Clinical trial NCT02807844
Conditions: Triple Negative Breast Cancer Pancreatic Carcinoma Melanoma Endometrial Carcinoma
Keywords: Triple negative breast cancer Pancreatic carcinoma Melanoma Endometrial Carcinoma Immuno oncology Monoclonal antibody PDR001 MCS110 Advanced malignancies metasteses advanced cancer malignant
Sponsor: Novartis Pharmaceuticals
Start date: 2016-06-29; Completion date: 2020-06-04
Enrollment: 141 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study of MCS110 with PDR001 was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics (PD), and antitumor activity of the combination of MCS110 with PDR001 in adult patients with solid tumors.

Detailed description:
Combined treatment with MCS110 and PDR001 was expected to result in Tumor-associated macrophages (TAM) depletion, enhanced T-cell activation and synergistic antitumor activity in the clinical setting.

This study was a Phase Ib/II, multi-center, open label study starting with a Phase Ib dose escalation part followed by a Phase II part. MCS110 and PDR001 were administered i.v. Q3W until the patient experienced unacceptable toxicity, progressive disease as per irRC and/or treatment was discontinued at the discretion of the investigator or the patient. Patients were not to discontinue treatment based on progressive disease per Response evaluation criteria in solid tumors (RECIST) v1.1. During the Phase Ib part of the study, cohorts of patients were treated with increasing doses of MCS110 and PDR001 every 3 weeks until a Recommended Phase 2 Dose (RP2D) was determined for this treatment combination.

To assure that the combination RP2D did not exceed the Maximum tolerated dose (MTD), the combination MCS110 and PDR001 dose escalation was guided by a Bayesian logistic regression model (BLRM) with overdose control (EWOC) principle based on dose limiting toxicity data in the context of available safety, Pharmacokinetics (PK) and Pharmacodynamics (PD) information. Once the MTD and/or RP2D was declared, additional patients were enrolled in the Phase II part in order to assess the preliminary anti-tumor activity of MCS110 in combination with PDR001 in anti-PD1/PD-L1-naive triple negative breast cancer (TNBC), pancreatic (PC), endometrial carcinoma (EC) and anti PD1/PD-L1-resistance melanoma (ME).

Arms: arm 1: Phase Ib: MCS110 1 mg/kg every 3 weeks (Q3W) + PDR001 100 mg Q3W arm 2: Phase Ib: MCS110 3 mg/kg Q3W + PDR001 100 mg Q3W arm 3: Phase Ib: MCS110 3 mg/kg Q3W + PDR001 300 mg Q3W arm 4: Phase Ib: MCS110 5 mg/kg Q3W + PDR001 300 mg Q3W arm 5: Phase Ib: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W arm 6: Phase Ib: MCS110 10 mg/kg Q3W + PDR001 300 mg Q3W arm 7: Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Triple negative breast cancer (TNBC) arm 8: Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Pancreatic cancer (PC) arm 9: Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Endometrial cancer (EC) arm 10: Phase II: MCS110 7.5 mg/kg Q3W + PDR001 300 mg Q3W - Melanoma (ME)
Interventions: intervention 1: MCS110 intervention 2: PDR001
Intervention descriptions: intervention 1: MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion. intervention 2: MCS110 and PDR001 - for administration once every 3 weeks via i.v. infusion.

Protocol documents:
Prot_000.pdf: 
Clinical Development 
MCS110 
Protocol CMCS110Z2102 / NCT02807844
A Phase Ib/II, open label, multicenter study of MCS110 in 
combination with PDR001 in patients with advanced 
malignancies 
Document type 
Amended Protocol Version 
EUDRACT number 
2016-000210-29 
Version number 
05 (Clean) 
Development phase 
Ib/II 
Document status 
Final 
Release date 
23-Jul-2019
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 17-Nov-2014 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 8 
Glossary of terms ............................................................................................................... 10 
Protocol summary: ............................................................................................................. 12 
Amendment 05 (23-Jul-2019) ........................................................................................... 15 
Amendment 04 (20-July-2018) ......................................................................................... 17 
Amendment 03 (14-Feb-2018) .......................................................................................... 21 
Amendment 02 (07-Feb-2017) .......................................................................................... 24 
Amendment 01 (11-Jul-2016) ........................................................................................... 27 
1 
Background ........................................................................................................................ 28 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 28 
1.1.1 
Overview of PD-1 ................................................................................. 28 
1.1.2 
Overview of CSF-1 ............................................................................... 29 
1.2 
Introduction to study treatment .............................................................................. 30 
1.2.1 
Overview of PDR001 ............................................................................ 30 
1.2.2 
Overview of MCS110 ........................................................................... 31 
1.3 
Overview of combination treatment ...................................................................... 35 
1.3.1 
Non-clinical ........................................................................................... 35 
1.3.2 
Clinical .................................................................................................. 35 
1.3.3 
Potential for drug-drug interactions ...................................................... 35 
1.3.4 
Expected overlapping toxicities ............................................................ 35 
2 
Rationale ............................................................................................................................ 36 
2.1 
Study rationale and purpose ................................................................................... 36 
2.2 
Rationale for the study design ............................................................................... 37 
2.3 
Rationale for dose and regimen selection .............................................................. 38 
2.4 
Rationale for choice of combination drugs ............................................................ 38 
3 
Objectives and endpoints ................................................................................................... 38 
4 
Study design ...................................................................................................................... 41 
4.1 
Description of study design ................................................................................... 41 
4.2 
Timing of interim analyses and design adaptations ............................................... 43 
4.3 
Definition of end of the study ................................................................................ 43 
4.4 
Early study termination .......................................................................................... 44 
5 
Population .......................................................................................................................... 44 


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5.1 
Patient population .................................................................................................. 44 
5.2 
Inclusion criteria .................................................................................................... 44 
5.3 
Exclusion criteria ................................................................................................... 45 
6 
Treatment ........................................................................................................................... 48 
6.1 
Study treatment ...................................................................................................... 48 
6.1.1 
Dosing regimen ..................................................................................... 48 
6.1.2 
Ancillary treatments .............................................................................. 49 
6.1.3 
Treatment duration ................................................................................ 49 
6.2 
Dose escalation guidelines ..................................................................................... 49 
6.2.1 
Starting dose rationale ........................................................................... 49 
6.2.2 
Provisional dose levels .......................................................................... 50 
6.2.3 
Guidelines for dose escalation and determination of MTD or RP2D ... 50 
6.2.4 
Definitions of dose limiting toxicities (DLTs) ...................................... 53 
6.3 
Dose modifications ................................................................................................ 54 
6.3.1 
Dose modification and dose delay ........................................................ 54 
6.3.2 
Follow-up for toxicities ......................................................................... 60 
6.3.3 
Anticipated risks and safety concerns of the study drug ....................... 60 
6.4 
Concomitant medications ...................................................................................... 60 
6.4.1 
Permitted concomitant therapy requiring caution and/or action ........... 61 
6.4.2 
Prohibited concomitant therapy ............................................................ 61 
6.5 
Patient numbering, treatment assignment or randomization ................................. 62 
6.5.1 
Patient numbering ................................................................................. 62 
6.5.2 
Treatment assignment or randomization ............................................... 62 
6.6 
Study drug preparation and dispensation ............................................................... 62 
6.6.1 
Study drug packaging and labeling ....................................................... 62 
6.6.2 
Drug supply and storage ........................................................................ 62 
6.6.3 
Study drug compliance and accountability ........................................... 63 
6.6.4 
Disposal and destruction ....................................................................... 63 
7 
Visit schedule and assessments ......................................................................................... 64 
7.1 
Study flow and visit schedule ................................................................................ 64 
7.1.1 
Screening ............................................................................................... 69 
7.1.2 
Treatment period ................................................................................... 69 
7.1.3 
Discontinuation of Study Treatment ..................................................... 70 
7.1.4 
Withdrawal of Consent ......................................................................... 71 
7.1.5 
Follow-up period ................................................................................... 72 
7.1.6 
Lost to follow-up ................................................................................... 73 


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7.2 
Assessment types ................................................................................................... 73 
7.2.1 
Efficacy assessments ............................................................................. 73 
7.2.2 
Safety and tolerability assessments ....................................................... 75 
7.2.3 
Pharmacokinetics and immunogenicity assessments ............................ 79 
 
 81 
8 
Safety monitoring and reporting ........................................................................................ 83 
8.1 
Adverse events ....................................................................................................... 83 
8.1.1 
Definitions and reporting ...................................................................... 83 
8.1.2 
Laboratory test abnormalities ................................................................ 85 
8.2 
Serious adverse events ........................................................................................... 85 
8.2.1 
Definitions ............................................................................................. 85 
8.2.2 
Reporting ............................................................................................... 86 
8.3 
Pregnancies ............................................................................................................ 87 
8.4 
Warnings and precautions ...................................................................................... 87 
8.5 
Data Monitoring Committee .................................................................................. 87 
9 
Data collection and management ....................................................................................... 88 
9.1 
Data confidentiality ............................................................................................... 88 
9.2 
Site monitoring ...................................................................................................... 89 
9.3 
Data collection ....................................................................................................... 89 
9.4 
Database management and quality control ............................................................ 90 
10 Statistical methods and data analysis ................................................................................ 90 
10.1 
Analysis sets .......................................................................................................... 91 
10.1.1 
Full Analysis Set ................................................................................... 91 
10.1.2 
Safety Set .............................................................................................. 91 
10.1.3 
Per-Protocol Set .................................................................................... 91 
10.1.4 
Dose-determining analysis set............................................................... 92 
10.1.5 
Pharmacokinetic analysis set ................................................................. 92 
10.2 
Patient demographics/other baseline characteristics ............................................. 92 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 92 
10.4 
Primary objective ................................................................................................... 93 
10.4.1 
Variable ................................................................................................. 93 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 94 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 99 
10.4.4 
Supportive analyses ............................................................................... 99 
10.5 
Secondary objective ............................................................................................... 99 
10.5.1 
Key secondary objective ....................................................................... 99 


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10.5.2 
Other secondary efficacy objectives ................................................... 100 
10.5.3 
Safety objectives ................................................................................. 100 
10.5.4 
Pharmacokinetics ................................................................................ 100 
 
 101 
10.7 
Interim analysis .................................................................................................... 103 
10.8 
Sample size calculation ........................................................................................ 103 
10.9 
Power for analysis of key secondary variables .................................................... 105 
11 Ethical considerations and administrative procedures .................................................... 105 
11.1 
Regulatory and ethical compliance ...................................................................... 105 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 105 
11.3 
Informed consent procedures ............................................................................... 105 
11.4 
Discontinuation of the study ................................................................................ 106 
11.5 
Publication of study protocol and results............................................................. 106 
11.6 
Study documentation, record keeping and retention of documents ..................... 107 
11.7 
Confidentiality of study documents and patient records ..................................... 107 
11.8 
Audits and inspections ......................................................................................... 108 
11.9 
Financial disclosures ............................................................................................ 108 
12 Protocol adherence .......................................................................................................... 108 
12.1 
Amendments to the protocol ................................................................................ 108 
13 References (available upon request) ................................................................................ 109 
14 Appendices ...................................................................................................................... 113 
14.1 
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival and Overall Survival (based on RECIST 1.1) . 113 
14.1.1 
Introduction ......................................................................................... 114 
14.1.2 
Efficacy assessments ........................................................................... 114 
14.1.3 
Efficacy definitions ............................................................................. 123 
14.1.4 
Data handling and programming rules ................................................ 132 
14.1.5 
References (available upon request) ................................................... 135 
14.2 
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) ................................. 136 
14.2.1 
Introduction ......................................................................................... 136 
14.2.2 
New lesions and non-target lesions ..................................................... 136 
14.2.3 
Follow-up evaluation of target and non-target lesions ........................ 136 
14.2.4 
Definitions of response categories and evaluation of overall lesion 
response ............................................................................................... 137 
14.2.5 
Only non-measurable disease at baseline ............................................ 138 
14.2.6 
References (available upon request) ................................................... 138 


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14.3 
Appendix 3: Statistical Details for the Phase Ib Part: Bayesian logistic 
regression model (BLRM): prior and design properties for hypothetical data 
scenarios .............................................................................................................. 139 
14.3.1 
Statistical Models ................................................................................ 139 
14.3.2 
Prior specifications .............................................................................. 139 
14.3.3 
Hypothetical on-study scenarios ......................................................... 145 
14.3.4 
Operating characteristics for MCS110 + PDR001 combination arm.. 146 
14.3.5 
References (available upon request) ................................................... 149 
 
List of figures 
Figure 1-1 
Blockade of PD-1/PD-1 interaction by PDR001 .................................. 29 
Figure 1-2 
Macrophage polarization and function .................................................. 29 
Figure 2-1 
Rationale for combined treatment with PDR001 and MCS110 ............ 36 
Figure 4-1 
Study design .......................................................................................... 42 
 
List of tables 
Table 1-1 
Clinical trials with MCS110.................................................................. 33 
Table 3-1 
Objectives and related endpoints .......................................................... 39 
Table 6-1 
Dose and treatment schedule ................................................................. 48 
Table 6-2 
Provisional dose levels .......................................................................... 50 
Table 6-3 
Criteria for defining dose-limiting toxicities......................................... 53 
Table 6-4 
Dose modification for drug related toxicities ........................................ 55 
Table 7-1 
Visit evaluation schedule ...................................................................... 65 
Table 7-2 
Disease assessment collection plan ....................................................... 74 
Table 7-3 
ECOG performance status ..................................................................... 76 
Table 7-4 
Local/Central Clinical laboratory parameters collection plan .............. 76 
Table 7-5 
Local ECG collection plan .................................................................... 78 
Table 7-6 
Phase Ib Part: Pharmacokinetic blood collection log for MCS110, 
PDR001 and IG samples ....................................................................... 79 
Table 7-7 
Phase II Part: Pharmacokinetic blood collection log for MCS110, 
PDR001 and IG samples ....................................................................... 80 
 
 81 
Table 10-1 
Pharmacokinetic Parameters to be analyzed ....................................... 101 
Table 10-2 
Operating characteristics of the design (Group 1, 3) .......................... 104 
Table 10-3 
Operating characteristics of the design (Group 4) .............................. 104 
Table 10-4 
Operating characteristics of the design (Group 2 at RP2D) ................ 105 


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Table 10-5 
Operating characteristics of the design (Group 2b) ............................ 105 
Table 14-1 
Response criteria for target lesions ..................................................... 119 
Table 14-2 
Response criteria for non-target lesions .............................................. 121 
Table 14-3 
Overall lesion response at each assessment ........................................ 122 
Table 14-4 
Overall lesion response at each assessment: patients with non-
target disease only ............................................................................... 129 
Table 14-5 
Options for event dates used in PFS, TTP, duration of response ........ 130 
Table 14-6 
Overall response at each assessment ................................................... 137 
Table 14-7 
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent MCS110 model parameters ....... 141 
Table 14-8 
Historical data from [CMCS110A2101] ............................................. 141 
Table 14-9 
Historical data from [CMCS110X2201] ............................................. 141 
Table 14-10 
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent PDR001 model parameters ........ 143 
Table 14-11 
Historical data from [CPDR001X2101] .............................................. 143 
Table 14-12 
A priori interaction at the provisional and reference dose levels ........ 144 
Table 14-13 
Prior distribution for the model parameters ........................................ 144 
Table 14-14 
Summary of prior distribution of DLT rates ....................................... 145 
Table 14-15 
Dose decisions recommended by BLRM under EWOC ..................... 145 
Table 14-16 
True underlying cumulative probabilities of DLT for different 
scenarios .............................................................................................. 147 
Table 14-17 
Results ................................................................................................. 148 


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List of abbreviations 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ASCO 
American Society for Clinical Oncology  
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
BLRM 
Bayesian Logistic Regression Model 
CBR 
Clinical Benefit Rate 
CDP 
Clinical Development Plan 
cfDNA 
Circulating free DNA 
CK 
Creatine Kinase 
CL 
Clearance 
Cmax 
maximum drug concentration 
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CRO 
Contract Research Organization 
 
CSF-1 
Colony Stimulating Factor 1 (see M-CSF) 
CSF-1R 
Colony Stimulating Factor 1 Receptor 
CSR 
Clinical study report 
CTLA-4 
Cytotoxic T-Lymphocyte-Associated protein 4 
CTX-1 
C-terminal Telopeptide of type I collagen 
CYPP450 
Cytochrome P450 
DCR 
Disease Control Rate 
DDI 
Drug-Drug Interaction 
DLT 
Dose Limiting Toxicity 
DOR 
Duration of Response 
DS&E 
Drug Safety and Epidemiology 
ECG 
Electrocardiogram 
EDC 
Electronic Data Capture 
EOT 
End Of Treatment 
eSAE 
Electronic Serious Adverse Event  
ESMO 
European Society for Medical Oncology 
EWOC 
Escalation With Overdose Control 
FIH 
First In Human 
GGT 
Gamma-glutamyl transferase 
GLP 
Good Laboratory Practice 
HNSTD 
Highest No Severely Toxic Dose 
HV 
Healthy Volunteer 
i.v. 
intravenous(ly) 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IG 
Immunogenicity 
IL-2 
Interleukin 2 
IRB 
Institutional Review Board 
irRC 
Immune-related Response Criteria 
Kd 
Constant of dissociation 
LDH 
Lactate Dehydrogenase 
mAb 
Monoclonal Antibody 


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MAP 
Master Analysis Plan documents project standards in the statistical methods which will 
be used within the individual clinical trial RAP documentation 
M-CSF 
Macrophage Colony stimulating factor 
MDSCs 
Myeloid-Derived Suppressor Cells 
MRT 
Mean Residence Time 
MTD 
Maximum Tolerated Dose 
NCCN 
National Comprehensive Cancer Network 
o.d. 
omnia die/once a day 
ORR 
Overall Response Rate 
OS 
Overall Survival 
p.o. 
per os/by mouth/orally 
PD 
Pharmacodynamic / Progressive Disease 
PD-1 
Programmed Death-1 
PD-L1 
Programmed Death-Ligand 1 
PD-L2 
Programmed Death-Ligand 2 
PFS 
Progression Free Survival 
PgP 
P-glycoprotein 1 also known as multidrug resistance protein 1 
PHI 
Protected Health Information 
PR 
Partial Response 
PVNS 
Pigmented VilloNodular Synovitis 
Q2W, Q3W, Q4W 
Respectively, every two, three, four week 
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence 
of preplanned analyses 
REB 
Research Ethics Board 
RP2D 
Recommended Phase two Dose 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SEB 
Staphylococcal Enterotoxin B 
SOP 
Standard Operating Procedure 
TAM 
Tumor Associated Macrophage 
TCP 
thrombocytopenia 
Tregs 
Regulatory T cells 


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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 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
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 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/subject/healthy 
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. 
Personal Data 
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological sample 
Randomization number 
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, 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. 


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Study treatment discontinuation 
Point/time when patient permanently stops 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. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints 
Withdrawal of Consent 
Withdrawal of consent occurs only when a patient does not want to 
participate in the study any longer, and does not allow any further collection 
of personal data 


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Protocol summary: 
Protocol number 
CMCS110Z2102 
Title 
A Phase Ib/II, open label, multicenter study of MCS110 in combination with PDR001 in 
patients with advanced malignancies  
Brief title 
Phase Ib/II study of MCS110 in combination with PDR001 in patients with advanced 
malignancies 
Sponsor and 
Clinical Phase 
Novartis 
Ib/II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and 
rationale 
The purpose of this study of MCS110 with PDR001 is to characterize the safety, 
tolerability, pharmacokinetics (PK), pharmacodynamics (PD) and antitumor activity of the 
combination of MCS110 with PDR001 in adult patients with solid tumors 
Combined treatment with MCS110 and PDR001 is expected to result in TAM depletion, 
enhanced T-cell activation and synergistic antitumor activity in the clinical setting. 
Primary 
Objectives 
• 
Phase Ib:To characterize the safety and tolerability of MCS110 in combination with 
PDR001 in patients with advanced solid malignancies and to identify a 
recommended dose combination for Phase II 
• 
Phase II: To estimate the anti-tumor activity of the combination of MCS110 with 
PDR001 
Secondary 
Objectives 
• 
To further characterize the safety and tolerability of MCS110 given in combination 
with PDR001 
• 
To characterize the pharmacokinetic profile of the combination of MCS110 with 
PDR001 
• 
To further evaluate the preliminary anti-tumor activity of the combination of MCS110 
with PDR001 by additional efficacy measures 
• 
To assess emergence of anti-MCS110 or anti-PDR001 antibodies 
• 
 
• 
To describe survival with MCS110 and PDR001 given in combination 
Study design 
• 
This study has been designed as a Phase Ib/II, multi-center, open-label study 
starting with a Phase Ib dose escalation part followed by a Phase II part. 
• 
MCS110 and PDR001 will be administered every 3 weeks until patient experiences 
unacceptable toxicity, progressive disease per immune related Response Criteria 
(irRC) and/or treatment is discontinued at the discretion of the investigator or the 
patient. 
Population 
The Phase Ib part of the study will be conducted in adult patients with advanced 
melanoma, endometrial, pancreatic and triple negative breast cancer. 
The Phase II part of the study will be conducted in adult patients enrolled in distinct 
groups: 
• 
PD1/PD-L1 treatment naïve TNBC 
• 
PD1/PD-L1 treatment naïve pancreatic cancer 
• 
PD1/PD-L1 treatment naïve endometrial carcinoma 
• 
PD1/PD-L1 treatment resistant melanoma. 


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Inclusion criteria 
• 
Age ≥ 18 years [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.] 
• 
Phase Ib part: Patients with advanced melanoma, endometrial carcinoma, 
pancreatic or triple negative breast cancer, with measurable or non-measurable 
disease as determined by RECIST version 1.1, who have progressed despite 
standard therapy or are intolerant of standard therapy, or for whom no standard 
therapy exists. 
• 
Phase II part: Patients with advanced solid tumors with at least one measurable 
lesion as determined by RECIST version 1.1, who have received standard therapy 
or are intolerant of standard therapy, who have progressed following their last prior 
therapy, and fit into one of the following groups: 
• 
Group 1: TNBC who did not receive prior anti-PD-1/PD-L1 treatment 
• 
Group 2: Pancreatic adenocarcinoma who did not receive prior anti-PD-
1/PD-L1 treatment 
• 
Group 3: Endometrial carcinoma who did not receive prior anti-PD-1/PD-L1 
treatment 
• 
Group 4: Melanoma who progressed on prior PD-1- and PD-L1-directed 
therapies. 
• 
ECOG Performance Status ≤ 2. 
• 
Patient 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, and during therapy on this 
study. Exceptions for patients with sites of disease not amenable to biopsy may be 
considered after discussion with the sponsor. 
Exclusion criteria 
• 
Presence of symptomatic CNS metastases, or CNS metastases that require local 
CNS-directed therapy 
• 
History of severe hypersensitivity reactions to other mAbs 
• 
Patient 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 ULN, except for patients with Gilbert’s syndrome who 
are excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
• 
Alanine aminotransferase (ALT) > 3 x ULN 
• 
Aspartate aminotransferase (AST) > 3 x ULN 
• 
Absolute neutrophil count < 1.0 x 109/L 
• 
Platelet count < 100 x 109/L 
• 
Hemoglobin (Hgb) < 9 g/dL 
• 
Impaired cardiac function or clinically significant cardiac disease 
• 
Active autoimmune disease or a documented history of autoimmune disease within 
three years before screening 
• 
Active infection, including active tuberculosis, requiring systemic antibiotic therapy 
• 
Known history of HIV infection 
• 
Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or requiring 
antiviral treatment 
• 
Malignant disease, other than that being treated in this study  
• 
Any medical condition that would prevent the patient’s participation in the clinical 
study due to safety concerns, compliance with clinical study procedures or 
interpretation of study results, including but not limited to: 
• 
Prior immune-related adverse events requiring treatment discontinuation 
• 
Ongoing symptomatic interstitial lung disease (ILD), noninfectious 
pneumonitis or history of drug induced interstitial lung disease 


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• 
Systemic anti-cancer therapy within 2 weeks or 5 x T ½, whichever is longer of the 
first dose of study treatment. Cytotoxic agents that have major delayed toxicity, e.g. 
mitomycin C and nitrosoureas, within 4 weeks and CTLA-4, PD-1 or PD-L1 
antagonists, within 6 weeks of the first dose of study treatment 
• 
Patients requiring chronic treatment with systemic steroid therapy or any 
immunosuppressive therapy 
• 
Use of any live vaccines against infectious diseases within 4 weeks of initiation of 
study treatment 
• 
Major surgery within 2 weeks of the first study drug 
• 
Radiotherapy within 2 weeks of the first dose of study drug 
• 
Participation in an interventional, investigational study within 2 weeks of the first dose 
of study treatment 
• 
Presence of ≥ CTCAE Grade 2 toxicity 
• 
Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF) ≤ 2 
weeks prior start or study drug. 
• 
Pregnant or lactating women 
• 
Women of child-bearing potential, unless they are using highly effective methods of 
contraception 
Investigational 
and reference 
therapy 
MCS110 and PDR001 
Efficacy 
assessments 
Tumor assessment per RECIST v1.1 and per irRC 
Safety 
assessments 
Incidence and severity of AEs and SAEs, including changes in laboratory values, vital 
signs and ECGs 
Other 
assessments 
• 
Serum PK parameters and immunogenicity 
• 
 
 
Data analysis 
The study data will be analyzed and reported based on all patients’ data of the Phase 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 Ib/II, MCS110, PDR001, immune checkpoint inhibitor, PD-1, PD-L1, CSF-1, 
tumor associated macrophage. 


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Amendment 05 (23-Jul-2019) 
Amendment rationale 
This protocol amendment revises the definition of end of study to include the option for patients 
still on study treatment and who, in the opinion of the investigator, are still deriving clinical 
benefit at the time of end of study, to transfer to another study to continue providing study 
treatment to these patients or to an alternative treatment option.  
In addition, based on a health authority request, the use of condoms for male study participants 
and pregnancy outcome collection for female partners of male study participants has been 
reintroduced only for patients treated in Korea. Exclusion criterion #21 has been updated 
accordingly. 
Lastly, PK and IG assessments are no longer mandated at the End of Treatment visit as 
sufficient data have already been collected. 
Study Status 
The CMCS110Z2102 study started enrollment on 29-Jun-2016. The last patient was enrolled 
on 10-Jan-2019. The pre-defined decision criteria for further expansion of the pancreatic cancer, 
TNBC, endometrial cancer and melanoma groups were not met (see Section 4.2 and 10.4.4.2). 
By consequence, no further patients will be enrolled in this study. A total of 141 patients have 
been treated: 60 patients in the dose escalation part and 81 patients in Phase II part of study (20 
in pancreatic group, 20 in TNBC group, 21 in endometrial group and 20 in melanoma group). 
As of 08-Jul-2019, 6 patients were still on treatment (in phase II only) and 41 patients in survival 
follow-up.  
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 4.3: Definition of end of study: 
• Addition of language to account for patients who would transfer into another study or an 
alternative treatment option to continue provision of study treatment. 
Section 5.3: Exclusion criteria: 
• 
Re-insertion of exclusion criteria 21 for Korea only where the use of condom for male study 
participants remains mandatory. 
Section 7.1.3: Discontinuation of study treatment: 
• Addition of language to specify that patients who transfer to another study or an alternative 
treatment option to continue provision of study treatment will complete end of treatment 
procedures. 
Section 7.1.5: Follow up period: 
• Addition of language to specify that patients who transfer into another study or an 
alternative treatment option to continue provision of study treatment will not complete the 


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safety, disease progression and survival follow up. For all other patients, the safety 
evaluation period will be completed but the disease-progression and survival follow up will 
not be performed or pursued. 
Section 7.2.3: Pharmacokinetics and immunogenicity assessments, Table 7-1: Visit evaluation 
schedule and Table 7-7: Phase II Part: Pharmacokinetic blood collection log for MCS110, 
PDR001 and IG samples: 
• 
Removal of PK and IG samples collection at End of Treatment. 
Section 8.3: Pregnancies: 
• 
Re-insertion of the pregnancy outcome collection for the female partners of any males 
which remains valid for Korea only. 
IRBs/IECs 
• A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
• The changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
• The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 
 


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Amendment 04 (20-July-2018) 
Amendment Rationale 
The main purpose for this amendment is to: 
• Allow exploration of an additional, lower dose of MCS110 in patients with pancreatic 
cancer. Data generated in the dose escalation part of the study show preliminary signals of 
efficacy (1 PR, 2 SD >1 year) at the lowest dose level of MCS110 (1 mg/kg, Q3W) in 
combination with PDR001 in pancreatic cancer patients. In order to further explore this, 
two additional groups, each consisting of up to 20 patients with pancreatic ductal 
adenocarcinoma (PDAC) may be enrolled at either 1 mg/kg Q3W or the RP2D (7.5mg/kg, 
Q3W) of MCS110 in combination with PDR001 (300 mg, Q3W) respectively. 
Recruitment into these two groups will be contingent upon evidence of clinical benefit in 
the first 20 PDAC patients treated at the RP2D. 
Additional changes to the protocol: 
• 
 
 
 
 
 
• Add laboratory measurements during study visits. Asymptomatic CK elevations were 
noted in healthy volunteers and in pigmented villonodular synovitis (PVNS) patients 
treated with MCS110. Maximal CK elevations in PVNS patients were observed 28-43 
days after a single dose of MCS100. In order to assess the dynamics of CK elevations later 
during the course of treatment with MCS110, additional blood chemistry samples have 
been added on Cycle 4 Day 8. 
• Remove the requirement for use of condom for male study participants. Monoclonal 
antibodies are not genotoxic due to their high molecular weight, and are not expected to 
interact with DNA. In addition, they have a low distribution to the semen, a relatively 
small volume of semen delivered to the partner, and very low absorption. Fetal harm from 
semen delivery is therefore biologically implausible and the amount of monoclonal 
antibodies able to gain access to the partner’s systemic circulation via trans-epidermal 
transfer would be expected to be extremely low. Therefore, the use of condom for male 
study participants is no longer required. 
• Include new guidance on dose modifications for suspected immune-related adverse events. 
To align with recently published guidelines on the clinical management of suspected 
immune-related toxicities, and to provide guidance for the management of immune related 
acute dermatologic adverse events seen in study with PDR001, the dose modification 
section of the protocol and corresponding table were updated. After the recent occurrence 
of a case of Stevens Johnson Syndrome in a study with PDR001, 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 


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as part of an urgent safety measure released on 15 June 2018. This protocol amendment is 
now formalizing these changes in the table describing the criteria for dose 
reduction/interruption and re-initiation of treatment for adverse drug reactions. 
• The withdrawal of consent language was revised to differentiate sample use after a patient 
withdraws consent based on the different regulations/laws around the world. 
Study status 
The CMCS110Z2102 study is ongoing in the phase 2 part with MCS110 at 7.5 mg/kg in 
combination with PDR001. As of 10 April 2018, 60 patients have received the combination of 
MCS110 and PDR001 at doses of 1 mg/kg and 100 mg (6 patients), 3 mg/kg and 100 mg (12 
patients), 3 mg/kg and 300 mg (12 patients), 5 mg/kg and 300 mg (13 patients), 7.5 mg/kg and 
300 mg (6 patients), and 10 mg/kg and 300 mg (11 patients), respectively. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the tracked changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 2.2: Rationale for study design 
• The text was updated to reflect the change of design for PDAC patients participating 
Phase II. 
Section 3: Objectives and endpoints 
• Table 3-1 Clinical benefit rate in the pancreatic cancer disease group, added as per 
Amendment 3 is now clearly indicated in the table. 
 
 


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Section 4.1: Description of study design 
• The description of the design of Phase II was updated.  
• Figure 4-1 was updated to reflect the change in study design. 
Section 4.2: Timing of interim analysis and design adaptations 
• The text was updated to reflect the change in the design of Phase II 
Section 5.3: Exclusion criteria 
• Exclusion criteria #21 was deleted as use of condom for male participants is no more 
required. 
Section 6.3.1: Dose modification and dose delay 
• The section was updated with new recommendations for the management of suspected 
immune-related adverse events. 
Table 6-4 Dose modification for drug related toxicities 
• The table was updated with new recommendations for the management of immune-related 
adverse events. 
Table 7-1: Visit evaluation schedule  
• Blood chemistry and hematology added at Cycle 4 Day 8. 
• 
 
• 
 
Section 7.1.4 Withdrawal of consent 
• The withdrawal of consent language was revised. 
 
