assumed 0.5 and a doubling in dose was assumed to double odds of DLT by a 
unit increase in the log of the square root of dose. To complete the specification, the prior 
standard deviation was set to sd(log(234) , log(234)) = (2,1), which allows for 
considerably prior uncertainty for the dose-toxicity profile and the correlation was set to, 
corr(log(234) , log(234)) = 0.
Since risk in cycle 2 is assumed to be higher than cycle 1 for MBG453. The mixture weights 
of the three components were set differently for the prior for first cycle toxicity, to that for the 
second cycle toxicity. See detail in Table 14-19.
Prior for the interaction parameter w
A weakly informative prior reflecting the current uncertainty about the toxicity of the 
combination treatment is used for >. A normal prior distribution for the interaction parameter >
is used, in order to allow for the potentiality of both synergy and antagonism of the safety 
profiles. Given that, exposure drug-drug interaction (PK DDI) is expected to be negligible, the 
following assumption is made for the interaction parameter:


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
> is normally distributed and median = 0 i.e. no increase in odds of DLT i.e. independence 
at the anticipated combination reference dose of 240 and 240.

97.5th percentile of > is =log(4.5) 234,5
6.8
2406.8
?
,5
6.8
2406.8
?
@ , i.e. 4.5-fold increase in 
odds of DLT at the combination reference dose of 240 and 240.
Therefore, the prior mean for > is 0 and the prior standard deviation is 0.767. 
Table 14-19
Prior distribution of model parameters
Parameter
Means
Standard 
deviations
Correlation
Weight
Cycle 1 risk for PDR001
log,B , log,B
-4.127, -0.472
1.560, 0.984
0.041
0.65
-2.532, -0.418
1.126, 1.129
0.334
0.35
Cycle 2 risk for PDR001
log, , log,
-4.127, -0.472
1.560, 0.984
0.041
0.65
-2.532, -0.418
1.126, 1.129
0.334
0.35
Cycle 1 risk for MBG453
log234,B , log234,B
-0.693, 0
2, 1
0
0.10
-4.220, -0.525
1.557, 1.009
0.025
0.61
-2.729, -0.522
1.033, 1.056
0.117
0.29
Cycle 2 risk for MBG453
log234, , log234,
-0.693, 0
2, 1
0
0.20
-4.220, -0.525
1.557, 1.009
0.025
0.54
-2.729, -0.522
1.033, 1.056
0.117
0.26
>
0
0.767
NA
NA




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Amended Version Protocol 06 (Clean)
Protocol No. CMBG453X2101
Scenario
Cohort
Dose combination MBG453 / 
PDR001 by cycle
Npat
Ntox
Next 
dose 
combination 
(NDC)
Pr(over) 
in NDC
11
1
2
3
  20,  20 / 80, 80
  80,  80 / 80, 80
240,    -  / 80,   -
3, 3
3, 3
3, -
0, 0
0, 0
1, -
240 / 80
0.136
12
1
2
3
20, 20 / 80, 80
80, 80 / 80, 80
240, 240 / 80, 80
3, 3
3, 3
3, 3
0, 0
0, 0
0, 1
240 / 80
0.122
13
1
2
3
  20, 20 / 80, 80
  80, 80 / 80, 80
240,   -  / 80,  -
3, 3
3, 3
3, -
0, 0
0, 0
2, -
80 / 80
0.102
14
1
2
3
  20,  20  / 80, 80
  80,  80  / 80, 80
240, 240 / 80, 80
3, 3
3, 3
3, 3
0, 0
0, 0
0, 0
800 / 80
0.170
15
1
2
3
  20,   20 / 80, 80
  80,   80 / 80, 80
240, 240 / 80, 80
3, 3
3, 3
3, 3
0, 0
0, 0
0, 2
80 / 80
0.101
16
1
2
3
4
20, 20 / 80, 80
80, 80 / 80, 80
240, 240 / 80, 80
240,    -   / 80,   -
3, 3
3, 3
3, 2
6, -
0, 0
0, 0
1, 0
0, -
800 / 80
0.247
17
1
2
3
4
20, 20 / 80, 80
80, 80 / 80, 80
240, 240 / 80, 80
240, 240 / 80, 80
3, 3
3, 3
3, 2
4, 4
0, 0
0, 0
1, 0
0, 0
800 / 80
0.233
18
1
2
3
20, 20 / 80, 80
80, 80 / 80, 80
80, 80 / 80, 80
3, 3
3, 2
3, 3
0, 0
1, 0
0, 0
240 / 80
0.127
Overall, the model is showing appropriate behaviors, in agreement with clinical sense and 
decision making process. The dose levels investigate correspond to the provisional dose levels 
specified in Section 6.2.2.
14.3.3.3 Operating characteristics
14.3.3.3.1
Scenarios
In order the design performs, 5 hypothetical scenarios are investigated:
8. Scenario 1 represents a scenario which is in line with the prior, i.e. the true underlying 
toxicity is set to the median values of the prior.
9. Scenario 2 represents a scenario assuming high toxicity for both compounds
10. Scenario 3 represents a scenario assuming low toxicity for both compounds
11. Scenario 4 represents a scenario assuming high toxicity occurs in cycle 1 risk set
12. Scenario 5 represents a scenario assuming high toxicity occurs in cycle 2 risk set




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Amended Version Protocol 06 (Clean)
Protocol No. CMBG453X2101
The number of patients to treat was defined as:

Minimum cohort size a fixed number of 3 patients 

Minimum number of patients treated: 15 

Maximum number of patients treated: 60
14.3.3.3.3
Simulation results
Metrics to assess operating characteristics
Operating characteristics are reviewed based on the simulation results under the three scenarios. 
The metrics reviewed are:
I.
Average number of patients receiving a target dose on study (I).
II.
Average number of patients receiving a dose with true P(DLT) ≥ 33% on study (II).
III.
Average number of patients receiving a dose with true P(DLT) < 16% on study (III).
IV.
Probability of recommending a target dose as the MTD (correct final decision) (IV).
V.
Probability of recommending a dose with true P(DLT) ≥ 33% as the MTD (patient 
risk) (V).
VI.
Probability of recommending a dose with true P(DLT) < 16% as the MTD (VI).
VII.
Probability of stopping a trial before declaring MTD because all doses levels are too 
toxic (Stopped).
Operating characteristics
Table 14-23 below summarizes the operating characteristics of the design under the four
scenarios. 
Table 14-23
Simulation results
Scenario
I
II
III
IV
(Target 
MTD)
V
(Overdose 
MTD)
VI
(Under-dose 
MTD)
V
Stopped
(all too 
toxic)
1
40.5
0
40.7
74.2
0
22.3
3.5
2
50.0
16.5
0
53.6
22.8
0
23.6
3
0
0
84.0
0
0
99.1
0.9
4
46.7
5.4
20.9
64.6
10.5
12.6
12.3
5
70.6
5.4
0
78.2
10.3
0
11.5
Scenario 3 represents a scenario in which all doses have P(DLT) below the target range, hence 
in this case metric IV is zero. In all other cases, metric IV indicates a high probability of 
identifying an MTD within the target range. In scenario 2, metric V is slightly inflated the 
inclusion of a dose for which P(DLT)=0.331, slightly above the upper limit of the target range, 
0.33.
In conclusion, the simulation results show that the BLRM performs reasonably well under the 
investigated hypothetical scenarios.


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Amended Version Protocol 06 (Clean)
Protocol No. CMBG453X2101
14.3.4
References (available upon request)
Neuenschwander B, Michael Branson M, Gsponer T (2008). Critical aspects of the Bayesian 
approach to phase I cancer trials Article first published online: Statistics in Medicine 27 (13): 
2420–39.

SAP_001.pdf: 


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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)
09-
Dec-
2015
Prior 
to 
DB 
lock
Creation 
of initial 
version
N/A 
-
First 
version
NA
31-
Aug-
2021
Prior 
to 
DB 
lock
Creation 
of 
the 
SAP for 
the final
CSR.
This 
version 
will be used for 
the final CSR
Structural update and various changes in 
wording,  in order to align with the TCO SAP 
template (SAP_TCO_V3.0). Corrections and 
additions to reflect the latest amended protocol 
version (v6.0) considering also the SAP version 
used for the interim CSR:
(CMBG453X2101_SAP_CSR_1_interim.docx).
Wording added for the managment of the 
COVID-19 situation.
29-
Sep-
2022
Prior 
to 
DB 
lock
Creation 
of 
the 
SAP for 
the final
CSR.
This amended 
version will be 
used for the 
final CSR
Update 
in 
the 
definition 
of 
the 
ADA 
determinants from the SAP version used for the 
interim CSR.
Information on which outputs from MBG453
single agent will be presented in the CSR, 
updating or adding the MBG453 single agent 
information provided in the interim CSR.


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Table of contents
Table of contents .................................................................................................................3
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................9
2
Statistical methods.............................................................................................................11
2.1
Data analysis general information .........................................................................11
2.1.1
General definitions................................................................................13
2.2
Analysis Set/ Patient Classification/Withdrawal of ICF/Subgroups .....................15
2.2.1
Analysis sets..........................................................................................15
2.2.2
Subject classification.............................................................................18
2.2.3
Withdrawal of Informed Consent..........................................................20
2.2.4
Subgroup of interest ..............................................................................20
2.3
Patient disposition, demographics and other baseline characteristics ...................20
2.3.1
Patient disposition.................................................................................20
2.3.2
Demographics and other baseline characteristics .................................20
2.3.3
Medical history......................................................................................21
2.3.4
Prior antineoplastic therapy...................................................................21
2.3.5
Diagnosis and extend of cancer.............................................................21
2.4
Protocol deviations ................................................................................................21
2.5
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................22
2.5.1
Study treatment .....................................................................................22
2.5.2
Prior, concomitant and post therapies...................................................24
2.6
Analysis of the primary objective..........................................................................24
2.6.1
Definition of the primary endpoint .......................................................25
2.6.2
Statistical hypothesis, model, and method of analysis..........................25
2.6.3
Handling of missing values/censoring/discontinuations.......................29
2.6.4
Supportive analyses...............................................................................30
2.7
Analysis of key secondary efficacy objective(s) ...................................................30
2.8
Analysis of secondary efficacy objective(s)..........................................................30
2.8.1
Definition of secondary endpoints ........................................................30
2.8.2
Statistical hypothesis, model, and method of analysis..........................31
2.8.3
Handling of missing values/censoring/discontinuations.......................32
2.9
Safety analyses.......................................................................................................33
2.9.1
Adverse events (AEs)............................................................................33