• 
  
• 
 
 
• 
 
Section 8.1: Adverse events 
• Reference to the dose modification recommendations provided in Section 6.3.1 was 
added. 
Section 8.3: Pregnancies 
• Collection of pregnancy outcome for female partners of male participants was removed. 
Section 8.5: Data Monitoring Committee 
• The text was updated to reflect the change in the design of Phase II 
Section 10: Statistical methods and data analysis 
• It was clarified that the outputs for Group 2 in expansion will be reported by dose level, 
when applicable. 


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Section 10.4.2.2: Statistical methods and data analysis for Phase II 
• Language about the Bayesian model for a lower dose group for Phase II Group 2 was 
added. 
 
• 
  
Section 10.7: Interim analysis 
• The text was updated to reflect the change in the design of Phase II 
Section 10.8: Sample size calculation 
• The sample size justification section was updated to reflect the changes in Phase II Group 
2 design. 
IRB/IEC 
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.  
All other changes described in this amended protocol require IRB/IEC approval prior to 
implementation.  
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 03 (14-Feb-2018) 
The main purpose for this amendment is to: 
1. Increase the number of pancreatic cancer patients to be enrolled in the Phase II part of the 
study from 20 to 40 
2. Change the primary endpoint for antitumor activity in pancreatic cancer from overall 
response rate (ORR) to clinical benefit rate (CBR) 
 
 
4. Mention that statins should be used with caution. 
These changes are proposed for the following reasons: 
• Preliminary data (data cut-off 24-Nov-2017) from this study show encouraging clinical 
activity in advanced pancreatic patients treated at a range of doses in dose escalation, with 
long-lasting clinical benefit (confirmed objective response or SD>4 months) in 2 of 30 
evaluable patients per RECIST v1.1. Evaluable patients are defined as patients with at 
least 1 post-baseline efficacy assessment or has discontinued study treatment. Per irRC, 
there is one patient who showed pseudo-progression per RECIST, but achieved SD > 4 
months. Therefore, under irRC, there is a 10% long-lasting clinical benefit in 3 out of 30  
advanced pancreatic patients. To allow further exploration of anti-tumor activity of the 
combination in this patient population, approximately 40 patients will be enrolled in the 
Phase II pancreatic cancer group. 
 
 
 
• Recent clinical data demonstrate that combined blockade of CSF-1R and PD-1 results in a 
long lasting (6 to 9 + months) objective response rate and clinical benefit rate (CBR) of 
13% and 16%, respectively, in patients with advanced pancreatic cancer (Wainberg et al., 
2017). Given that objective responses are rare in advanced pancreatic cancer and that long 
lasting stable disease is considered beneficial to patients, the primary endpoint for 
antitumor activity in this study will be changed from objective response to clinical benefit 
rate (confirmed objective response or SD>4 months). 
• 
 
 
  
• Statins are known to be frequently associated with CK elevations and transient CK 
elevations were noted in healthy volunteers and patients studies with MCS110. 
Study status 
The CMCS110Z2102 study is ongoing in the dose escalation part of the study. As of 29 January 
2018, 56 patients have received the combination of MCS110 and PDR001 at doses of 1 mg/kg 
and 100 mg (6 patients), 3 mg/kg and 100 mg (12 patients), 3 mg/kg and 300 mg (12 patients), 
5 mg/kg and 300 mg (13 patients), 7.5 mg/kg and 300 mg (6 patients), and 10 mg/kg and 300 
mg (7 patients), respectively. 


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Changes to the protocol 
Changes to specific sections of the protocol are shown in the tracked changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
Section 2.2: Rationale for study design 
• The text was updated to specify that clinical benefit rate will be evaluated in 
approximately 40 patients in the pancreatic cancer group 
Section 3: Objectives and endpoints 
• Table 3.1 was updated to mention clinical benefit rate in the pancreatic cancer disease 
group, 
 
 
Section 4.1: Description of study design 
• The text is updated to mention that 40 pancreatic cancer patients will be enrolled  
• Figure 4.1 is updated to reflect the change in study design. 
Section 4.2: Timing of interim analysis and design adaptations 
• The text is updated to reflect the change introduced between pancreatic cancer and other 
disease group. 
Section 6.4.1: Permitted concomitant therapy requiring caution and/or action 
• Statins are mentioned as to be used with caution 
Table 7.1: Visit evaluation schedule  
• 
 
 
• 
 
Section 10.4.1: Variables 
• Clinical benefit rate is defined as the primary efficacy variable for the pancreatic cancer 
group, while overall response rate remains the primary efficacy variable for the other 
cancer groups. 
Section 10.4.2.2: Phase II 
• The text has been updated to differentiate between pancreatic cancer group (Group 2) 
and other groups (groups 1, 3 and 4). 
• Parameters of priors of BLRM are defined for clinical benefit rate in pancreatic cancer 
patients. 
Section 10.5.2: Other secondary efficacy objectives 
• Duration of stable disease of 4 months is defined for clinical benefit 


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10.8: Sample size calculation 
• Pancreatic cancer is deleted from table 10-2 and a new table 10-4 is introduced for 
pancreatic cancer 
13: References 
• The list of references was updated 
14.3: recommended management algorithms for suspected toxicities 
• Management of neurological adverse events is now mentioned 
IRB/IEC 
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 Form for the patients. Sites are required to 
update and submit for approval a revised Informed Consent Form that takes into account the 
changes described in this protocol amendment. 


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Amendment 02 (07-Feb-2017) 
The main reasons for this amendment are to make changes requested by the Health Authorities 
(HA), to prepare the protocol for inclusion of Japanese patients and to update safety monitoring. 
Furthermore, clarifications and correction of typos have been made to the protocol. 
As requested by HA, patients with active tuberculosis, interstitial lung disease or non-infectious 
pneumonitis or history of drug induced interstitial lung disease will be excluded from enrolment 
in the study. Additionally, a washout period of 7 days for immunosuppressive therapy and 
corticosteroids will be required before starting study treatment. Furthermore, country-specific 
wordings have been added to the protocol to allow Japanese patients to participate in the phase 
II part of the study. In accordance with HA requirements, Japanese patients will remain 
inpatients during the first treatment cycle and will have repeat chest X -rays performed at 
baseline and after one week of treatment. 
Given that Grade 1-2 adverse events, possibly related to cytokine release (fever, weight gain 
and pleural effusion) have been observed during study treatment, an extended immune 
modulation marker panel will be assessed at any safety events suspected to be related to 
cytokine release to further characterize these events. In addition, urinalysis to evaluate possible 
protein leakage will be performed for all patients at the beginning of each treatment cycle. 
Furthermore, since the safety follow-up period after PDR001 treatment was extended from 90 
to 150 days in the last amendment, additional safety follow-ups will be performed at 30 and 90 
days. To add flexibility all safety follow-ups may be performed by phone. Consequently, the 
protocol-specified lab tests or visits will not be requested during the safety follow-up period. 
This protocol amendment clarifies 
 
 the definition of post-menopausal status, 
corrects the imaging assessment schedule 
 
 
 
Lastly, the criteria for 
Hy’s law has been corrected in Table 6-3 Criteria for defining dose-limiting toxicities. 
Study status 
The CMCS110Z2102 study is currently enrolling. As of 12th January 2017, seventeen patients 
have received the combination of MCS110 and PDR001 at doses of 1  mg/kg and 100 mg (6 
patients) and 3 mg/kg and 100 mg (11 patients), respectively. No drug limiting toxicities were 
observed at this date. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the tracked changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
• Table 1-1 was updated with information of the ongoing phase 1 study in Japan. 
• 
 
• Section 5.2: Inclusion criteria 2 was updated with text specific for Japan. 


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• Section 5.3: Exclusion criteria 6 was updated to specify that patients with active 
tuberculosis are excluded from the study. Exclusion criteria 10 was updated to specify that 
patients with interstitial lung disease, non-infectious pneumonitis, history of drug induced 
interstitial lung disease or history of immune related adverse events are excluded from the 
study.  The requirement of a washout period of 7 days for immunosuppressive treatment 
and corticosteroids was added to exclusion criteria 12.  Repeat text was deleted from 
exclusion criteria 18. Definition of post-menopausal status was updated in exclusion 
criteria 20. 
•  Table 6-3: The typo in the definition dose limiting toxicity linked with bilirubin increase 
was corrected. 
• Section 6.3.3 : Management of anticipated risks were further clarified 
• Section 7.1 : Japanese patients will need to stay hospitalized during the first cycle of 
treatment 
• Table 7-1 was updated to delete the optional tests planned during the safety follow up visits. 
• Table 7-1 and section 7.2.2.5.3 were updated to include regular urinalysis testing. 
• Section 7.2.1: The imaging assessment schedule was corrected to be performed until week 
51 after start of treatment to align with the assessment schedule in patients still on treatment. 
• 
 
 
• 
 
  
• Section 7.1.5, the definition of safety follow-up, disease progression follow-up, and 
survival follow-up periods were clarified. Phone contacts with the patients are now 
requested also on day 30 and 90 after treatment discontinuation. 
• Section 7.2.2.1 : oxygen saturation will be measured with vital signs in Japanese patients  
• Table 7-4 was updated to reflect that an extended cytokine panel will be tested in case of 
adverse event suspected to be related to cytokine release. 
 
 
 
 
• Section 7.2.2.7 : chest x-ray will be performed in Japanese patients at screening and Day 
8 of Cycle 1 
• Section 8.2.2 was updated with language specific for Japan. 
• Groupings for safety analysis was updated under Section 10.4.2.1.2. 
• Section 11.5 was updated to better describe Novartis publication policy 


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


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Amendment 01 (11-Jul-2016) 
Amendment rationale 
The main reason for this amendment is to add more specific guidance for dose modifications 
and to revise definitions for dose limiting toxicities (DLTs), following Health Authority (HA) 
feed-back. In addition the routine chemistry lab test Lactate dehydrogenase (LDH) has been 
added since a recent publication suggest that TNBC and metastatic melanoma patients with 
aggressive tumor growth, with elevated LDH, may have less benefit of PD-1 inhibition 
compared to those with more slowly growing tumors (Diem et al., 2016, Nanda et al., 2016). 
 
 
With the available PK data obtained from the single agent first-in-human study 
CPDR001X2101, an exploratory population PK (PopPK) analysis showed that the T1/2 of 
PDR001 in man is 20 [17, 23] days (mean [90% CI]). Using five times the upper limit of the 
half-life of 23 days and an added safety margin, the protocol is amended to increase the duration 
of contraception and safety follow-up periods post PDR001 treatment from 90 days to 150 days. 
These changes are related to an Urgent Safety Measure communicated on 08-June-2016 to all 
investigators. 
Minor corrections of typos/clarifications of text were also made. The details are provided in the 
below section “Changes to the protocol”. 
Study status 
The CMCS110Z2102 study is currently under review by Health authorities . 
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 Dosing regimen. Adding instructions to resume treatment at a lower level 
after skipping an administration (if meeting criteria for DLT) 
• Section 6.2.4 Definitions of dose limiting toxicities. The following Grade 4 AEs should be 
defined as DLTs: Electrolyte abnormalities and CK elevation 
• Section 6.3.1 Dose modification and dose delay. Update of dose modification 
recommendations for drug related toxicities and instructions to reduce dose after DLT. 
• Section 4 Study design, and Section 7.1.5 Follow-up period. Update of the safety period 
duration 
• Section 7.2.2.5 Laboratory evaluation: LDH was added in the list of clinical laboratory 
parameters to be analyzed. 
• Information about update of the follow-period duration were inserted in Section 5.3, 
Section 6.3.2., Section 7.2.2.5.8, Section 8.1.1, Section 8.2.2, Section 10.4.2 and Table 7-
1. 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Immunotherapies that target immune checkpoints are currently emerging as key agents in 
cancer therapy. Antibodies inhibiting cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) 
and programmed death-1 (PD-1) demonstrate strong efficacy, durable antitumor effects and an 
acceptable safety profile. Response to checkpoint inhibition differs strongly across tumor types, 
with highest rates of response observed in advanced melanoma. Both non-responsiveness to 
checkpoint inhibition as well as initial response followed by progression have been observed, 
indicating the presence of intrinsic resistance and therapy-induced acquired resistance 
(Kelderman 2014). Tumor associated macrophages (TAMs) and myeloid-derived suppressor 
cells (MDSCs) are among the most abundant immune cells in the tumor microenvironment and 
are known to mediate therapeutic resistance in cancer (Jiang 2015, Ruffell 2015). Thus, immune 
escape mediated by TAMs and MDSCs is a potential cause of limited clinical benefit of immune 
check-point blockade (Zhou 2014). Recently, a clinical study showed an association between 
circulating MDSCs and intrinsic resistance to PD-1 inhibition in melanoma patients 
(Zhou 2014, Weber 2015). Additionally, preclinical studies show that single agent blockade of 
CSF-1/CSF-1R or PD-1 results in limited efficacy by restraining tumor growth, but combined 
blockade of CSF-1R and PD-1 potently elicits tumor regressions (Zhu 2014). Currently, several 
clinical studies are ongoing evaluating the efficacy of dual targeting of PD-1 and TAMs, 
supported by synergistic antitumor activity demonstrated in a preclinical pancreatic cancer 
model (Zhou 2014). 
1.1.1 
Overview of PD-1 
PD-1 is a critical co-inhibitory receptor that is upregulated on T cells upon activation 
(Freeman 2008). It is also expressed by B cells, NK cells, dendritic cells, and activated 
monocytes. The ligands for PD-1, programmed death-ligand 1 (PD-L1) and programmed death-
ligand 2 (PD-L2), are expressed by macrophages and monocytes, and can be induced on 
numerous cell types (T cells, endothelial cells, and tumor cells) during inflammation 
(Keir 2008). Engagement of PD-1 by its ligands transduces a signal that inhibits T-cell 
proliferation, cytokine production, and cytolytic function (Riley 2009). During tumorigenesis, 
cancer cells from a wide range of tumor types exploit immune checkpoint pathways, such as 
PD-1, to avoid detection by the adaptive immune system (Murphy 2011). Blockade of the PD-
1 pathway has been shown to lead to both accumulation and increased activity of antitumor 
effector T cells and reduced numbers of regulatory T cells (Tregs) at the tumor site (Wang 2009, 
Mangsbo 2010, Mkrtichyan 2011, Rosenblatt 2011). 


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Figure 1-1 
Blockade of PD-1/PD-1 interaction by PDR001 
 
APC: antigen presenting cell; MHC: major histocompatibility; TCR: T cell receptor 
1.1.2 
Overview of CSF-1 
CSF-1, also known as macrophage colony-stimulating factor (M-CSF) is a protein that is 
produced by several cell types and tissues, including various cancer cell types (Aharinejad 2007, 
Priceman 2010, Tarhini 2012). CSF-1 binds to the tyrosine kinase receptor, CSF-1 receptor 
(CSF-1R), on myeloid cells, which results in increased proliferation and differentiation of 
myeloid cells into type M2 macrophages (TAMs) and MDSCs, and recruitment into tumors 
(Dai 2001, Li 2006). TAMs and MDSCs use several mechanisms to induce T-cell inhibition; 
directly through PD-L1 and indirectly through secretion of IL-10, leading to an 
immunosuppressive tumor environment (Gabrilovich 2009, Kuang 2009, Ruffell 2015). 
Figure 1-2 
Macrophage polarization and function 
 
Modified figure from Sica 2006. TAMs induce T-cell inhibition resulting in immune suppression. 


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Preclinical and clinical studies demonstrate that blockade of CSF-1 or CSF-1R activates the 
immune system by limiting tumor infiltration by TAMs and MDSCs, or altering macrophage 
polarization, resulting in significantly enhanced antigen presentation and an increase in CD8+ 
T-cells (DeNardo 2011, Pyonteck 2013, Ruffel 2014, Ries 2014, Zhou 2014). However, 
inhibition of CSF-1 signaling upregulates checkpoint molecules, including PDL1 and CTLA4, 
thereby limiting the potential beneficial therapeutic effects (Zhu 2014). 
1.2 
Introduction to study treatment 
1.2.1 
Overview of PDR001 
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody that blocks 
the binding of PD-L1 and PD-L2 to PD-1. PDR001 recognizes PD-1 in cynomolgus monkeys 
and shows functional activity in vitro and ex vivo. For further details, please refer to the 
[PDR001 Investigator’s Brochure]. 
1.2.1.1 
Non-clinical experience of PDR001 
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the 
constant of dissociation (KD) of PDR001 on human PD-1 is 0.827 nM. In ex vivo lymphocyte 
stimulation assays using human blood, PDR001 enhances interleukin-2 (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 thus, 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. The affinity of 
PDR001 for cynomolgus PD-1 is 0.929 nM, nearly the same for human PD-1, as noted above. 
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. All 
main phase data as well as recovery pathology data are reported here. All other recovery phase 
data are pending. 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, were also 
observed 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 period. 
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 


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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. There were no test article related effects seen in the cardiovascular assessments. 
All other microscopic findings were considered spontaneous or otherwise unrelated to PDR001 
administration. 
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 Highest Non-Severely Toxic Dose 
(HNSTD) in this study was 100 mg/kg. PDR001 has a favorable safety profile in monkeys that 
supports a projected human starting dose of 1 mg/kg in the first in human study 
[CPDR001X2101]. For further details, please refer to the [PDR001 Investigator’s Brochure]. 
1.2.1.2 
Clinical experience of PDR001 
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 [CPDR001X2101] study started enrollment on 27 April 2015 and is ongoing. As of 17 
December 2015, a total of 58 patients had been treated in the study at the dose levels of 1, 3 and 
10 mg/kg Q2W and 3 and 5 mg/kg Q4W. No patient experienced a dose limiting toxicity (DLT) 
and the toxicity profile appears to be similar to that of marketed inhibitors of PD-1. The PK 
data obtained from the dose escalation, and modeling of the exposure data, support the use of 
flat dosing for PDR001 of 400 mg given every 4 weeks. The expected PDR001 Ctrough 
concentrations are in line with observed steady state mean Ctrough concentrations for 
pembrolizumab, which is approved with substantial efficacy in several cancer types. The data 
also support the use of 300 mg Q3W as an alternative dose regimen if it is more convenient for 
scheduling purposes, for example in combination treatment regimens. 
1.2.2 
Overview of MCS110 
MCS110 is a high-affinity, humanized monoclonal antibody directed against human 
macrophage colony stimulating factor (M-CSF; also known as colony-stimulating factor-1 
[CSF-1]). CSF-1 binds to the receptor tyrosine kinase CSF-1R (CSF-1 Receptor) to drive the 
differentiation, migration and survival of tissue macrophages. MCS110 neutralizes multiple 
forms of human CSF-1 inhibiting its effect on monocytes and macrophages. See [MCS110 
Investigator’s Brochure] for further information. 
1.2.2.1 Non-clinical experience of MCS110 
The ability of MCS110 to neutralize the activity of CSF-1 was established in several in vitro 
and in vivo studies. 
The preclinical pharmacokinetics (PK) and pharmacodynamics (PD) of MCS110 were 
evaluated in cynomolgus monkeys following a single intravenous (i.v) bolus injection of 0.2, 2 


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or 20 mg/kg, or multiple weekly iv bolus injections of 10 mg/kg for 3 weeks and 2, 20 or 100 
mg/kg for up to 13 weeks. Free MCS110 (unbound to target CSF-1) exhibited dose-dependent 
PK, with decreasing clearance (CL) and increasing mean residence time (MRT) or effective 
t1/2 when dose increased. The PK profiles of free MCS110 were notably nonlinear at 
concentrations below approximately 20 μg/mL, presumably due to target-mediate disposition. 
In the 13-week study, 2 out of 22 animals tested had anti-drug antibodies detected in serum, 
which correlated with lower MCS110 exposure at the corresponding time points. For PD, time 
and dose dependent increase in total CSF-1 was observed in the 13-week study following 
MCS110 administration, presumably due to slower clearance of the CSF-1 after it formed 
immune complexes with MCS110, indicating target engagement. Decreases in other 
downstream biomarkers such as circulating monocytes and serum NTx were also observed 
following MCS110 administration. 
The cynomolgus monkey was selected as the relevant species for toxicology studies because 
MCS110 showed similar functional activity against cynomolgus monkey and human CSF-1 in 
in vitro bioassays. In cynomolgus monkey studies there were no severe toxicological effects in 
any animal given MCS110 intravenously as a single dose or as multiple doses once weekly up 
to 13 weeks and up to doses of 100 mg/kg, showing good tolerability of MCS110 with systemic 
administration. Mild increases in liver enzymes were seen in all studies without 
histopathological correlates, which resolved with clearance of the drug. This included consistent 
mild/moderate, dose-dependent increases in lactate dehydrogenase (LDH), mild increases in 
AST, and minimal increases in gamma-glutamyl transpeptidase (GGT) and ALT. 
All parameters returned to baseline levels with the clearance of MCS110 from the serum. The 
most likely cause of these increases is reduced clearance rate of the serum enzymes due to the 
diminished numbers of Kupffer cells in the liver. This was demonstrated in cynomolgus 
monkey study with a single intravenous dose of MCS110, which showed a decreased clearance 
of histidine-tagged creatine kinase injected in parallel to MCS110. After 13 weekly doses, 
minimal or mild interstitial edema was seen in multiple organs histopathologically in all dose 
groups, including the low-dose group. Although periorbital swelling was observed to occur 
sporadically in all groups (including controls), the increased incidence and severity of 
periorbital swelling observed at 100 mg/kg suggested a relationship of this effect with MCS110 
administration. No interstitial or periorbital edema was present at the end of the recovery period 
showing the reversal of this effect. All other effects seen, such as bone morphology changes 
and monocyte depletion, were due to the expected pharmacological effects of MCS110. The 
data support the intravenous use of MCS110 in clinical trials at the doses selected (Section 2.3). 
Please refer to the most recent edition of the [MCS110 Investigator’s Brochure] for further 
information. 
1.2.2.2 
Clinical experience 
Four clinical trials with MCS110 have been initiated. Brief information on clinical experience 
of relevant MCS110 studies is provided below. For additional information, please refer to 
[MCS110 Investigator Brochure]. 


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Table 1-1 
Clinical trials with MCS110 
Trial 
Study type 
Study objectives 
Patients 
MCS110 dose range 
and schedule 
[MCS110A2101] 
Closed 
First in 
human, 
dose 
escalation 
MTD, safety, PK/PD, 
preliminary efficacy 
Prostate cancer with 
bone metastases, n=3 
0.01mg/kg every 14 
days 
[MCS110X2101] 
Completed 
Healthy 
volunteers, 
dose 
escalation 
MTD, safety, PK/PD 
Healthy, n= 52 
0.01-20 mg/kg, 1-2 iv 
infusions every 21-56 
days 
[MCS110X2201] 
Ongoing 
Efficacy 
study 
Safety, tolerability, 
PK/PD, efficacy 
Pigmented Villonodular 
Synovitis (PVNS), 
n=16 
10 mg/kg, 1-4 iv 
infusions every 28 days 
[MCS110Z2201] 
Ongoing 
Efficacy 
study 
Safety, tolerability, 
PK/PD, efficacy 
Triple Negative Breast 
Cancer (TNBC), n=24 
10 mg/kg iv infusions 
every 21 days 
(additional dose C1D8) 
[MCS110Z1101] 
(ongoing) 
Healthy 
volunteers, 
dose 
escalation in 
Japanese 
population 
Safety, tolerability, 
PK/PD 
Japanese healthy 
male, n= 21 
1,3,5,10mg/kg iv 
infusion single dose. 
1.2.2.2.1 CMCS110X2101, a clinical trial in healthy volunteers 
[CMCS110X2101] was a Phase I study designed to evaluate safety, tolerability and MTD of 
MCS110 in 52 healthy volunteers (HV). MCS110 was delivered to 27 HV at increasing single 
doses from 0.01-20 mg/kg. Additionally, 6 HV received 2 doses (5 mg/kg) given 21 days apart, 
and another 6 received 2 doses (10 mg/kg) given 56 days apart. 
Clinical safety and tolerability 
Asymptomatic and reversible creatine kinase (CK) elevations (Grade 1 to Grade 4) were seen 
in 15 of 52 HV. The CK elevation did not appear to reflect muscle damage since neither troponin 
T (marker for cardiac muscle damage) nor aldolase (marker for skeletal muscle tissue damage) 
was elevated. The CK elevations are thought to be caused by the pharmacological effect of 
MCS110. 
Mild periorbital edema (Grade 1), was observed in 4 of 52 HV and was transient, lasting 
between 2 and 158 days. None of the subjects who presented with periorbital edema had 
developed anti-drug antibodies. 
The dose limiting toxicity was identified at 20 mg/kg, based on CK elevations exceeding more 
than 5 times the upper limit of normal. The recommended dose for future studies was set at 
10mg/kg. 
Clinical pharmacokinetics 
Following intravenous administration of MCS110 in healthy volunteers, serum free MCS110 
exhibited concentration/dose-dependent pharmacokinetics (PK), with decreasing clearance 
(CL) and increasing mean residence time (MRT) or effective t1/2 when doses increased from 


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0.01 to 20 mg/kg across 8 dose levels. The shape of the serum free MCS110 PK profiles 
indicated target mediated disposition, where the MCS110 concentration declined more rapidly 
at concentrations lower than approximately 10 μg/mL. This was presumably due to binding of 
MCS110 to the target, suggesting that serum free MCS110 concentrations above approximately 
10 μg/mL are required to saturate circulating CSF-1. At the 10 mg/kg single dose level, 
MCS110 concentrations were maintained above 10 μg/mL for up to 42 days post-dose. As 
expected, total CSF-1 exhibited a dose-dependent increase in plasma following MCS110 
treatment, presumably due to slower clearance of CSF-1 after it formed immune complexes 
with MCS110, indicating successful target engagement. The total CSF-1 concentration reached 
a plateau at the single-dose level at or above 10 mg/kg, and it was maintained at the plateau for 
at least 42 days at the 10 mg/kg dose. 
Clinical pharmacodynamics 
Expected pharmacological responses were observed in downstream biomarkers including dose-
dependent decreases in circulating CD14+ or CD14+CD16+ monocytes and C-terminal 
telopeptide of type I collagen (CTX-1), a bone resorption marker. In addition, dose-dependent 
increases in CK were observed. Simulation of steady-state dose-response relationships for 
biomarkers showed that with the once-every-4 week (Q4W) iv administration of MCS110 the 
response of PD biomarkers (CD14+ and CD14+CD16+ monocytes, and CTX-1) was expected 
to be close to maximal at doses at or above 5 mg/kg and minimal at doses at or below 1 mg/kg. 
1.2.2.2.2 CMCS110X2201, a Phase II study in pigmented villonodular synovitis 
[CMCS110X2201] is an ongoing Phase II study designed to evaluate safety, tolerability and 
efficacy of MCS110 in pigmented villonodular synovitis (PVNS). PVNS is a benign tumor 
consisting of macrophages and multinucleated giant cells, most commonly located to joints. As 
of 19-Feb-2015, 16 patients with PVNS have been treated with MCS110. In Part A of the study, 
7 patients received a single dose of 10 mg/kg MCS110. In the multiple dose part B of the study, 
at the cut-off date of 19-Feb-2015, 9 patients were randomized and had received at least one 
infusion. 
Clinical safety and tolerability 
As of February 19 2015, the most common adverse events reported include elevated CK (Grade 
2-4), periorbital edema (Grade 1) and AST elevations (Grade 1). 
Clinical pharmacokinetics 
PK analysis is ongoing. Preliminary data of the first 3 patients with single i.v. infusion of 10 
mg/kg in the ongoing study suggested a similar PK profile as that observed in HV. 
Clinical pharmacodynamics 
Preliminary data from the ongoing study in PVNS patients showed an expected decrease in 
monocytes and CTX-1, while an increase was seen in CK. Maximum values are generally 
observed at Day 28 or Day 43 and then return to baseline. 


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Clinical efficacy 
Efficacy data from four PVNS patients receiving a single dose of 10 mg/kg MCS110 
demonstrated a clear efficacious effect with a mean reduction in tumor volume of 40%. 
1.3 
Overview of combination treatment 
1.3.1 
Non-clinical 
No preclinical data exist for the combination of MCS110 and PDR001. 
1.3.2 
Clinical 
No clinical data exist for the combination of MCS110 and PDR001. However, several clinical 
studies are ongoing evaluating the efficacy of dual targeting of PD-1/PD-L1 and TAMs in 
advanced 
malignancies 
(ClinicalTrials.gov: 
[NCT02452424], 
[NCT02526017], 
[NCT02323191]). 
1.3.3 
Potential for drug-drug interactions 
Specific studies to investigate drug-drug interactions (DDI) have not been conducted. MCS110 
and PDR001 are monoclonal antibodies, not metabolized by Cytochrome P450 (CYP450) 
enzymes or transported by P-glycoprotein (PgP) or related ABC membrane transporters. 
Therefore DDIs at the level of these enzymes and transporters are not expected. MCS110 
specifically neutralizes CSF-1 and is not expected to modulate cytokines. Cytokines produced 
by PDR001-activated lymphocytes may impact levels of PgP or CYP450 enzyme activity. The 
clinical relevance of this is unknown but considered unlikely. 
1.3.4 
Expected overlapping toxicities 
PD-1 inhibitors are known to cause immune mediated adverse events e.g. pneumonitis, colitis 
etc, whereas no apparent immune related adverse events have been reported with MCS110 and 
other CSF-1/R targeting drugs (USPI/SPC nivolumab/pembrolizumab; Cassier ASCO 2014, 
Rugo ESMO 2014). However, since both MCS110 and PDR001 are immune activating drugs 
there is a potential risk for higher frequency or aggravation of immune mediated adverse events. 
As of 03-Sep-2015, no liver enzyme elevations have been reported from treatment with PDR001 
[CPDR001X2101], nonetheless, liver enzyme elevations and immune related hepatitis have 
been reported with other PD-1-inhibitors and a class effect should be suspected, (USPI/SPC 
nivolumab/pembrolizumab). Clinical studies with MCS110 report frequent asymptomatic and 
transient CK (Grade 3) and AST elevations (Grade 1-2), whereas ALT elevations (< Grade 1) 
were only seen in occasional patients. The increase of enzymes did not reflect muscle damage 
since markers for cardiac or skeletal muscle damage were evaluated and found to be normal. 
Isolated CK/AST elevation (without ALT elevation) is not considered to be consistent with liver 
damage (Krishnamurthy 2009). The elevation of CK and liver transaminases is considered a 
pharmacological effect of MCS110 due to reduction in the number of liver macrophages 
(Kupffer cells) responsible for elimination of these enzymes from circulation. Nonetheless, 
overlapping liver enzyme elevations may be expected with the combination treatment of 
MCS110 and PDR001, therefore liver enzymes will be carefully monitored in this study. 