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2.9.2
Deaths....................................................................................................33
2.9.3
EudraCT and clinicaltrials.gov requirements for AEs and Deaths 
summaries .............................................................................................34
2.9.4
Adverse events of special interest / grouping of AEs ...........................34
2.9.5
Laboratory data .....................................................................................34
2.9.6
Other safety data ...................................................................................36
2.10
Pharmacokinetic endpoints....................................................................................38
2.11
PD and PK/PD analyses.........................................................................................39
2.12
Immunogenicity.....................................................................................................39
2.13
Patient-reported outcomes .....................................................................................41
2.14
Biomarkers.............................................................................................................41
2.14.1
Introduction...........................................................................................41
2.14.2
Outline of the data analysis...................................................................42
2.14.3
Biomarker objectives ............................................................................42
44
2.16
Interim analysis......................................................................................................44
3
Sample size calculation .....................................................................................................44
4
Change to protocol specified analyses ..............................................................................45
4.1
Planned analysis due to COVID-19.......................................................................46
5
Appendix ...........................................................................................................................46
5.1
Imputation rules.....................................................................................................46
5.1.1
Study drug.............................................................................................46
5.1.2
AE date imputation ...............................................................................46
5.1.3
Concomitant medication date imputation .............................................47
5.1.4
End date.................................................................................................48
5.1.5
Deaths....................................................................................................48
5.1.6
Other imputations..................................................................................49
5.2
AEs coding/grading ...............................................................................................49
5.3
Laboratory parameters derivations ........................................................................49
5.4
Statistical models...................................................................................................50
5.4.1
Primary analysis....................................................................................50
5.4.2
Key secondary analysis.........................................................................50
5.5
Rule of exclusion criteria of analysis sets..............................................................50
6
Reference...........................................................................................................................50


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List of abbreviations
AE
Adverse Event
AESI
ATC
Adverse Event of Special Interest
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BHLRM
Bayesian Hierarchical Logistic Regression Model
BLRM
Bayesian Logistic Regression Model
BOR
Best Overall Response
CI
Confidence Interval
CR
Complete Response
CRO
Contract Research Organization
SCLC
Small Cell Lung Cancer
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dosage Administration Record
DBL
Database Lock
DDS
Dose-Determining Analysis Set
DI
Dose Intensity
DLT
Dose Limiting Toxicity
DMC
Data Monitoring Committee 
DMS
Document Management System
DOR
Duration of Response
DRL
Drug Reference Listing
ECG
Electrocardiogram
eCRF
eCSR
FAS
HGLT
HLT
Electronic Case Report Form
Electronic Case Retrieval Strategy
Full Analysis Set
High Group Level Term
High Level Term
IB
Investigator’s Brochure
iCSR
Interim CSR
irAE(s)
Immune-related Adverse Event(s)
irCR
Immune-related Complete Response
irPD
Immune-related Progressive Disease
irPFS
Immune-related Progression Free Survival
irPR
Immune-related Partial Response
irSD
Immune-related Stable Disease
irRC
Immune-related Response Criteria
IVR
Interactive Voice Response
IWR
Interactive Web Response
MTD
Maximum Tolerated Dose
MedDRA
Medical Dictionary for Drug Regulatory Affairs


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CMBG453X2101
NA
Not Assessed
NCI
NMQ
National Cancer Institute
Novartis MedDRA Query
NSCLC
Non-Small Cell Lung Carcinoma
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Progressive Disease
PD
Pharmacodynamics
PD-1
Programmed Death-1
PD-L1
Programmed Death-Ligand 1
PDI
Planned Dose Intensity
PDS
Programming Datasets Specifications
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
PT
Partial Response
Preffered Term
QoL
Quality of Life
Q2W
Every 2 weeks
Q4W
Every 4 weeks
RAP
Reporting and Analysis Process
RCC
Renal Cell Carcinoma
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
Recommended Phase II dose
ROW
Rest Of the World
SAE
Serious Adverse Event
SAP
SMQ
Statistical Analysis Plan
Standardized MedDRA Query
SOC
System Organ Class
TFLs
Tables, Figures, Listings
TIM-3
T-cell Immunoglobulin domain and Mucin domain-3
TIL
Tumor Infiltrating Lymphocytes
UNK
Unknown
WHO
World Health Organization


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CMBG453X2101 that will be presented in the Clinical Study Report (CSR). 
The output shells (in-text and post-text) accompanying this document can be found in the
Tables-Figures-Listings (TFL) shells document. The specifications for derived variable and 
datasets can be found in the Programming Datasets Specifications (PDS) document.
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend.
The SAP, TFL shells and PDS documents may also serve as a reference for the creation of any 
outputs required outside of the CSR, e.g., MTD/RP2D declaration, Investigator’s Brochure (IB)
updates, abstracts, posters, presentations, manuscripts and management updates. Data used for 
these analyses will have a status aligned to the database lock guidance.
1.1
Study design
This is a first-in-human, open-label, phase I-Ib/II multicenter study of parallel cohorts with 
single agent MBG453, MBG453 in combination with PDR001. The study consists of the 
following parts: 

A phase I dose escalation part with MBG453 as single agent (including a separate Japanese 
single agent dose escalation part) in advanced solid tumors. For the distinction of the 
different escalation parts the labels Japanese vs. rest of the world (ROW) will be used, as 
shown in Figure 1-1. 

A phase Ib dose escalation part with MBG453 in combination with PDR001 in advanced 
solid tumors. This part of the study will start after at least two cohorts of MBG453 as single 
agent have been completed and dose is assessed safe and tolerable.

MBG453 and PDR001 will be administered i.v. Q2W or Q4W until a patient experiences 
unacceptable toxicity, progressive disease as per irRC and/or treatment is discontinued at 
the discretion of the Investigator or the patient. Patients should not discontinue treatment 
based on progressive disease per RECIST v1.1 unless clinical deterioration or increase in 
tumor markers is observed.

Should signs of anti-tumor activity (defined as at least one confirmed objective Partial 
Response (PR) or Complete Response (CR)) be detected in the phase I-Ib dose escalation 
parts, a dose ranging part will be opened, in which different dose levels of MBG453 alone 
and/or in combination with PDR001 will be also evaluated.

A phase II part to evaluate clinical efficacy of MBG453 in combination with PDR001 at the 
MTD or RP2D (if that is lower than MTD) in the selected study disease indications, as 
shown in Figure 1-1.
Should signs of anti-tumor activity (defined as at least one confirmed objective PR) be detected 
in the phase I dose escalation part, a phase II part will be opened to evaluate clinical efficacy of 
MG453 alone.






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Objective
Endpoint
To make an initial comparison for MBG453 and PDR001 
administered in combination on a Q2W and Q4W dosing 
schedules

Safety: Incidence and severity of AEs and SAEs, 
including changes in laboratory parameters, vital 
signs and ECGs

Tolerability: Dose interruptions, reductions and dose 
intensity

Serum PK parameters (e.g., AUC, Cmax, Tmax, half-
life); Serum concentration vs. time profiles

ORR, BOR, PFS and DOR per RECIST v1.1; ORR 
and PFS per irRC
Phase I-Ib/II parts: 
To characterize the pharmacokinetic profile of MBG453 as 
single agent and in combination with PDR001
Serum PK parameters (e.g., AUC, Cmax, Tmax, half-life);
Serum concentration vs. time profiles
Phase I-Ib/II parts: 
To assess emergence of anti-MBG453 and anti-PDR001 
antibodies following one or more i.v. infusions of MBG453 
single agent and in combination with PDR001
Presence and/or concentration of anti-MBG453 and anti-
PDR001 antibodies
Phase I-Ib/II parts:
To assess potential predictors of efficacy of MBG453 single 
agent and in combination with PDR001 in tumor samples
Assess potential associations between expression of PD-
L1 and other immunological markers such as, but not 
restricted to TIM-3, CD8, FoxP3  and anti-tumor activity
Phase I-Ib/II parts: 
To assess the pharmacodynamic effect of MBG453 as 
single agent and in combination with PDR001 in tumor 
samples
Tumor Infiltrating Lymphocytes (TIL) counts
Phase I-Ib/II parts: 
To describe the survival distribution of patients treated with 
MBG453 as single agent and in combination with PDR001 
for each disease group
Overall survival (OS)


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2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated SAS® version, and for the Bayesian modeling the most updated versions for R (v 3.0.2 
or later) and JAGs (v 4.0.0 or later). PK parameters will be calculated using non-compartmental 
methods available in Phoenix WinNonlin version 5.2.
The study data will be analyzed and reported in a final CSR based on all patients’ data of the 
Phase I-Phase Ib and Phase II parts, up to the time when all patients have discontinued the study. 
The final CSR will include all outputs planned within the TFL shells document. 
An interim CSR (iCSR) was prepared, as it was considered appropriate by the study team. 
Though the main focus of the iCSR was on the data and results of the phase I part of the study 
(MBG453 single agent treatment arm), it also included all outputs planned within the TFL shells 
document for all treatment arms with treated patients. Additional data for patients in the other 
parts of the study (phase Ib/II of MBG453 in combination with PDR001) past the data cutoff 
date of the iCSR, will be reported once all patients have discontinued the study in the final CSR.
Since there is no addition or update in the single agent data presented in the iCSR, no outputs 
will be produced for MBG453 single agent in the final analysis apart from the following: 

EUdraCT and clinicaltrials.gov requirements for AE and death summaries (see Section 
2.9.3), as well as DSUR tables with subjects exposed by sex, age and race , as they were
not included in the iCSR.

Adverse events of special interest (AESIs; See Section 2.9.4), as they were not included 
in the iCSR .

Listings for PK parameters , as this was considered important for publication issues and 
were not included in the iCSR.

Table for demographic data for the whole number of patients of the study, as this is 
required for publication issues (clinicaltrials.gov).

Immunogenicity analysis (IG), as there will be an update in the definitions of 
determinants (see Section 2.12).

Tables of adverse events per system organ class and preferred term, as they will be used 
as source tables for the AESIs in-text tables.

Biomarker analysis presented by treatment group, as per reporting requirements, though 
it was not initially considered appropriate due to the small number of patients per dose 
level.

Duration of response outputs presented by treatment group, as per reporting activities, 
though it was not initially considered appropriate due to the small number of patients 
per dose level. Also listings of time to onset and duration of overall response, as those 
will be used as source listings for the duration of response.