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Skin toxicity have been reported from studies with CSF-1/R inhibitors as well as PD-1 
inhibitors; thus, skin toxicity may be an overlapping toxicity with the study drug combination 
(USPI/SPC nivolumab/pembrolizumab; Cassier ASCO 2014, Rugo ESMO 2014). 
2 
Rationale 
2.1 
Study rationale and purpose 
Treatment with PD-1 checkpoint inhibitors results in clinically important anti-tumor activity in 
several tumor types (Topalian 2014, Gettinger 2015, Rizvi 2015). However, intrinsic as well as 
acquired resistance to PD-1 inhibition has been observed (Section 1.1). Therapeutic resistance 
to 
various 
cancer 
treatments, 
including 
PD-1 
inhibition, 
is 
mediated 
through 
immunosuppressive cells (TAMs and MDSCs) in the tumor microenvironment (Ruffell 2015, 
Weber 2015). Preclinical and clinical studies have demonstrated that tumor infiltrating M2 
macrophages (TAMs) can be depleted or polarized into M1 macrophages by CSF-1 signaling 
blockade (Figure 1-1, DeNardo 2011, Pyonteck 2013, Ruffel 2014, Ries 2014). 
Furthermore,combined targeting of PD-1 and CSF-1 signaling resulted in synergistic antitumor 
activity in a preclinical pancreatic cancer model (Zhou 2014). 
Figure 2-1 
Rationale for combined treatment with PDR001 and MCS110 
 
TAMs induce T-cell inhibition leading to an immunosuppressive tumor environment (Gabrilovich 2009, 
Kuang 2009, Ruffell 2015). Tumor cells exploit immune checkpoint pathways to inhibit T-cell 
proliferation and avoid detection by the immune system (Murphy 2011). Combined treatment with 
MCS110 and PDR001 is expected to result in TAM depletion, enhanced T-cell activation and 
synergistic antitumor activity in the clinical setting. 
Combined treatment with MCS110 and PDR001 will be evaluated in disease indications where 
single agent PD-1/PD-L1 inhibition did not result in clinically meaningful responses and 
therapeutic resistance may be mediated by TAMs: 


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1. Anti-PD-1/PD-L1 treatment naïve TNBC, pancreatic and endometrial cancer 
Clinical studies show modest, but limited response to PD-1/PD-L1 inhibition in TNBC and 
pancreatic cancer indicating intrinsic resistance (Nanda 2014, Emens 2015, Segal 2014). 
Additionally, TNBC, pancreatic and endometrial cancers are characterized by an immune 
suppressive tumor microenvironment consisting of a high content of TAMs, known mediators 
of intrinsic drug resistance (Yuan 2014, Mielgo 2013, Kübler 2014). 
2. Anti-PD-1/PD-L1 treatment resistant melanoma 
Clinical studies show high response rates to PD-1/PD-L1 inhibition in melanoma; however, 
non-responsiveness (intrinsic resistance) as well as initial response followed by progression 
(acquired resistance) have been observed (Topalian 2014). Clinical data demonstrate that 
MDSCs mediate intrinsic resistance to PD-1 inhibition in melanoma (Weber 2015). 
The purpose of this study is to evaluate the safety, tolerability and efficacy of combined 
treatment with MCS110 and PDR001. In addition, the mechanisms of intrinsic and acquired 
resistance to PD-1/PD-L1 inhibition as well as the ability of MCS110 to overcome resistance 
will be explored. 
2.2 
Rationale for the study design 
This is an open-label, Phase Ib/II study of the combination of MCS110 and PDR001. The study 
consists of two parts: a dose escalation in the Phase Ib part and a Phase II part where four groups 
will be treated at the recommended Phase II dose (RP2D). 
Phase Ib 
In the Phase Ib part, cohorts of patients will receive escalating doses of MCS110 and PDR001 
until a MTD/RP2D is identified. The dose escalation decision will be guided by a Bayesian 
logistic regression model (BLRM) with overdose control (EWOC) principle based on DLT data 
in the context of available safety, PK and PD information. For details of the dose escalation, 
please refer to Section 6.2. 
This open-label dose escalation study design using a BLRM is a well-established method to 
estimate the MTD, or identify a lower RP2D in cancer patients. The adaptive BLRM with 
EWOC principle controls the risk of DLT in future patients on study. The decisions on the dose 
of MCS110 in combination with PDR001 are made by the Investigators and Novartis study 
personnel and will be based upon the dose identified to satisfy the EWOC criterion under the 
appropriate BLRM, patient tolerability and safety, PK and PD data available at the time of the 
decision Section 6.2.3. 
Phase II 
The Phase II part of the study will begin after the RP2D is determined for the combination of 
MCS110 and PDR001. The primary objective of the Phase II part is to estimate the preliminary 
anti-tumor activity of MCS110 in combination with PDR001 in diseases known to respond to 
PD-1/PD-L1 inhibition or where limited response may be attributed to immune escape mediated 
by the tumor microenvironment (TAMs, MDSC). These disease indications include melanoma, 
TNBC, endometrial and pancreatic cancer. 


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The efficacy of the combination will be explored both in patients that are naïve to anti-PD-
1/PD-L1 treatment (TNBC, pancreatic, endometrial cancer) and patients that have progressed 
on previous anti-PD-1/PD-L1 treatment (melanoma). Twenty patients are expected to be 
enrolled in each of the TNBC, endometrial and melanoma groups, but enrollment will be 
expanded up to approximately 40 patients in those groups in which objective responses (CR or 
PR) are observed (≥ 3 of 20 patients in the anti-PD-1/PD-L1 naïve groups or ≥ 2 of 20 patients 
in the anti-PD-1/PD-L1 resistant groups).  In addition, 20 patients will be enrolled in the 
pancreatic group at RP2D. Enrollment may be expanded up to approximately a total of 40 
patients at RP2D in this group if at least 3 pts with CR, PR or SD > 4 months are observed 
(addition of Group 2a, see Figure 4-1). Further, an exploratory group of 20 patients at a lower 
dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be opened if the above 
mentioned gating criteria are met (Group 2b, see Figure 4-1). 
A Bayesian design will be used to estimate the overall response rate (ORR) in each of the 
TNBC, endometrial and melanoma groups and the clinical benefit rate (CBR) in the pancreatic 
group. For Group 2 (pancreatic cancer), a separate model with same prior assumptions will be 
used to estimate CBR for the different dose levels. The Phase II groups are designed to detect 
efficacy signals indicating a patient population where further studies of the combination of 
MCS110 with PDR001 are warranted. 
2.3 
Rationale for dose and regimen selection 
PD-1 inhibition has demonstrated objective responses in several different malignancies, 
whereas blockade of CSF1/R signaling has led to TAM depletion and immune activation, but 
no objective responses have been reported so far (Ries 2014, Gomez-Roca 2015). The PDR001 
dose will start at 100 mg, a dose expected to demonstrate antitumor activity, and MCS110 will 
start at 3 mg/kg. These doses were selected based on preclinical and clinical studies as described 
in Section 6.2.1. Both antibodies will be administered via i.v. infusion every 3 weeks in 
accordance 
with 
ongoing 
studies 
of 
MCS110 
combined 
with 
chemotherapy 
[CMCS110Z2201] and single agent PDR001 [CPDR001X2101]. 
2.4 
Rationale for choice of combination drugs 
Currently, nivolumab and pembrolizumab are the only PD-1 inhibitors approved by FDA and 
EMA for the treatment of advanced melanoma and non-small cell lung cancer; however, none 
are approved for the treatment of TNBC, pancreatic cancer or endometrial cancer. PDR001 is 
Novartis’ PD-1 inhibitor currently being evaluated in various advanced malignancies 
[CPDR001X2101]. Therapeutic resistance to PD-1 inhibitors seems to be mediated through 
TAMs (Weber 2015). Several compounds directed towards CSF-1/CSF-1R have been reported 
to deplete TAMs in preclinical and clinical studies (Ries 2014, DeNardo 2011); however, none 
of these compounds are approved yet. MCS110 is Novartis’ anti-CSF-1 antibody currently 
being 
evaluated 
in 
several 
studies 
in 
PVNS 
and 
TNBC. 
Refer 
to 
Section 1.1 and Section 2.1. 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
Phase Ib part: 
To characterize the safety and tolerability of MCS110 given in 
combination with PDR001 and to identify a recommended dose 
combination for Phase II. 
 
Frequency, severity and seriousness of AEs, laboratory abnormalities 
and other safety parameters. 
Dose interruptions, reductions, and dose intensity. 
Incidence rate of DLTs during the first two cycles of study treatment. 
 
Phase II part: 
To estimate the anti-tumor activity of the combination of 
MCS110 with PDR001 
 
-Overall response rate (ORR) per Response Evaluation Criteria in 
Solid Tumors (RECIST v1.1) (groups 1, 3 and 4).  
-Clinical benefit rate (CBR) per Response Evaluation Criteria in Solid 
Tumors (RECIST v1.1), which is defined as confirmed objective 
response or SD>4 months. (Group 2) 
 
Secondary 
 
Refer to Section 10.5 
Phase Ib part: 
To estimate the preliminary anti-tumor activity of the 
combination of MCS110 with PDR001 
 
ORR, progression free survival (PFS), CBR,duration of response 
(DOR) and disease control rate (DCR) per RECIST v1.1 and per 
immune related Response Criteria (irRC) 
 
Phase II part: 
To further characterize the safety and tolerability of MCS110 
given in combination with PDR001 
 
Frequency, severity and seriousness of AEs, laboratory abnormalities 
and other safety parameters. 
 
Phase II part: 
To evaluate the preliminary anti-tumor activity of the 
combination of MCS110 with PDR001 by additional efficacy 
measures 
 
ORR per irRC, PFS, DOR, DCR, CBR per RECIST v1.1 and per irRC 
(Group 1, 3 and 4) 
CBR per irRC, PFS, DOR, DCR, ORR per RECIST v1.1 and per irRC 
(Group 2) 
 
Phase Ib and Phase II parts: 
To characterize the pharmacokinetics of MCS110 and PDR001 
in combination  
 
Serum concentration of MCS110 and PDR001 and PK parameters 
 
To assess immunogenicity of MCS110 and PDR001 
Presence and/or concentration of anti-PDR001 or anti-MCS110 
antibodies 
 
To describe survival with MCS110 and PDR001 in combination 
Overall survival (OS) 
 


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4 
Study design 
4.1 
Description of study design 
This study is a Phase Ib/II, multi-center, open-label study starting with a Phase Ib dose 
escalation part followed by a Phase II part. MCS110 and PDR001 will be administered i.v. 
every three weeks (Q3W) until the 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. The study design is summarized in Figure 4-1. 
Phase Ib part 
During the Phase Ib part of the study, cohorts of patients will be treated with increasing doses 
of MCS110 and PDR001 every three weeks until a RP2D is determined for this treatment 
combination. 
It is expected that an RP2D will be established before the MTD is reached. The RP2D for the 
combination will not exceed the RP2Ds for the single agent administration of MCS110 and 
PDR001. To assure that the combination RP2D does not exceed the MTD, combination 
MCS110 and PDR001 dose escalation will also be guided by an adaptive Bayesian logistic 
regression model (BLRM) following the escalation with overdose control (EWOC) principle. 
At least 15 patients are required during dose escalation to define the MTD; however, fewer than 
15 patients may be treated if the RP2D is determined without reaching the MTD (for further 
details see Section 6.2.3). 
Phase II part 
Once the MTD and/or RP2D have been declared, additional patients will be enrolled in the 
Phase II part in order to assess the preliminary anti-tumor activity of MCS110 in combination 
with PDR001. 
In the Phase II part, patients will be assigned to different groups depending on the tumor type 
as shown in Figure 4-1. Please refer to Section 5.1 for further details. 
All groups will enroll approximately 20 patients each initially. Enrollment to any of these 
groups may be stopped at fewer patients if achieving these enrollment targets is not logistically 
feasible.  
For Groups 1 and 3, the sample size may be extended to approximately 40 patients, if at least 3 
patients out of the first 20 treated in that group have an objective response (CR or PR) per 
RECIST v1.1 or irRC. Twenty patients will be enrolled into Group 2 at RP2D. Enrollment may 
be expanded up to approximately 40 patients if clinical benefit per RECIST v1.1 or irRC (CR, 
PR or SD > 4 months) is observed in at least 3 pts (addition of Group 2a, see Figure 4-1). In 
addition, an exploratory group of 20 patients at a lower dose (1 mg/kg MCS110 in combination 
with PDR001 300 mg) may be opened if the above mentioned gating criteria is met (Group 2b, 
see Figure 4-1). Group 4 may similarly be expanded if at least 2 patients out of the first 20 
treated in that group have an objective response (Figure 4-1). A Bayesian design will be used 


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in order to estimate ORR within each expansion group. Details of the sample size calculations 
leading to the patient numbers are provided in Section 10.8. 
Figure 4-1 
Study design 
 
The primary clinical study report (CSR) will be based on all patients’ data from the Phase Ib 
and Phase II parts, up to the time when all patients have completed at least six cycles of 
treatment or discontinued treatment. Patients who are on study beyond cycle 6 may remain on 
treatment until they discontinue the study. Any additional data (after the data cut-off date for 
the primary CSR) will be further summarized in a final CSR at completion of the study, as 
defined in Section 4.3. 
Screening period 
The screening period begins once the patient has signed the study informed consent. Patients 
will be evaluated against study inclusion and exclusion criteria (Table 7-1 and Section 5.2, 
Section 5.3 and Section 7.1.1). 
 
  
 


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Treatment period 
The treatment period will begin on Cycle 1 Day 1. For the purpose of scheduling and 
evaluations, a treatment cycle will consist of 21 days. 
Further details are provided in Table 7-1 and Section 7.1.2. 
Follow-up (FU) period 
Patients will be followed up for safety evaluations 150 days after the last administration of 
PDR001. For patients who had to stop PDR001 treatment but continued taking MCS110 at the 
time of treatment stop, the follow-up evaluation will take place 90 days after the last 
administration of MCS110 or 150 days after the last administration of PDR001, whichever 
duration is longer (Table 7-1 and Section 7.1.5). 
Disease progression FU 
Patients who discontinue study treatment for any reason other than disease progression as per 
irRC will be followed up for progression of disease (Section 7.1.5). The disease progression 
follow-up will be performed until all patients enrolled in the Phase II part of the study have had 
progression of disease or discontinued the study for any reason. 
Survival FU 
Patients enrolled in Phase Ib and Phase II part will be followed for survival (Section 7.1.5) until 
the end of the study is reached, unless patients withdraw consent or are lost to follow-up. 
4.2 
Timing of interim analyses and design adaptations 
No formal interim analyses are planned in the study. However, in the Phase Ib part, the dose-
escalation design foresees that decisions based on the current data are taken before the end of 
the study. In the Phase II part the number of patients with tumor response will be monitored in 
each disease group to decide if the enrollment should be extended (see Section 2.2, Section 4.1 
and Section 10.7). The decision of whether to expand a certain group will be made at the time 
when at least 3 patients, for Group 1or 3, or at least 2 patients for Group 4 have an objective 
response (CR or PR) per RECIST v1.1 or irRC, or the last patient has been on treatment for at 
least 6 months, whichever occurs earlier. For Group 2, the decision to expand will be made if 
clinical benefit per RECIST v1.1 or irRC (CR, PR or SD > 4 months) is observed in at least 3 
patients or the last patient has been on treatment for at least 6 months. The decision to extend 
enrolment will be made separately for each of the groups.  
4.3 
Definition of end of the study 
The end of the study will be when: 
• 80% of the patients have completed the survival follow-up period (minimum 18 months 
after the first dose of treatment) or discontinued the study for any reason, and all patients 
have completed treatment and the safety follow-up period (150 days after last PDR001 
dose or 90 days for patients who stopped PDR001 and continued with MCS110 alone 
for more than 60 days),  


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or 
• the study is terminated early 
or 
• another clinical study becomes available that can continue to provide study treatment in 
this patient population, all patients ongoing are transferred to that clinical study and all 
discontinued patients have completed the safety follow-up period. The follow-up for 
disease progression and survival will not be performed or pursued (see Section 7.1.5). 
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative treatment option to patients who, in the opinion of the 
investigator, are still deriving clinical benefit.  
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 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 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 
2. Age ≥ 18 years [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.] 
3. Phase Ib part: Patients with advanced melanoma, endometrial carcinoma, pancreatic or 
TNBC, with measurable or non-measurable disease as determined by RECIST v 1.1 (refer 
to Appendix 1), who have progressed despite standard therapy or are intolerant of standard 
therapy, or for whom no standard therapy exists. 
4. Phase II part: Patients with advanced solid tumors, with at least one measurable lesion as 
determined by RECIST version 1.1, who have received standard therapy (no more than 3 
prior lines of treatment) or are intolerant of standard therapy, have progressed following 
their last prior therapy, and fit into one of the following groups: 
• Group 1: TNBC who did not receive prior anti-PD-1/PD-L1 treatment 


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• Group 2: Pancreatic adenocarcinoma who did not receive prior anti-PD-1/PD-L1 
treatment 
• Group 3: Endometrial carcinoma who did not receive prior anti-PD-1/PD-L1 
treatment 
• Group 4: Melanoma who progressed on prior anti PD-1/ PD-L1-directed treatment. 
5. ECOG performance status ≤ 2 
6. Patient 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, and during therapy on this study. Patients with an 
available archival tumor tissue collected less than 6 months before study startup do not 
need to perform a tumor biopsy at screening. 
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). 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 other monoclonal antibodies (mAbs). 
3. Patient 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 ULN, except for patients with Gilbert’s syndrome who are 
excluded if total bilirubin > 3.0 x ULN or direct bilirubin > 1.5 x ULN 
• Alanine aminotransferase (ALT) > 3 x ULN 
• Aspartate aminotransferase (AST) > 3 x ULN 
• Absolute neutrophil count < 1.0 x 109/L 
• Platelet count < 100 x 109/L 
• Hemoglobin (Hgb) < 9 g/dL 
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 ECG or congenital long QT syndrome 
• Acute myocardial infarction or unstable angina pectoris < 3 months prior to study 
entry 
5. Active autoimmune disease or a documented history of autoimmune disease within three 
years before screening, including the following: 
• A documented history of inflammatory bowel disease (ulcerative colitis or Crohn’s 
disease, within three years). 


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• Recent (< 12 months) active diverticulitis. 
• Patients with vitiligo, resolved childhood asthma/atopy and type I diabetes mellitus, 
residual hypothyroidism due to an autoimmune condition and only requiring hormone 
replacement, are not excluded. 
6. Active infection, including active tuberculosis requiring systemic antibiotic therapy  
7. Known human immunodeficiency virus (HIV) infection (no testing required). 
8. Active hepatitis B virus (HBV) or hepatitis C virus (HCV) infection, or HBV/HCV 
carriers/infections requiring antiviral treatment (testing required). 
9. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers; any malignancy considered to be indolent and that has never required 
therapy; and completely resected carcinoma in situ of any type. 
10. 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, including but not limited to: 
• Prior immune-related adverse events requiring treatment discontinuation 
• Ongoing symptomatic interstitial lung disease (ILD), noninfectious pneumonitis or 
history of drug induced interstitial lung disease 
11. Systemic anti-cancer therapy within 2 weeks or 5 x T ½, whichever is longer 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. For patients 
receiving CTLA-4, PD-1 or PD-L1 antagonists, 6 weeks is indicated as the washout 
period. 
12. Patients requiring chronic treatment with systemic steroid therapy or any 
immunosuppressive therapy, other than replacement-dose steroids in the setting of adrenal 
insufficiency. Any previous steroid or immunosuppressive therapy must be stopped at 
least 7 days before start of study treatment. Topical, inhaled, nasal and ophthalmic steroids 
are not prohibited. 
13. Use of any live vaccines against infectious diseases (e.g. varicella, pneumococcus) within 
4 weeks of initiation of study treatment. 
14. 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). 
15. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative 
radiotherapy to a limited field. To allow evaluation for response to treatment, patients 
enrolled in the Phase II part must have remaining measurable disease that has not been 
irradiated. 
16. Participation in an interventional, investigational study within 2 weeks of the first dose of 
study treatment. 
17. Presence of ≥ 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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18. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF) 
≤ 2 weeks prior start or 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. 
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 hCG laboratory 
test. 
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 dosing and for 150 days after the last dose of PDR001 or 90 days after the last dose 
of MCS110 for patients who stopped PDR001 and continued MCS110 alone for more than 
60 days. 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 1.5 months before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow-up hormone level assessment 
• Male sterilization (at least 6 months prior to screening). For female patients on the 
study the vasectomized male partner should be the sole partner for that patient. 
• Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other 
forms of hormonal contraception that have comparable efficacy (failure rate <1%), for 
example hormone vaginal ring or transdermal hormone contraception. 
In case of use of oral contraception women should have been stable on the same pill for a 
minimum of 3 months before taking study treatment. 
Women are considered post-menopausal and not of child bearing potential if they have had over 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile age 
appropriate (e.g. generally 40-59 years), history of vasomotor symptoms (e.g. hot flushes) in 
the absence of other medical justification or have had surgical bilateral oophorectomy (with or 
without hysterectomy), total hysterectomy, or tubal ligation at least 1.5 months ago. In the case 
of oophorectomy alone, only when the reproductive status of the woman has been confirmed 
by follow-up hormone level assessment is she considered not of child bearing potential. 
21. For Korea only: Sexually active males unless they use a condom during intercourse while 
taking treatment and for 150 days after the last dose of PDR001 or 90 days after the last 
dose of MCS110 for patients who stopped PDR001 and continued MCS110 alone. They 
should not father a child in this period. A condom is required to be used also by 
vasectomized men in order to prevent delivery of the drug via seminal fluid. 


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6 
Treatment 
6.1 
Study treatment 
For this study, the investigational drugs are MCS110, an anti-CSF-1 recombinant humanized 
monoclonal antibody, and PDR001, an anti-PD-1 receptor recombinant humanized monoclonal 
antibody. The study treatment is the combination of MCS110 and PDR001, or single agent 
MCS110 or PDR001 if one of the investigational drug need to be discontinued. 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
MCS110 
Liquid concentrate in vial 
i.v. infusion 
3 mg/kg (starting dose) 
Every 3 weeks 
PDR001 
Powder for solution for 
infusion 
100 mg (starting dose) 
Every 3 weeks 
MCS110 and PDR001 will be administered once every 3 weeks via i.v. infusions over 1 hour 
and30 minutes, respectively. The drugs will be administered separately with at least a 30 min 
break between the two antibodies. Infusions of each antibody can be extended to up to 2 hours 
if clinically indicated. 
Both study drugs may be infused using the same i.v. access site. The same administration 
sequence must be followed for all patients, i.e. PDR001 should be infused first. If an infusion 
reaction occurs after administration of PDR001, the subsequent MCS110 infusion must be 
delayed until it is safe for the patient to receive MCS110 based on the clinical discretion of the 
investigator. The delay between PDR001 and MCS110 infusions can be up to 4 hours if 
clinically indicated. 
A scheduled dose of ongoing study drugs may be delayed by up to 7 days to recover from 
previous AEs or a missed visit (see Section 6.3.2). If a scheduled dose of ongoing study drugs  
is delayed longer than 7 days due to an unresolved AE, the administration should be skipped 
and treatment resumed at a lower dose level (if meeting criteria for DLT) at the next scheduled 
dose. The assessment schedule will be shifted accordingly. Dose delays refer to all ongoing 
study drugs: for combination treatment both MCS110 and PDR001 and for single agent 
treatment MCS110 or PDR001. Dose modifications should follow Section 6.3.1 and 
Section 6.3.2. 
The dose for MCS110 study drug will be calculated from the individual subjects’ body weight 
as measured at the screening visit and subsequent visits prior to the administration. 
After Phase Ib part, if emerging PK, PD, and safety data indicate that a flat dosing strategy of 
MCS110 is appropriate, then a flat dosing strategy may be implemented in the Phase II part of 
the study. The PK data obtained during Phase Ib part of this study will be combined with PK 
data from the other MCS110 clinical studies to assess the flat dosing vs. body-weight based 
dosing, and a flat dose may be identified for the Phase II part of this study. 


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6.1.2 
Ancillary treatments 
Patients should not receive pre-medication to prevent infusion reactions before the first infusion 
of the study treatment, 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. The pre-medication should be chosen per institutional standard of care at the discretion 
of the treating physician; however, steroids should be avoided if possible. 
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 may only continue on the study following discussion with Novartis. 
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 infusion reactions are provided in Table 6-4. 
The CTCAE category of “Infusion related reaction” should be used to describe infusion 
reactions, unless the investigator considers another category, such as “Allergic reaction,” 
“Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific situation. 
6.1.3 
Treatment duration 
A patient may continue to receive study treatment 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. In addition to safety and efficacy criteria, investigator’s 
opinion of the patients best interest and clinical benefit from treatment may be discussed on a 
case by case basis with Novartis. Refer to Section 6.3.1, Section 7.1.4 and Section 7.1.6. 
6.2 
Dose escalation guidelines 
6.2.1 
Starting dose rationale 
This is the first study evaluating the combination of MCS110 and PDR001. Potential 
overlapping toxicities include liver enzyme elevations caused by immune induction (PDR001) 
or reduced elimination of liver enzymes (MCS110), higher frequency or aggravation of immune 
mediated adverse events and skin toxicity. 
The starting dose and regimen of MCS110 will be 3 mg/kg iv every 3 weeks, corresponding to 
approximately 40 % of the single agent dose administered in PVNS patients (10 mg/kg every 4 
weeks in study [MCS110X2201]) and 30 % of the dose administered in combination with 
carboplatin/gemcitabine in TNBC (10 mg/kg every 3 weeks in study [MCS110Z2201]). An 
MCS110 dose of 10mg/kg was well tolerated in HV and PVNS patients ([CMCS110X2101] 
and [CMCS110X2201]) and showed significant tumor reduction in PVNS patients. After a 
single dose of 3 mg/kg of MCS110 in HV, it was observed that CSF-1 has been saturated by 
MCS110 for approximately 21 days [CMCS110X2101]. PD analyses performed in HV studies 
indicate that circulating biomarker response should be close to maximal with dose at or above 
5mg/kg and minimal with doses below 3 mg/kg. Considering the risk of potential overlapping 


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toxicities, the dose of 3 mg/kg MCS110 was selected as the starting dose for the dose escalation 
part of the study. 
The starting dose and regimen of PDR001 will be 100 mg iv every 3 weeks. As of 30-Nov-
2015, PDR001 has been tested up to the dose of 10 mg/kg every 2 weeks in the ongoing 
[CPDR001X2101] study. No MTD has been determined and the planned RP2D is 300 mg (3.75 
mg/kg) given every 3 weeks or 400 mg (5 mg/kg) given every 4 weeks. Both of the proposed 
RP2Ds would be expected to achieve the steady mean Ctrough concentrations that are 
approximately 77 fold higher than the in vitro/ex vivo potency EC50 for PDR001 assessed as 
0.42 µg/mL. In addition, the expected PDR001 Ctrough concentrations are in line with observed 
steady state mean Ctrough concentrations for pembrolizumab whose ex vivo potency EC50 is 
approximately 0.4 µg/mL utilizing the same assay. Pembrolizumab has been approved with 
substantial efficacy in several cancer types. The PDR001 exposure at a starting dose of 100 mg 
Q3W is within the range of those observed in the CPDR001X2101 study with no DLTs (section 
1.2.1.2). PDR001 is expected to demonstrate antitumor activity at doses of 100 mg or above 
every 3 weeks.The starting dose is in accordance with clinical experience of nivolumab and 
pembrolizumab (Topalian 2012, Topalian 2014, Hamid 2013b, Robert 2014). 
6.2.2 
Provisional dose levels 
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this trial. 
Table 6-2 
Provisional dose levels 
Dose level * 
Proposed dose MCS110 
Proposed dose PDR001 
-2** 
0.3 mg/kg Q3W 
100 mg Q3W 
-1** 
1 mg/kg Q3W 
100 mg Q3W 
1 (starting dose) 
3 mg/kg Q3W 
100 mg Q3W 
2 
3 mg/kg Q3W 
300 mg Q3W 
3 
5 mg/kg Q3W 
300 mg Q3W 
4 
10 mg/kg Q3W 
300 mg Q3W 
* 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 
** Dose level -1 or -2 represent provisional dose levels and/or treatment doses for patients requiring 
a dose reduction from the starting dose level. No dose reduction below dose level -2 is permitted for 
this study 
6.2.3 
Guidelines for dose escalation and determination of MTD or RP2D 
The maximum tolerated dose (MTD) is defined as the highest combination drug that is unlikely 
(< 25% posterior probability) to cause DLT in 33% or more of the treated patients in the first 
two cycles (42 days) of treatment. 
The applied adaptive Bayesian methodology provides an estimate of the combinations of 
MCS110 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 6-3. 


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For the purposes of dose escalation decisions, each cohort will consist of 3 to 6 newly enrolled 
patients who will be treated at the specified dose level. The first cohort will be treated with the 
starting doses of 3 mg/kg MCS110 Q3W and 100 mg PDR001 Q3W. 
Patients must complete a minimum of two cycles of treatment with the minimum safety 
evaluation and drug exposure or have had a DLT within the first two cycles of treatment to be 
considered evaluable for dose escalation decisions (Section 10.1.4). Dose escalation decisions 
will occur when the cohort of patients has met these criteria. If only 2 of the 3 patients in a 
cohort are evaluable and neither subject has experienced a treatment-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 and 2, PK, and PD data from evaluable patients. The recommended 
dose for the next cohort of subjects will be guided by the BLRM with EWOC principle 
evaluating the probability of DLT (Section 10.4.2) 
The adaptive Bayesian methodology provides an estimate of all dose levels of the combination 
MCS110/PDR001 that do not exceed the MTD and incorporates all DLT information at all dose 
levels for this estimation. In general, the next dose will have the highest chance that the DLT 
rate will fall in the target interval [16-33%) and will always satisfy the EWOC principle (less 
than 25% probability that the DLT rate is ≥ 33%). In all cases, the dose for the next cohort will 
not exceed a 100% increase from the previous dose (except for the first dose escalation step 
where MCS110 remains at 3 mg/kg, while PDR001 is allowed to have a 200% increase from 
100 mg). Smaller increases in dose may be recommended by the Investigators and Sponsor 
upon consideration of all of the available clinical data. 
If 2 patients in a previously untested dose level experience a DLT, enrollment to that cohort 
will stop, the BLRM will be updated and the next cohort will be opened at the next lower dose 
level or an intermediate dose level (see Table 6-2 for provisional dose levels 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 DLTs 
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 level or a lower dose level as agreed by Investigators and Novartis 
personnel and if the BLRM predicts that the risk for this dose to exceed the MTD(s) remains 
below 25% (EWOC). Re-escalation may then occur 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 is expected to occur before 
the MTD is reached. This will occur when the following conditions are met: 
1. at least 6 patients have been treated at this dose 
2. this dose satisfies one of the following conditions: 
a. the posterior probability of targeted toxicity at this dose exceeds 50% and is the 
highest among potential doses, or 


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b. minimum of 15 patients have already been treated on the trial to identify the MTD. 
Recommendation of RP2D may be made with fewer patients, without identification of 
MTD. 
3. it is the dose recommended for patients, either per the model or by review of all clinical 
data by Novartis and Investigators in a dose-escalation teleconference, see Section 6.2.3.1. 
To better understand the safety, tolerability and PK of both MCS110 and PDR001, additional 
cohorts of patients may be enrolled at preceding dose levels, or to intermediate dose levels 
before or while proceeding with further dose escalation. 
If a decision is made to escalate to a higher dose level but one or more additional patient(s) 
treated at the preceding dose level experiences a DLT during the first two cycles of treatment, 
then the BLRM will be updated with this new information before any additional patients are 
enrolled at that higher dose level. Subjects ongoing will continue treatment at their assigned 
dose levels. 
6.2.3.1 
Implementation of Dose Escalation Decisions 
To implement dose escalation decisions, the available toxicity information (including all safety 
data, AEs Grade ≥ 2 and laboratory abnormalities that are not DLTs), the assessment of those 
doses satisfying the EWOC criterion from the BLRM, and the available PK and PD information 
will all be evaluated by the Investigators and Novartis study personnel (including the study 
physician and statistician) during a dose decision meeting by teleconference. All occurrences 
of DLT will be discussed and agreed at the dose decision teleconference among participating 
investigators and Novartis study personnel. 
Cohort enrollment and drug administration at the next higher dose level may not proceed until 
the investigator receives written confirmation from Novartis indicating that the results of the 
previous dose level were evaluated and that it is permissible to proceed to a higher dose level 
with written confirmation of the next higher dose level to be tested. 
6.2.3.2 
Intra-Patient dose escalation 
Intra-patient dose escalation is not permitted at any time within the first 6 months of treatment. 
After the 6 months of treatment is completed, individual patients may be considered for 
treatment at doses of MCS110 and PDR001 in combination higher than the doses to which they 
were initially assigned. Only one of the study drugs will be escalated at any one time. Study 
drugs will be escalated as detailed in Section 6.2.2. In order for a patient to be treated at a higher 
treatment dose, he or she must have tolerated the lower dose of MCS110 and PDR001 
combination for at least two cycles of therapy (e.g., he or she must not have experienced a 
toxicity of CTCAE Grade ≥ 2 at the lower dose pair for which relationship to study drug cannot 
be ruled out). Moreover, the new, higher dose pair with which the patient is to be treated must 
be a dose pair that has completed evaluation in a dose-escalation meeting and that has satisfied 
the EWOC criterion under the Bayesian model. 
There is no limit to the number of times a patient may have his or her treatment dose increased. 
Any further increases after the initial intra-patient dose escalation are subject to the same rules 
as for the initial intra-patient escalation. Consultation with Novartis must occur prior to any 


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intra-patient dose escalation occurring. These changes must be recorded on the Dosage 
Administration Record CRF. 
6.2.4 
Definitions of dose limiting toxicities (DLTs) 
A dose-limiting toxicity (DLT) is defined as an adverse event or abnormal laboratory value of 
CTCAE Grade ≥ 3 assessed as unrelated to disease, disease progression, inter-current illness, 
or concomitant medications that occurs within the first two cycles of treatment with the 
combination treatment and meets any of the criteria included in Table 6-3. 
Emerging data from the new field of immune-immune combination studies suggest that some 
immune-related adverse events have a prolonged latency (Wolchok 2013). As such, the DLT 
window for the combination cohort in this trial is extended to the length of two cycles or 42 
days. 
National Cancer Institute Common Terminology Criteria for Adverse events (NCI CTCAE) 
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. 
The investigator must notify the Sponsor immediately of any unexpected CTCAE Grade ≥ 3 
adverse events or laboratory abnormalities. Prior to enrolling patients into a higher dose level, 
CTCAE Grade ≥ 2 adverse events will be reviewed for all patients at the current dose level. 
DLTs include any adverse event of CTCAE Grade 3 or higher occurring in the first two cycles 
of treatment during the Phase Ib dose escalation part of the study, for which relationship to 
study treatment cannot be ruled, with the exceptions defined in Table 6-3. 
Table 6-3 
Criteria for defining dose-limiting toxicities 
For the purpose of dose escalation and cohort expansion, DLT will be defined as follows: 
Any Grade 4 AEs will be considered DLTs with the exception of: 
 
Neutropenia lasting ≤ 5 days that is not associated with fever or other clinical symptoms. 
 