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
Protocol deviations outputs, as there were additional deviations included for MBG453 
single agent after iterim data base lock. 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) and pharmacodynamics (PD) measurements using descriptive statistics 
(n, mean, standard deviation, median, minimum, and maximum) for quantitative data and 
contingency tables (frequencies and percentages) for qualitative data.
Treatment group is defined by the study treatment, the dose level and the frequency of the study 
treatment (e.g. MBG453 80mg Q2W, MBG453 80mg Q2W + PDR001 240mg Q2W, etc.). 
Therefore, a treatment group may consist of more than one cohort.
The following rules will be followed for reporting results unless stated otherwise:

For the phase I part, cohorts and patient groups treated with the same dose (dose levels 
and schedules) will be pooled into a single treatment group. Japanese patients and ROW 
patients will be separated into each of their respective single treatment group. All 
summaries, listings, figures and analyses will be performed by treatment group.

For the phase Ib part, cohorts and patient groups treated with the same dose or dose 
combination (dose levels and schedules) will be pooled into a single treatment group. 
All summaries, listings, figures and analyses will be performed by treatment group. The 
additional phase Ib part referring to the SCLC patients (run-in part) will be analyzed 
separately.

For the phase II part, all summaries, listings, figures for primary efficacy analysis and 
safety analyses will be presented by patient group. Patients from the phase II part will 
be classified according to the patient group to which they were assigned at baseline 
based on the disease type.
Single agent phase I:

Up to two indications for which response has been observed in the phase I dose 
escalation may be explored.
Combination phase II:

Group 1: Melanoma (naïve to anti-PD-1/PD-L1)

Group 2: Melanoma (pre-treated with anti-PD-1/PD-L1)

Group 3: NSCLC (naïve to anti-PD-1/PD-L1)

Group 4: NSCLC (pre-treated with anti-PD-1/PD-L1)

Group 5: RCC (naïve to anti-PD-1/PD-L1)

Group 6: RCC (pre-treated with anti-PD-1/PD-L1)
Note that for one of the combination phase II groups an exploration of Q2W versus Q4W dosing 
may be conducted. The group to be used for this comparison will be chosen based on feasibility. 
Data from the two dosing schedules will be summarized separately.
Groups 1, 3, 5 and 6 were finally not populated and no patient was treated in a Q2W dosing at 
phase II. As a result, no outputs will be produced for those groups and the secondary phase II 


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objective “To make an initial comparison for MBG453 and PDR001 administered in 
combination on a Q2W and Q4W dosing schedules” will not be analyzed and presented.   
Note: patients from the Phase I-Ib dose escalation parts and the Phase II part will not be pooled 
in any analyses unless otherwise specified. In addition, Japanese patients will not be pooled 
with ROW patients in any analyses.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in
analyses, but will be reported in the CSR as separate listings.
2.1.1
General definitions
Study drug and study treatment
Investigational drug will refer to MBG453 and PDR001. The terms investigational drug and 
study drug are used interchangeably.
Investigational treatment will refer MBG543 as single agent and MBG453 in combination 
with PDR001. The term investigational treatment may also be referred to as study treatment.  
For consistency across studies, the term study treatment will be used throughout this document.
Date of first/last administration of study drug and study treatment
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of any component of study treatment was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment
Note, the day of start of study treatment is day 1, and the day before the date of first study 
treatment is day – 1, not day 0.
Study day will be displayed in the data listings.
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 
year, duration in days will be divided by 365.25.


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Baseline
Baseline is the result of an investigation describing the “true” state of the patient before start of 
study treatment administration.
Baseline is the last available and valid assessment performed or value measured on or before 
the date of first administration of study treatment. 
Baseline can also be  the same day as first treatment administration if a pre-dose 
assessment/value is available (e.g., ECG, PK samples, samples for biomarkers).

If time is recorded for the first treatment dose and for a specific assessment performed the 
day of first dose, this assessment will be considered as baseline only if it is actually 
performed before the first dose, as checked using both times.

If time is not recorded, a specific assessment performed the day of first dose administration 
will be considered as baseline if, according to protocol, it should be performed before the 
first dose.
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter.
For pregnancy test, baseline will be within 72 hours before first administration of study 
treatment. 
Computation of baseline for ECG are described in  section 2.9.6.1.
On-treatment assessment/event
For all safety reporting the overall observation period will be divided into three mutually 
exclusive segments:

Pre-treatment period: from day of patient’s informed consent to the day before first dose of 
study medication

On-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication

Post-treatment period: starting at day 31 after last dose of study medication.
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.
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).
Last contact
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the latest complete date reported in the data base related to study visits or communication 


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with the patient 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.
The last contact date will be used for censoring of patients in the analysis of time to event 
endpoints.
New anticancer therapy
New anticancer therapy is defined as any therapy (medication, radiotherapy or surgery) given 
after the first study treatment administration. For more information on concomitant  medication 
see Section 6.4 of the protocol.
The following categories of the eCRF “Antineoplastic Therapy Since Discontinuation of Study 
Treatment” shall be taken into consideration for the censoring of the patients in the analysis of 
the relevant endpoints (see Section 2.8.3):

For medication, all cases with setting: adjuvant, neoadjuvant, prevention, palliative or 
other.

For radiotherapy, all cases with setting: adjuvant, neoadjuvant, palliative or other.

For surgery, all cases using the procedures:  debulking, dissection, resection or 
excision/removal/ablation.
2.2
Analysis Set/ Patient Classification/Withdrawal of ICF/Subgroups
2.2.1
Analysis sets
2.2.1.1
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of assigned 
single agent MBG453, or at least one full or partial dose of assigned combination of study drugs. 
Patients will be analyzed according to the planned treatment. 
The FAS will be used for all listings of raw data. Unless otherwise specified, the FAS will be 
the default analysis set used for all analyses.
2.2.1.2
Safety Set
The Safety Set includes all patients from the FAS
Patients for the safety set will be classified according to treatment received, where treatment 
received is defined as:

The treatment assigned if it was received at least once, or

The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
The safety set will be used for the safety summary of the study.


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2.2.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) consists of a subset of FAS patients in the phase II part who meet 
the following criteria:

Presence of at least one measurable lesion according to RECIST v1.1 (see Appendix 1 of 
the protocol).

At least 2 post-baseline tumor assessments (unless disease progression as per RECIST v1.1 
is observed before that time).

For Group 1, 3 and 5, patients have not been previously treated with PD-1 or PD-L1 directed 
therapy. For Group 2, 4 and 6 patients must have previously received a PD-1 or PD-L1 
directed therapy.

Histologically documented advanced or metastatic solid tumors (for Groups 1-6).

Baseline ECOG performance status ≤ 2.

Phase II part (MBG453 single agent): pre-specified tumor type.

Phase II part (MBG453 in combination with PDR001): melanoma, NSCLS or RCC.
Patients will be classified according to planned treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint Section 10.4 of the protocol. If the PPS and the 
FAS are identical, then analyses described by the PPS below (Section 2.5.4) will not be 
performed.
2.2.1.4
Dose-determining analysis set (DDS)
Phase I part (MBG453 single agent) 
The DDS analysis consists of all patients from the safety set in the dose escalation part who 
either meet the minimum exposure criterion and have sufficient safety evaluations, or have 
experienced a dose limiting toxicity (DLT) during Cycle 1. This constitutes an evaluable patient 
for the determination of MTD. 
A patient is considered to have met the minimum exposure criterion if having received all 
planned doses of MBG453 during Cycle 1. Patients who do not experience a DLT during the 
first cycle are considered to have sufficient safety evaluations if they have been observed for ≥ 
28 days following the first dose, and are considered by both Novartis and the Investigators to 
have enough safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be 
regarded as ineligible for the DDS and additional patients may be enrolled if required to meet 
the minimum cohort size for decision making, as described in Section 6.2.3 of the protocol.
Phase Ib part (MBG453 in combination with PDR001)
Cycle 1 risk set
The Cycle 1 risk set consists of all patients from the safety set in the dose escalation part who 
either meet the minimum exposure criterion for cycle 1 and have sufficient safety evaluations, 
or have experienced a DLT during Cycle 1. 


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A patient is considered to have met the minimum exposure criterion for Cycle 1 if they have 
received all planned dose of both MBG453 and PDR001 during Cycle 1.
For the cycle 1 risk set, patients who do not experience a DLT during the first cycle are 
considered to have sufficient safety evaluations if they have been observed for ≥ 28 days 
following the first dose, and are considered by both Novartis and the Investigators to have 
enough safety data to conclude that a DLT did not occur.
Cycle 2 risk set (for MBG453 in combination with PDR001)
The Cycle 2 risk set consists of all patients in the cycle 1 risk set who (a) did not experience a 
DLT in Cycle 1, and (b) satisfy the minimum exposure criterion for Cycle 2 and have sufficient 
safety evaluations, or have experienced a DLT during Cycle 2.
A patient is considered to have met the minimum exposure criterion for Cycle 2 if they have 
received at least one planned dose of both MBG453 and PDR001 (at the same level as 
administered in Cycle 1) during Cycle 2.
For the Cycle 2 risk set, patients who do not experience a DLT during the second cycle are 
considered to have sufficient safety evaluations if they have been observed for ≥ 28 days 
following the first dose of Cycle 2, and are considered by both Novartis and the Investigators 
to have enough safety data to conclude that a DLT did not occur.
Patients who do not meet these minimum dosing and safety evaluation requirements will be 
excluded from the relevant risk set(s) and additional patients may be enrolled if required to meet 
the minimum cohort size for decision making, as described in Section 6.2.3 of the protocol.
2.2.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) consists of all patients who have at least one blood 
sample providing evaluable PK data. The PAS will be used for all PK analyses.
Note: Patients may be removed from the estimation of any or certain PK parameters on an 
individual basis depending on the number of available blood samples. These patients will be 
identified at the time of analysis.
2.2.1.6
Immunogenicity analysis sets
The immunogenicity (IG) set includes two parts (IG prevalence set and IG incidence set) that 
will be defined for MBG453 (as single agent and in combination with PDR001) and PDR001 
in combination with MBG453. Definitions of the IG sets are the following:
The IG prevalence set includes all subjects in the FAS with a determinant baseline IG sample 
or at least one determinant post-baseline IG sample.
The IG incidence set includes all subjects in the IG prevalence set with a determinant baseline 
IG sample and at least one determinant post-baseline IG sample.
See Section 2.12 for the definition of determinant.