Lymphopenia or leukopenia at any grade 
Any Grade 3 AEs will be considered DLTs with the exception of: 
 
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected to ≤ 
Gr1 with appropriate management or supplementation within 72 hours of onset. 
 
Infusion reaction that resolves to ≤ Grade 1 within 6 hours. 
 
Nausea and vomiting persisting for < 2 days with optimal anti-emetic therapy. 
 
Thrombocytopenia without significant bleeding. 
 
Diarrhea persisting for < 2 days with optimal anti-diarrhea therapy. 
 
Hypertension persisting < 7 days with optimal therapy.  
 
Infection or fever in the absence of neutropenia persisting < 7 days.  
 
Rash or photosensitivity persisting < 7 days after treatment. 
 
Fatigue lasting < 7 days. 
 
Immune-related adverse events persisting at Grade3 < 7 days after treatment with 
corticosteroids. 
 
*CK elevation without associated muscle damage per investigator discretion 
 
*Isolated AST elevations (without bilirubin or ALT elevations ≥ Grade 1) 
The following Grade 2 AEs will be considered as DLTs: 
 
Total bilirubin > 2 x ULN with ≥ CTCAE Grade 2 AST/ALT. 


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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 may be considered as DLT’s. 
* MCS110 treatment results in CK and AST elevations without any association to muscle damage (Radi 2011). 
The CK/AST elevations are caused by reduced clearance rate from the circulation due to the diminished 
numbers of macrophages (Kupffer cells) in the liver (Section 1.2.2.1). 
6.3 
Dose modifications 
6.3.1 
Dose modification 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, except during the first 
two cycles when dose modifications are only allowed if the patient experiences a DLT. 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, 
treatment should be withheld. Dose modifications for toxicities related to the study 
medication are summarized in Table 6-4. 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 than is being tested at that time (on the same dosing schedule), if there is no evidence 
of disease progression as per irRC. A decision to resume treatment following the 
occurrence of a DLT is at the discretion of the Investigator. Following an AE meeting 
criteria for DLT, if a patient resumes study treatment, it should be at the next lower dose 
level.  Dose reductions to doses below MCS110 0.3mg/kg / PDR001 100 mg Q3W are not 
permitted. 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 unless the patient 
experiences clinical benefit in the opinion of the investigator. In this case, treatment can 
be continued at a dose agreed by Novartis and the investigator. 
• 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//wwwnccn.org/professionals/physician_gls/default.aspx#immunotherapy), the 
American Society for Clinical Oncology clinical practice guideline for Management of 
Immune-Related Adverse Events in Patients Treated With Immune Checkpoint Inhibitor 
Therapy (Brahmer 2018) or the European Society for Medical Oncology (ESMO) Clinical 
Practice Guidelines for Management of Toxicities from Immunotherapy (Haanen 2017).  
Note that in general, study treatment should be interrupted for grade 3 and 4 toxicities and 
for a subset of lower grade toxicities. 
• Consider early referral to specialists with expertise in the diagnosis and management of 
immune-related AEs to thoroughly investigate events of uncertain etiology. 
• Events not included in the study protocol or the reference guidance documents should be 
managed per institutional preference. 


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• If one of the study drugs is discontinued the patient may continue with the remaining 
study drug, if the investigator considers it to be in the patient’s best interest. The dose of 
the remaining study drug must be agreed by Novartis and the investigator. 
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. 
Table 6-4 
Dose modification for drug related toxicities 
Toxicity 
Dose Adjustment Rules* 
Hematology 
Neutropenia (ANC) 
Grade 3 or Grade 4. 
Hold study treatment.  
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification, after discussion with the Novartis 
Medical Monitor 
Febrile neutropenia 
Grade 3 or Grade 4 
Hold study treatment. 
Upon resolution of fever and improvement of neutropenia to ≤ Grade 2 or 
baseline, resume study treatment without dose modification, after discussion 
with the Novartis Medical Monitor. 
Thrombocytopenia 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 2 or baseline, resume study treatment without 
dose modification. 
For Grade 3 associated with major bleeding, discontinue study treatment. 
Grade 4 
Discontinue study treatment. 
Anemia 
Grade 3 or Grade 4 
Hold study treatment.  
Upon resolution to ≤ Grade 2 or baseline within ≤ 7 days, resume study 
treatment without dose modification. 
Lymphopenia 
Any grade 
Treatment-related lymphopenia does not require study treatment hold or 
discontinuation. 
Gastrointestinal  
Diarrhea/colitis* 
Grade 1 
May continue study treatment without dose modification.  Manage per 
institutional standard guidelines which should include anti-diarrheal 
treatment, consideration of corticosteroid therapy, and hydration. 
Grade 2 
Hold study treatment. 
GI consultation. 
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to ≤ 10 mg 
prednisone per day, resume study treatment without dose modification after 
discussion with the Novartis Medical Monitor. 
Grade 3 
Hold study treatment. 
GI consultation. 
Upon resolution to ≤ Grade 1 and tapering of steroid requirement to ≤ 10 mg 
prednisone per day, consider resuming study treatment after discussion with 
the Novartis Medical Monitor. 
Grade4 
Discontinue study treatment. 


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Toxicity 
Dose Adjustment Rules* 
Hepatic (AST and/or ALT elevation) 
Grade 2 AST and/or ALT 
Hold study treatment. 
Manage per institutional practice. 
Upon resolution to ≤ Grade 1 or baseline, consider resuming study treatment 
without dose modification. 
Grade 2 transaminitis with 
bilirubin >1.5 x ULN (unless 
Gilbert’s syndrome) 
Discontinue study treatment. 
Grade 3 AST and/or ALT 
Hold study treatment. 
Manage per institutional practices. 
Upon resolution to ≤ Grade 1 or baseline within 7 days, consider resuming 
study treatment without dose modification after discussion with the Novartis 
Medical Monitor. 
Otherwise, discontinue study treatment 
Grade 4 AST and/or ALT 
Discontinue study treatment. 
Isolated total bilirubin elevation** 
Grade 2 
Hold study treatment.  
Upon resolution to ≤ Grade 1 or baseline, may continue study treatment 
without dose modification. 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 1 or baseline, may consider resuming study 
treatment after discussion with the Novartis Medical Monitor. 
Grade 4 
See footnote**.  Otherwise, discontinue study treatment. 
Asymptomatic amylase and/or lipase elevation*** 
Grade 3 or Grade 4, not 
associated with symptoms or 
clinical manifestations of 
pancreatitis*** 
Continue study treatment.  
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial report, 
hold study treatment. 
Upon resolution to ≤ Grade 2, may resume study treatment without dose 
modification, after discussion with the Novartis Medical Monitor. 
Pancreatitis 
Grade 2 / radiologic evidence 
Hold study treatment. 
Manage per institutional practice. 
Upon resolution to ≤ Grade 1, may resume study treatment without dose 
modification, if no clinical evidence of pancreatitis and after discussion with 
the Novartis Medical Monitor. 
Grade 3-4 
Discontinue from treatment. 
CK elevation 
Grade 3-4 
Monitor CK-MB isoenzyme, troponin (I or T), and creatinine. 
 
● If CK-MB and troponin (I or T) are normal, creatinine ≤ 1.5 x baseline and 
patient asymptomatic, continue treatment. 
 
● If CK-MB and troponin (I or T) are abnormal or creatinine (> 1.5 x baseline 
and > ULN) or patient symptomatic, delay treatment and explore alternative 
causes for elevated CK (for example myositis and rhabdomyolysis) 
according to local guidelines. 
 
After recovery of CK-MB, troponin (I or T) and creatinine to Grade 1 
or baseline, restart treatment. Decrease MCS110 1 dose level. 
Cytokine Release Syndrome (CRS) 
Grade 2 
See instructions for Grade 2 Infusion Reaction. 


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Toxicity 
Dose Adjustment Rules* 
Grade 3 and Grade 4 
Discontinue study treatment. 
Follow-up CRS as per institutional guidelines. 
Take blood for cytokine measurements as specified in Section 7.2.2.5.5 
Laboratory evaluations. 
Renal (creatinine) 
Grade 2 
Hold study treatment. 
Consider resuming study treatment without dose modification upon 
resolution to ≤ Grade 1 with appropriate management.. 
Grade 3 or 4 
Discontinue study treatment. 
Endocrine 
Hypothyroidism or hyperthyroidism 
Grade 2 
May continue study treatment without dose modification. 
Management according to institutional practice. 
Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 with appropriate management, may resume 
study treatment without dose modification. 
Grade 4 
May resume therapy following resolution or control with physiologic hormone 
replacement. 
Other endocrine disorders 
Grade 2 and Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 with appropriate management, may resume 
study treatment without dose modification. 
Grade 4 
Hold study treatment. 
Grade 4 treatment-related endocrinopathies, such as  
adrenal insufficiency, adrenocorticotropic hormone  
(ACTH) deficiency, hyper- or hypothyroidism, or glucose intolerance, which 
resolve or are adequately controlled with physiologic hormone replacement 
(corticosteroids, thyroid hormones) or glucose-controlling agents, 
respectively, may not require discontinuation after discussion with and 
approval from the Novartis Medical Monitor. 
Pulmonary (pneumonitis) 
Grade 1 
Consider study treatment hold. 
Manage per institutional practice. 
Consider resuming study treatment upon radiographic evidence of 
improvement. 
Grade 2 
Hold study treatment. 
Pulmonary and infection workup. 
Upon resolution to ≤ Grade 1, may resume study treatment without dose 
modification 
Grade 3 or 4 
Discontinue study treatment. 
Ocular (uveitis) 
Grade 1 
Continue study treatment without dose modification. 
Ophthalmology consultation. 
Grade 2  
Hold study treatment. 
Urgent ophthalmology consultation. 
Upon resolution to ≤ Grade 1 may consider resuming study treatment without 
dose reduction after discussion with the Novartis Medical Monitor and in 
consultation with ophthalmology 


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Toxicity 
Dose Adjustment Rules* 
Grade 3 or 4 
Discontinue from treatment. 
Urgent ophthalmology consultation. 
Periorbital edema 
Grade 2 
Delay treatment until resolved to ≤ Grade 1. Decrease MCS110 1 dose level. 
Grade 3-4 
Discontinue from treatment. 
Dermatology (rash) 
Grade 1 
Continue study treatment without dose modification. Topical steroids, 
antihistamines, topical emollients 
Grade 2 
Consider holding study treatment. 
Topical or oral steroids, antihistamines. 
If study treatment is held and resolution to ≤ Grade 1, resume study 
treatment without dose modification. 
Grade 3 or Grade 4 
Hold study treatment. 
Manage per institutional practice. 
After resolution to ≤ Grade 1, consider resuming study treatment after 
discussion with the Novartis Medical Monitor. 
Bullous dermatitis 
Hold study treatment. 
Grade 1-2 bullous dermatitis: discussion with the Novartis Medical Monitor is 
required before considering resuming study treatment.   
Grade 3 bullous dermatitis: consider resuming therapy after expert 
consultation and documented discussion with the Novartis medical monitor. 
Grade 4 bullous dermatitis: discontinue study treatment. 
Stevens-Johnson syndrome 
(SJS), or Lyell syndrome/toxic 
epidermal necrolysis (TEN) 
Permanently discontinue study treatment. 
Cardiovascular 
ECG QTc-Interval prolonged; hypertension 
Grade 3 
Hold study treatment.  
Upon resolution to Grade ≤ 1 or baseline (hypertension, QTc) or < 30 msec 
difference from baseline (QTc) within ≤ 7 days, may resume study treatment 
without dose modification after discussion with the Novartis Medical Monitor. 
Baseline ECG refers to the ECG(s) collected at screening 
Grade 4 
Discontinue study treatment 
Other cardiovascular disorders 
Grade 2 (except myocarditis) 
Hold study treatment. 
Upon resolution to Grade ≤ 1 or baseline, may resume study treatment 
without dose modification after discussion with the Novartis Medical Monitor.. 
Grade 2 myocarditis, or  
Grade ≥ 3 other cardiac 
disorders related to study 
treatment 
Discontinue study treatment 
Musculoskeletal 
Grade 2 or Grade 3 
Hold study treatment. 
Consider resuming study treatment without dose modification upon 
resolution to ≤ Grade 1 with appropriate management. 
Grade 4 
Discontinue study treatment. 
In some cases, resuming study treatment may be considered after 
discussion with the Novartis Medical Monitor and consultation with a 
rheumatologist. 


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Toxicity 
Dose Adjustment Rules* 
Neurology 
Grade 1 
Consider study treatment hold, particularly for clinical  
suspicion of Guillain-Barre syndrome, encephalitis, aseptic meningitis, 
transverse myelitis, or peripheral neuropathy. 
Grade 2 
Hold study treatment.   
In some cases, resuming study treatment may be  
considered after discussion with the Novartis Medical  
Monitor. 
Grade 3 or Grade 4 
Discontinue study treatment. 
Infusion Reaction 
Grade 1 
Decrease infusion rate until recovery 
Grade 2 
Stop infusion. 
 
Before restarting - 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 infusion. 
 
Restart infusion at 50% of previous rate under continuous observation. 
Ensure that there is a minimum observation period of 1 hour prior to 
restarting the infusion(s). 
 
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-
medication, then discontinue patient from treatment. 
Grade 3 or 4 
Discontinue infusion immediately, and discontinue study treatment. 
Provide supplemental oxygen, fluids, and other resuscitative measures as 
needed. Monitor vital signs (e.g. blood pressure, pulse, respiration, and 
temperature) every 15 ± 5 minutes until resolution. 
Other laboratory adverse events, not specified elsewhere in table and not included in the 
consensus guidelines 
Grade 3 
Hold study treatment.  
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification. 
Grade 4 
Isolated Grade 4 electrolyte abnormalities not associated with clinical 
sequelae and corrected after appropriate management within 72 hours of 
their onset do not require discontinuation. 
In the case of Grade 4 electrolyte imbalances associated with clinical 
sequelae, or not resolved to ≤ Grade 1 within 72 hours despite appropriate 
management, discontinue study treatment. 
Other non-laboratory adverse events, not specified elsewhere in table and not included in 
the consensus guidelines 
Grade 2 
Consider study treatment hold, at Investigator discretion. 
Upon resolution to ≤ Grade 1, resume study treatment without dose 
modification. 
Grade 3 
Hold study treatment. 
Upon resolution to ≤ Grade 1, resuming study treatment must be discussed 
with the Novartis Medical Monitor. 
Grade 4 
Discontinue from treatment. 
*Delay: treatment may be delayed for 7 days due to AEs. If a scheduled dose of ongoing study drugs is 
delayed longer than 7 days due to an unresolved AE, the administration should be skipped and treatment 
resumed at a lower dose level (if meeting the criteria for DLT) at the next scheduled dose (Section 6.1.1). 
Treatment: refers to both study drugs, unless one has been discontinued. 


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Toxicity 
Dose Adjustment Rules* 
**Note: If Grade 3 or 4 hyper-bilirubinemia is due to the indirect (non-conjugated) component only, and 
hemolysis as the etiology has been ruled out as per institutional guidelines (e.g., review of peripheral blood 
smear and haptoglobin determination), then delay study treatment until resolved ≤ Grade 1, and resume study 
treatment at the discretion of the investigator. 
***Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed 
within one week of the first occurrence of any ≥ Grade 3 of amylase and/or lipase. 
6.3.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed-up at least once a week (or more if clinically 
indicated) for 4 weeks, and subsequently at approximately 4-week intervals, until resolution or 
stabilization of the event, whichever comes first. Appropriate clinical experts should be 
consulted as deemed necessary. Consensus management algorithms for immune-related AEs 
have been developed and are available to assist investigators in assessing and managing 
immune-related AEs (refer to Section 6.3.1). In case of a toxicity suspected to be a cytokine 
release syndrome, the assessments outlined in Section 7.2.2.5.5  must be performed. 
All patients must be followed up for AEs and SAEs for 150 days after the last dose of PDR001 
or 90 days after the last dose of MCS110 for patients who stopped PDR001 and continued 
MCS110 alone for more than 60 days. 
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 immune related adverse events, are provided in Table 6-4. The risk to subjects in 
this trial may be minimized by compliance with the eligibility criteria and study procedures as 
well as, close clinical monitoring. There may be unforeseen risks with MCS110 in combination 
with PDR001 which could be serious. Refer to preclinical toxicity and or clinical data found in 
the MCS110 and PDR001 Investigator’s Brochure. 
6.4 
Concomitant medications 
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 
administration of bisphosphonates is permitted. 
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 and Concomitant Medications or the Surgical and Medical Procedures 
eCRF. Prior antineoplastic therapies including medications, radiotherapy, and surgery are to be 
recorded on the separate Prior Antineoplastic Therapy eCRF during screening. Medication 
entries should be specific to trade name, dose and unit, the frequency and route of 
administration, the start and discontinuation date and the reason for therapy. 


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6.4.1 
Permitted concomitant therapy requiring caution and/or action 
Therapeutic treatment with hematopoietic colony-stimulating growth factors G-CSF or GM-
CSF may only be initiated after the first two cycles in the dose escalation part of the study, 
unless the patient has already experienced a DLT. If available GM-CSF is preferred over G-
CSF (Eyles 2006). 
Treatment with erythroid stimulating agents may not be initiated during the first two cycles in 
the dose escalation part of the study, unless the patient has already experienced a DLT. If a 
patient is using an erythroid stimulating agents prior to enrollment (at least 2 weeks before start 
of study treatment), they may continue at the same dose. 
Anticoagulants are permitted if the patient is already at stable doses of warfarin or taking stable 
doses of low molecular weight heparin for >2 weeks at time of first dose and INR should be 
monitored as clinically indicated per investigator’s discretion. However, ongoing anticoagulant 
therapy should be temporarily discontinued to allow tumor biopsy according to the institutional 
guidelines. 
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with MCS110 
and PDR001. 
Statins should be used with caution since CK elevations are commonly seen and transient CK 
elevations were noted in healthy volunteers and patients studies with MCS110. 
6.4.2 
Prohibited concomitant therapy 
During the course of the study, patients may not receive other additional investigational drugs, 
agents, devices, chemotherapy, or any other therapies that may be active against cancer. 
Additionally, no other therapeutic monoclonal antibodies and no immunosuppressive 
medication may be administered while on this study. 
Prophylactic treatment with hematopoietic colony-stimulating growth factor G-CSF or GM-
CSF is prohibited since it may induce immune suppression and promote tumor growth 
(Eyles 2006). 
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. Systemic corticosteroids required for the control 
of infusion reactions or irAEs must be tapered and be at doses ≤ 10 mg/day of prednisone or 
equivalent before the next study drug administration. Systemic steroid therapy required during 
the course of the study to manage other concurrent medical conditions should be discussed with 
Novartis. 
The use of live vaccines is not allowed through the whole duration of the study. 


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6.5 
Patient numbering, treatment assignment or randomization 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first pre-screened (if applicable) or when the patient is enrolled for screening. The 
subject number is retained as the primary identifier for the patient throughout his/her entire 
participation in the trial. The Subject No. consists of the Center Number (Center No.) (as 
assigned by Novartis to the investigative site) with a sequential patient number suffixed to it, 
so that each subject is numbered uniquely across the entire database. Upon signing the informed 
consent form, the patient is assigned to the next sequential Subject No. available to the 
investigator through the Oracle Clinical RDC interface. Once assigned, the Subject No. must 
not be reused for any other subject and the Subject No. for that individual must not be changed, 
even if the patient is re-screened. If the patient fails to start treatment for any reason, the reason 
will be entered into the Screening Disposition page. 
6.5.2 
Treatment assignment or randomization 
The assignment of a patient to a particular cohort will be coordinated by the sponsor. No 
randomization will be performed in this study. 
6.6 
Study drug preparation and dispensation 
PDR001 (100 mg powder for solution for infusion) will be administered first as a 30 minute 
intravenous infusion (up to 2 hour, if clinically indicated). MCS110 (7.5ml of 20 mg/ml 
concentrate in vial) will be administered intravenously as an 1 hour infusion (up to 2 hour, if 
clinically indicated). At least 30 min break should occur between the two infusions. 
Further instructions for the preparation and dispensation of MCS110 and PDR001 are described 
in the [Pharmacy Manual]. 
All dosages prescribed to the patient, all dose interruptions and all dose changes during the 
study must be recorded on the Dosage Administration Record CRF. 
6.6.1 
Study drug packaging and labeling 
MCS110 is provided as open label bulk medication in a glass vial each containing 150 mg 
MCS110 as a 20 mg/ml concentrate solution for infusion. 
PDR001 100 mg powder for solution for infusion will be supplied as open label bulk 
medication. 
Medication labels will be coded, printed in the local language, and will comply with local 
regulatory requirements. The storage conditions for study drug will be provided on the 
medication label. 
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, the study treatment should be stored according to the 


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instructions specified on the drug labels and in the MCS110 and PDR001 Investigator’s 
Brochure. 
6.6.3 
Study drug compliance and accountability 
6.6.3.1 
Study drug compliance 
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 in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table (“Category” column) indicates which assessments produce data to be 
entered into the clinical database (D) or remain in source documents only (S). 
No CRF will be used as a source document. 
Screening/baseline evaluations must be performed ≤ 21 days before Cycle 1 Day 1, except for 
baseline radiological evaluations which must be done within 28 days. Assessments performed 
as part of the screening evaluations and within 3 days prior to the first dose of study treatment, 
are not required to be repeated on the first dosing day. 
Laboratory and radiological assessments performed as part of standard of care prior to signing 
informed consent may be used if performed within 21 days and 28 days respectively, of Cycle 
1 Day 1. 
During the course of the study visits, test and/or procedures should occur on schedule whenever 
possible. A visit window of ± 7 days is allowed. If the infusion of MCS110 and/or PDR001 is 
delayed, the visits assessments will be shifted accordingly. On PK collection days the windows 
are provided in Section 7.2.3. 
Radiological assessments must be performed ± 1 week of the scheduled date of the assessment. 
For Japan only, patients are required to be hospitalized during Cycle 1. 


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Table 7-1 
Visit evaluation schedule 
 
Screening 
Phase 
Treatment Phase 
Follow-
up 
 
 
Visit name 
Category 
Protocol Section 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 
Subsequent 
cycles 
EOT 
Safety F/U 
Disease 
Progression F/U 
Survival F/U 
Day of cycle 
 
 
-21 to -1 
1 
2 
4 
8 
15 
1 
15 
1 
1 
2 
4 
8 
15 
1 
 
 
 
 
Obtain Informed 
Consent 
D 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion criteria 
D 
5.2 and 
5.3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Medical History 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and 
extent of cancer 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
ER, PR, HER2, 
BRCA1 and 
BRCA2 status 
(TNBC) 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior 
antineoplastic 
therapy 
D 
7.1.1.2 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Screening 
Phase 
Treatment Phase 
Follow-
up 
 
 
Visit name 
Category 
Protocol Section 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 
Subsequent 
cycles 
EOT 
Safety F/U 
Disease 
Progression F/U 
Survival F/U 
Day of cycle 
 
 
-21 to -1 
1 
2 
4 
8 
15 
1 
15 
1 
1 
2 
4 
8 
15 
1 
 
 
 
 
Prior/concomitant 
medications, 
surgery and 
medical 
procedures 
D 
7.1.1.2 
7.1.5 
and 6.4 
X 
Continuous1 
 
 
Physical 
examination 
S 
7.2.2.1 
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 
X 
 
 
 
Vital signs 
D 
7.2.2.2 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
 
 
X 
X 
 
 
 
Performance 
status 
D 
7.2.2.4 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
Hematology 
D 
7.2.2.5.1 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Chemistry 
D 
7.2.2.5.2 
X 
X 
 
 
X 
X 
X 
X 
X 
X 
 
 
X 
 
X 
X 
 
 
 
Coagulation 
D 
7.2.2.5.6 
X 
Only if clinically significant 
X 
 
 
 
Urinalysis 
D 
7.2.2.5.3 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
Thyroid function 
D 
7.2.2.5.4 
X 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
 
 
 
Cytokines  
(E.g. IFN-γ; IL-6, 
IL-1, TNFα) 
D 
7.2.2.5.5 
 
X  
In case of cytokine release syndrome 
 
 
 
Pregnancy test 
D 
7.2.2.5.7 
X 
 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X 
X 
X2 
 
 


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Screening 
Phase 
Treatment Phase 
Follow-
up 
 
 
Visit name 
Category 
Protocol Section 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 
Subsequent 
cycles 
EOT 
Safety F/U 
Disease 
Progression F/U 
Survival F/U 
Day of cycle 
 
 
-21 to -1 
1 
2 
4 
8 
15 
1 
15 
1 
1 
2 
4 
8 
15 
1 
 
 
 
 
Virology 
D 
7.2.2.5.8 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X7 
X7 
Tumor evaluation 
as per RECIST 
v1.1 and as per 
irRC. 
D 
7.2.1 
X 
Every 2 cycles from Cycle 3 Day 1 up to Cycle 9 Day 1 (C3D1, C5D1, C7D1, C9D1), then every 3 cycles 
until Cycle 18 Day 1 (C12D1, C15D1 C18D1). Assessment will be performed every 4 cycles thereafter, 
starting from Cycle 22 Day 1. 
 
For disease progression f/u, every 9 weeks ± 1 week until week 51 after study start, then every 12 weeks± 
1 week until progression of disease per irRC, withdrawal of consent, or lost to follow-up. 
 
Tumor markers 
D 
7.2.1 
X 
X 
 
 
 
12-leads ECG 
D 
7.2.2.6.1 
X 
X 
 
 
 
 
 
 
 
X 
 
 
 
 
 
X 
 
 
 
Chest x-ray [for 
Japan only] 
D 
7.2.2.7 
X 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Adverse events 
D 
8 
Continuous 
 
 
 
Study drug 
administration  
D 
6.1.1 
 
i.v. every 3 weeks for MCS110 and PDR001 
 
 
 
PK sampling 
D 
7.2.3 
 
X 
X4 
X4 
X 
X4 
X 
 
X 
X 
X4 
X4 
X 
X4 
X5 
 
 
 
 


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Protocol No. CMCS110Z2102 
 
 
Screening 
Phase 
Treatment Phase 
Follow-
up 
 
 
Visit name 
Category 
Protocol Section 
Screening 
Cycle 1 
Cycle 
2 
Cycle 
3 
Cycle 4 
Subsequent 
cycles 
EOT 
Safety F/U 
Disease 
Progression F/U 
Survival F/U 
Day of cycle 
 
 
-21 to -1 
1 
2 
4 
8 
15 
1 
15 
1 
1 
2 
4 
8 
15 
1 
 
 
 
 
Immunogenicity 
(IG) sampling 
D 
7.2.3 
 
X 
 
 
 
 
X 
 
X 
X 
 
 
 
 
X5 
 
 
 
 
Survival contact 
D 
7.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
1 Concomitant medications are only collected until 30 day of follow-up or the start of antineoplastic therapy, whichever comes first. 
2 Urine pregnancy test should be performed every month during and at the end of 150 days safety follow-up (90 days in case patient is only taking MCS110 alone, for 
more than 60 days). 
 
4 Day 2, 4, 15 sampling times are only applicable to the Phase Ib part, 
5 Cycles 5 and 6 only, 
6 Only on C5D1 
7 In reference to Section 7.1.5, the follow-up for safety, disease progression and survival will not be performed for patients who transfer to another clinical study to 
continue provision of study treatment or an alternative treatment option. For all other patients, the safety evaluation period will be completed but the disease-
progression and survival follow up will not be performed. 
 


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7.1.1 
Screening 
The study IRB/IEC approved informed consent form must be signed and dated before any 
screening procedures are performed, except for laboratory and radiological evaluations 
performed as part of standard of care within the screening window. 
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1. Screening assessments must be repeated if 
performed outside of the specified screening window (Section 7.1). 
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 will be entered on the Screening Phase Disposition Page. 
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 (see 
Section 8.2 for SAE reporting details). 
7.1.1.2 
Patient demographics and other baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of cancer, details of prior anti-neoplastic 
treatments, prior medication, procedures, significant non-drug therapies and any other 
assessments that are done for the purpose of determining eligibility for inclusion in the study. 
For patients with breast cancer, ER, PR and HER2 status will be collected. In addition BRCA1 
and BRCA2 genotype must be collected. 
7.1.2 
Treatment period 
A treatment cycle is defined as 21 days for the purposes of scheduling procedures and 
evaluations. Please refer to Table 7-1 for details of the timing of required assessments and 
Section 7.1 for visit windows. 
Patients will be treated until they experience unacceptable toxicity, progressive disease per irRC 
and/or treatment is discontinued at the discretion of the investigator or the patient, as described 
in Section 7.1.3 and Section 4.3. 
Patients should not discontinue treatment based on progressive disease per RECIST v1.1. 
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”) (Wolchok 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 irRC. An outline of the irRC is provided in Appendix 2. 


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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. 
The following criteria should be considered for treatment continuation decision making: 
• Patients with partial response or stable disease as well as patients with unconfirmed 
progressive disease (per irRC) should continue to receive study treatment until the next 
cycle. 
• Patients with confirmed irPD will discontinue study drug(s) and enter the Follow-up 
period (see Section 7.1.5). Patients who have either a poor performance status or toxicity 
requiring both MCS110 and PDR001 discontinuation and do not have a confirmed irPD 
will enter the Follow-up period until confirmed irPD, initiation of a new treatment, 
completion of all Follow-up visits. Patients will then enter the Survival Follow-up period. 
• Patients with confirmed PD/irPD in stable or improved clinical status can remain under 
treatment, after discussion with Novartis, until there is a further progression or clinical 
deterioration under the following circumstances: 
• Absence of signs and symptoms (including worsening of laboratory values) indicating 
disease progression; 
• No decline in ECOG performance status; 
• Absence of rapid progression of disease; 
• Absence of progressive tumor at critical anatomical sites (e.g., cord compression) 
requiring urgent alternative medical intervention. 
7.1.3 
Discontinuation of Study Treatment 
Patients may voluntarily discontinue from the study treatment for any reason at any time. If a 
patient decides to discontinue from the study treatment, the investigator must make every effort 
(e.g. telephone, e-mail, letter) to determine the primary reason for this decision and record this 
information in the patient’s chart and on the appropriate CRF pages. They may be considered 
withdrawn if they state an intention to withdraw, fail to return for visits, or become lost to 
follow-up for any other reason. 
The investigator should discontinue study treatment for a given patient if, on balance, he/she 
believes that continuation would be detrimental to the patient’s well-being. 
Study treatment may be discontinued if any of the following occur: 
• Adverse event 
• Lost to follow-up 
• Physician’s decision 
• Progressive disease per irRC (not per RECIST v1.1) 


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• Study terminated by Novartis 
• Subject/guardian decision 
• Protocol deviation 
Study treatment must be discontinued in case of pregnancy. 
At the time patients discontinue study treatment, a visit should be scheduled as soon as possible, 
and within 14 days of the last dose of study treatment or within 14 days of the decision to 
permanently discontinue study treatment, at which time all of the assessments listed for the 
EOT visit will be performed (Table 7-1). If the decision to withdraw the patient occurs at a 
regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit. An End of Treatment Phase Disposition CRF page should be 
completed, giving the date and reason for stopping the study treatment. End of 
treatment/Premature withdrawal visit is not considered as the end of the study. 
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be made to 
contact them as specified in Section 7.1.6. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments. At that time, the reason for study completion 
should be recorded on the Study Phase Completion Disposition CRF page. 
Patients who transfer into another study to continue provision of study treatment or an 
alternative treatment option will perform the end of treatment procedures. 
7.1.3.1 
Replacement policy 
Phase Ib dose escalation part: 
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
dose determination and cannot be part of the Dose Determination Set (DDS), enrollment of a 
new patient to the current cohort will be considered if there is less than the required number of 
evaluable subjects. Enrollment of new subjects may be considered until at least the minimum 
number (3) or at most the maximum number (6) of evaluable subjects is achieved within the 
cohort. Minimum and maximum numbers of evaluable subjects per cohort are defined in 
Section 6.2.3. 
Phase II part: 
During the Phase II dose expansion part no replacements will be needed. 
7.1.4 
Withdrawal of Consent 
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient: 
• Does not want to participate in the study anymore, and 
• Does not allow further collection of personal data 


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In this situation, the investigator should make a reasonable effort (e.g. telephone, 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 
communicating or follow-up. 
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the subject’s study withdrawal should be made as detailed in the 
assessment table.  
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law. 
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.  
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements. 
7.1.5 
Follow-up period 
Safety Follow-up 
All patients must have safety evaluations until 150 days after the last dose of PDR001 or 90 
days after the last dose of MCS110 (whichever the longer). The 30-, 90- and 150-day safety 
follow-up can be done by telephone call or visit. 
Concomitant medications will be collected until the 30-day safety follow-up has been 
completed or the start of a new antineoplastic therapy, whichever occurs first.  
Data collected should be added to the Adverse Events CRF, the antineoplastic therapies since 
discontinuation of study treatment CRF, and the Concomitant Medications CRF.  
For a female participant of child bearing potential, a pregnancy test will be performed on a 
monthly basis after stopping the study treatment (Section 7.2.2.5.7). 
For patients who transfer to another clinical study to continue provision of study treatment or 
an alternative treatment option, as described in Section 4.3, the follow-up for safety will not be 
performed. For all other patients, the safety evaluation period will be completed but the disease-
progression and survival follow up will not be performed. 
Disease progression follow-up period 
Patients who discontinue study treatment for any reason other than death, disease progression 
per irRC, lost to follow-up, consent withdrawal, start of new cancer therapy or study 


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termination, should return for tumor evaluation assessments every 9 weeks until 51 weeks, then 
every 12 weeks until progression of disease per irRC, withdrawal of consent, lost to follow-up 
(Section 7.2.1), or until the end of the study is reached as described in Section 4.3. 
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. 
For patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment, the follow-up for disease progression will not be performed. 
Survival follow-up period 
Upon completion of the safety follow-up and disease progression follow-up (if applicable), all 
patients enrolled in the Phase Ib and Phase II parts 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, as described 
in Section 4.3, 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. 
For patients who transfer to another clinical study or an alternative treatment option to continue 
provision of study treatment, the follow-up for 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, 
registered letters, etc. A patient should not be considered lost to follow-up until due diligence 
has been completed. Patients lost to follow-up should be recorded as such on the appropriate 
Disposition CRF. 
7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response will be determined locally according to two sets of criteria: 
1. RECIST v1.1 (Appendix 1) 
2. irRC (Appendix 2) 
The local investigator’s assessment will be used for the analysis of response according to both 
RECIST v1.1 and irRC, and for treatment decision making (study discontinuation due to PD is 
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. 
At screening, all patients will undergo CT with i.v. contrast of the 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 


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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. See Table 7-2 for further details. 
Tumor assessments will be performed at the following time points until progression of disease 
per irRC or patient withdrawal: 
• Screening 
• Every 2 cycles from Cycle 3 Day 1 up to Cycle 9 Day 1, then every 3 cycles until Cycle18 
Day 1 (1 year of treatment). Assessment will be performed every 4 cycles thereafter, 
starting from Cycle 22 Day1. 
• At the End of Treatment, if a scan was not conducted within 30 days prior to End of 
Treatment 
• After EOT, during disease progression follow-up, every 9 weeks (± 1 week) until week 
51, then every 12 weeks (± 1 week), until progression of disease per irRC. 
• PR or CR, per both RECIST v1.1 and irRC, will be confirmed by a new assessment after 
at least 4 weeks. Also Progressive Disease (PD), as per irRC, will be confirmed after at 
least 4 weeks. 
If available, tumor markers collected as per local guidelines will be collected at the same time 
as RECIST tumor evaluation. 
Efficacy assessments should be performed ± 1 week from the calculated study day as described 
in Section 7.1. Disease progression follow-up should be performed as described in 
Section 7.1.5. 
Table 7-2 
Disease assessment collection plan 
Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Chest, abdomen and pelvis 
CT or MRI (with intravenous 
contrast enhancement)  
Mandated 
● Every 6 weeks until end of cycle 8 (C3D1, 
C5D1, C7D1, C9D1) 
● Thereafter every 9 weeks (C12D1, 
C15D1, C18D1). 
● During year two, assessment can be 
performed every 4 cycles, starting from 
C22D1. 
● End of treatment, if not conducted within 
30 days prior to EOT. 
Tumor markers 
If available as per local guideline 
Same time as CTor MRI tumor 
assessment, if available as per local 
guideline 
Brain CT or MRI 
If clinically indicated 
If lesions were documented at baseline, 
follow same schedule as CT/MRI of chest, 
abdomen, and pelvis 
Localized bone CT, MRI or 
x-ray of other metastatic 
sites (eg neck or bone) 
For any lesions already identified 
that are not visible on the chest, 
abdomen and pelvis CT or MRI 
If lesions were documented at baseline, 
follow same schedule as CT/MRI of chest, 
abdomen, and pelvis 


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Procedure 
Screening/Baseline 
During Treatment/Follow-up 
Color photography (with 
scale/ruler) 
For any skin lesions present 
If lesions were documented at baseline, 
follow same schedule as CT/MRI of chest, 
abdomen, and pelvis 
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, thyroid function, pregnancy, ECG, as well 
as collecting the AEs at every visit. For details on AE collection and reporting, refer to 
Section 8. 
7.2.2.1 Physical examination 
Physical examination will be performed according to Table 7-1. 
At Screening and Cycle 1 Day 1, prior to treatment administration, 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. 
From Cycle 1 Day 8 onwards, a short physical examination will be performed. A short physical 
exam will include the examination of general appearance, vital signs (body temperature, blood 
pressure [BP] and pulse) and body sites as directed by symptoms. 
Significant findings that were present prior to the signature of the informed consent must be 
included in the Medical History CRF page. Significant new findings that begin or worsen after 
informed consent must be recorded on the Adverse Event CRF page. 
[For Japan only: oxygen saturation (SpO2) will be measured by pulse oximetry for Japanese 
patients every time physical examination is performed as indicated in Table 7-1.] 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator if medically 
indicated, and will be recorded as unscheduled assessment. 
7.2.2.3 Height and weight 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, 
but without shoes) will be measured as indicated in Table 7-1. 
7.2.2.4 
Performance status 
ECOG performance status will be assessed according to Table 7-1 and Table 7-3. 


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Table 7-3 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all 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 
7.2.2.5 
Laboratory evaluations 
Abnormal laboratory values that are clinically significant (e.g., require an interruption or delay 
of study treatment, lead to clinical symptoms, or require therapeutic intervention) must be 
documented in the Adverse Event eCRF. 
Novartis will be provided with a copy of the site’s local laboratory certification and tabulation 
of the normal ranges for each parameter required at study start and should be kept up to date on 
an ongoing basis. In addition, if at any time a patient has laboratory parameters obtained from 
a different outside laboratory, Novartis must be provided with a copy of the certification and a 
tabulation of the normal ranges for that laboratory. 
Table 7-4 
Local/Central Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells with differential (neutrophils, 
lymphocytes, monocytes, basophils, eosinophils, ) 
Chemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, 
Phosphate, Chloride, Magnesium, Creatinine, Glucose (non fasting), Creatine kinase, 
Lactate dehydrogenase (LDH), Total Bilirubin (also measure direct and indirect bilirubin 
if total bilirubin is > Grade 1), Blood Urea Nitrogen (BUN) or Urea, Uric Acid. 
 
CK-MB isoenzyme, Troponin I/T, Aldolase or Myoglobin or other skeletal muscle 
marker- if required per local guidelines to rule out myositis/rhabdomyolysis (see 
Section 7.2.2.6.2) 
Cytokines * 
IFN-γ, IL-6, IL-1,TNF-α 
Urinalysis 
Macroscopic panel (Dipstick) (Bilirubin, Blood, Glucose, Ketones, White blood cells, pH, 
Protein, Specific Gravity) 
Myoglobin-if required to rule out myositis/rhabdomyolysis per local guidelines 
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), Partial thromboplastin 
time (PTT), Activated partial thromboplastin time (APTT) 
Thyroid 
T3 [free], T4 [free], TSH 
Virology 
HBV and HCV 
*To be performed by a Central Laboratory 
7.2.2.5.1 Hematology 
Hematology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 


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7.2.2.5.2 Clinical chemistry 
Clinical chemistry panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1. 
7.2.2.5.3 Urine analysis 
Urine analysis panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 
7.2.2.5.4 Thyroid function 
Thyroid function panel outlined in Table 7-4 will be performed as per the assessment schedule 
in Table 7-1. 
7.2.2.5.5 Cytokines 
Samples for the cytokine panel outlined in Table 7-4 will be collected at the following time 
points: 
• Baseline (predose C1D1) 
• On an ad-hoc basis, in case a patient has an adverse event suspected to be a cytokine 
release syndrome. 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. 
Samples for cytokine panel assessment will be stored locally below -70°C. The samples will be 
analyzed retrospectively in batches by the Novartis designated central laboratory. Immediate 
analysis of the samples by the central lab will be done only for patients who experienced an 
adverse event suspected to be a cytokine release syndrome and had follow-up samples collected. 
7.2.2.5.6 Coagulation 
Coagulation markers outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 
7.2.2.5.7 Pregnancy 
Pregnancy tests will be performed for women of child bearing potential per Table 7-1. 
At screening, a serum pregnancy test must be performed within 3 days before the first dose. 
During the study (Day 1 of each Cycle starting with Cycle 2), and at the End of Treatment visit, 
a serum pregnancy test must also be performed. 
A urine pregnancy test should be performed every month during and at the end of the safety 
follow-up period (i.e. 150 days after the last dose of PDR001 or 90 days after the last dose of 
MCS110 for patients who stopped PDR001 and continued MCS110 alone for more than 60 
days). 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. 


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7.2.2.5.8 Virology 
Virology panel outlined in Table 7-4 will be performed as per the assessment schedule in 
Table 7-1. 
7.2.2.6 
Cardiac assessments 
7.2.2.6.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed as per the assessment schedule in Table 7-1 and 
Table 7-5. Blood samples scheduled at the same time point should be taken after the ECGs are 
completed. The ECGs on C1D1, and C4D1 must be performed in triplicate. For the Screening, 
EOT and Unscheduled visits only one ECG per visit is required. 
Table 7-5 
Local ECG collection plan 
Cycle 
Day 
Time 
Screening 
-21 to -1 
Anytime 
1 
1 
*Pre-dose (0 hr) 
1 
1 
*1hr (±5 min) hour post last treatment administration 
4 
1 
*Pre-dose 
4 
1 
*1hr (±5 min) hour post last treatment administration 
EOT 
- 
Anytime 
Unscheduled** 
- 
Anytime 
* ECGs performed in triplicate at these PK matched timepoints only. 
** A PK sample should be collected just after an ECG was performed due to an unexpected cardiac signal. 
Interpretation of the tracing must be made by a qualified physician and documented on the ECG 
CRF page. Each ECG tracing should be labeled with the study number, patient initials (where 
regulations permit), patient number, date, and kept in the source documents at the study site. 
Clinically significant abnormalities present at screening should be reported on the Medical 
History CRF page. Clinically significant findings must be discussed with Novartis prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the Adverse Events CRF page. 
7.2.2.6.2 Cardiac and skeletal muscle markers. 
Due to known asymptomatic creatine kinase elevations associated with MCS110, additional 
labs will be analyzed to rule out cardiac muscle damage (CK-MB and Troponin I/T) or skeletal 
muscle damage (aldolase, myoglobin or other skeletal muscle marker per local guidelines). The 
muscle damage markers will be measured at baseline and anytime during the study in case of 
CK elevation ≥5 x ULN. 
7.2.2.7 
[For Japan only] Radiological examinations 
7.2.2.7.1  Chest x-ray 
A 2-view chest x-ray will be performed at screening and Day 8 of Cycle 1.  


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7.2.3 
Pharmacokinetics and immunogenicity assessments 
PK profiles to assess PK properties of MCS110 and PDR001 will be collected from all enrolled 
patients. However, only the patients from Phase Ib part will have additional PK collected on 
day 2, 4 and 15. 
Immunogenicity (IG) samples will also be collected to monitor appearance of anti-drug 
antibodies directed against MCS110 or PDR001. Please refer to Table 7-6 and Table 7-7 for 
details on PK and IG sample collections. 
If the dosing of Cycle 4 Day 1 is delayed, the PK sampling for the full PK profile should be 
delayed accordingly to match the scheduled time points for Cycle 4 as outlined in Table 7-6 and 
Table 7-7. After the primary CSR data cut-off date is reached, no additional PK and IG samples 
will be collected for the patients still on-going on the study. 
 
 
 
 
Table 7-6 
Phase Ib Part: Pharmacokinetic blood collection log for MCS110, 
PDR001 and IG samples 
Cycle 
Study 
day 
Analytes 
Scheduled time point (Sampling 
window) 
Total volume of 
Blood sample 
1 
1 
MCS110, PDR001 
and IG a 
Pre-dose b (0 hr) 
6 mL 
1 
1 
MCS110, PDR001 
1 hr (± 5 min) post end of C1D1 infusion 
dose c 
4 mL 
1 
2 
MCS110, PDR001 
24 hr (± 2 hr) post dose 
4 mL 
1 
4 
MCS110, PDR001 
72 hr(± 6 hr) post dose 
4 mL 
1 
8 
MCS110, PDR001 
168 hr (± 8 hr) post dose 
4 mL 
1 
15 
MCS110, PDR001 
336 hr (± 8 hr) post dose  
4 mL 
2 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 2 (0 hr) 
6 mL 
3 
1  
MCS110, PDR001 
and IG a 
Pre-dosed b of cycle 3 (0 hr) 
6 mL 
4 
1  
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 4 (0 hr) 
6 mL 
4 
1 
MCS110, PDR001 
1 hr (± 5 min) post end of C4D1 infusion 
dose c 
4 mL 
4 
2 
MCS110, PDR001 
24 hr (± 2 hr) post dose of cycle 4 
4 mL 
4 
4 
MCS110, PDR001 
72 hr (± 6 hr) post dose of cycle 4 
4 mL 
4 
8 
MCS110, PDR001 
168 hr (± 8 hr) post dose of cycle 4 
4 mL 
4 
15 
MCS110, PDR001 
336 hr (± 8 hr) post dose of cycle 4 
4 mL 
5 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 5 (0 hr) 
6 mL 
6 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 6 (0 hr) 
6 mL 
EOT 
 
MCS110, PDR001 and IG a 
6 mL 


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Cycle 
Study 
day 
Analytes 
Scheduled time point (Sampling 
window) 
Total volume of 
Blood sample 
Blood samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will 
need to be flushed with 10 mL of saline. 
a Immunogenicity (IG) (Anti-Drug [MCS110 or PDR001] Antibody): blood samples to be collected for anti-drug 
antibody together with PK samples 
b Pre-dose blood samples should be collected prior to start of infusion of any treatment 
c MCS110 sampling time is relative to the end of MCS110 infusion; PDR001 sampling time is relative to the end 
of PDR001 infusion 
Table 7-7 
Phase II Part: Pharmacokinetic blood collection log for MCS110, 
PDR001 and IG samples 
Cycle 
Study 
day 
Analytes 
Scheduled time point (Sampling 
window) 
Total volume of 
Blood sample 
1 
1 
MCS110, PDR001 
and IG a 
Pre-dose b (0 hr)  
6 mL 
1 
1 
MCS110, PDR001 
1 hr (± 5 min) post end of C1D1 infusion 
dose c 
4 mL 
1 
8 
MCS110, PDR001 
168 hr (± 8 hr) post dose 
4 mL 
2 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 2 (0 hr) 
6 mL 
3 
1  
MCS110, PDR001 
and IG a 
Pre-dosed b of cycle 3 (0 hr) 
6 mL 
4 
1  
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 4 (0 hr) 
6 mL 
4 
1 
MCS110, PDR001 
1 hr (± 5 min) post end of C4D1 infusion 
dose c 
4 mL 
4 
8 
MCS110, PDR001 
168 hr (± 8 hr) post dose of cycle 4 
4 mL 
5 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 5 (0 hr) 
6 mL 
6 
1 
MCS110, PDR001 
and IG a 
Pre-dose b of cycle 6 (0 hr) 
6 mL 
Blood samples are to be collected from the arm opposite from infusion site, or alternatively, infusion site will 
need to be flushed with 10 mL of saline. 
a Immunogenicity (IG) (Anti-Drug [MCS110 or PDR001] Antibody): blood samples to be collected for anti-drug 
antibody together with PK samples 
b Pre-dose blood samples should be collected prior to start of infusion of any treatment 
c MCS110 sampling time is relative to the end of MCS110 infusion; PDR001 sampling time is relative to the end 
of PDR001 infusion 
7.2.3.1 
Analytical method 
Bioanalysis for pharmacokinetic samples will employ the following validated assays: 
1. The assay to quantify MCS110 will be a validated ELISA assay. 
2. The assay to quantify PDR001 will be a validated LCMS assay. 
3. The assay to quantify and assess the anti-MCS110 antibody will be a validated 
homogeneous ELISA. 
4. The assay to quantify and assess the anti-PDR001 antibody will be a validated 
homogeneous ELISA. 


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7.2.3.2 
PK and immunogenicity sample handling, labeling, and shipping 
instructions 
A total of 4 mLs of blood will be collected at each time point for MCS110 and PDR001 PK. 
After clotting and centrifugation, the resulting serum will be separated into 6 aliquots (3 for 
MCS110 and 3 for PDR001) and will be stored frozen until analysis. For time points when 
MCS110 and PDR001 PK and IG for both molecules are to be measured, a total of 6 mLs of 
blood will be collected at each time point. The samples will be prepared as serum and will be 
aliquoted into 12 aliquots (3 aliquots for each analyte MCS110 PK, PDR001 PK, MCS110 IG 
and PDR001 IG). Blood samples should be collected from the arm opposite from the 
investigational drug infusion, or from another site. Please see the [Laboratory Manual] for 
detailed instructions about collection, handling and shipment of samples. 
The actual collection date and time of each sample will be entered on the 
Pharmacokinetics/Immunogenicity Blood Collection eCRF pages. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for 150 days after the last dose of PDR001 or 90 days after the last dose of 
MCS110 for patients who stopped PDR001 and continued MCS110 alone for more than 60 
days). 


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After initiation of new post-treatment antineoplastic therapy, only AEs suspected to be related 
to study treatment will be collected in the Adverse Events CRF. 
Adverse events (including lab abnormalities that constitute AEs) should be described using a 
diagnosis whenever possible, rather than individual underlying signs and symptoms. When a 
clear diagnosis cannot be identified, each sign or symptom should be reported as a separate 
Adverse Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1 - 4, will be 
used. CTCAE Grade 5 (death) will not be used in this study but is collected as a seriousness 
criteria; rather, information about deaths will be collected through a Death form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 
• 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 sequalae, fatal, unknown) 
• Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1 
and which seriousness criteria have been met. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event CRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC or as per RECIST), should not be reported as a serious adverse 
event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 


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8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• 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 


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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 
to document the objective progression of underlying malignancy. 
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 
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 (90 
days for patients who stopped PDR001 and continued MCS110 alone for more than 60 days). 
If a patient starts a post treatment antineoplastic therapy, then only SAEs suspected to be related 
to study treatment will be reported. 
Any SAEs experienced after this follow-up 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 only: complete the SAE report form in English or Japanese], and 
submit the completed form within 24 hours to Novartis. Detailed instructions regarding the 
submission process and requirements for signatures are to be found in the investigator folder 
provided to each site. 
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, 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 Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, an oncology Novartis 


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Chief Medical Office and Patient Safety (CMO&PS) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
8.3 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. After the mother has provided consent, the newborn will be 
followed-up for 12 months. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis CMO&PS department. 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. 
For Korea only: Pregnancy outcomes should be collected for the female partners of any males 
who took study treatment in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
8.4 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.5 
Data Monitoring Committee 
A formal data monitoring board will not be used for this study. This is an open-label, Phase 
Ib/II study in which patients will receive MCS110 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 Ib 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 two cycles 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. 


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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). 
During the Phase II part of the study individual patient data will be reviewed on an ongoing 
basis. Overall response rate (ORR) for Group 1, 3, 4 and clinical benefit rate (CBR) for Group 
2 per RECIST v1.1 and irRC and aggregate safety data will be monitored quarterly by the study 
team across the duration of the trial. Enrollment of each of Group 1, 3 and 4 will be expanded 
up to approximately 40 patients when objective responses (CR or PR) per RECIST v1.1 or irRC 
are observed (≥ 3 of 20 patients in each of the PD-1/PD-L1 therapy naïve groups or ≥ 2 of 20 
patients in the PD-1/PD-L1 therapy resistant group). In Group 2, enrollment may be expanded 
up to approximately 40 patients at RP2D if clinical benefit per RECIST v1.1 or irRC (CR, PR 
or SD > 4 months) is observed in at least 3 pts. In addition, an exploratory group of 20 patients 
at a lower dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be opened if the 
above mentioned gating criteria is met (Group 2b). The decision of whether to expand a certain 
expansion group will be made at the time when the required number of responses is observed, 
or the last patient (out of 20 patients) has been on treatment for 6 months, whichever occurs 
earlier. The data review and analysis will be based on the available investigator reported data 
in the clinical database at that time Section 10.7. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 


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Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 
have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK 
 samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory and/or contracted central laboratories. ECG data collected during the study will be 
reviewed locally by a cardiologist. 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 


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staff will enter the information required by the protocol into the appropriate eCRF and/or 
designated laboratory requisition forms. Field monitors will review the eCRFs and laboratory 
paper requisition forms for accuracy and completeness and instruct site personnel to make any 
required corrections or additions. One copy of the requisition form will be forwarded to each 
analytical laboratory with the respective sample(s) by the field monitor or by the designated 
investigational site staff; and one copy will be retained at the investigational site. 
9.4 
Database management and quality control 
For studies using eCRFs, Novartis personnel will review the data entered by investigational 
staff for completeness and accuracy. Electronic data queries stating the nature of the problem 
and requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
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. 
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site. 
10 
Statistical methods and data analysis 
The data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation. 
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. The data will be summarized with 
respect to demographic and baseline characteristics, efficacy observations and measurements, 
safety observations and measurements, and all relevant PK and PD measurements using 
descriptive statistics (quantitative data) and contingency tables (qualitative data). 
The study data will be analyzed and reported based on all patients’ data of the Phase Ib 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. 
The following rules will be followed for reporting results unless stated otherwise: 
• Phase Ib dose escalation data: cohorts treated during the dose escalation with the same 
dose levels of MCS110 and PDR001 will be pooled into a single treatment group. All 
summaries, listings, figures and analyses will be performed by treatment group. 


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• Phase II data: All summaries, listings, figures for non-safety analysis will be reported by 
group. Safety analysis of Phase II will be reported by group and all patients. For Group 2, 
all summaries, listings, figures will be reported by dose level, when applicable. The 
groups are the following: 
• Group 1: TNBC (naive to PD-1/PD-L1 directed therapy) 
• Group 2: Pancreatic cancer (naive to PD-1/PD-L1 directed therapy) 
• Group 3: Endometrial cancer (naive to PD-1/PD-L1 directed therapy) 
• Group 4: Melanoma (resistant to PD-1/PD-L1 directed therapy) 
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented. 
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 (see Section 7.1.1.1) will 
not be included in analyses, but will be reported in the CSR as separate listings. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) comprises all patients who received at least one dose of MCS110 
or PDR001. Patients will be analyzed according to the planned treatment combination. Unless 
otherwise specified, FAS is the default set used for all analyses. 
10.1.2 
Safety Set 
The Safety Set (SS) includes all patients who have received at least one dose of MCS110 or 
PDR001. Patients will be classified according to treatment received, where treatment received 
is defined as: 
1. The treatment assigned if it was received at least once, or 
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
The safety set will be used for the safety summary of the study. 
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 
• Have at least one post-baseline tumor assessment evaluable per RECIST v1.1, or have 
withdrawn due to clinical progression. 
• Have received the planned treatment 
• Have not been previously treated with PD-1 or PD-L1-directed therapy except patients in 
the melanoma pretreated group (Group 4), who must have previously received a PD-1 or 
PD-L1-directed therapy. 
Patients will be classified according to planned treatment. 


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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 
The DDS consists of all patients from the safety set in the Phase Ib dose escalation part who 
either meet the following minimum exposure criterion and have sufficient safety evaluations, 
or have experienced a DLT during first two cycles. 
A patient is considered to have met the minimum exposure criterion if he/she received two 
doses of MCS110 and PDR001 during the first two cycles. 
Patients who do not experience DLT during the first two cycles are considered to have sufficient 
safety evaluations if they have been observed for ≥ 42 days following the first dose, and are 
considered by both the Sponsor and Investigators to have enough safety data to conclude that a 
DLT did not occur. 
Patients who do not meet these minimum safety evaluation requirements nor experience a DLT 
will be regarded as ineligible for the DDS and an additional patient may be recruited (see 
Section 7.1.3.1). 
10.1.5 
Pharmacokinetic analysis set 
The Pharmacokinetic analysis set (PAS) includes all subjects who provide an evaluable PK 
profile. A profile is considered evaluable if all of the following conditions are satisfied: 
• Subject receives the planned treatment 
• Subject provides at least one primary PK parameter 
Note: patients will 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 the analyses 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be listed in detail. 
Qualitative data (e.g. performance status) and quantitative data (e.g. weight) will be 
summarized by appropriate descriptive statistics for each treatment cohort in Phase Ib and for 
each group in Phase II. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
For each of MCS110 and PDR001, the actual dose and duration in days of treatment as well as 
the dose intensity (actual dose received/actual duration) and relative dose intensity (the ratio of 
dose intensity to planned dose/planned duration) will be listed and summarized by means of 
descriptive statistics by treatment group. Categories for relative dose intensity of MCS110 or 
PDR001 will be specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The 
number and proportion of patients within each category will be presented by treatment group. 


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Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be listed by patient and summarized by ATC term and treatment group. 
The reason for discontinuation from treatment will be summarized and listed, along with dates 
of first and last dose of MCS110 and PDR001 (if applicable), duration of exposure to MCS110 
and PDR001 (if applicable) and date of discontinuation for each patient. 
Compliance with the protocol will be assessed by the number and proportion of patients with 
protocol deviations. Protocol deviations will be identified prior to database lock and will be 
listed and summarized. 
10.4 
Primary objective 
Phase Ib 
The primary objective of the Phase Ib part is to characterize the safety and tolerability of 
MCS110 given in combination with PDR001 and to identify a recommended dose for Phase II. 
Phase II 
The primary objective of the Phase II part of this study is to estimate the anti-tumor activity of 
the combination of MCS110 with PDR001 in each expansion group. 
10.4.1 
Variable 
Phase Ib 
The primary variables of Phase Ib are: 
• Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, 
vital signs, and ECGs; 
• Tolerability: Dose interruptions, reductions, and dose intensity; 
• Incidence of DLTs in the first two cycles of study treatment 
Phase II 
For TNBC, endometrial carcinoma and melanoma the primary variable of Phase II is the Overall 
Response Rate (ORR), defined as the proportion of patients with a best overall response of 
complete response (CR) or partial response (PR) based on local Investigator assessment, as 
defined in RECIST v1.1. Estimation of the true ORR in this part of the study will be based upon 
the observed BOR for patients in the FAS, using a Bayesian analysis. 
For pancreatic patients, the primary variable of Phase II is the Clinical Benefit Rate (CBR), 
defined as the proportion of patients with a best overall response of complete response (CR) or 
partial response (PR) (with at least two assessments 4 weeks apart) or stable disease (SD) > 4 
months based on local Investigator assessment, as defined in RECIST v1.1. 


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10.4.2 
Statistical hypothesis, model, and method of analysis 
10.4.2.1 Phase Ib 
10.4.2.1.1 
Identification of a recommended dose 
The dose escalation part of this study will be guided by a Bayesian analysis of first two cycles 
dose limiting toxicity (DLT) data for MCS110 and PDR001 in combination. The Bayesian 
analysis will be based on a model with three parts, representing: 
• Single agent MCS110 : 
logit(π1(d1)) = log(α1) + β1log(d1/d1*); d1* = 5 mg/kg Q3W 
• Single agent PDR001: 
logit(π2(d2)) = log(α2) + β2log(d2/d2*); d2* = 300 mg Q3W 
• Interaction: Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2)) 
= exp(η(d1/d1*)(d2/d2*))(π1(d1)+ π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))), 
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 5 mg/kg and d2*= 300 mg are the reference 
doses of MCS110 and PDR001 respectively, α1, α2, β1, β2 > 0 and -∞ < η < ∞. 
Single agent toxicity is modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose. The odds of a DLT are then calculated under no 
interaction for the two single agent toxicities, and interaction is accounted for by adjusting these 
odds with an additional model parameter (odds multiplier). Details of the model are given in 
(Appendix 3). 
Assessment of patient risk 
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated. The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals: 
Under-dosing: 
[0 , 0.16) 
Targeted toxicity: 
[0.16 , 0.33) 
Excessive toxicity: 
[0.33 , 1] 
The escalation with overdose control (EWOC) principle 
Dosing decisions are guided by the escalation with overdose control principle  
(Rogatko 2007). A combination dose may only be used for newly enrolled patients if the risk 
of excessive toxicity at that combination dose is less than 25%. 
Prior distributions 
For each single agent model, a mixture prior was derived. For MCS110, this study uses a 
mixture prior consisting of two components. Component 1 is the distribution derived based on 
dose-DLT data. The assigned weight for Component 1 is 80%. Component 2 allows for a higher 
toxicity case. The assigned weight for Component 2 is 20%. For PDR001, this study uses a 
mixture prior consisting of three components. Component 1 and 2 are derived based on dose-
DLT data. The assigned total weight for Component 1 and 2 is 80%. Component 3 allows for a 
higher toxicity case. The assigned weight for Component 3 is 20%. 