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2.2.2
Subject classification
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations (PD) entered in the database and/or on specific classification rules defined in Table 
2-1.
Table 2-1
Classification based on PDs and non-PD criteria
Analysis set
Protocol deviations leading to exclusion
(DVSPID)
Non protocol deviation 
leading to exclusion
Full analysis 
set 
No 
written 
inform 
consent
(INCL19, 
INCL16)
No dose of study treatment 
(in both drugs for the 
combination arms) 
administered
Safety set
No 
written 
inform 
consent
(INCL19, 
INCL16)
No dose of study treatment 
(in both drugs for the 
combination arms) 
administered
Dose-
determining 
set
No 
written 
inform 
consent
(INCL19, 
INCL16)
For MBG453 single agent: 

Not all planned dose 
administered at cycle 1, 
or 

Not followed up for ≥ 
28 days after first dose 
administration, unless 
patient had a DLT 
during this period.
For MBG453 + PDR001: 

Not all planned dose of 
both drugs 
administered  at cycle 
1, or

Not  at least one 
planned dose of both 
drugs was administered 
at cycle 2, unless 
patient had a DLT 
during 1st cycle, or
Not followed up for ≥ 28 
days after first dose 
administration of cycle 2, 
unless patient had a DLT 
during this period.patient 


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had a DLT during this 
period.
Per-protocol 
set

No written inform consent (INCL19, 
INCL16)

No presence of measurable and no 
measurable lesion for phase I/Ib parts or 
no presence of measurable lesion for 
phase I part according to RECIST v1.1 
(INCL04, INCL06, INCL09).

For Groups 1, 3 and 5 (see Figure 1-1), 
patients previously treated with PD-1 or 
PD-L1 directed therapy (INCL21). For 
Group 2, 4 and 6 patients not previously 
treated with PD-1 or PD-L1 directed 
therapy.

Not histologically documented advanced 
or metastatic solid tumors (for Groups 1-
6) (INCL09).

Baseline ECOG performance status > 2
(INCL12).

Phase II part (MBG453 single agent): not 
pre-specified tumor type. (INCL11).

Phase II part (MBG453 in combination 
with PDR001): no melanoma, NSCLS or 
RCC (INCL11).

No
dose 
of 
study 
treatment (in both drugs 
for 
the 
combination 
arms) administered.

Less than 2 post-
baseline tumor 
assessments (unless 
disease progression is 
observed before that 
time).
PK 
Analysis 
Set
No 
written 
inform 
consent 
(INCL19, 
INCL16)
No blood sample providing 
evaluable PK data.
IG 
Analysis 
sets:

IG 
prevalence 
set

IG 
incidence 
set
No 
written 
inform 
consent 
(INCL19, 
INCL16)

No dose of study 
treatment (in both 
drugs for the 
combination arms) 
administered

No determinant 
baseline IG sample and 
no determinant post-
baseline IG sample, for 
the IG prevalence test.

No determinant 
baseline IG sample or 
no determinant post-
baseline IG sample, for 
the IG incidence test.


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2.2.3
Withdrawal of Informed Consent
Any data collected in the clinical database after a patient 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), given that 
local law and patient informed consent permits.
For more details on withdrawal of informed consent, please refer to Section 7.1.4 of the protocol.
2.2.4
Subgroup of interest
Not Applicable. 
2.3
Patient disposition, demographics and other baseline 
characteristics
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS.
2.3.1
Patient disposition
The number and percentage of the patients included in the FAS, the ones who are still on 
treatment at the time of the data cut-off, the ones who discontinued the study phases, as well as 
the reason for discontinuation will be presented.
In particular, the following summaries will be provided (with % based on the total number of 
FAS patients):

Number (%) of patients still on-treatment at the time of the data cut-off (based on non-
completion of the ‘End of Treatment’ page)

Number (%) of patients having discontinued the study treatment (based on completion of
the ‘End of Treatment’ page with discontinuation date and reason entered)

Primary reason for study treatment discontinuation (based on discontinuation reason entered 
in the ‘End of Treatment’ page)

Number (%) of patients having discontinued the study (based on completion of the ‘End of 
Post treatment Phase’ page with discontinuation date and reason entered)

Primary reason for study evaluation completion (based on discontinuation reason entered in 
the ‘End of Post treatment Phase’ page).
2.3.2
Demographics and other baseline characteristics
Demographic data including age, sex, race, ethnicity, height, and baseline weight and ECOG
performance status as well as other baseline data including disease characteristics (primary site 
of cancer, histological grade, predominant histology/cytology, stage at initial diagnosis and 
stage at time of study entry) and metastatic sites will be listed and summarized descriptively. In 
addition, child bearing potential and pregnancy test results will be listed, and age (18- <65 years,
65- < 85 years, and ≥ 85 years) categories summarized.


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These data 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) will be summarized by descriptive statistics (N, mean, median, standard deviation, 
minimum and maximum).
2.3.3
Medical history
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be summarized and listed. Separate summaries will be presented for current 
and historical medical conditions by primary system organ class and preferred term. Medical 
history and current medical conditions are coded using the latest Medical Dictionary for 
Regulatory Activities (MedDRA) terminology available at the time of reporting.
2.3.4
Prior antineoplastic therapy
The number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), immuno-oncology therapeutic class 
at last treatment, setting at last treatment and best response at last treatment (defined to be the 
best response during the last treatment regimens recorded). Prior antineoplastic medications 
will also be summarized by Anatomical Therapeutic Chemical (ATC) class and preferred term.
The summary of prior anti-neoplastic radiotherapy will include the radiotherapy locations, 
(including all locations recorded for each Subject) and setting at last radiotherapy.
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment, procedure at last surgery and residual 
disease at last surgery.
All prior anti-neoplastic medication, radiotherapy and surgery will be listed.
2.3.5
Diagnosis and extend of cancer
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer (diagnosis of disease), details of tumor histology/cytology, histologic grade, stage 
at initial diagnosis, time (in months) since initial diagnosis of primary site, time (in months) 
from initial diagnosis to first recurrence/relapse, time (in months) since most recent 
recurrence/relapse,  types of lesions (target and non-target lesions) at baseline, current extent of 
disease (metastatic sites).
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listing. The number (%) 
of Subjects with any CSR-reportable protocol deviation will be tabulated by the deviation 
category (entry criteria not satisfied; wrong treatment or incorrect dose; developed withdrawal 
criteria, but not withdrawn; took an excluded concomitant medication; others). The full list of 
protocol deviations is documented in the Study Specification Document (SSD).


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COVID-19 specific protocol deviations will be included in the protocol deviation listing. 
Details about COVID-19 impact are provided in Section 4.1.
2.5
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
2.5.1
Study treatment
The safety set will be used for all summaries and listings regarding study treatment.
2.5.1.1
Data handling
Imputation rules regarding last and first treatment administration of study drug can be found in 
Appendix, Section 5.1.1.
2.5.1.2
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug or control, and any combination partner, if applicable:
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 the 
investigational drug of the treatment arm.
The definition of last date of exposure to investigational drug (days) is defined as follows:

For MBG453: the date of last administration of a non-zero dose + 

13 days, for the Q2W treatment schedule

27 days, for the Q4W treatment schedule.

For PDR001: the date of last administration of a non-zero dose + 

13 days, for the Q2W treatment schedule

27 days, for the Q4W treatment schedule.
Note: If a patient died or was lost to follow-up before the derived last date of exposure, the last 
date of exposure for this patient will be 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.
Definition of date of last contact can be found in Section 2.1.1.Summary of duration of exposure 
of investigational drug will include categorical summaries (based on clinically meaningful time 
intervals) and continuous summaries (i.e. mean, standard deviation, etc.) using appropriate units 
of time.
2.5.1.3
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.


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The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the patient is on study treatment, as documented in the DAR eCRF.
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero 
for that drug.
2.5.1.4
Dose intensity and relative dose intensity
Dose intensity (DI) for patients with non-zero duration of exposure is defined as follows:

For the Q4W regimens: DI (mg/28 days) = 28 * Actual cumulative dose (mg) / Actual 
duration of exposure = 28 * Actual cumulative dose (mg) / [Last dosing date – First dosing 
date + Dose interval (28 days)].

For the Q2W regimens: DI (mg/14 days) = 14 * Actual cumulative dose (mg) / Actual 
duration of exposure = 14 * Actual cumulative dose (mg) / [Last dosing date – First dosing 
date + Dose interval (14 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 the Q4W regimens: PDI (mg/28 days) = Planned dose (mg) per cycle (28 days).

For the Q2W regimens: PDI (mg/14 days) = Planned dose (mg) per cycle (14 days).
Relative dose intensity (RDI) is defined as follows:
RDI = DI / PDI.
The duration of exposure considered for the derivation of the DI and the RDI will be derived 
from the start date of study treatment (first dosing date) to the end of the last cycle initiated (last 
dosing date + dose interval, where dose interval is 28 or 14 days for Q4W or Q2W schedule, 
respectively), irrespective of date of death, date of last contact and cut-off date.
DI and RDI (including categories: ≤75%, > 75% - ≤90%, > 90% - ≤110% and > 110%) will 
be summarized separately for each of the study treatment components, using the duration of 
exposure of each of the components.
2.5.1.5
Dose reductions, interruptions or permanent discontinuations
The number of patients who have dose reductions, permanent discontinuations or interruptions, 
and the reasons, will be summarized separately for each of the study treatment components.
‘Dose changed’, ‘Dose interrupted’ and ‘Dose permanently discontinued’ fields from the DAR 
eCRF pages will be used to determine the dose reductions, dose interruptions, and permanent 
discontinuations, respectively. Dose reductions will be derived programmatically using the 
dosing information as described below.
The corresponding fields ‘Reason for dose change/dose interrupted’ 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’, ‘dispensing error’, 
etc., where actual dose administered is different from the prescribed dose.


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Dose interruption: Actual dose equal to zero, between the first and last non-zero doses, 
following a non-zero actual dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days/time periods with different reasons will be 
counted as separate interruptions. However, if the reason is the same in this mentioned multiple 
entries on consecutive days, then it will be counted as one interruption.
Intermediate interruptions that end up in a non-zero dose administration should not be 
considered dose interruptions.
Dose reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered is lower than the calculated dose 
amount based on the prescribed dose. Only dose change is reported in the eCRF, number of 
reductions will be derived programmatically based on the change and the direction of the change.
2.5.2
Prior, concomitant and post therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system. The non-drug therapies will be coded 
using MedDRA.
Any concomitant therapies starting prior to or after the start of study treatment will be listed.
Imputation rules regarding last and first treatment administration of concomitant therapies can 
be found in Appendix, Section 5.1.3.
2.6
Analysis of the primary objective
Phase I-Ib parts
To characterize the safety and tolerability of MBG453 as a single agent in ROW and Japanese 
patients separately and in combination with PDR001 and to identify recommended doses for 
future studies.
Phase I-Ib dose ranging part
To further investigate the safety and tolerability of different doses of the MBG453 as single 
agent or in combination with PDR001 (optional). 
Phase II part
To estimate the anti-tumor activity of MBG453 as single agent and in combination with 
PDR001.