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A meta-analytic-predictive (MAP) approach was used to derive Component 1 of the prior 
distribution for the single agent MCS110 model parameters, and Component 1 and 2 of the prior 
distribution for the single agent PDR001 model parameters. The MAP prior for the logistic 
model parameters for this study is the conditional distribution of the parameters given the 
historical data (see Spiegelhalter 2004, Neuenschwander 2010, Neuenschwander 2014). MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies. 
For this study, available clinical data were taken from the following clinical studies: 
For MCS110: [CMCS110A2101] first-in-human MCS110 study. This study is completed. 
[CMCS110X2201] a Phase II study in PVNS patients. This study is ongoing. 
For PDR001: [CPDR001X2101] first-in-human PDR001 oncology study. This study is 
ongoing. 
For each of the single agent prior, an additional high toxic component is introduced to allow for 
a higher toxicity case. A full description of the application of the MAP approach to derive the 
prior distributions of the single agent MCS110 and PDR001 model parameters is given in 
(Appendix 3) 
The prior distribution for the interaction parameter was based upon prior understanding of 
possible drug safety interactions (Section 1.3.3). This prior allows for the possibility of either 
synergistic or antagonistic interaction, and is fully described in (Appendix 3). 
Starting dose 
The starting dose is 3 mg/kg for MCS110, and 100 mg for PDR001 which will be administered 
every 3 weeks (see Section 6.2.1). For this dose the prior risk of excessive toxicity is 10.4%, 
which satisfies the EWOC criterion. A full assessment of the prior risk to patients is given in 
(Appendix 3). Before first patient first visit (FPFV), the BLRM will be updated with additional 
PDR001 single agent data (if available) to ensure the starting dose still satisfies EWOC. 
Listing of DLTs 
DLTs will be listed, and their incidence summarized by primary system organ class and worst 
grade (CTCAE version 4.03). Listings and summaries will be based on the DDS. 
10.4.2.1.2 
Safety analyses 
Analyses 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 treatment 
2. on-treatment period: from day of first dose of study medication to 30 days after the last 
dose of study treatment 


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3. post-treatment period: from 31 days after date of last administration of study treatment 
Safety summaries will primarily be based on all data from the on-treatment period.  Following 
last administration of study treatment, adverse events (including serious adverse events), and 
new antineoplastic therapies are collected for a period of 150 days.  Following start of new 
antineoplastic therapy, only treatment related adverse events will be collected.  Select 
summaries of related adverse events will be produced for the combined on-treatment and post-
treatment periods for patients receiving PDR001. 
Adverse events (AEs) 
Summary tables for 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 AEs (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of AE, relation to study treatment by treatment group. 
Deaths reportable as SAEs and non-fatal SAEs will be listed by patient and tabulated by type 
of AE and treatment group. 
Specific safety event categories (SEC) may 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), which is specified in case retrieval 
strategy (CRS). SEC will be specified in the statistical analysis plan (SAP) 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. 
Laboratory abnormalities 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03 the study’s biostatistical and reporting team will grade laboratory data 
accordingly. For laboratory tests covered by CTCAE, a Grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges. 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• Frequency table for newly occurring on-treatment grades 3 or 4 (see below for details). 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value. 
• Listing of all clinically relevant laboratory data with values flagged to show the 
corresponding CTCAE grades and the classifications relative to the laboratory normal 
ranges. 


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In addition to the above mentioned tables and listings, 
 analyses may be 
specified in the SAP. 
ECG 
• shift table baseline to worst on-treatment result for overall assessments 
• listing of ECG evaluations 
• listing of ECG evaluations for all patients with at least one abnormality 
Vital signs 
Definitions of notably abnormal results will be specified in the SAP. 
• Listing of vital signs 
• shift table baseline to worst on-treatment result 
10.4.2.1.3 
Tolerability 
Tolerability of study treatment will be assessed by summarizing the number of treatment dose 
interruptions and dose reductions. Reasons for dose interruptions and dose reductions will be 
listed by patient and summarized (Section 10.3). 
10.4.2.2 Phase II 
A Bayesian design will be used in order to estimate ORR (Group 1, 3 and 4) or CBR (Group 2) 
for each of the following groups in the Phase II part of the study. 
• Group 1: MCS110+PDR001, TNBC (naïve to PD-1/PD-L1 directed therapy) 
• Group 2: MCS110+PDR001, Pancreatic adenocarcinoma (naïve to PD-1/PD-L1 directed 
therapy) 
• Group 3: MCS110+PDR001, Endometrial carcinoma (naïve to PD-1/PD-L1 directed 
therapy) 
• Group 4: MCS110+PDR001, Melanoma (progressed on previous PD-1/PD-L1 therapy) 
Groups 1, 3 and 4 will enroll approximately 20 patients, and may be extended to approximately 
40 patients (if at least 3 patients have an objective response for Group 1 and 3; and if at least 2 
patients have an objective response for Group 4). In Group 2, 20 patients will be enrolled at 
RP2D, and enrollment may be extended to approximately 40 patients if clinical benefit is 
observed in at least 3 pts. In addition, an exploratory group of 20 patients at a lower dose (1 
mg/kg MCS110 in combination with PDR001 300 mg) may be opened if the above mentioned 
gating criterion is met (Group 2b). See timing of the decision-making in Section 4.2.  The 
primary analysis will be performed when all patients have completed at least 6 cycles of 
treatment or discontinued prior to that time for any reason. 
Group 1, 3: Minimally informative unimodal Beta prior distribution is defined such that the 
prior mean ORR is set to be equal to 30% and the parameters of the minimally informative Beta 
prior distribution of ORR have been set up as following: 
• a/(a+b) = 0.3 
• a = 0.43 


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• b = 1. 
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. See sample size estimation in Section 10.8. 
Once updated, the estimate ORR and probability of ORR lies in the following categories will 
be reported: 
• [0%, 15%) unacceptable efficacy 
• [15%, 30%) moderate efficacy 
• [30%, 100%] clinically relevant efficacy 
If the observed ORR is equal to or greater than 30% (i.e. ≥ 12 responses (CR or PR) of out 40 
patients) then this will be considered as preliminary evidence of antitumor activity of 
MCS110+PDR001 in the respective patient group naive to PD-1/PD-L1 directed therapy. 
Note that, for a sample size of n = 40, if the observed ORR is 30% then the posterior probability 
of true ORR greater than 20% is 93.0%. 
Group 2: Minimally informative unimodal Beta prior distribution is defined such that the prior 
mean CBR is conservatively set to be equal to 15% and the parameters of the minimally 
informative Beta prior distribution of CBR have been set up as following: 
• a/(a+b) = 0.15 
• a = 0.18 
• b = 1. 
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. See sample size estimation in Section 10.8. 
If the lower MCS110 dose level is explored (Group 2b), a separate model with the same prior 
assumption will be used to estimate CBR. 
Once updated, the estimate CBR and probability of CBR lies in the following categories will 
be reported: 
• [0%, 7.5%) unacceptable efficacy 
• [7.5%, 15%) moderate efficacy 
• [15%, 100%] clinically relevant efficacy 
Observed CBR will be analyzed by dose level. If the observed CBR is equal to or greater than 
15% (i.e. ≥ 6 responses (CR, or PR, or SD for at least 4 months) out of 40 patients at RP2D; or 
≥ 3 responses (CR, or PR, or SD for at least 4 months) out of 20 patients at lower dose group 
(Group 2b) then this will be considered as preliminary evidence of antitumor activity of 
MCS110+PDR001 in the pancreatic patient group naive to PD-1/PD-L1 directed therapy. 
Note that, for a sample size of n = 40, if the observed ORR is 15% then the posterior probability 
of true CBR greater than 7.5% is 93.5%; for a sample size of n = 20, if the observed ORR is 
15% then the posterior probability of true CBR greater than 7.5% is 84.3%. 


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Group 4 
Minimally informative unimodal Beta prior distribution is defined such that the prior mean 
ORR is conservatively set to be equal to 15% and the parameters of the minimally informative 
Beta prior distribution of ORR have been set up as following: 
• a/(a+b) = 0.15 
• a = 0.18 
• b = 1. 
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. See sample size estimation in Section 10.8. 
Once updated, the estimate ORR and probability of ORR lies in the following categories will 
be reported: 
• [0%, 7.5%) unacceptable efficacy 
• [7.5%, 15%) moderate efficacy 
• [15%, 100%] clinically relevant efficacy 
If the observed ORR is equal to or greater than 15% (i.e. ≥ 6 responses (CR or PR) of out 40 
patients) then this will be considered as preliminary evidence of antitumor activity of 
MCS110+PDR001 in the respective patient group resistant to PD-1/PD-L1 directed therapy. 
Note that, for a sample size of n = 40, if the observed ORR is 15% then the posterior probability 
of true ORR greater than 7.5% is 93.5%. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Continuing events (e.g., AEs, concomitant medication, etc.) will be summarized using the data 
cut-off date as the date of completion, with a flag to indicate within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event. 
The reason for discontinuation from study will be summarized and listed, along with dates of 
first and last study drug treatment, duration of exposure to study drug treatment and date of 
discontinuation for each patient. 
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 PPS. Additional 
exploratory and supportive analyses will be performed if appropriate as defined in the SAP. 
10.5 
Secondary objective 
10.5.1 
Key secondary objective 
Not applicable. 


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10.5.2 
Other secondary efficacy objectives 
Tumor response will be determined per local investigators’ assessment, according to RECIST 
v1.1 and irRC. Response related efficacy assessments will be defined and analyzed based on 
both RECIST v1.1 and irRC. For the purpose of this study, Clinical benefit rate (CBR) is 
defined as the proportion of patients with a best overall response of CR or PR , or an overall 
lesion response of SD which lasts for more than 4 months. 
Secondary efficacy endpoints include:  
• Phase Ib part: ORR, PFS, CBR, DOR and DCR per RECIST v1.1 and per immune related 
Response Criteria (irRC) 
• Phase II part: (1) For Group 1, 3, 4, ORR per irRC, PFS, DOR, DCR, CBR per RECIST 
v1.1 and per irRC; (2) For Group 2, CBR per irRC, PFS, DOR, DCR, ORR per RECIST 
v1.1 and per irRC 
For all secondary efficacy parameters, data will be listed, summarized, or analyzed by treatment 
group for the Phase Ib part, and by disease group (groups 1 to 4) for Phase II patients treated at 
the MTD/ RP2D. 
ORR, CBR and DCR will be summarized with accompanying 90% confidence interval. 
PFS, along with DOR for patients who experience a CR or PR at any time on study will be 
listed by patient. PFS will be analyzed using Kaplan-Meier estimates (including graphical 
representation) with 90% CIs of median survival for each treatment group/disease group. 
OS data will be listed for all patients enrolled in the Phase 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 for patients 
treated at the MTD/RP2D in the Phase II part. 
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. Best overall response per RECIST v1.1 and per irRC will be listed and 
tabulated. 
Any additional analyses of efficacy endpoints will be described in the SAP. 
10.5.3 
Safety objectives 
Another secondary objective is to further characterize the safety and tolerability of MCS110 in 
combination with PDR001 during Phase II part. Safety and tolerability analyses as described in 
Section 10.4.2.1.2 and Section 10.4.2.1.3 will be performed. 
10.5.4 
Pharmacokinetics 
The pharmacokinetic parameters will be determined by profile using noncompartmental 
method(s) for both MCS110 and PDR001 as presented in Table 10-1, and PAS will be used in 
all pharmacokinetic data analysis and PK summary statistics. 


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Table 10-1 
Pharmacokinetic Parameters to be analyzed 
AUClast 
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x 
time x volume-1) 
AUCinf 
The AUC from time zero to infinity (mass x time x volume-1) 
Cmax 
The maximum (peak) observed plasma, blood, serum, or other body fluid drug concentration 
after single dose administration (mass x volume-1) 
Tmax 
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time) 
T1/2 
The elimination half-life associated with the terminal slope (λz) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives 
CL 
The total body clearance of drug from the plasma (volume x time-1) 
Vz 
The apparent volume of distribution during terminal phase (associated with λz) (volume) 
AR 
Accumulation Ratio=Cmax (multiple Dose)/Cmax (single dose) 
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 MCS110 and PDR001 serum concentrations at each 
scheduled time point. Descriptive graphical plots of individual serum concentration versus time 
profiles and mean concentration versus time profiles will be generated. 
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation will be handled as zero in summary statistics, and reported as is in 
data listings. Any missing pharmacokinetic parameter data will not be imputed. 
The presence of immunogenicity for MCS110 and PDR001, at each scheduled time point, will 
be listed by treatment group, disease and patient. Overall immunogenicity will be summarized. 
More details will be provided in SAP or separate analysis plan. 


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10.7 
Interim analysis 
No formal interim analyses are planned. 
Phase Ib 
However, in Phase Ib, the dose-escalation design foresees that decisions based on the current 
data are taken before the end of the study. More precisely, after each cohort in the dose 
escalation part, the next dose will be chosen depending on the observed data (based on safety, 
tolerability, PK and PD, guided by the recommendations from the BLRM of DLT using EWOC, 
and recommendations from participating investigators). Details of this procedure and the 
process for communication with Investigators are provided in Section 6.2.3. 
Phase II 
Data from patients in the Phase II part will be reviewed on an ongoing basis to monitor the 
safety and tolerability of the RP2D in that part of the study. The sample size in any of Group 1, 
3 or 4  may be extended to approximately 40 patients (if ≥ 3 of 20 patients in each of the PD-
1/PD-L1 therapy naïve groups or ≥ 2 of 20 patients in the PD-1/PD-L1 therapy resistant group 
have tumor responses of CR or PR per RECIST v1.1 or irRC). In Group 2, 20 patients will be 
enrolled at RP2D, and enrolment may be expanded up to approximately 40 patients if at least 3 
pts with CR, PR or SD > 4 months per RECIST v1.1 or irRC are observed. In addition, an 
exploratory group of 20 patients at a lower dose (1 mg/kg MCS110 in combination with 
PDR001 300 mg) may be opened if the above mentioned gating criterion is met (Group 2b). 
The decision of whether to expand a certain expansion group will be made at the time when the 
required number of responses is observed, or the last patient (out of 20 patients) has been on 
treatment for at least 6 months, whichever occurs earlier. The Investigators and Novartis will 
make the decision based on a synthesis of all relevant data available including safety, PK and 
PD information. 
10.8 
Sample size calculation 
Phase Ib 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation Phase including at 
least six patients at the MTD/RP2D level, as described in Section 6.2.3. Multiple cohorts may 


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be sequentially enrolled to the same dose level. Additional cohorts of 3 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 15 patients are expected to be treated in the 
dose escalation Phase for the model to have reasonable operating characteristics relating to its 
estimation of MTD. 
Phase II 
Approximately 20 patients will initially be enrolled to each of groups 1, 3 and 4. Enrollment 
may be expanded up to approximately 40 patients in these groups if objective responses (CR or 
PR) per RECIST v1.1 or irRC are observed (≥ 3 of 20 patients in each of the PD-1/PD-L1 
therapy naïve groups or ≥ 2 of 20 patients in the PD-1/PD-L1 therapy resistant group) 
(Section 2.2).  In Group 2, 20 patients will be enrolled at RP2D, and enrolment may be 
expanded up to approximately 40 patients if at least 3 pts with CR, PR or SD > 4 months per 
RECIST v1.1 or irRC are observed. In addition, an exploratory group of 20 patients at a lower 
dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be opened if the above 
mentioned gating criterion is met (Group 2b). The operating characteristics of the designs are 
provided in Table 10-2 (for Group 1, 3), Table 10-3 (for Group 4), and Table 10-4 (for Group 
2 at RP2D), Table 10-5 (for Group 2b). 
Table 10-2 
Operating characteristics of the design (Group 1, 3) 
True ORR 
Probability to observe >=3 
responses in first 20 
patients 
Group 1: TNBC 
Group 3: Endometrial cancer 
probability to observe an ORR ≥ 30% with 40 patients 
(Overall success rate) 
15% 
59.5% 
1.2% 
20% 
79.4% 
8.7% 
25% 
90.9% 
28.4% 
30% 
96.5% 
55.8% 
40% 
99.6% 
92.8% 
50% 
100.0% 
99.7% 
Table 10-3 
Operating characteristics of the design (Group 4) 
True ORR 
Probability to observe >=2 
responses in first 20 
patients 
Groups 4: resistant melanoma 
probability to observe an ORR ≥ 15% with 40 patients 
(Overall success rate) 
7.5% 
44.9% 
7.1% 
15% 
82.4% 
54.2% 
20% 
93.1% 
81.5% 
30% 
99.2% 
98.6% 
40% 
99.9% 
99.9% 
50% 
100.0% 
100% 


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Table 10-4 
Operating characteristics of the design (Group 2 at RP2D) 
True 
CBR 
Probability to observe >=3 
responses (CR, PR or SD > 4 
months) in first 20 patients 
Group 2: Pancreatic cancer  
probability to observe a CBR ≥ 15% with 40 patients 
7.5% 
18.6% 
5.5% 
15% 
59.5% 
46.1% 
20% 
79.4% 
73.4% 
30% 
96.5% 
96.1% 
Table 10-5 
Operating characteristics of the design (Group 2b) 
True CBR 
Groups 2b: Pancreatic cancer  
probability to observe a CBR ≥ 15% with 20 patients 
7.5% 
18.6% 
15% 
59.5% 
20% 
79.4% 
30% 
96.5% 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
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 
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 


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documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their CRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 
11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g. clinicaltrials.gov , before study start. In 
addition, results of interventional clinical trials in adult patients are posted on 
novartisclinicaltrials.com, a publicly accessible database of clinical study results within 1 year 
of study completion  
(i.e., LPLV) and those for interventional clinical trials involving pediatric patients within 6 
months of study completion. 
Novartis follows the ICMJE authorship guidelines (icmje.org) and other specific guidelines of 
the journal or congress to which the publication will be submitted. 
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations. 
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable. 
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 


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11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
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. 


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


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13 
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Cancer Res 74(18): 5057-5069. 


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


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Glossary 
CR 
Complete response 
CRF 
Case Report Form 
CSR 
Clinical Study Report 
CT 
Computed tomography 
DFS 
Disease-free survival 
eCRF 
Electronic Case Report Form 
FPFV 
First patient first visit 
LPLV 
Last patient last visit 
MRI 
Magnetic resonance imaging 
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 intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment. 
• Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment. 
• For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow-up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis. 
• 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 biopsies are 
obtained. 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian cancer, 
PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) can be 
integrated as non-target disease. If markers are initially above the upper normal limit they 
must normalize for a patient to be considered in complete clinical response when all 
lesions have disappeared. 
• Cytology and histology: Cytology and histology can be used to differentiate between PR 
and CR in rare cases (i.e., after treatment to differentiate between residual benign lesions 
and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed). 
• Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended. 
14.1.2.3 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 


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organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ). 
Minimum target lesion size at baseline 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.2.1.1. 
• 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. 
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 


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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. 
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 


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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 CRF 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. 
• Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK. 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase in the 
size of nodes. 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) 
of the two split lesions should be added together and the sum recorded in the diameter 
field on the case report form under the original lesion number. This value will be included 
in the sum of diameters when deriving target lesion response. The individual split lesions 
will not be considered as new lesions, and will not automatically trigger a PD designation. 


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• Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced. 
• The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications. 
• Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared. 
• Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions. 
• Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 
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 


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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 CRF page. 
• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.2.5). 
• 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 


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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. 
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. 


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• 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) 
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. 


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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. 
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 
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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. 
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 


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a response, may have a longer time to respond, and tend to relapse quickly when they do 
respond. Potent agents induce a response in both good risk and poor risk patients. Less potent 
agents induce a response mainly in good risk patients only. This is described in more detail by 
Morgan (1988). 
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response. 
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis). 
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. 


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• at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV) 
• at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding 
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint. 
14.1.3.2.7 
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 


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is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8). 
Example (if protocol defined schedule of assessments is 3 months): tumor assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months. 
• Date of discontinuation is the date of the end of treatment visit. 
• Date of last contact is defined as the last date the patient was known to be alive. This 
corresponds to the latest date for either the visit date, lab sample date or tumor assessment 
date. If available, the last known date patient alive from the survival follow-up page is 
used. If no survival follow-up is available, the date of discontinuation is used as last 
contact date. 
• Date of secondary anti-cancer therapy is defined as the start date of any additional 
(secondary) antineoplastic therapy or surgery. 
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. 


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For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as 
“responders” with respect to ORR and all other patients as “non-responders”. 
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease. 
14.1.3.2.9 
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) 


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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. 
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. 


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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). 
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 
• Subject/guardian decision 
• Death 
• Progressive disease per irRC (not per RECIST) 
• Study terminated by the sponsor 
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 


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• Technical problems 
• Subject/guardian decision 
• Death 
• New therapy for study indication 
• Progressive disease 
• Study terminated by the sponsor 
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 


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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. 
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 
*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: 


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• This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off). 
• The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment. 
• This reason will also be used to censor in case of no baseline assessment. 
14.1.5 
References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465 
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 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 measurable lesions. Up to five new measurable (and a maximum 
of two per organ) are allowed in total and will be included in the overall tumor assessment. 
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 
at baseline and any new non-measurable lesions that have appeared during the study). If after 
worsening a non-target lesion becomes measurable, it should still be followed as a non-target 
lesion. Worsening of non-target lesions and new non-measurable lesions only indicate disease 
progression if there is unequivocal evidence of disease progression (Table 14-6). 
14.2.3 
Follow-up evaluation of target and non-target lesions 
To assess tumor response, the sum of diameters for all target lesions is calculated (at baseline 
and throughout the study). The diameters of any new measurable lesions are included in the 
sum of diameters at each assessment to provide the total tumor burden. At each assessment, 
percent change in the sum of diameters is calculated and compared to baseline or to nadir in 
order to evaluate the target lesion response (including new measurable lesions) (Section 14.2.4). 
This evaluation combined with the status of non-target lesions (baseline and new non-
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: 
• Immune related Complete Response (irCR): Disappearance of all non-nodal target lesions 
and non-target lesions in two consecutive observations not less than 4 weeks apart. In 
addition, any pathological lymph nodes assigned as target lesions must have a reduction in 
short axis to < 10 mm. (Sum of diameters may be greater than zero at the time of CR, if 
nodal lesions are included as target lesions). 
• Immune related Partial Response (irPR): At least a 30% decrease in the sum of diameters 
of all target lesions including new target lesions in two consecutive observations not less 
than 4 weeks apart, taking as reference the baseline sum of diameters. 
• Immune related Progressive Disease (irPD): At least a 20% increase in the sum of 
diameters of all measured target lesions including new measurable lesions. The irPD must 
be confirmed in a second evaluation not less than 4 weeks later, taking as reference the 
smallest sum of diameter of all target lesions recorded at or after baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. Worsening of non-target lesions (existing or new) only indicate 
PD when there is unequivocal evidence of progression, confirmed in a second evaluation 
not less than 4 weeks later. 
• Immune related Stable Disease (irSD): Neither a sufficient shrinkage to qualify for irPR or 
irCR, nor an increase in lesions which would qualify for irPD. 
• Unknown (UNK): Progression has not been documented and one or more target lesions 
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 b 
Absent/Stable/not evaluated 
irPRa 
>-30 b and<+20 c 
Absent/Stable/not evaluated 
irSD 
≥+20 c 
Any 
irPDa 
Any 
Unequivocal progression 
irPDa 


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Target and new measurable lesions 
(Tumor burden), * (%) 
Non-target lesions 
(both baseline and new non-
measurable) 
Overall 
lesion response 
* the longest diameter of new measurable lesions is included in the calculation of the sum of longest diameters. 
a To be confirmed after at least 4 weeks. 
b From baseline 
c From nadir 
If the evaluation of any of the target lesions could not be made during follow-up, the overall 
status must be ‘unknown’ unless progression was documented. 
If the evaluation of any non-target lesions is not made, and all target lesions disappeared, irCR 
cannot be determined and overall response must be “irPR”. 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the irCR. 
14.2.5 
Only non-measurable disease at baseline 
For patients with only non-measurable disease at baseline, unequivocal progression of non-
target lesions will constitute an irPD (i.e. worsening of the overall tumor burden which is 
substantial enough to lead to discontinuation or change of therapy). In addition, the appearance 
of new lesions (measurable or non-measurable) consistent with unequivocal progression taking 
into account the overall disease burden will constitute an irPD. The absence of all non-target 
lesions and no new lesions will qualify for irCR. Otherwise the overall response will be 
considered as irNon-CR/Non-PD (irNCRNPD) similar to RECIST 1.1. Confirmation of irPD 
and irCR as specified above in Section 14.2.4 is required. If any baseline non-target lesion or a 
new lesion observed at an earlier post-baseline evaluation was not/could not be assessed at a 
later post-baseline tumor evaluation then the overall response will be irUNK. No confirmation 
is required for irNCRNPD. 
14.2.6 
References (available upon request) 
Bohnsack O, Ludajic K, Hoos A (2014) Adaptation of the immune-related response criteria: 
irRECIST. ESMO 2014; Abstract 4958 visible at: 
//webges.com/cslide/library/esmo/browse/search/eTT#9faE02tu. 
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013) Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-Related Response Criteria Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-3943. 
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. 


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14.3 
Appendix 3: Statistical Details for the Phase Ib Part: Bayesian 
logistic regression model (BLRM): prior and design properties 
for hypothetical data scenarios 
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical and pre-clinical data, the results of the Bayesian analyses and respective dosing 
decisions for some hypothetical data scenarios, and a simulation study of the operating 
characteristics of the model. 
14.3.1 
Statistical Models 
The statistical model comprises single-agent toxicity parts, which allow the incorporation of 
single-agent toxicity data, and an interaction part. 
14.3.1.1 Single agent part 
Let 𝜋𝜋1(𝑑𝑑1) be the risk of DLT for MCS110 given as a single agent at dose 𝑑𝑑1; 𝜋𝜋2(𝑑𝑑2) be the 
risk of DLT for PDR001 given as a single agent at dose 𝑑𝑑2. These single agent dose-DLT 
models are logistic: 
MCS110: logit൫𝜋𝜋1(𝑑𝑑1)൯ =  log(𝛼𝛼1) + 𝛽𝛽1 log(𝑑𝑑1 𝑑𝑑1
∗
⁄
) 
PDR001: logit൫𝜋𝜋2(𝑑𝑑2)൯ =  log(𝛼𝛼2) + 𝛽𝛽2 log(𝑑𝑑2 𝑑𝑑2
∗
⁄
) 
where 𝑑𝑑1
∗= 5 mg/kg and 𝑑𝑑2
∗= 300 mg (reference doses) are used to scale the doses of MCS110 
and PDR001, respectively. Hence, 𝛼𝛼1 and 𝛼𝛼2 (>0) are the single-agent odds of a DLT at 𝑑𝑑1
∗ and 
𝑑𝑑2
∗, respectively; and 𝛽𝛽1 and 𝛽𝛽2 (>0) are the increase in the log-odds of a DLT by a unit increase 
in log-dose. 
14.3.1.2 Interaction 
Under the situation of no interaction, the risk of a DLT at dose 𝑑𝑑1 of MCS110 and dose 𝑑𝑑2 of 
PDR001 is: 
𝜋𝜋12
0 (𝑑𝑑1, 𝑑𝑑2) = 1 − ൫1 −𝜋𝜋1(𝑑𝑑1)൯൫1 −𝜋𝜋2(𝑑𝑑2)൯ 
To allow for interaction between MCS110 and PDR001, an odds multiplier is introduced. The 
risk of DLT for combination dose (𝑑𝑑1, 𝑑𝑑2) is then given by: 
odds൫𝜋𝜋12(𝑑𝑑1, 𝑑𝑑2)൯= exp(𝜂𝜂12 × 𝑑𝑑1 𝑑𝑑1
∗
⁄
× 𝑑𝑑2 𝑑𝑑2
∗
⁄
) × odds൫𝜋𝜋12
0 (𝑑𝑑1, 𝑑𝑑2)൯ 
where odds(𝜋𝜋) = 𝜋𝜋(1 −𝜋𝜋)
⁄
; and 𝜂𝜂12 is the log-odds ratio between the interaction and no 
interaction model at reference doses. Here 𝜂𝜂12 = 0 corresponds to no interaction, with 𝜂𝜂12 > 0 
and 𝜂𝜂12 < 0 representing synergistic and antagonistic toxicity respectively. 
14.3.2 
Prior specifications 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log(𝛼𝛼1), log(𝛽𝛽1) for MCS110, log(𝛼𝛼2), log(𝛽𝛽2) for 
PDR001, and the interaction parameter 𝜂𝜂12. A meta-analytic-predictive (MAP) approach was 
used to derive the prior distribution for the single-agent model parameters. 


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14.3.2.1 Prior distribution for the logistic parameters 
For each of MCS110 and PDR001 single agent, a mixture prior was derived. 
A MAP approach was used to incorporate the dose-DLT data from [CMCS110A2101] (first-
in-human MCS110 study in prostate cancer patients) and [CMCS110X2201] (a Phase II study 
in PVNS patients, with the cutoff date Nov 28, 2015) for MCS110; and [CPDR001X2101] 
(first-in-human PDR001 oncology study, with the cutoff date Nov 28, 2015) for PDR001. To 
make the prior more robust, an additional mixture component corresponding to high toxicity 
was introduced. 
14.3.2.1.1 
Description of the meta-analytic-predictive (MAP) approach 
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
൫log(𝛼𝛼∗),  log(𝛽𝛽∗)൯ of the new trial using DLT data from historical studies. 
Let 𝑟𝑟𝑑𝑑𝑑𝑑 and 𝑛𝑛𝑑𝑑𝑑𝑑 be the number of patients with a DLT, and the total number of patients at dose 
𝑑𝑑 in historical trial 𝑠𝑠 (𝑠𝑠= 1, … , 𝑆𝑆). The corresponding probability of a DLT is 𝜋𝜋𝑑𝑑𝑑𝑑. The model 
specifications for the derivation of the MAP prior are as follows: 
𝑟𝑟𝑑𝑑𝑑𝑑 | 𝜋𝜋𝑑𝑑𝑑𝑑 ~ Bin(𝜋𝜋𝑑𝑑𝑑𝑑, 𝑛𝑛𝑑𝑑𝑑𝑑) 
logit(𝜋𝜋𝑑𝑑𝑑𝑑) = log(𝛼𝛼𝑠𝑠) + 𝛽𝛽𝑠𝑠 log(𝑑𝑑/𝑑𝑑∗) 
 ൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼𝑠𝑠), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽𝑠𝑠)൯ ห 𝜇𝜇, 𝜓𝜓 ~ BVN(𝜇𝜇, 𝜓𝜓),
s = 1, … , 𝑆𝑆 
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห 𝜇𝜇, 𝜓𝜓 ~ BVN(𝜇𝜇, 𝜓𝜓) 
The parameters 𝜇𝜇 = (𝜇𝜇1, 𝜇𝜇2) and 𝜓𝜓 are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations τ1, τ2, and correlation ρ. The parameters 
τ1 and τ2 quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters: 
• normal priors for 𝜇𝜇1 and 𝜇𝜇2, 
• log-normal priors for τ1 and τ2, and 
• a uniform prior for ρ. 
The MAP prior for single-agent model parameters in the new trial, ൫log(α∗), log(β∗)൯, is the 
predictive distribution 
൫𝑙𝑙𝑙𝑙𝑙𝑙(𝛼𝛼∗), 𝑙𝑙𝑙𝑙𝑙𝑙(𝛽𝛽∗)൯ ห (𝑟𝑟𝑑𝑑𝑑𝑑, 𝑛𝑛𝑑𝑑𝑑𝑑∶𝑠𝑠= 1, … , 𝑆𝑆) 
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution. This is implemented using JAGS version 3.12. The sample from this 
distribution is then approximated by a mixture of bivariate normal (BVN) distributions. BVN 
mixtures with increasing numbers of mixture components are fitted to the sample using the 
expectation-maximization (EM) algorithm (Dempster 1977). The optimal number of 
components of the mixture is then identified using the Akaike information criterion (AIC) 
(Akaike 1974). 


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14.3.2.1.2 
 Single agent MCS110 
For MCS110, this study uses a mixture prior consisting of two components. Component 1 is 
the distribution derived based on dose-DLT data from [CMCS110A2101] (first-in-human 
MCS110 study in prostate cancer patients) and [CMCS110X2201] (a Phase II study in PVNS 
patients) by MAP approach (Section 14.3.2.1.1). The assigned weight for Component 1 is 80%. 
Component 2 allows for a higher toxicity case. The assigned weight for Component 2 is 20%. 
Component 1: 
For the MAP model for MCS110, reference dose 𝑑𝑑1
∗= 5 mg/kg is used, and data from 𝑆𝑆= 2 
historical studies is available. (Table 14-8 and Table 14-9) [CMCS110A2101] is a Phase I study 
with 3 prostate cancer patients with bone metastasis receiving 0.01 mg/kg MCS110 in a once 
every 2 week dosing schedule on a 28-day cycle for 3 cycles. [CMCS110X2201] is a Phase II 
proof of concept study in patients with PVNS (pigmented villonodular synovitis). As of Nov-
28-2015, there are 18 patients treated with single dose of MCS110 at 10 mg/kg. 
Weakly informative normal priors are assumed for 𝜇𝜇1 and 𝜇𝜇2, with means corresponding to a 
risk of DLT of 10% at the reference dose, and a doubling in dose leading to a doubling in the 
odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their 
medians correspond to large between trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations (Neuenschwander 2014). 
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 14-7. 
Table 14-7 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent MCS110 model parameters 
Parameter 
Prior distribution 
𝜇𝜇1 
N(mean = logit(0.10), sd = 2) 
𝜇𝜇2 
N(mean = 0, sd=1) 
τ1 
log-normal(mean = log(1), sd = log(2)/1.96) 
τ2 
log-normal(mean = log(0.500), sd = log(2)/1.96) 
ρ 
uniform(-1,1) 
Historical data 
Table 14-8 
Historical data from [CMCS110A2101] 
Dose level of MCS110 (mg/kg) 
Number DLTs/Number of evaluable patients 
0.01 
0/3 
Table 14-9 
Historical data from [CMCS110X2201] 
Dose level of MCS110 (mg/kg) 
Number DLTs/Number of evaluable patients 
10 
0/18 
Component 2: 
This weakly informative bivariate normal prior allows for a case with higher toxicity. 


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• For the intercept parameter log(α2), the prior mean of -1.658 is derived based on the a-
priori median of an assumed 16% DLT rate at the reference dose d2*= 5 mg/kg. By setting 
the standard deviation =2, the respective 95% a-priori interval for probability of DLT at 
dose 5 mg/kg is wide (0.4%, 90.6%), which represents weak prior information. 
• For the log-slope parameter log(β2), the prior mean of 0 and prior standard deviation of 1 
allow for very flat to very steep slopes. Therefore, it is a weakly informative prior. The 
interpretation is as follows: when tripling the dose, the odds of having a DLT are 
multiplied by a factor of 3β. 
• The Component 2 is set to be (-1.658, 0, 2, 1, 0) 
14.3.2.1.3 
Single agent PDR001 
For PDR001, this study uses a mixture prior consisting of three components. Component 1and 
2 are derived based on dose-DLT data from First-in-human PDR001 oncology study 
[CPDR001X2101] by MAP approach (Section 14.3.2.1.1). The assigned total weight for 
Component 1 and 2 is 80%. Component 3 allows for a higher toxicity case. The assigned weight 
for Component 3 is 20%. 
Component 1 and 2 
For the MAP model for PDR001, reference dose 𝑑𝑑2
∗= 300 mg is used, and data from 𝑆𝑆= 1 
historical study is available. (Table 14-11) [CPDR001X2101] is a Phase I study with two dose 
schedules: three cohorts of patients on a Q2W schedule; and two cohorts on a Q4W schedule. 
PDR001 dose levels in Q2W and Q4W dosing schedules are converted to Q3W by finding out 
the dose level in Q3W which provides equivalent area under the curve (AUC0-6weeks) for dose 
levels in Q2W and Q4W regimens studied in [CPDR001X2101] trial. Using the popPK model 
developed from [CPDR001X2101] PK data following steps are conducted: (1) Target AUCs 
are simulated for studied dose levels in [CPDR001X2101] trial at their respective regimens for 
AUC0-6weeks; (2) Corresponding Q3W AUC0-6weeks are generated for dose levels every 10 mg on 
Q3W regimen; i.e 50 through 2000 mg with every 10 mg interval; (3) The dose level on Q3W 
regimen that minimized the absolute difference between target AUC and Q3W AUC0-6weeks are 
selected as candidate dose. 
After the dose conversion is performed as described above, PDR001 single agent data is then 
used to derive MAP prior. Firstly, weakly informative priors are assumed for 𝜇𝜇1 and 𝜇𝜇2, with 
means corresponding to a risk of DLT at the reference dose of 10%, and a doubling in dose 
leading to a doubling in the odds of the risk of a DLT, respectively. Priors for τ1 and τ2 are 
assigned such that (1) their medians correspond to substantial between trial heterogeneity, and 
(2) their uncertainty (95% prior interval) cover plausible between-trial standard deviations 
(Neuenschwander 2014). PDR001 data was then used to update the prior described above. 
The prior distributions for the model used for deriving the MAP priors are specified in 
Table 14-10. 


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Table 14-10 
Prior distributions for the parameters of the MAP model used to derive 
the prior for the single-agent PDR001 model parameters 
Parameter 
Prior distribution 
𝜇𝜇1 
N(mean = logit(0.10), sd = 2) 
𝜇𝜇2 
N(mean = 0, sd=1) 
τ1 
log-normal(mean = 0.500, sd = log(2)/1.96) 
τ2 
log-normal(mean = 0.250, sd = log(2)/1.96) 
ρ 
uniform(-1,1) 
Historical data 
Table 14-11 
Historical data from [CPDR001X2101] 
Dose 
schedule 
Dose level 
(mg/kg) 
Flat dose 
(mg) 
Equivalent dose level in Q3W 
(mg)* 
Total Number of DLT 
/Number of evaluable 
patients 
Q2W 
1 
80 
110 
0/16 
Q2W 
3 
240 
330 
0/12 
Q2W 
10 
800 
1110 
0/3 
Q4W 
3 
240 
220 
0/6 
Q4W 
5 
400 
360 
0/6 
* Equivalent dose level in Q3W is calculated based on simulation described under Component 1 and 2 
Component 3: 
This weakly informative bivariate normal prior allows for a case with higher toxicity. 
• For the intercept parameter log(α2), the prior mean of -1.099 is derived based on the a-
priori median of an assumed 25% DLT rate at the reference dose d2*= 300 mg. By setting 
the standard deviation =2, the respective 95% a-priori interval for probability of DLT at 
dose 300 mg/kg is wide (0.7%, 94.4%), which represents weak prior information. 
• For the log-slope parameter log(β2), the prior mean of 0 and prior standard deviation of 1 
allow for very flat to very steep slopes. Therefore, it is a weakly informative prior. The 
interpretation is as follows: when tripling the dose, the odds of having a DLT are 
multiplied by a factor of 3β. 
• The Component 3 is set to be (-1.099, 0, 2, 1, 0) 
All the information to derive the prior distributions for the model parameters is provided in 
Table 14-13. 
14.3.2.2 Prior distribution for the interaction parameters 
Although no interaction is expected, considerable uncertainty remains. A normal prior 
distribution for the interaction parameter η12 is to be derived to reflect the current uncertainty 
about the toxicity profile of the combination of MCS110 and PDR001. The risk of significant 
positive interaction between MCS110 and PDR001 cannot be totally excluded. The interaction 
parameter η12 was chosen accordingly but with a degree of uncertainty in order to allow for the 


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possibility that the interaction may be positive or negative. Therefore the following assumption 
is made for the interaction parameter: 
• 𝜂𝜂12 is normally distributed, with mean 0, and standard deviation 2.803; 
• At the starting dose of d1start=3 mg/kg and d2start=100 mg the corresponding distribution for 
the odds ratio has mean 1 and a 97.5th percentile of 3.00, i.e. 3-fold increase in odds of 
DLT due to interaction compared to no interaction. 
Since the interaction is dose-dependent (see model definition in Section 10.4.2), the prior for 
the interaction parameter has a simple interpretation only at the anticipated combination 
reference dose of MCS110 = 5 mg/kg and PDR001 = 300 mg. Table 14-12 shows the prior 
median and 95% confidence interval of fold increase in odds of DLT due to interaction 
compared to no interaction at all provisional dose levels, as well as the reference dose level. 
Table 14-12 
A priori interaction at the provisional and reference dose levels 
MCS110 
(mg/kg, Q3W) 
PDR001 
(mg, Q3W) 
 
100 
300 
3 
1 
(0.333, 3.000) 
1 
(0.037,27.000) 
5 
1 
(0.160, 6.240) 
1 
(0.004, 243.000) 
10 
1 
(0.026, 38.941) 
1 
(0.000,59049.000) 
* Presented are median (95% confidence interval). The prior median of fold increase in odds of DLT with 95% 
confidence interval at the combination reference dose level is highlighted in bold. 
14.3.2.3 Summary of prior distributions 
The prior distributions of the model parameters are summarized in Table 14-13. 
Prior summaries for DLT rates for are summarized in Table 14-14. 
Table 14-13 
Prior distribution for the model parameters 
Parameter 
Mean 
Standard deviations 
correlation 
weight 
Single agent MCS110 prior 
BVN Mixture ൫log(𝛼𝛼1), log(𝛽𝛽1)൯ 
Component 1 
(MAP prior) 
(-4.302 , -0.356) 
(1.852, 1.030) 
-0.050 
0.80 
Component 2 
(high toxicity) 
(-1.658 , 0) 
(2, 1) 
0 
0.20 
Single agent PDR001 prior 
BVN Mixture ൫log(𝛼𝛼2), log(𝛽𝛽2)൯ 
Component 1 
(MAP prior) 
(-5.166 , -0.582) 
(1.454, 0.956) 
-0.275 
0.43 
Component 2 
(MAP prior) 
(-4.115 , -0.008) 
(1.083, 0.647) 
-0.212 
0.37 
Component 3 
(high toxicity) 
(-1.099 , 0) 
(2, 1) 
0 
0.20 


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Parameter 
Mean 
Standard deviations 
correlation 
weight 
Interaction parameter 
Normal 
𝜂𝜂12 
0 
2.803 
N/A 
N/A 
Table 14-14 
Summary of prior distribution of DLT rates 
MCS110 
dose 
(mg/kg) 
Prior probabilities that P(DLT) is in the 
interval : 
Mean 
SD 
Quantiles 
[0, 0.16) 
[0.16, 0.33) 
[0.33,1] 
2.5% 
50% 
97.5% 
 
In combination with PDR001 100 mg 
3 
0.803 
0.093 
0.104 
0.111 
0.187 
0.001 
0.03 
0.747 
5 
0.74 
0.11 
0.15 
0.145 
0.22 
0.001 
0.044 
0.845 
10 
0.604 
0.117 
0.279 
0.244 
0.309 
0.001 
0.082 
0.981 
 
In combination with PDR001 300 mg 
3 
0.687 
0.112 
0.201 
0.183 
0.262 
0.001 
0.052 
0.932 
5 
0.601 
0.104 
0.295 
0.256 
0.328 
0 
0.074 
0.988 
10 
0.516 
0.063 
0.421 
0.381 
0.418 
0 
0.131 
1 
Note: bold values indicate dose combinations not meeting the overdose criterion. 
14.3.3 
Hypothetical on-study scenarios 
To illustrate the performance of the Bayesian model used to guide dose escalation, hypothetical 
dose escalations scenarios following the provisional dose levels specified in Table 6-2 are 
displayed. In each case, the maximum dose that can be used in the next cohort of patients is 
shown. This maximum dose is determined using the model based assessment of the risk of DLT 
in future patients and the dose escalation rules as described in Section 6.2.3. In practice a dose 
below the maximum might be chosen based on additional safety, PK or PD information 
(Section 6.2.3). 
Table 14-15 shows on-study dosing recommendations for some hypothetical data scenarios. 
Note that the next dose combination is selected in concordance with the provisional dose levels 
specified in Section 6.2.2 of the protocol wherever it is allowed, to mimic possible on-study 
escalation steps. 
Table 14-15 
Dose decisions recommended by BLRM under EWOC 
Scenario 
Dose 
combination 
MCS110 
(mg/kg)/PDR001 
(mg) 
Number of 
Next dose level 
patients 
DLTs 
Dose 
(mg/kg / 
mg) 
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
1 
Cohort1:3/100 
3 
0 
3/300 
0.101 
0.097 
0.031 
2 
Cohort1:3/100 
3 
1 
3/100 
0.260 
0.219 
0.150 
3 
Cohort1:3/100 
3 
2 
STOP 
 
 
 
4 
Cohort1:3/100 
Cohort2:3/100 
3 
5 
1 
0 
3/300 
0.189 
0.212 
0.110 
5 
Cohort1:3/100 
Cohort2:3/300 
3 
5 
0 
0 
5/300 
0.075 
0.061 
0.014 


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Scenario 
Dose 
combination 
MCS110 
(mg/kg)/PDR001 
(mg) 
Number of 
Next dose level 
patients 
DLTs 
Dose 
(mg/kg / 
mg) 
P(Target 
toxicity) 
P(excessive 
toxicity) 
Median 
P(DLT) 
6 
Cohort1:3/100 
Cohort2:3/300 
3 
5 
0 
1 
3/300 
 
0.256 
0.092 
0.109 
7 
Cohort1:3/100 
Cohort2:3/300 
3 
5 
0 
2 
3/100 
0.175 
0.043 
0.075 
8 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:3/300 
3 
5 
4 
0 
1 
0 
5/300 
0.199 
0.200 
0.110 
9 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
3 
5 
4 
0 
0 
0 
10/300 
0.055 
0.104 
0.003 
10 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
3 
5 
4 
0 
0 
1 
5/300 
0.263 
0.125 
0.119 
11 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
3 
5 
4 
0 
0 
2 
3/300 
0.255 
0.030 
0.110 
12 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:3/300 
Cohort4:5/300 
3 
5 
4 
3 
0 
1 
0 
1 
3/300 
0.222 
0.015 
0.102 
13 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
Cohort4:3/300 
3 
5 
4 
3 
0 
0 
2 
1 
3/300 
0.380 
0.048 
0.144 
14 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
Cohort4:10/300 
3 
5 
4 
6 
0 
0 
0 
1 
10/300 
0.244 
0.086 
0.101 
15 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
Cohort4:10/300 
3 
5 
4 
6 
0 
0 
0 
2 
5/300 
0.081 
0.002 
0.067 
16 
Cohort1:3/100 
Cohort2:3/300 
Cohort3:5/300 
Cohort4:10/300 
Cohort5:5/300 
3 
5 
4 
6 
3 
0 
0 
0 
2 
1 
5/300 
0.163 
0.005 
0.094 
Note that the overdose criterion is defined as P(over) < 0.25.  
*Additional dose levels may be added if allowed by the BLRM. 
Within Table 14-15, it can be seen that the model generally leads to decisions that are in 
agreement with clinical sense. The dose levels investigated correspond to the provisional dose 
levels specified in Section 6.2.2. 
14.3.4 
Operating characteristics for MCS110 + PDR001 combination arm 
A simulation study is used to illustrate the long run performance of the Bayesian dose escalation 
model. Several example scenarios were investigated (Section 14.3.4.1), and in each case 1000 
trials were simulated, with results summarized in Section 14.3.4.3. 


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14.3.4.1 Scenarios 
In order to show how the design performs, 3 hypothetical scenarios were investigated: 
1. For scenario 1, the odds of DLT are aligned with the prior information, i.e. the DLT rates 
for dose combinations are set to the median values derived from the prior. 
2. For scenario 2, the odds of DLT are assumed to be 100% increase from scenario 1 
3. For scenario 3, the odds of DLT are assumed to be 4-folds increase from scenario 1 
To note, under scenario 1, there’s not any dose level have DLT rate falls into target or over-
toxic DLT interval. Therefore, we didn’t explore any scenarios which assume smaller odds of 
DLT than scenario 1. Under scenario 2, there’s only one combination dose level fall into 
target toxicity interval and no over-toxic DLT rate. Under scenario 3, there are three 
combination dose levels fall into target toxicity interval and one over-toxic DLT rate. 
The true probabilities used in the simulation are presented in Table 14-16 for each scenario 
above. 
Table 14-16 
True underlying cumulative probabilities of DLT for different 
scenarios 
MCS110 (mg/kg) 
PDR001 (mg) 
100 
300 
Scenario 1 
 
 
0.3 
0.013 
0.026 
1 
0.018 
0.033 
3 
0.030 
0.052 
5 
0.044 
0.074 
10 
0.082 
0.131 
Scenario 2 
 
 
0.3 
0.026 
0.051 
1 
0.035 
0.064 
3 
0.058 
0.099 
5 
0.084 
0.138 
10 
0.152 
0.232 
Scenario 3 
 
 
0.3 
0.050 
0.096 
1 
0.068 
0.120 
3 
0.110 
0.180 
5 
0.155 
0.242 
10 
0.263 
0.376 
- Grey shaded cells indicate True probability fall within target interval (0.16, 0.33] 
14.3.4.2 Simulation details 
1000 trials were used to simulate each scenario. The starting dose combination was chosen as 
3 mg/kg for MCS110 and 100 mg for PDR001, and the maximal dose to jump to was 
orthogonal, and follows the protocol specifications (Section 10.4.2 of the protocol). The number 
of patients to enroll in each cohort and stopping rules used to declare MTD were defined as: 
• Maximum number of patients treated: 60 


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Protocol No. CMCS110Z2102 
 
 
• Minimum cohort size: 3 
• Minimum number of patients treated at a given dose combination in order to declare 
MTD: 6 
• Posterior probability of targeted toxicity at this combination dose > 50% and is the highest 
among potential doses, or 
• Minimum number of patients treated in the trial: 15 
Metrics 
Operating characteristics were reviewed for the simulations to compare the relative 
performance under each true scenario. The metrics reviewed were: 
1. Average proportion of patients receiving a target dose combination on study (I) 
2. Average proportion of patients receiving a dose combination with true P(DLT) ≥ 33% on 
study (II) 
3. Average proportion of patients receiving a dose combination with true P(DLT) < 16% on 
study (III) 
4. Proportion of trials that were recommended a target dose combination as the MTD (IV) 
5. Proportion of trials that were recommended a dose combinations with true P(DLT) ≥ 33% 
as the MTD (patient risk) (V) 
6. Proportion of trials that were recommended a dose combination with true P(DLT) < 16% 
as the MTD (VI) 
14.3.4.3 Simulation results 
Table 14-17 below summarizes the simulated operating characteristics of the model for the 3 
different scenarios studied, additionally showing the percentage of trials stopped before 
declaring MTD when all dose combinations were considered too toxic. 
Table 14-17 
Results 
Scenario 
Metric 
 
I 
II 
III 
IV 
V 
VI 
Stopped 
1 
0.000 
0.000 
1.000 
0.000 
0.000 
0.998 
0.002 
2 
0.128 
0.000 
0.872 
0.098 
0.000 
0.897 
0.005 
3 
0.455 
0.065 
0.480 
0.603 
0.040 
0.333 
0.024 
The simulated operating characteristics presented show that the combination model performs 
reasonably and well under the hypothetical scenarios investigated. 
Scenario 1: 
Since there’s no dose combination which has median DLT rate in the target or over toxicity 
intervals, no patient receive a target dose or over-toxic dose combination (metric I and II) on 
study, and no trial was recommended with a target dose or over-toxic dose as MTD (metric IV 
and V). Under this scenario, since both study drugs demonstrate good safety profile with low 
DLT rate (<16%), it may be expected to identify a RP2D before identifying the MTD. 


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Protocol No. CMCS110Z2102 
 
 
Scenario 2: 
The proportion of patients receiving target dose is low (12.8%) as is the proportion of trial with 
target dose as recommended dose (9.8%). This is because only the highest combination dose 
(MCS110=10 mg/kg and PDR001=300 mg) falls into the target toxicity interval [16%, 33%). 
Further investigation reveals that there are additionally 54.4% of trials with MTD dose 
identified at just one dose level below the target dose (MCS110=5 mg/kg, PDR001=300 mg or 
MCS110=10 mg/kg, PDR001=100 mg). Of note, the probability of DLT for these dose 
combinations lies just below the lower limit of the target interval. 
Scenario 3: 
The proportion of patients receiving target dose is 45.5% and proportion of trial with target dose 
as recommended dose 60.3%. Further investigation reveals that there are additionally 22.8% of 
trials with MTD dose identified at just one dose level below the target dose (MCS110=5 mg/kg, 
PDR001=100 mg or MCS110=1 mg/kg, PDR001=300 mg). The proportion of patients 
receiving a dose combination with true P(DLT) ≥ 33% or trials that were recommended a dose 
combinations with true P(DLT) ≥ 33% as the MTD (patient risk) is very low (metric II: 6.5% 
and metric V: 4%) 
In all scenarios, the percentages of trials that were stopped when all dose combinations were 
considered too toxic are low (< 3%) in all scenarios. 
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics. 
14.3.5 
References (available upon request) 
Akaike, H.: A new look at the Statistical Model Identification. IRRR. Transactions on 
Automatic Control, AC-19 716-723, 1974 
Dempster P; Laird N. M; Rubin D.B. Maximum likelihood from incomplete data via the EM 
algorithm. Journal of the Royal Statistical Society. Series B (Methodological), Vol. 39, No. 1. 
(1977), pp.1-38. 
Neuenschwander B, Capkun-Niggli G, Branson M, and Spiegelhalter DJ. Summarizing 
Historical Information on Controls in Clinical Trials. Clinical Trials 2010; 7:5-18. 
Neuenschwander B, Matano A, Tang Z, Roychoudhury S, Wandel S and Bailey S. A 
Bayesian Industry Approach to Phase I Combination Trials in Oncology. In Statistical 
Methods in Drug Combination Studies. Zhao W and Yang H (eds), Chapman & Hall/CRC, 
2014. 
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian Approaches to Clinical Trials and Health-
Care Evaluation. John Wiley & Sons, New York, 2004. 

SAP_001.pdf: 
Clinical Development
MCS110
CMCS110Z2102 / NCT02807844
A Phase Ib/II, open label, multicenter study of MCS110 in 
combination with PDR001 in patients with advanced 
malignancies
Statistical Analysis Plan (SAP)
Author:
, Trial Statistician
Document type:
SAP Documentation
Document status:
Final version 2.0
Release date:
29-JUN-2020
Number of pages:
39
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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CMCS110Z2102
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title impacted (Current)
24-
May-
2016
Prior 
to 
FPFV
Creation of 
final version
N/A – First version
NA
29-
JUN-
2020
Prior 
to 
DBL
Final for 
approval
Amendment 1
Section 1.1 Study design
Section 1.2 Study objectives and endpoints
Section 2.1 Data analysis general 
information
Section 2.1.1 General definitions
Section 2.2 Analysis sets / Withdrawal of 
ICF / Subgroups
Section 2.4.1 Study treatment/compliance
Section 2.5.1 Primary endpoints
Section 2.5.2 Statistical hypothesis, model, 
and method of analysis
Section 2.5.4 Supportive analyses
Section 2.7.1 Secondary endpoints
Section 2.8 Safety analyses
Section 2.8.3 Laboratory data
Section 3 Sample size calculation
Section 5.5 Rule of exclusion criteria of 
analysis sets


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CMCS110Z2102
Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................7
1.1
Study design.............................................................................................................7
1.2
Study objectives and endpoints ...............................................................................8
2
Statistical methods.............................................................................................................10
2.1
Data analysis general information .........................................................................10
2.1.1
General definitions................................................................................11
2.2
Analysis sets/Withdrawal of ICF/Subgroups.........................................................13
2.2.1
Full Analysis Set ...................................................................................13
2.2.2
Safety Set ..............................................................................................13
2.2.3
Dose-determining Set............................................................................13
2.2.4
Pharmacokinetic Analysis Set...............................................................14
2.2.5
Withdrawal of Informed Consent..........................................................14
2.2.6
Subgroup of interest ..............................................................................14
2.3
Patient disposition, demographics and other baseline characteristics ...................14
2.3.1
Patient disposition.................................................................................14
2.3.2
Demographics .......................................................................................15
2.3.3
Other baseline characteristics................................................................15
2.4
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance)............................................................................................................16
2.4.1
Study treatment/compliance..................................................................16
2.4.2
Concomitant therapies...........................................................................18
2.4.3
Anti-neoplastic therapies since discontinuation....................................18
2.5
Analysis of the primary objective..........................................................................18
2.5.1
Primary endpoint...................................................................................19
2.5.2
Statistical hypothesis, model, and method of analysis..........................19
2.5.3
Handling of missing values/censoring/discontinuations.......................23
2.5.4
Supportive analyses...............................................................................23
2.6
Analysis of the key secondary objective ...............................................................23
2.7
Analysis of secondary efficacy objective(s)..........................................................23
2.7.1
Secondary endpoints .............................................................................23
2.7.2
Statistical hypothesis, model, and method of analysis..........................23
2.7.3
Handling of missing values/censoring/discontinuations.......................24
2.8
Safety analyses.......................................................................................................24
2.8.1
Adverse events (AEs)............................................................................25


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2.8.2
Deaths....................................................................................................26
2.8.3
Laboratory data .....................................................................................26
2.8.4
Other safety data ...................................................................................27
2.9
Pharmacokinetics Analyses ...................................................................................29
2.9.1
Data handling principles .......................................................................30
2.9.2
Immunogenicity ....................................................................................30
2.10
Patient-reported outcomes .....................................................................................30
30
30
30
31
32
33
2.13
Interim analysis......................................................................................................33
3
Sample size calculation .....................................................................................................33
4
Change to protocol specified analyses ..............................................................................35
5
Appendix ...........................................................................................................................37
5.1
Imputation rules.....................................................................................................37
5.1.1
Study drug.............................................................................................37
5.1.2
AE date imputation ...............................................................................37
5.1.3
Concomitant medication date imputation .............................................38
5.1.4
Prior therapies date imputation .............................................................38
5.1.5
Post therapies date imputation ..............................................................38
5.1.6
Other imputations..................................................................................39
5.2
Laboratory parameters derivations ........................................................................39
5.3
Rule of exclusion criteria of analysis sets..............................................................40
6
Reference...........................................................................................................................40


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List of abbreviations
AE
Adverse event
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
AR
Accumulation Ratio
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
BLRM
Bayesian Logistic Regression Model
CBR
Clinical Benefit Rate
CK
Creatine Kinase
CL
Clearance
Cmax
maximum drug concentration
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or 
Paper
CSP
Clinical Study Protocol
CSR
Clinical Study report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DAR
Dose Administration Record
DCR
Disease Control Rate
DDS
Dose-determining Set
DI
Dosing Intensity
DLT
Dose Limiting Toxicity
DOR
Duration of Response
DRL
Drug Reference Listing
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EWOC
Escalation With Overdose Control
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
irRC
Immune-related Response Criteria
IB
Investigator’s Brochure
MedDRA
Medical Dictionary for Drug Regulatory Affairs
MSI
Microsatellite Instability
MTD
Maximum Tolerated Dose
NCI
National Cancer Institute
ORR
Overall Response Rate
OS
Overall Survival
PAS
Pharmacokinetic Analysis Set
PD
Pharmacodynamic
PDI
Planned Dose Intensity
PDS
Programming Datasets Specifications


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CMCS110Z2102
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PR
Partial Response
Q2W, Q3W, 
Q4W
Respectively, every two, three, four weeks
RAP
Report and Analysis Process
RDI
Relative Dose Intensity
RECIST
Response Evaluation Criteria in Solid Tumors 
RP2D
Recommended Phase two Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFL
Tables, Figures, Listings
TNBC
Triple Negative Breast Cancer
WHO
World Health Organization


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CMCS110Z2102
1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CMCS110Z2102 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 Table 
Figure Listing (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, IB updates, abstracts, posters, 
presentations, manuscripts and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance.
RAP documents, including SAP and TFL shells, were created based on final protocol version 05
released on 23 July, 2019.
1.1
Study design
This study is a phase Ib/II, multi-center, open-label study starting with a phase Ib dose 
escalation part followed by a phase II part. MCS110 and PDR001 will be administered i.v. 
every three weeks (Q3W) until the 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. The study design is summarized in Figure 1-1.
Figure 1-1
Study design


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CMCS110Z2102
Phase Ib part
During the phase Ib part of the study, cohorts of patients will be treated with increasing doses 
of MCS110 and PDR001 every three weeks until a RP2D is determined for this treatment 
combination.
It is expected that an RP2D will be established before the MTD is reached. The RP2D for the 
combination will not exceed the RP2Ds for the single agent administration of MCS110 and 
PDR001. To assure that the combination RP2D does not exceed the MTD, combination 
MCS110 and PDR001 dose escalation will also be guided by an adaptive Bayesian logistic 
regression model (BLRM) following the escalation with overdose control (EWOC) principle. 
At least 15 patients are required during dose escalation to define the MTD; however, fewer than 
15 patients may be treated if the RP2D is determined without reaching the MTD (for further 
details see [CMCS110Z2102-CSP-Section 6.2.3]).
Phase II part
Once the MTD and/or RP2D have been declared, additional patients will be enrolled in the 
Phase II part in order to assess the preliminary anti-tumor activity of MCS110 in combination 
with PDR001.
In the phase II part, patients will be assigned to different groups depending on the tumor type 
as shown in Figure 1-1. Please refer to [CMCS110Z2102-CSP-Section 5.1] for further details.
All groups will enroll approximately 20 patients each. Enrollment to any of these groups may 
be stopped at fewer patients if achieving these enrollment targets is not logistically feasible. For 
groups 1 and 3, the sample size may be extended to approximately 40 patients, if at least 
3 patients out of the first 20 treated in that group have an objective response (CR or PR) per 
RECIST v1.1 or irRC. Twenty patients will be enrolled into Group 2 at RP2D. Enrollment may 
be expanded up to approximately 40 patients if clinical benefit per RECIST v1.1 or irRC (CR, 
PR or SD > 4 months) is observed in at least 3 pts. In addition, an exploratory group of 20 
patients at a lower dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be 
opened if the above mentioned gating criteria is met. Group 4 may similarly be expanded if at 
least 2 patients out of the first 20 treated in that group have an objective response. A Bayesian 
design will be used in order to estimate ORR within each expansion group. Details of the sample 
size calculations leading to the patient numbers are provided in [CMCS110Z2102-CSP-Section 
10.8].
The primary CSR will be based on all patients’ data from the phase Ib and phase II parts, up to 
the time when all patients have completed at least six cycles of treatment or discontinued 
treatment. Patients who are on study beyond cycle 6 may remain on treatment until they 
discontinue the study. Any additional data (after the data cut-off date for the primary CSR) will 
be further summarized in a final CSR at completion of the study, as defined in 
[CMCS110Z2102-CSP-Section 4.3].
1.2
Study objectives and endpoints
Objectives and related endpoints are described in Table 1-1 below.