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2.6.1
Definition of the primary endpoint
2.6.1.1
Phase I-Ib parts

Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs

Tolerability: Dose interruptions, reductions and dose intensity

Incidence of DLTs:
-
For MBG453 single agent, in the first cycle of treatment. 
-
For MBG453 in combination with PDR001, in the first two cycles of treatment. 
Estimation of the MTD(s)/RP2D(s) will be based upon the estimation by the BHLRM (phase I) 
or BLRM (phase Ib) of the probability of a DLT in the DLT window for patients in the 
applicable analysis set.
2.6.1.2
Phase I-Ib dose ranging part

Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs

Tolerability: Dose interruptions, reductions and dose intensity.
2.6.1.3
Phase II part
Overall Response Rate (ORR): is defined as the proportion of patients with a best overall 
response of CR or PR based on local Investigator assessment, as defined in RECIST v1.1 (see 
Appendix 1 of the protocol).
Estimation of the true ORR in this part of the study will be based upon the observed ORR for 
patients in FAS, using Bayesian analysis.
2.6.2
Statistical hypothesis, model, and method of analysis
2.6.2.1
Phase I-Ib parts
Safety and Tolerability
See Section 2.9 for details on safety analysis
Phase I part single agent MBG453 dose escalation
A Bayesian hierarchical logistical regression model (BHLRM) will be applied to estimate the 
relationship between dose and the probability of a patient experiencing a DLT for patients 
treated every two weeks (Q2W, stratum 1) and patients treated every four weeks (Q4W, stratum 
2).
The standard Bayesian hierarchical model assumes full exchangeability of strata parameters; 
for the methodology and an application to binary data (Thall 2003, Chugh 2009). Here, we 
extend the standard Bayesian hierarchical model to dose-toxicity data, and exchangeable as well 
as non-exchangeable strata parameters. 


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In order to facilitate the inclusion of prior data in the model, a third stratum is added to the 
model. This additional stratum incorporated dose/DLT data from the dose escalation of PDR001, 
another checkpoint inhibitor expected to have a similar dose/toxicity profile to MBG453. By 
incorporating the prior data in this way the exchangeability (or otherwise) of the prior data with 
the on-study data will be assessed in an ongoing fashion, and if necessary the model will be 
able to compensate for differences between the prior data and data seen in the dose escalation 
of MBG453. 
For the three patient strata, the probability of experiencing a DLT is modeled as follows:
logit
	

 = log
 +  log( 240
⁄
)
logit
	

 = log
 +  log( 240
⁄
)
logit
	

 = log() +  log( 240
⁄
)
where  denotes dose; 240 is a fixed reference dose for each respective strata; 
	

	
, and 

	
, are the probability of a patient experiencing a DLT at dose  on the Q2W and Q4W 
dosing schedules, and in the CPDR001X2101 study respectively; and the parameters  =
log(), log()
, 
 = log(), log()
, 
and 
 =
(log(), log()), describe the relationship between dose and toxicity for the three strata.
We further allow the parameters , , and , to be either exchangeable or non-
exchangeable, with probability , 1 −
,
, 1 −
, and (, 1 −
) respectively.

Under exchangeability, the parameters , , and  are assumed to follow a 
bivariate normal distribution:
, ,  ~ #$%(&'()*, S'()*)
Prior distributions for the parameters &'()* and S'()* of the exchangeability distribution 
complete the model specifications for the exchangeability component of the model: 
&'()* ~ ,-, S'()*~ ./
The prior distributions for &'()* will be normal and the prior distributions for the standard 
deviations and the correlation in S'()* will be log-normal and uniform, respectively.

Under non-exchangeability, the parameters  and , and  are assumed to have 
a weakly informative bivariate normal prior distribution.
, ,  ~ #$%(&0, S0).
Phase I part single agent MBG453 dose escalation with Japanese patients
Further, two BHLRM guided by EWOC principle will be used to make dose recommendations 
and estimate the MTD(s)/RP2D(s) during the dose escalation of the Japanese patients for both 
Q2W and Q4W schedules. Currently, available information about the dose-DLT relationships 
of single agent MBG453 in ROW patients will be used to inform the dose-DLT relationship of 
Japanese patients by taking into consideration of heterogeneity between Japanese patients 
(stratum 1) and ROW patients (stratum 2). For further details on the statistical model including 


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the prior specification for the model parameters refer to Section 14.3 (Appendix 3) of the 
protocol. Data from the ROW patients will be updated in the model on an ongoing basis during 
the course of the study.
Phase Ib part combination of MBG453 and PDR001 dose escalation
For the combination phase Cycle 1 and Cycle 2, a 5-parameter model is used:
logit123,4
	

 = log123,4
 + 123,4 log123,4
5.7
2405.7
⁄

logit,4
	

 = log,4
 + ,4 log,4
5.7
2405.7
⁄

where i = 1 and 2 for Cycle 1 and 2, respectively; logit(.
	) = log[ .
	/{1- .
	 }]; 240 is the 
reference dose of both MBG453 and PDR001.
Under independence, the odds of a DLT during cycle i at a given combination is 
123,4
	
+ ,4
	
−123,4
	
,4
	
(1 −123,4
	
)(1 −,4
	
)
The possibility of synergism or antagonism between the safety profiles of the two drugs is then 
captured in modifying the odds by a dose-dependent factor:
89123:,4
	
=
123:,4
1 −123:,4
= exp >? 123,4
5.7
2405.7
@
,4
5.7
2405.7
@
A 123,4
	
+ ,4
	
−123,4
	
,4
	
(1 −123,4
	
)(1 −,4
	
)
Here,

123,4 and ,4 are the odds of a DLT at the reference doses;

123,4 and ,4 are the increase in the log-odds of a DLT by a unit increase in the log of 
the square root of dose;

? is the interaction term. 
The model is fitted to data from those patients eligible for the Cycle 1 and Cycle 2 risk sets (see 
Section 10.1.4 of the protocol), and provides estimates of the cumulative risk of DLT 
(B123:) up to the end of cycle 2 given doses 123,4 and ,4 for i = 1,2. This cumulative 
risk is calculated as follows:
B123: = 123:,C + 1 −123:,C
 × 123:,
No combination that exceeds the EWOC criteria (Section 6.2.3.1 of the protocol) will be 
considered for the next combination doses. A dose will not be tested in the Cycle 2 before 
having being studied successfully in Cycle 1. Any dose in Cycle 2 is always equal to or lower 
than the dose used in Cycle 1.


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Optional: additional dose escalation using Q4W dosing schedule during Phase 
Ib dose escalation part
Should the optional dose escalation for MBG453 in combination with PDR001 following a 
Q4W dosing schedule take place, then a new model will be constructed. This model will follow 
the same functional form as that described above. Data from the Q2W dose escalation will be 
used to construct an informative prior distribution, which will be derived prior to first patient 
first treatment on the new dosing schedule. The priors will be fully documented in the RAP.
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels (or combinations) are obtained. Dose recommendation will be based on 
posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories:

[0,16%) under-dosing

[16%,33%) targeted toxicity

[33%,100%] excessive toxicity
For the MBG453 single agent and MBG453
in combination with PDR001 dose 
recommendation will also be guided by the EWOC principle, which mandates the dose for the 
next cohort and the full 2 cycle period for the combination to have less than 25% chance of 
excessive toxicity. 
The final estimate of the MTD(s)/ RP2D(s) will also satisfy this condition.
Listing of DLTs
DLTs will be listed and their incidence summarized by primary system organ class, preferred 
term and worst grade based on the CTCAE version 4.03. The DDS will be used for these 
summaries. 
2.6.2.2
Phase I-Ib dose ranging part
Safety and Tolerability
See Section 2.9 for details on safety analysis.
2.6.2.3
Phase II part
A Bayesian design will be used in order to estimate ORR for each of the following patient 
groups. The primary analysis will be on ORR as defined under RECIST 1.1.
MBG453 single agent

Up to two indications for which response has been observed in the phase I dose escalation
MBG453 in combination with PDR001

Group 1: Melanoma (naïve to anti-PD-1/PD-L1)

Group 2: Melanoma (pre-treated with anti-PD-1/PD-L1)


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
Group 3: NSCLC (naïve to anti-PD-1/PD-L1)

Group 4: NSCLC (pre-treated with anti-PD-1/PD-L1)

Group 5: RCC (naïve to anti-PD-1/PD-L1)

Group 6: RCC (pre-treated with anti-PD-1/PD-L1)
Note that for one of the combination phase II groups an exploration of Q2W versus Q4W dosing 
may be conducted. Data from the two dosing schedules will be summarized separately.
Groups 1, 3, 5 and 6 were finaly not populated and no patient was treated in a Q2W dosing at 
phase II. As a result, no outputs will be produced for those groups.   
Initially, approximately 15 patients will be enrolled to each of the above defined patient groups. 
Should enrollment for any of these groups not be feasible, then enrollment to that group may 
be closed before the 15 patient target is met. Should 3 or more responses be observed in any 
patient group, then enrollment to that group may be extended to 25 patients.
For all patient groups, a minimally informative unimodal beta prior distribution of the true ORR 
is derived as follows. A priori it is assumed that the true mean of the ORR equals 20%. A true 
ORR of 20% is the midpoint between limited and moderate efficacy and serves as a compromise 
between a skeptical view assuming the treatment has only limited efficacy and an optimistic 
view assuming the treatment has moderate efficacy. The parameter of the minimally 
informative beta prior distribution of the ORR are then derived as a = 1/4 and b = 1.
At completion of the study, this prior distribution will be updated with all of the data available. 
Once updated, the estimate of ORR and probabilities that the true ORR lies in the following 
categories will be reported:

[0, 10%) unacceptable efficacy

[10%, 20%) limited efficacy

[20%, 50%) moderate efficacy

[50%, 100%] clinically relevant efficacy
For patient groups with a minimum of 15 patients, if the observed ORR is equal to or greater 
than 20%, then this will be considered as preliminary evidence of at least moderate efficacy in 
the respective patient group. 
For n = 15, if the observed ORR is less than 10% (i.e. 1 CR or PR), then unacceptable efficacy 
will be concluded. If the observed ORR is greater than or equal to 20% (i.e. ≥ 3 CR or PR), then 
the true ORR has a posterior probability of 85.4% of at least limited efficacy.
For n = 25, if the observed ORR is less than 10% (i.e. < 3 CR or PR), then unacceptable efficacy 
will be concluded. If the observed ORR is greater than or equal to 20% (i.e. ≥ 5 CR or PR), then 
the true ORR has a posterior probability of 92.1% of at least limited efficacy.
Operating characteristics of the design can be found in Table 3-2.
2.6.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the 
BLRM analysis, although their data will be used for all remaining analyses. 


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Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be 
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST v1.1 (see Appendix 1 of the protocol) and 
irRC (see Appendix 2 of the protocol).
Other missing data will simply be noted as missing on appropriate tables/listings.
2.6.4
Supportive analyses
ORR and corresponding 90% confidence intervals (CIs) based on the exact binomial 
distribution will also be presented.
For the phase II part, the primary analysis on ORR will be repeated using the PPS. Additional 
supportive 
 analyses will be conducted to support the primary objective, if 
considered appropriate.
2.7
Analysis of key secondary efficacy objective(s)
Not applicable.
2.8
Analysis of secondary efficacy objective(s)
Phase I-Ib parts
To evaluate the preliminary anti-tumor activity and the survival distribution of patients treated 
with MBG453 single agent or in combination with PDR001.
Phase II part
To evaluate the preliminary anti-tumor activity and the survival distribution of patients treated 
with MBG453 single agent or in combination with PDR001.
To make an initial comparison for MBG453 and PDR001 administered in combination on a 
Q2W and Q4W dosing schedules. As no patients were treated on a Q2W dosing schedule in 
phase II part of the study, this objective will not be analyzed. 
2.8.1
Definition of secondary endpoints
2.8.1.1
Phase I-Ib/II parts
ORR per irRC, Best Overall Response (BOR) per RECIST v1.1and irRC, Progression-free
Survival (PFS) per RECIST v1.1 and irRC and Duration of Response (DOR) per RECIST v1.1, 
Overall survival (OS).
Definitions of the relevant endpoints is given below:

Best Overall Response (BOR): is defined as the best response recorded from the start of 
the treatment until disease progression/recurrence as defined for RECIST v1.1 and irRC. 
Complete and partial responses must be confirmed by repeat assessments that should be 
performed not less than 4 weeks after the criteria for response are first met. Additionally, 
for irRC, progressive disease should be confirmed in a similar manner.

Overall Response Rate (ORR): see Section 2.6.1.2.


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
Progression-free Survival (PFS):

For RECIST v1.1, PFS is defined as the time from the date of start of treatment to the 
date of the first documented progression or death due to any cause.

For irRC, PFS is defined as the time from the date of start of treatment to the date of 
the first documented and confirmed progression, or death due to any cause. 
Progressive disease should be confirmed by a repeat assessment that should be 
performed not less than 4 weeks after the criteria for progression are first met. The date 
of progression will then be the date of the first of these two assessments. 
For patients without a confirmation assessment, and with no subsequent assessments 
of SD, or better, a single assessment will be used as date of progression. 
If a patient has not experienced an event at the time of the analysis or has started a new 
anticancer therapy, PFS will be censored at the date of the last adequate tumor 
evaluation before the start of a new anticancer therapy, if any.

Duration of Response (DOR): is defined for responder as the time between the date of first 
documented response (CR or PR) and the date of first documented progression or death due 
to underlying cancer (“study indication” - see section 0). 
If progression or death due to underlying cancer (“study indication”) has not occurred or 
patient has started a new anticancer therapy, then the patient is censored at the date of last 
adequate tumor assessment before the start of a new anticancer therapy, if any.

Overall Survival (OS): is defined as the time from date of start of treatment to date of death 
due to any cause. 
If a patient is not known to have died, OS time will be censored at the date of last contact.
2.8.1.2
Phase II part (combination)
ORR per irRC, BOR per RECIST v1.1 and irRC, PFS per RECIST v1.1 and irRC and DOR per 
RECIST v1.1 and OS (see definition of endpoints in 2.8.1.1).
2.8.2
Statistical hypothesis, model, and method of analysis
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. BOR will be listed and tabulated. BOR will be summarized as observed 
proportion for each treatment group/patient group, and corresponding 90% exact CI.
The primary analysis of ORR will be as described in Section 2.6.2.3. Additionally, ORR will 
be summarized as point estimate and corresponding 90% exact confidence interval (CI) 
according to Clopper-Pearson method (Clopper and Pearson, 1934).
A Kaplan-Meier plot for PFS will be presented. Median PFS (in months) with corresponding 
90% CI, 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 
1997) and Kaplan-Meier estimated probabilities (PFS rate) with corresponding 90% CIs 
(Greenwood’s formula, Kalbfleisch and Prentice 1980) at several time points (6, 12, 18 and 24 
months) will be presented for each treatment group/patient group. The number (%) of 
progressions, deaths and censored patients will also be summarized.


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OS data will be listed for all patients enrolled in the Phase I-Ib and Phase II parts. A Kaplan-
Meier plot for OS will be presented. Median OS (in months) with corresponding 90% CI, 25th 
and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) and 
Kaplan-Meier estimated probabilities (OS rate) with corresponding 90% CIs (Greenwood’s 
formula, Kalbfleisch and Prentice 1980) at several time points (6, 12, 18 and 24 months) will 
be presented for each treatment group/patient group. The number (%) of deaths and censored 
patients will also be summarized.
DOR will be listed for all patients who achieved a response of CR or PR. Only if there is a large 
enough number of patients achieving response (i.e. 10 or more patients), a Kaplan-Meier plot 
for DOR will be also be produced and presented. Median DOR (in months) with corresponding 
90% CI, 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 
1997) and Kaplan-Meier estimated probabilities (DOR rate) with corresponding 90% CIs 
(Greenwood’s formula, Kalbfleisch and Prentice 1980) at several time points (6, 12, 18 and 24 
months) will be presented. The number (%) of progressions, deaths due to underlying cancer
(“study indication”) and censored patients will also be summarized.
Construction of waterfall graphs
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient for 
RECIST v1.1, and best percentage change from baseline in the Total Measured Tumor Burden 
(TMTB) for irRC. The FAS will be used. 
2.8.3
Handling of missing values/censoring/discontinuations
Patients in the phase II part who have BOR of Unknown (UNK) or not assessed (NA) will be 
considered as a treatment failure in the primary analysis of ORR. Patients with individual scans 
of UNK or NA will be handled according to RECIST v1.1 (see Appendix 1 of the protocol) and 
irRC (see Appendix 2 of the protocol). If any new anticancer therapy (see Section 2.1.1) is taken 
while on study, any subsequent assessments will be excluded from the best overall response 
determination.
For the analysis of PFS, patients without documented disease progression or death due to any 
cause will be censored at the time of last adequate tumor assessment documenting non-
progression (one of complete response, partial response, or stable disease) before the start of a 
new anticancer therapy (see Section 2.1.1), if any. Patients without any valid post-baseline 
tumor assessment response (one of CR, PR, SD, or PD) will be censored on the start date of 
treatment. Patients who have a PFS event (progression or death due to any cause) after two or 
more consecutive missing assessments from the last valid tumor assessment will be censored 
on the last valid tumor assessment (or on the start date of treatment among those without a 
postbaseline tumor assessment).
For the analysis of DOR, patient without documented disease progression or death due to 
underlying cancer (“study indication”) will be censored at the date of last adequate tumor 
assessment documenting non-progression (one of complete response, partial response, or stable 
disease) before the start of a new anticancer therapy (see Section 2.1.1), if any.


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For the analysis of OS, patient without an event (death) will be censored at the date of last 
contact.
Other missing data will simply be noted as missing on appropriate tables/listing.
2.9
Safety analyses
The assessment of safety is based on the type and frequency of Adverse Events (AEs) as well 
as on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs.
The Safety set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used.
For all safety reporting the overall observation period and safety summaries will follow the 
instructions mentioned in section 2.1.1.
2.9.1
Adverse events (AEs)
Adverse events will be coded using the latest available version of the Medical dictionary for 
regulatory activities (MedDRA) and assessed according to the Common Terminology Criteria 
for Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an AE, grades 
1, 2, 3, or 4 corresponding to the severity of mild, moderate, severe, and life-threatening, 
respectively, will be used. 
The following AE summaries will be produced:

AEs regardless of study drug relationship (including CTCAE grade 3/4)

AEs suspected to be study drug related (including CTCAE grade 3/4)

AEs regardless of study drug relationship leading to discontinuation of study drug

AEs suspected to be study drug related leading to discontinuation of study drug

AEs regardless of study drug relationship requiring dose adjustment or study drug 
interruption

SAEs regardless of study drug relationship

SAEs suspected to be study drug related
Complete listings of AEs as well as AEs for not treated patients will also be provided.
2.9.2
Deaths
CTCAE grade 5 (death) will not be used in this study. Death information will be collected on 
the “Death” eCRF as well as on the following disposition eCRF pages: “End of screening”, 
“End of treatment” and End of post treatment phase” disposition).
The following summaries will be produced:

On-treatment deaths with cause of death by preferred term

All deaths with cause of death by primary system organ class and preferred term


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2.9.3
EudraCT and clinicaltrials.gov requirements for AEs and Deaths 
summaries

For the legal requirements of clinicaltrials.gov and EudraCT, two on-treatment tables 
are required.On-treatment deaths resulting from SAEs suspected to be study drug related 
and SAEs regardless of study drug relationship by SOC and PT.

Non-serious AEs regardless of study drug relationship, with an incidence rate greater 
than 5% by SOC and PT.  
These summaries will include any events starting or worsening in the on-treatment period. 
If for the same participant, several consecutive AEs (irrespectively 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. 
The presence of at least one SAE / SAE suspected to be study drug related / non SAE has to be 
checked in a block e.g., among AEs in a ≤ 1 day gap block, if at least one SAE is occurring, 
then one occurrence is calculated for that SAE.
2.9.4
Adverse events of special interest / grouping of AEs
An adverse event of special interest (AESI) is a grouping of adverse events that are of scientific 
and medical concern specific to compound MBG453. These groupings are defined using 
MedDRA terms, SMQs (standardized MedDRA queries), HGLTs (high group level 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. These searches will be defined in the eCRS (electronic Case Retrieval Strategy) 
in the DMS (Document Management System) and a listing of search terms will be provided in 
the CSR.
Especially for the MBG453X2101 study, the following two safety topics of interest will only 
be presented as they were considered relevant by the study team:  

Immune mediated disorders

Infusion related reactions
For each specified AESI, number (%) of subjects with at least one event of the AESI occurring 
during on treatment period will be summarized together with the individual preferred terms in 
that grouping.
2.9.5
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE v4.03. Grade 5 will not be used.


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A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher.
For other cases, a Grade 0 CTC grade will be set when laboratory value is:

Within LLN and ULN and grading in both direction,

Below ULN and grading in hyper direction,

Above LLN and grading in hypo direction.
Laboratory data for which a CTC grading does not exist will be classified into low, normal, or 
high based on local laboratory normal ranges as applicable.
Laboratory summaries will include all assessment available for the laboratory parameters 
collected no later than 30 days after the last study treatment administration date.
The following summaries will be produced for hematology and coagulation, biochemistry 
parameters:

Worst post-baseline abnormalities

For parameters with CTC grades: Worst post-baseline abnormalities based on CTC grades 
for hematology and biochemistry, as well as Shifts from baseline to the worst on-treatment
CTC  grade for hematology and biochemistry,

For parameters with no CTC grades defined: Shifts from baseline to the worst on-
treatment classification, using the low/normal/high classifications,
The following listings will be produced:

Listing of patients with laboratory abnormalities of CTC grade 3 and 4

Listing of patients with Virology parameter assessment
Table 2-2and Table 2-3 list all laboratory parameters that will be summarized.
Table 2-2
Laboratory parameters for which CTCAE grades are defined
Hematology and 
coagulation
Biochemistry
White Blood Cells 
(WBC)
↑
↓
Creatinine
↑
Hemoglobin
↓
Sodium
↑
↓
Platelets counts
↓
Potassium 
↑
↓
Absolute Neutrophils
↓
Calcium
(corrected for 
Albumine)
↑
↓
Absolute Lymphocytes
↑
↓
Magnesium 
↑
↓
APTT
↑
Albumin
↓
INR
↑
AST (SGOT)
↑
ALT (SGPT)
↑


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Total Bilirubin
↑
Inorganic 
Phosphate
↓
Glucose (fasting)
↑
↓
Amylase
↑
Lipase
↑
Alkaline 
Phosphatase
↑
↑Indicates that CTC grade increases as the parameter increases.
↓Indicates that CTC grade increases as the parameter decreases.
Table 2-3
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined
Hematology 
and 
coagulation
Biochemistry
Prothrombin 
time (PT)
Blood urea nitrogen (BUN) / 
Urea
Absolute 
Basophils
Absolute 
Eosinophils
TSH
Absolute 
Monocytes
Total T4
Hematocrit
Direct bilirubin                       
Indirect bilirubin           
Chloride
Bicarbonate
2.9.6
Other safety data
2.9.6.1
ECG and cardiac imaging data
As described in Section 2.1.1, baseline is the last available and valid assessment performed or 
value measured on or before the date of first administration of study treatment. Especially for 
ECG, where study requires multiple replicates per timepoint, the average of all these available 
ECG measurements associated with the baseline assessment will be calculated. Scheduled study 
day 1 pre-dose ECGs will be considered to have been obtained prior to study drug 
administration if dosing time is missing.
If a patient has more than one post-baseline measurement at a specific time point, the average 
of all available measurements associated with the nominal time point will be used for the 
analyses. Especially for the EOT visit, the average of all available measurements associated 
with the EOT visit will be used for the analyses.
ECG data will be reviewed and processed centrally by a specialist CRO.


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The following summaries will be provided for each applicable ECG parameter:

Number (%) of patients having notable ECG values according to Table 2-4.
Table 2-4
Criteria for notable ECG values
ECG parameter
Criteria for notable ECG values
QT, QTcF(ms)
New: > 450, > 480, > 500 ms
Increase from baseline >30 ms, >60 ms
HR (bpm)
Increase from baseline >25% and new value >100 bpm
Decrease from baseline >25% and new value <50 bpm
PR (ms)
New: >200 ms
Increase from baseline >25% and new value >200 ms
QRS (ms)
New: > 120 ms
Increase from baseline >25% and new value >120 ms
A listing of all notable ECG assessments will be produced by treatment arm. In the listing, the 
assessments collected during the post-treatment period will be flagged.
2.9.6.2
Vital signs
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), respiratory rate (breaths per minute), body temperature (°C), and weight 
(kg). Vital sign values considered notably abnormal are defined in Table 2-5.
Table 2-5
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values
Systolic blood pressure 
[mmHg]
High: ≥180 mmHg with increase from baseline of ≥20 mmHg 
Low: ≤90 mmHg with decrease from baseline of ≥20 mmHg
Diastolic blood pressure 
[mmHg]
High: ≥105 mmHg with increase from baseline of ≥15 mmHg 
Low: ≤50 mmHg with decrease from baseline of ≥15 mmHg
Pulse rate [bpm]
High: ≥100 bpm with increase from baseline of ≥25 bpm
Low: ≤50 bpm with decrease from baseline of ≥25 bpm
Body temperature [°C]
High: ≥39.1 °C
Weight [kg]
High: ≥10% increase from baseline
Low: ≥10% decrease from baseline

Vital signs table based on values classified as notable low or notable high will be produced.

Patients with any clinically notable vital sign value will be listed.
2.9.6.3
Tolerability
Tolerability of study treatment will be assessed by summarizing the number of dose 
interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group. 
Cumulative dose, dose intensity and relative dose intensity of study treatment (see Section 2.5) 
will be also be used to assess tolerability.


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2.10
Pharmacokinetic endpoints
All PK analyses will be performed based on the PAS. Patient data may be removed on an 
individual basis.
PK parameters will be calculated using noncompartmental methods and summarized as 
described in Table 2-6. The PK parameters considerd primary are AUClast, AUCtau, Cmax, 
and Tmax. Other PK parameters (CL, V, T1/2, AR) are considered as secondary. All PK 
parameters or as appropriate they will be summarized in tables and  will be listed.
Concentration values below the lower limit of quantitation (LLOQ) (< 1.0 μg/mL) or missing
data will be handled as zero in summary statistics and figures. PK concentration values will be 
fully listed.
Descriptive statistics of all pharmacokinetic parameters will include arithmetic and geometric 
mean, median, SD, and CV, geometric CV, minimum and maximum. Zero concentrations will 
not be included in the geometric mean calculation. Since Tmax is generally evaluated by a 
nonparametric method, median values and ranges will be given for this parameter.
Summary statistics will be presented for MBG453 and PDR001 serum concentrations at each 
scheduled time point. Descriptive graphical plots of mean concentration versus time profiles 
will be generated.
Further analyses may be conducted using population PK approaches. In addition, a model based 
approach may be used to explore the potential relationship between efficacy, safety, and/or 
biomarker endpoints (e.g., soluble receptor and/or receptor occupancy) and MBG453 and/or 
PDR001 concentration and/or exposure metrics. All analyses will be reported either in the CSR
or a stand-alone report.
Table 2-6
PK parameters – descriptive statistics
Parameters
Descriptive statistics
AUCtau, AUClast, Cmax
Mean, standard deviation, CV% mean, geometric mean, 
CV% geometric mean, median, minimum and maximum
Tmax
Median, minimum and maximum
CV% = coefficient of variation (%) = sd/mean*100
CV% geometic mean = sqrt (exp (variance for log transformed data)-1)*100
Dose proportionality and day effect
Analysis of dose-proportionality will be performed if at least three doses of MBG453 are 
investigated. Same applies for the analysis of dose-proportionality of PRD001.
Cmax and AUC will be used for dose proportionality analysis using the power model (Gough 
1995). The power model empirical relationship between a PK parameter and dose is of the form




dose
Exp
PK 
,
where “PK” represents the PK parameter AUCinf or Cmax. For analysis, this equation is log-
transformed (natural log), obtaining the equation




Dose
PK
e
e
log
log



,




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Determinant samples are defined as samples which are not unevaluable (where unevaluable = 
sample where assay is not available).
The following definitions apply only to determinant samples:
o ADA-negative sample: Determinant sample where assay is ADA negative. and PDR001 
or MBG453 PK concentration at the time of IG sample collection is less than the drug 
tolerance level. 
o ADA-positive sample: Determinant sample where assay is ADA positive.
o ADA-inconclusive sample: Sample where assay is ADA negative and PDR001 or 
MBG453 PK concentration at the time of IG sample collection is greater than or equal 
to the drug tolerance level or missing.  
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing:
o
Treatment-induced ADA-positive sample: ADA-positive sample post-baseline with 
ADA-negative sample at baseline. 
o
Treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with 
titer that is at least the fold titer change greater than the ADA-positive baseline titer.
o
Treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with 
titer that is less than the fold titer change greater than the ADA-positive baseline titer.
NOTE: PK concentrations which are flagged for exclusion will still be used to determine ADA-
inconclusive and ADA-negative samples.
The following summaries of ADA sample status (n and %) will be provided using 
Immunogenicity prevalence set: 

ADA-positive samples (i.e. ADA prevalence) overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of subjects at 
that time point with a determinant sample.
Listings will be provided of sample ADA status (including titer for positive samples).
2.12.1.2 Subject ADA status
Any IG sample collected after 150 days or more form the last dose administration of PDR001
or MBG453 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. 






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The following listings will be produced for interpretable data:

CD8+ expression at screening

PD-L1 expression at screening

TIM-3 expression at screening

LAG-3 expression at screening

CD163 expression at screening

FOXP3 expression at screening

TILS intratumoral presence at screening
Usual descriptive statistics will be displayed for interpretable biomarker data:

Mean, standard deviation, median, minimum, and maximum for quantitative data 
measured at baseline

N, % in each category for categorical data
If there are post-baseline data available the following descriptive statistics will be presented:

Mean, standard deviation, median, minimum, and maximum of raw data, absolute change 
from baseline and relative change form baseline (depending on the biomarker) for 
quantitative data measured at baseline and at different time points.
Descriptive statistics computed for each time point separately.


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
In case we have more than one measurements on the same day, then the average of those 
measurements will be used. Reason for this is to acount for cases where more than one slides 
of the same patient and at the same time-point were analyzed. 
2.16
Interim analysis
An interim analysis was performed and reported in an interim CSR (iCSR), as it was considered 
appropriate by the study team. 
3
Sample size calculation
Phase I-Ib dose escalation parts
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD(s)/RP2D(s) level, as described in Section 6.2.3 of the protocol. Multiple 
cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 patients 
may be enrolled at any dose level below the estimated MTD(s)/RP2D(s) for further elaboration 
of safety and pharmacokinetic parameters as required. At least 21 patients are expected to be 
treated in the single agent and 15 patients are expected to be treated in the combination of in 
the dose escalation part, for the model to have reasonable operating characteristics relating to 
its MTD recommendation.
Phase I-Ib dose ranging part (optional)
A sample size of approximately 30-50 patients with advanced solid tumors will be treated at 
different dose levels of MBG453 alone or in combination with PDR001. The aim is to gain 
more information about the overall safety and tolerability, and to provide additional PK and PD 
data to guide the selection of dosing for future studies with the combination and identify anti-
tumor activity. A minimum of 30 patients will result in 95.8% probability of detecting at least 
one special adverse event of interest with a true rate of 10%. This probability rises as the true 
adverse event rate increases. 
There is no statistical hypothesis being tested for efficacy within this group. Patients within this 
group will have their activity monitored to assess if there is any indication of potential impact 
on tumor lesions, and the data will be used for internal decision making on the future 
development of the combination in alternative indications and dose levels. 
Table 3-1
Probability to detect at least one special adverse event of interest
Special AE of interest 
incidence rate
Number of patients
10
20
30
50
10%
0.651
0.878
0.958
0.995


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Special AE of interest 
incidence rate
Number of patients
15%
0.803
0.961
0.992
1.000
20%
0.893
0.988
0.999
1.000
Phase II part
Approximately 15 patients will be initially enrolled to each of the patient groups. However, 
should enrollment for any of these groups not be feasible, then enrollment to that group may be 
closed before the 15 patient target is met. Any of the groups may be extended to approximately 
25 patients in the event that 3 or more responses are observed.
The operating characteristics of the design is shown in Table 3-2, including the probability of 
stopping the enrollment at 15 patients (fewer than 3 responses in the first 15 patients) and 
posterior probability of true ORR of at least limited efficacy. It was assessed how likely it is to 
wrongly declare activity as defined by observing at least “moderate efficacy” (i.e. seeing ≥ 5 
responses out of 25 patients) given the true ORR = 10%, and how likely it is to correctly declare 
activity given the true ORR = 30% when 25 patients are evaluated.

If the true ORR = 10%, the probability to wrongly declare activity is 9.8%.

If the true ORR = 30%, the probability to correctly declare activity is 91.0%.
Table 3-2
Operating characteristics of the design for ORR
Pr(observe < 20% responses in N patients)
N / True ORR
0.1
0.15
0.2
0.25
0.3
0.4
10
73.6
54.4
37.6
24.4
14.9
4.6
15
81.6
60.4
39.8
23.6
12.7
2.7
20
86.7
64.8
41.1
22.5
10.7
1.6
25
90.2
68.2
42.1
21.4
9.0
0.9
Posterior probability of a true ORR corresponding to at least limited efficacy (i.e. ≥10%)
N / True ORR
0.1
0.15
0.2
0.25
0.3
0.4
10
44.7
64.5
79.5
89.3
94.9
99.1
15
45.5
69.2
85.4
94.1
98.0
99.8
20
46.0
72.8
89.4
96.7
99.2
100
25
46.4
75.8
92.1
98.1
99.6
100
Testing of Q2W versus Q4W dosing scheduling during the Phase II 
combination part
To facilitate comparison between Q2W and Q4W dosing in the chosen indication, patients will 
be randomized between the two dosing schedules. Initially 15 patients will be enrolled to each 
arm, should 3 or more responses be observed in either arm, then enrollment for both arms will 
be extended to 25 patients. 
4
Change to protocol specified analyses
Confidence intervals for all endpoints was set to 90% for consistency in the study results.


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For DOR, summaries of estimates using the Kaplan-Meier method will be reported only if there 
is a large enough number of patients achieving response (i.e. 10 or more patients). Definition 
of the per-protocol analysis set was updated, as this was considered more relevant by the study 
team.
Additional analysis sets were included (immunogenicity prevalence set and immunogenicity 
incidence set) for the analysis of immunogenicity data. An update of the definitions of the 
sample determinants was decided by the study team in order be consistent across studies of the 
same program.After protocol amendment 6 (31-Aug-2020) the following changes have been 
implemented: 

For the phase Ib/II part of MBG453 in combination with decitabine, as it was decided by 
Novartis to not open enrolment, no outputs will be presented in the CSR.
Various minor changes were applied in the analysis described in the protocol, as considered 
appropriate by the study team.
All changes were defined in the statistical analysis plan before the data base lock.
4.1
Planned analysis due to COVID-19
The COVID COVID-19 pandemic had minimal impact on this study because at the start of the 
pandemic, the vast majority of subjects had discontinued the study treatment and completed the 
safety follow-up phase. COVID-19 specific protocol deviations will be included in the protocol 
deviation listing.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
Not applicable.
5.1.2
AE date imputation
A missing AE start date will be imputed using the following logic matrix described in Table 5-
1.
Table 5-1
Imputation rules for a partially missing AE start date
AEM MISSING
AEM < TRTM
AEM = TRTM
AEM > TRTM
AEY MISSING
No imputation
No imputation
No imputation
No imputation
AEY < TRTY
(D)
(C)
(C)
(C)
AEY = TRTY
(B)
(C)
(B)
(A)
AEY > TRTY
(E)
(A)
(A)
(A)
AEM: Month AE started; AEY: Year AE started


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TRTM: Month treatment started; TRTY: Year treatment started
Table 5-2 is the legend to the logic matrix shown in Table 5-1 and details the relationship of 
AE start date to study treatment start date.
Table 5-2
Imputation legend and AE/treatment start date relationship
AE start date relationship
Imputation
(A)
After treatment start or Uncertain
MAX( 01MONYYYY, TRTSTD+1 )
(B)
Uncertain
TRTSTD+1
(C)
Before treatment start
15MONYYYY
(D)
Before treatment start
01JULYYYY
(E)
After treatment start
01JANYYYY
Before treatment start: Partial date indicates AE start date is prior to treatment start date.
After treatment start: Partial date indicates AE start date is after treatment start date.
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date.
5.1.3
Concomitant medication date imputation
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.1.2). No imputation will be performed for concomitant 
medication end dates.
5.1.3.1
Prior therapies date imputation
Start date
The same rule which is applied to the imputation of AE/concomitant medication start date (see 
Section 5.1.2) will be used, with the exception that TRTSTD-1 will be used instead of
TRTSTD+1.
End date
Imputed date = min (start date of study treatment, last day of the month), if day is missing;
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date
5.1.3.2
Post therapies date imputation
Start date
Imputed date = max (End of Treatment date + 1, first day of the month), if day is missing;
Imputed date = max (End of Treatment date + 1, 01JAN), if day and month are missing.
Imputed date = End of treatment date +1, if the date is completely missing.


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5.1.4
End date
No imputation.
5.1.5
Deaths
Due to the fact that the reason of death is inserted as a free text into the database, a wider 
categorization should be applied in order to be able to distinguish the cases where a death is 
considered an event for the endpoint “duration of SD” (namely deaths due to study indication). 
For this wider categorization, the preferred term of the primary reason of death will be used.
The two basic categories will be the following ones:

“Study indication”: for all cases where death is due to underlying cancer. This category 
will include the cases with following preferred terms: 
-
Adenocarcinoma gastric
-
Adenocarcinoma pancreas
-
Bladder cancer
-
Cachexia
-
Disease progression
-
Glioblastoma
-
Hepatocellular carcinoma
-
Ileus
-
Leiomyosarcoma metastatic
-
Lung cancer metastatic
-
Malignant melanoma
-
Malignant neoplasm progression
-
Metastatic neoplasm
-
Metastatic renal cell carcinoma
-
Nasopharyngeal cancer
-
Neoplasm malignant
-
Neoplasm progression
-
Non-small cell lung cancer
-
Non-small cell lung cancer metastatic
-
Ovarian cancer
-
Pancreatic carcinoma 
-
Synovial sarcoma
-
Rectal cancer
-
Renal cancer
-
Renal cell carcinoma
-
Small cell lung cancer extensive stage
-
Small cell lung cancer metastatic


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-
Synovial sarcoma

“Other”: for all other cases where death is not due to underlying cancer.
Regarding incomplete death dates, the following imputatioin rules will be used:  

When only the day of death is missing, then 
death date=max [(01-MMM-YYYY), min (last contact date + 1, cut-off date)]. 

When day and month of death is missing, then 
death date=max[(01-JAN-YYYY, min (last contact date + 1, cut-off date)].
The imputed dates will not appear in the listings
5.1.6
Other imputations
For date of diagnosis and date of previous progression, when reconded as a partial date, the 
missing day is imputed to the 1st of the month (e.g., DEC2007 imputed to 01DEC2007), and if 
the day and month are both missing then to 1st of January of that year (e.g., 2007 imputed to 
01JAN2007). Such imputed data will not appear in the listings.
For date of tumor assessment, all investigation dates (e.g. MRI scan, CT scan) must be 
completed with day, month and year. If one or more assessment dates are incomplete but other 
investigation dates are available, and if the overall response at that assessment is 
CR/PR/SD/UNK, this/these incomplete date(s) are not considered for calculation of the 
assessment date and assessment date is calculated as the latest of all investigation dates (e.g. 
MRI scan, CT scan). Otherwise – if overall response is progression – the assessment date is 
calculated as the earliest date of all investigation dates at that evaluation number. If all 
measurement dates have no day recorded, the 1st of the month is used. If the month is not 
completed, for any of the investigations, the respective assessment will be considered to be at 
the date which is exactly between previous and following assessment. If previous and following 
assessment are not available, this assessment will not be used for any calculation.
In case there is an entry with a date completely missing (e.g. in tumor assessments, in prior 
therapies, in post-treatment therapies, etc.), no imputation will be performed and the entry will 
be ignored.
5.2
AEs coding/grading
Not Applicable.
5.3
Laboratory parameters derivations
CTC grading for blood differentials is based on absolute values.
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential:
xxx count = (WBC count) * (xxx %value / 100)


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Corrected calcium, can be derived using the reported total calcium value and albumin at the 
same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium.
5.4
Statistical models
5.4.1
Primary analysis
Not Applicable.
5.4.2
Key secondary analysis
Not Applicable.
5.5
Rule of exclusion criteria of analysis sets 
See section 2.2.2.
6
Reference
Chugh R, Wathen JK, Maki RG, et al (2009). Phase II multicenter trial of imatinib in 10 
histologic subtypes of sarcoma using a bayesian hierarchical statistical model. J Clin 
Oncol.;27(19):3148-53.
Clopper CJ and Pearson ES (1934). The Use of Confidence or Fiducial Limits Illustrated in the 
Case of the Binomial. Biometrika.; 26,(4):404-13.
Kaplan, EL and Meier, P (1958). Nonparametric estimation from incomplete observations. 
Journal of the American Statistical Association.;53:457-81.
Thall PF, Wathen JK, Bekele BN, et al (2003). Hierarchical Bayesian approaches to phase II 
trials in diseases with multiple subtypes. Stat Med.;22(5):763-80