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Table 1-1
Objectives and related endpoint
Objective
Endpoint
Analysis
Primary
Phase Ib part:
To characterize the safety and 
tolerability of MCS110 given in 
combination with PDR001 and 
to identify a recommended dose 
combination for Phase II.
Frequency, severity and seriousness of AEs, 
laboratory 
abnormalities 
and 
other 
safety 
parameters.
Dose interruptions, reductions, and dose intensity.
Incidence rate of dose limiting toxicities (DLTs)
during the first two cycles of study treatment.
Refer 
to 
Section 2.8
Refer 
to 
Section 
2.5.2.1
Phase II part:
To estimate the anti-tumor 
activity of the combination of 
MCS110 with PDR001
-Overall response rate (ORR) per Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1) 
(groups 1, 3 and 4). 
-Clinical 
benefit 
rate 
(CBR) 
per 
Response 
Evaluation Criteria in Solid Tumors (RECIST v1.1), 
which is defined as confirmed objective response or 
SD > 4 months. (Group 2)
Refer 
to 
Section 
2.5.2.2
Secondary
Phase Ib part:
To estimate the preliminary 
anti-tumor 
activity 
of 
the 
combination of MCS110 with 
PDR001
ORR, progression free survival (PFS), clinical 
benefit rate (CBR), duration of response (DOR) and 
disease control rate (DCR) per RECIST v1.1 and 
per immune related Response Criteria (irRC)
Refer 
to 
Section 2.7
Phase II part:
To further characterize the 
safety 
and 
tolerability 
of 
MCS110given in combination 
with PDR001
Frequency, severity and seriousness of AEs, 
laboratory 
abnormalities 
and 
other 
safety 
parameters.
Refer 
to 
Section 2.8
Phase II part:
To evaluate the preliminary 
anti-tumor 
activity 
of 
the 
combination of MCS110 with 
PDR001 by additional efficacy 
measures
ORR per irRC, PFS, DOR, DCR, CBR per RECIST 
v1.1 and per irRC (Group 1, 3 and 4)
CBR per irRC, PFS, DOR, DCR, ORR per RECIST 
v1.1 and per irRC (Group 2)
Refer 
to 
Section 2.7
Phase Ib and Phase II parts: 
To 
characterize 
the 
pharmacokinetics of MCS110 
and PDR001 in combination 
Serum concentration of MCS110 and PDR001 and 
PK parameters
Refer 
to 
Section 2.9
To assess immunogenicity of 
MCS110 and PDR001
Presence and/or concentration of anti-PDR001 or 
anti-MCS110 antibodies
Refer 
to 
Section 2.9


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CMCS110Z2102
Objective
Endpoint
Analysis
To 
describe 
survival 
with 
MCS110 
and 
PDR001 
in 
combination
Overall survival (OS)
Refer 
to 
Section 2.7
2
Statistical methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS 
version 9.4, for Bayesian logistic regression model (BLRM) modeling, R version 3.0.2  and 
JAGS version 3.12 will be applied and for other bayesian analyses, R version 3.4.3 will be used.
PK parameters will be calculated using non-compartmental methods available in Pharsight 


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CMCS110Z2102
Phoenix version 6.4 (or newer compatible version). Newer compatible version may be used for 
all programs. Any data analysis carried out independently by the investigator must be submitted 
to Novartis before publication or presentation.
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. The data will be summarized with 
respect to demographic and baseline characteristics, efficacy observations and measurements, 
safety observations and measurements, and all relevant PK and PD measurements using 
descriptive statistics (quantitative data) and contingency tables (qualitative data).
The study data will be analyzed and reported based on all patients’ data of the Phase Ib and 
Phase II parts up to the time when all patients have potentially completed at least six cycles of 
treatment or discontinued the study. Phase Ib data and Phase II data will be reported separately. 
Any additional data for patients continuing to receive study treatment past the data cutoff date 
for the primary CSR, as allowed by the protocol, will be reported at completion of the study as 
defined in [CMCS110Z2102-CSP-Section 4.3].
The following rules will be followed for reporting results unless stated otherwise:

Phase Ib dose escalation data: cohorts treated during the dose escalation with the same 
dose levels of MCS110 and PDR001 will be pooled into a single treatment group. All 
summaries, listings, figures and analyses will be performed by treatment group and “All 
Phase Ib Subjects”.

Phase II data: All summaries, listings, figures for non-safety analysis will be reported by 
arm. Safety analysis of phase II will be reported by arm and “All Phase II Subjects”
Column. The arms to which they were assigned at baseline based on disease types consist 
of the following:

Group 1: TNBC (naive to PD-1/PD-L1 directed therapy)

Group 2: Pancreatic cancer (naive to PD-1/PD-L1 directed therapy)

Group 3: Endometrial cancer (naive to PD-1/PD-L1 directed therapy)

Group 4: Melanoma (resistant to PD-1/PD-L1 directed therapy)
Categorical data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, minimum, and maximum will be presented.
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 (see [CMCS110Z2102-
CSP-Section 7.1.1.1]) 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
Study drug refers to the individual compound i.e., MCS110, or PDR001. The study treatment 
is defined as MCS110 in combination with PDR001, or single agent MCS110 or PDR001 if 
one of the study drugs needs to be discontinued.


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Date of first/last administration of study drug and study treatment
The date of first (last) administration of study drug is derived as the first (last) date when a non-
zero dose of study drug was administered and recorded on the Dosage Administration Record 
(DAR) eCRF. 
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. Dates of first/last administration of study 
treatment are defined as:

Date of first administration of study treatment = min (first date of MCS110 
administration, first date of PDR001 administration)

Date of last administration of study treatment = max (last date of MCS110 
administration, last date of PDR001 administration)
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1
Therefore, the first day of study treatment is study day 1.
For all assessment/events occurring prior to the start of the study treatment, study day will be 
negative and will be calculated as:
Study day (days) = Event date – Start date of study treatment
Study day will be displayed in the data listings.
Baseline
Baseline is the last available and valid assessment performed or value measured within 21 days
(28 days for baseline radiological evaluations) before the first administration of study treatment, 
unless otherwise stated under the related assessment section. Baseline can be the day before 
first treatment administration or the same day as first treatment administration if a pre-dose 
assessment/value is available (e.g., ECG, PK samples, 
).
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.


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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, 
 and other endpoints are described in each specific 
section.
On-treatment assessment/event
An on-treatment assessment/event is defined as any assessment/event obtained in the time 
interval from the start date of study treatment until the last date of study treatment (i.e., 
including combination partner) + 30 days inclusive.
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 efficacy assessments would be excluded from all relevant efficacy 
summary.
2.2
Analysis sets/Withdrawal of ICF/Subgroups
2.2.1
Full Analysis Set
The full analysis set (FAS) comprises all patients who received at least one dose of MCS110 or 
PDR001. Patients will be analyzed according to the planned treatment combination. Unless 
otherwise specified, FAS is the default set used for all analyses.
2.2.2
Safety Set
The safety set (SS) includes all patients who have received at least one dose of MCS110 or 
PDR001. Patients will be classified according to treatment received, where treatment received 
is defined as:
1. The treatment assigned if it was received at least once, or
2. The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received.
The safety set will be used for the safety summary of the study.
2.2.3
Dose-determining Set
The dose-determining set (DDS) consists of all patients from the safety set in the phase Ib dose 
escalation part who either meet the following minimum exposure criterion and have sufficient 
safety evaluations, or have experienced a DLT during the first two cycles.
A patient is considered to have met the minimum exposure criterion if he/she received two 
doses of MCS110 and PDR001 during the first two cycles.


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Patients who do not experience a DLT during the first two cycles are considered to have 
sufficient safety evaluations if they have been observed for ≥ 42 days following the first dose, 
and are considered by both the Sponsor and Investigators to have enough safety data to conclude 
that a DLT did not occur.
Patients who do not meet these minimum safety evaluation requirements nor experience a DLT 
will be regarded as ineligible for the DDS and an additional patient may be recruited 
(see [CMCS110Z2102-CSP-Section 7.1.3.1]).
2.2.4
Pharmacokinetic Analysis Set
The pharmacokinetic analysis set (PAS) includes all patients who provide an evaluable 
PK profile. A profile is considered evaluable if all of the following conditions are satisfied:

Patient receives one of the planned treatments

Patient provides at least one primary PK parameter
Patients will be classified according to planned treatment group.
The PAS will be used for summaries of PK concentration data, PK parameters 
 
2.2.5
Withdrawal of Informed Consent
Any data collected in the clinical database before informed consent is obtained and after a 
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. 
2.2.6
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 FAS will be used for the patient disposition summary tables and listings. The following
will be tabulated:

Number (%) of patients who are still on-treatment (based on non-completion of the ‘End 
of Treatment’ page),

Number (%) of patients who discontinued treatment (based on completion of the ‘End of 
Treatment’ page with discontinuation date entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason
entered in the ‘End of Treatment’ page),


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
Number (%) of patients who discontinued from post-treatment follow-up (based on 
completion of the ‘End of Post Treatment Phase Disposition’ page with discontinuation
date entered),

Primary reasons for post-treatment follow-up discontinuation (based on discontinuation 
reason entered in the ‘End of Post Treatment Phase Disposition’ page).
Protocol Deviation
Major protocol deviations leading to exclusion from analysis sets will be tabulated separately 
by treatment group for phase Ib and by patient group for phase II part. All protocol deviations
will be listed. The full list of protocol deviations are documented in the Study Specification 
Document (SSD). Protocol deviations leading to exclusion from analysis sets and associated 
severity codes are specified in Section 5.3.
2.3.2
Demographics
Demographic data including age, sex, predominant race, ethnicity, baseline weight and 
WHO/ECOG performance status will be listed and summarized. 
In addition, child bearing potential, pregnancy test results will be listed, and age (18-< 65, 65-
< 85, ≥85 years) categories summarized. 
2.3.3
Other baseline characteristics
Medical history
Medical history and current (ongoing) medical conditions, including cancer-related conditions
and symptoms, will be listed. Medical history and current medical conditions are coded using 
the latest Medical Dictionary for Regulatory Activities (MedDRA v23.0) terminology available 
at the time of reporting.
Prior anti-neoplastic therapies
Prior anti-neoplastic therapies will be listed for medication, radiotherapy and surgery.
The number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized, separately.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting at last medication, and time 
(in days) from start of last medication to progression. 
The last medication is defined based on the last end date of all prior regimen components. 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 patient) 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 (non-
biopsy procedure) and residual disease at last surgery.


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Consider specific imputation rules for patial dates in Section 5.1.4.
Diagnosis and extent of cancer
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, histological grade, stage at initial diagnosis, time (in months) from initial 
diagnosis of primary site to start of study treatment, time (in months) since most recent 
recurrence/relapse or progression to start of study treatment, time (in months) from initial 
diagnosis of primary site to first recurrence/relapse or progression, current stage of cancer, 
current extent of disease (metastatic sites).
2.4
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance)
The Safety Set will be used for all medication data summaries and listings.
2.4.1
Study treatment/compliance
Study treatment
MCS110 in combination with PDR001 (Q3W):

Last date of exposure to study drug (MCS110) = last date of administration of 
MCS110 + 20 days

Last date of exposure to study drug (PDR001) = last date of administration of PDR001 
+ 20 days

Last date of exposure to study treatment (MCS110 + PDR001) = max (last date of 
MCS110 administration, last date of PDR001 administration) + 20 days = Date of last 
administrion of study treatment + 20 days
Planned treatment: Planned treatment is the treatment to which a patient is assigned during 
enrollment.
Received treatment: Please refer to Section 2.2.2.
Planned dose: Planned dose is the dose level(s) of study drug(s) corresponding to the planned 
treatment.
Prescribed dose: Prescribed dose is the dose level(s) of study drug(s) prescribed by doctor 
before study treatment is administered at beginning of each cycle.
Dose administered (mg/kg) for MCS110 = Dose prescribed (mg/kg) * Total volume 
administered (mL)/Total volume planned to be administered (mL);
Dose administered (mg) for PDR001 = Dose prescribed (mg) * Total volume administered 
(mL)/Total volume planned to be administered (mL);
Definitions of duration of exposure, cumulative dose, actual dose intensity (DI), planned dose 
intensity (PDI), relative dose intensity (RDI), as well as intermediate calculations, are as follows: 

Duration of exposure (days) to study drug: last date of exposure to study drug − first 
date of study drug + 1 (periods of interruption are not excluded);


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
Duration of exposure (days) to study treatment: last date of exposure to study 
treatment − first date of study treatment + 1 (periods of interruption are not excluded);

Duration of exposure (weeks) = Duration of exposure (days)/7;

Cumulative dose: sum of all dose administered (mg/kg) to a patient for MCS110; sum of 
all dose administered (mg) to a patients for PDR001;

Cumulative planned dose: sum of all planned dose (mg/kg) of MCS110 that were
intended to have been taken during the treatment period by a patient; sum of all planned 
dose (mg) of PDR001 that were intended to have been taken during the treatment period 
by a patient;

Number of doses scheduled per protocol : number of doses given to a patient if each 
actual cycle length is exactly 21 days and study treatment is given on day 1 of each cycle, 
which is calculated as: [Duration of exposure to study drug (days)/ 21 (days)] + 
1*I{ Duration of exposure to study drug (days) mod 21 (days) ≠ 0}. [x] is the largest 
integer less than or equal to x. b = mod(a, m) returns the remainder after division of a by 
m , where a is the dividend and m is the divisor. I{∙} is a indicator function. This will be 
calculated for MCS110 and PDR001 separately and used for calculation of dose intensity 
below.

DI:

For MCS110 (mg/kg/3wks): cumulative dose (mg/kg)/ number of doses scheduled per 
protocol during treatment period;

For PDR001 (mg/3wks): cumulative dose (mg)/ number of doses scheduled per 
protocol during treatment period;

PDI:

For MCS110 (mg/kg/3wks): cumulative planned dose (mg/kg)/ number of doses 
scheduled per protocol during treatment period (i.e., this is equivalent to planned dose 
level);

For PDR001 (mg/3wks): planned cumulative dose (mg)/ number of doses scheduled 
per protocol during treatment period (i.e., this is equivalent to planned dose level);

RDI (%):

For MCS110: 100 × DI (mg/kg/3wks)/PDI (mg/kg/3wks)

For PDR001: 100 × DI (mg/3wks)/PDI (mg/3wks)
Note: If a patient is still on treatment at the time of data cut-off, the end date of study 
treatment/drug will be replaced by the data cut-off date and the above respective 
algorithm will be used.
Dose interruption: Actual dose equal to zero, between the first and last non-zero doses, 
following a non-zero actual dose.
Dose reduction: A non-zero actual dose that is less than the immediate previous non-zero actual
dose (if not the first dose) and below the treatment received dose.
Note: actual dose for MCS110 (mg/kg) = Dose prescribed (mg/kg) * Total volume 
administered (ml)/Total volume planned to be administered (ml); actual dose for PDR001
(mg) = Dose prescribed (mg) * Total volume administered(ml)/Total volume planned to 
be administered(ml).


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The duration of exposure to each of the two study drugs and study treatment (including 
categories: ≤3, 3-≤6, 6-≤9, 9-≤12, 12-≤15, 15-≤18, > 18 weeks) will be summarized. In 
addition, the cumulative dose, DI, and RDI (including categories: < 0.5, 0.5-< 0.75, 0.75-< 0.9, 
0.9-< 1.1, ≥1.1) will be summarized for each study drug. 
To assess tolerability, the number (%) of patients who have dose reductions and interruptions , 
and the corresponding reasons, will be provided for each study drug. The number of dose 
reductions and interruptions per patient will be summarized for each study drug.
All doses of the study treatment along with reasons for any dose change will be listed.
Compliance
Compliance to study drug will be evaluated by dose reduction and dose interruption. 
2.4.2
Concomitant therapies
Concomitant therapies are defined as any medications (excluding study treatment and
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.
Any concomitant therapies starting prior to or after the start of study treatment will be listed.
Concomitant and significant non-drug therapies will be summarized by ATC class and preferred 
term to include medications or therapies starting on or after the start of study treatment but 
starting no later than 30 days after last dose of study treatment.
All medications or therapies starting prior to the first dose of study treatment and continuing 
after the start of study treatment will be listed.
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.
2.4.3
Anti-neoplastic therapies since discontinuation
Any anti-neoplastic therapies since discontinuation of study treatment will be listed.
2.5
Analysis of the primary objective
Phase Ib
The primary objective of the Phase Ib part is to characterize the safety and tolerability of 
MCS110 given in combination with PDR001 and to identify a recommended dose for Phase II.
Phase II
The primary objective of the Phase II part of this study is to estimate the anti-tumor activity of 
the combination of MCS110 with PDR001 in each expansion group.


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2.5.1
Primary endpoint
2.5.1.1
Phase Ib part
The primary variables of Phase Ib are:

Safety: Incidence and severity of AEs and SAEs, including changes in laboratory values, 
vital signs, and ECGs;

Tolerability: Dose interruptions, reductions, and dose intensity;

Incidence of DLTs in the first two cycles of study treatment.
2.5.1.2
Phase II part
For TNBC, endometrial carcinoma and melanoma the primary variable of Phase II is the Overall 
Response Rate (ORR), defined as the proportion of patients with a best overall response of 
complete response (CR) or partial response (PR) based on local Investigator assessment, as 
defined in RECIST v1.1. Estimation of the true ORR in this part of the study will be based upon 
the observed BOR for patients in the FAS, using a Bayesian analysis.
For pancreatic patients, the primary variable of Phase II is the Clinical Benefit Rate (CBR), 
defined as the proportion of patients with a best overall response of complete response (CR) or 
partial response (PR) (with at least two assessments 4 weeks apart) or stable disease 
(SD) > 4 months based on local Investigator assessment, as defined in RECIST v1.1. Estimation 
of the true CBR in this part of the study will be based upon the observed BOR for patients in 
the FAS, using a Bayesian analysis.
2.5.2
Statistical hypothesis, model, and method of analysis
2.5.2.1
Phase Ib part
2.5.2.1.1 Identification of a recommended dose
The dose escalation part of this study will be guided by a Bayesian analysis of first two cycles 
dose limiting toxicity (DLT) data for MCS110 and PDR001 in combination based on dose-
determing set (DDS). If the two doses in first 2 cycles differs for one patient, the lower dose 
will be considered as the dose level from conservative aspect. The Bayesian analysis will be 
based on a model with three parts, representing:

Single agent MCS110:
logit(π1(d1)) = log(α1) + β1log(d1/d1*); d1* = 5 mg/kg Q3W

Single agent PDR001:
logit(π2(d2)) = log(α2) + β2log(d2/d2*); d2* = 300 mg Q3W

Interaction: Odds(π12(d1,d2))) = π12(d1,d2)/(1- π12(d1,d2))
= exp(η(d1/d1*)(d2/d2*))(π1(d1) + π2(d2) – π1(d1) π2(d2))/((1- π1(d1))(1- π2(d2))),
where logit(π.(d.)) = log[π.(d.)/{1- π.(d.)}], d1* = 5 mg/kg and d2*= 300 mg are the reference 
doses of MCS110 and PDR001 respectively, α1, α2, β1, β2 > 0 and -∞ < η < ∞.
Single agent toxicity is modelled using logistic regression for the probability of a patient 
experiencing a DLT against log-dose. The odds of a DLT are then calculated under no 
interaction for the two single agent toxicities, and interaction is accounted for by adjusting these 


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odds with an additional model parameter (odds multiplier). Details of the model are given in 
[CMCS110Z2102-CSP-Section 14.4].
Assessment of patient risk
After each cohort of patients, the posterior distribution for the risk of DLT for new patients at 
combination doses of interest will be evaluated. The posterior distributions will be summarized 
to provide the posterior probability that the risk of DLT lies within the following intervals:
Under-dosing:
[0 , 0.16)
Targeted toxicity:
[0.16 , 0.33)
Excessive toxicity:
[0.33 , 1]
The escalation with overdose control (EWOC) principle
Dosing decisions are guided by the escalation with overdose control principle (Rogatko 2007). 
A combination dose may only be used for newly enrolled patients if the risk of excessive 
toxicity at that combination dose is less than 25%.
Prior distributions
For each single agent model, a mixture prior was derived. For MCS110, this study uses a 
mixture prior consisting of two components. Component 1 is the distribution derived based on 
dose-DLT data. The assigned weight for component 1 is 80%. Component 2 allows for a higher 
toxicity case. The assigned weight for component 2 is 20%. For PDR001, this study uses a 
mixture prior consisting of three components. Component 1and 2 are derived based on dose-
DLT data. The assigned total weight for component 1 and 2 is 80%. Component 3 allows for a 
higher toxicity case. The assigned weight for component 3 is 20%.
A meta-analytic-predictive (MAP) approach was used to derive component 1 of the prior 
distribution for the single agent MCS110 model parameters, and component 1 and 2 of the prior 
distribution for the single agent PDR001 model parameters. The MAP prior for the logistic 
model parameters for this study is the conditional distribution of the parameters given the 
historical data (see Spiegelhalter 2004, Neuenschwander 2010, Neuenschwander 2014). MAP 
priors are derived from hierarchical models, which take into account possible differences 
between the studies.
For this study, available clinical data were taken from the following clinical studies:
For MCS110: [CMCS110A2101] first-in-human MCS110 study. This study is completed. 
[CMCS110X2201] a Phase II study in PVNS patients. This study is ongoing.
For PDR001: [CPDR001X2101] first-in-human PDR001 oncology study. This study is ongoing.
For each of the single agent prior, an additional high toxic component is introduced to allow for 
a higher toxicity case. A full description of the application of the MAP approach to derive the 
prior distributions of the single agent MCS110 and PDR001 model parameters is given in 
[CMCS110Z2102-CSP-Section 14.4].


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The prior distribution for the interaction parameter was based upon prior understanding of 
possible drug safety interactions (see [CMCS110Z2102-CSP-Section 1.3.3]). This prior allows 
for the possibility of either synergistic or antagonistic interaction, and is fully described in 
[CMCS110Z2102-CSP-Section 14.4].
Listing of DLTs
DLTs will be listed, and their incidence summarized by primary system organ class and 
preferred term and worst grade (CTCAE version 4.03). Listings and summaries will be based 
on the DDS.
2.5.2.1.2 Safety and tolerability analyses
See Section 2.8 for details of analysis.
2.5.2.2
Phase II part
A Bayesian design will be used in order to estimate ORR (Group 1, 3 and 4) or CBR (Group 2) 
for each of the following groups in the Phase II part of the study. 

Group 1: MCS110 + PDR001, TNBC (naïve to PD-1/PD-L1 directed therapy)

Group 2: MCS110 + PDR001, Pancreatic adenocarcinoma (naïve to PD-1/PD-L1 directed 
therapy) 

Group 3: MCS110 + PDR001, Endometrial carcinoma (naïve to PD-1/PD-L1 directed 
therapy)

Group 4: MCS110 + PDR001, Melanoma (progressed on previous PD-1/PD-L1 therapy)
Each group will enroll approximately 20 patients, and may be extended to 40 patients (if at least 
3 patients have an objective response for group 1, 2 and 3;and if at least 2 patients have an 
objective response for group 4). In addition, an exploratory group of 20 patients ar as lower 
dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be opened if at least 3 
patients have an objective response for group 2. See timing of the decision-making in
[CMCS110Z2102-CSP-Section 4.2]. The primary analysis will be performed when all patients 
have completed at least 6 cycles of treatment or discontinued prior to that time for any reason.
Group 1, 3: Minimally informative unimodal Beta prior distribution are defined such that the 
prior mean ORR is set to be equal to 30% and the parameters of the minimally informative Beta 
prior distribution of ORR have been set up as following:

a/(a + b) = 0.3

a = 0.43

b = 1.
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. Once updated, the estimate ORR and probability of ORR lies in the 
following categories will be reported:

[0%, 15%] unacceptable efficacy

[15%, 30%] moderate efficacy

[30%, 100%] clinically relevant efficacy


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If the observed ORR is equal to or greater than 30% (i.e. ≥ 12 responses (CR or PR) of out 
40 patients) then this will be considered as preliminary evidence of antitumor activity of 
MCS110 + PDR001 in the respective patient group naive to PD-1/PD-L1 directed therapy.
Group 2: Minimally informative unimodal Beta prior distribution is defined such that the prior 
mean CBR is conservatively set to be equal to 15% and the parameters of the minimally 
informative Beta prior distribution of CBR have been set up as following:

a/(a + b) = 0.15

a = 0.18

b = 1.
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. If the lower MCS110 dose level is explored (Group 2b), a separate model 
with the same prior assumption will be used to estimate CBR.
Once updated, the estimate CBR and probability of CBR lies in the following categories will 
be reported:

[0%, 7.5%] unacceptable efficacy

[7.5%, 15%] moderate efficacy

[15%, 100%] clinically relevant efficacy.
Observed CBR will be analyzed by dose level. If the observed CBR is equal to or greater than 
15% (i.e. ≥ 6 responses (CR, or PR, or SD for at least 4 months) out of 40 patients at RP2D; or 
≥ 3 responses (CR, or PR, or SD for at least 4 months) out of 20 patients at lower dose group 
(Group 2b) then this will be considered as preliminary evidence of antitumor activity of 
MCS110 + PDR001 in the pancreatic patient group naive to PD-1/PD-L1 directed therapy.
Note that, for a sample size of n = 40, if the observed CBR is 15% then the posterior probability 
of true CBR greater than 7.5% is 93.5%; for a sample size of n = 20, if the observed CBR is 
15% then the posterior probability of true CBR greater than 7.5% is 84.3%.
Group 4
Minimally informative unimodal Beta prior distribution are defined such that the prior mean 
ORR is conservatively set to be equal to 15% and the parameters of the minimally informative 
Beta prior distribution of ORR have been set up as following:

a/(a + b) = 0.15

a = 0.18

b = 1.
At primary analysis, this prior distribution will be updated with all the data available from the 
patients in the FAS. Once updated, the estimate ORR and probability of ORR lies in the 
following categories will be reported:

[0%, 7.5%] unacceptable efficacy

[7.5%, 15%] moderate efficacy

[15%, 100%] clinically relevant efficacy.


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If the observed ORR is equal to or greater than 15% (i.e. ≥ 6 responses (CR or PR) of out 
40 patients) then this will be considered as preliminary evidence of antitumor activity of 
MCS110 + PDR001 in the respective patient group resistant to PD-1/PD-L1 directed therapy.
2.5.3
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 according to RECIST v1.1.
If any alternative cancer therapy is taken while on study any subsequent efficacy assessments 
would be excluded from all relevant efficacy summary.
Continuing events (e.g., AEs, concomitant medication, etc.) will be summarized using the data 
cut-off date as the date of completion, with a flag to indicate within listings that the event is 
continuing. For patients who discontinue the study with ongoing events, the discontinuation 
date will be used as the completion date of the event.
The reason for discontinuation from study will be summarized and listed.
Other missing data will simply be noted as missing on appropriate tables/listings.
2.5.4
Supportive analyses
Not applicable.
2.6
Analysis of the key secondary objective
Not applicable.
2.7
Analysis of secondary efficacy objective(s)
2.7.1
Secondary endpoints
2.7.1.1
Phase Ib part
Overall response rate (ORR), Progressive Free Survival (PFS), Clinical Benefit Rate (CBR), 
Duration of Response (DOR), Disease Control Rate (DCR) per RECIST v1.1 and per immune 
related Response Criteria (irRC), and Overall Survival (OS).
2.7.1.2
Phase II part
For Group 1, 3 and 4: ORR per irRC, PFS, DOR, DCR, CBR per RECIST v1.1 and per irRC, 
and OS.
For Group 2: CBR per irRC, PFS, DOR, DCR, ORR per RECIST v1.1 and per irRC, and OS.
2.7.2
Statistical hypothesis, model, and method of analysis
Tumor response will be determined per local investigators’ assessment, according to RECIST 
v1.1 and irRC. For the purpose of this study, Clinical benefit rate (CBR) is defined as the 


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proportion of patients with a best overall response of CR or PR , or an overall lesion response 
of SD which lasts for a minimum time duration of 16 weeks (4 months). 
For all efficacy parameters, data will be listed, summarized, or analyzed by treatment group for 
the phase Ib part, and by disease group (groups 1 to 4) for phase II patients treated at the 
MTD/RP2D.
Bayesian analysis described in Section 2.5.2.2 will be performed and reported based on 
response data per irRC.
ORR, CBR and DCR will be summarized with accompanying 90% confidence intervals.
PFS, along with DOR for patients who experience a CR or PR at any time on study will be 
listed by patient. PFS will be analyzed using Kaplan-Meier estimates (including graphical 
representation) with 90% CIs of median survival for each treatment group/disease group.
OS data will be listed for all patients enrolled in the Phase 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 if applicable by treatment group and furthermore by disease group for patients treated 
at the MTD/RP2D in the Phase II part.
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. Best overall response per RECIST v1.1 and per irRC will be listed and 
tabulated.
2.7.3
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 secondary analysis of ORR according to irRC.
For the analysis of PFS, patients without documented disease progression or death are censored 
at the time of last valid tumor assessment documenting non-progression (one of complete 
response, partial response, or stable disease). 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) 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 with only one valid postbaseline tumor 
assessment).
Other missing data will simply be noted as missing on appropriate tables/listing.
If any alternative cancer therapy is taken while on study any subsequent efficacy assessments 
would be excluded from all relevant efficacy summary.
2.8
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.


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The safety set will be used for summaries and listings of safety data with the exception of DLTs 
for which the DDS will be used.
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 treatment
2. on-treatment period: from day of first dose of study medication to 30 days after the last 
dose of study treatment
3. post-treatment period: from 31 days after date of last administration of study treatment
Safety summaries will primarily be based on all data from the on-treatment period. Following 
last administration of study treatment, adverse events (including serious adverse events), and 
new antineoplastic therapies are collected for a period of 150 days for PDR001 and 90 days for 
MCS110. Following start of new antineoplastic therapy, only treatment related adverse events 
will be collected. Select summaries of related adverse events will be produced for the combined 
on-treatment and post-treatment periods for patients receiving PDR001 (see Section 2.8.1).
2.8.1
Adverse events (AEs)
Adverse events will be coded and graded using the latest version of MedDRA and CTCAE, 
respectively, available at the time of reporting. If CTCAE grading does not exist for an AE, 
grades 1, 2, 3, or 4 corresponding to the severity of mild, moderate, severe, and life-threatening, 
respectively, will be used. CTCAE grade 5 (death) will not be used in this study. Death 
information will be collected on the “Death” eCRF page.
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s).
All AEs will be listed. All AE summaries will be summarized (frequency counts and 
percentages) by system organ class and/or preferred term, and maximum severity grades, unless 
noted otherwise.
Summary tables for 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 following AE summaries will be produced:

AEs regardless of study drug relationship (including CTC grade 3-4)

AEs suspected to be study drug related (including CTC grade 3-4)

AEs regardless of study drug relationship leading to discontinuation of study drug

AEs which are not SAEs regardless of study drug relationship (for CTRD)

SAEs regardless of study drug relationship
A patient with multiple CTC grades for an AE will be summarized under the maximum CTC 
grade recorded for the event. A subject with multiple occurrences of an AE is counted only once 
in the AE category (e.g. system organ class, preferred term).


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2.8.1.1
Adverse events of special interest / grouping of AEs
An adverse event of special interest is a grouping of adverse events that are of scientific and 
medical concern specific to compound PDR001. These groupings are defined using MedDRA 
terms, SMQs (standardized MedDRA queries), HGLTs (high level group terms), HLT (high 
level terms) and PTs (preferred terms). Customized SMQs (Novartis MedDRA queries, NMQ) 
may also be used. A NMQ is a customized group of search terms which defines a medical 
concept for which there is no official SMQ available or the available SMQ does not completely 
fit the need. It may include a combination of single terms and/or an existing SMQ, narrow or 
broad. 
For each specified AESI, number and percentage of subjects with at least one event of the AESI 
occurring during on-treatment period will be summarized. 
Summaries of these AESIs will be provided by study treatment.
A listing of all grouping levels down to the MedDRA preferred terms used to define each AESI 
will be generated. 
2.8.2
Deaths
All deaths occurred in the study will be listed with principal cause reported/preferred term and 
following summaries will be produced:

All deaths with cause of death by primary system organ class and preferred term
2.8.3
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis Oncology Statistical 
Programming) into CTC grades according to CTCAE v4.03 as applicable. Grade 5 will not be 
used.
Baseline comparisons will be done based on shift tables but not considered for derivation of 
CTC grade.
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.
The following summaries will be produced for hematology and coagulation, biochemistry, 
urinalysis parameters:

For parameters with CTC grades: Shifts from baseline to the worst post-baseline CTC 
grade,

For parameters with no CTC grades defined: Shifts from baseline to the worst post-
baseline using low/normal/high classifications.
The following listings will be produced:

Listing of all laboratory data with values flagged to show corresponding CTC grades and 
the classifications relative to the laboratory reference ranges (i.e., High (H) or Low (L)).
Both fasting glucose and non-fasting glucose will be summarized and listed for information 
integrity. Both of glucoses will be combined and reported based on CTCAE v4.03. Fasting 
glucose values will be flagged in the listing.


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Table 2-1 and Table 2-2 lists all laboratory parameters that will be summarized.
Table 2-1
Laboratory parameters for which CTCAE grades are defined
Hematology and coagulation
Biochemistry
Urinalysis
White Blood Cells (WBC)
↑↓
Creatinine
↑
Protein
↑
Hemoglobin
↓
Uric acid
↑
Platelets
↓
Magnesium 
↑↓
Neutrophils(absolute or %) 
↓
Calcium
↑↓
Lymphocytes(absolute or %)
↑↓
Phosphate
↓
Partial thromboplastin time (PTT)
↑
Albumin
↓
Activated partial thromboplastin time (APTT)
↑
AST (SGOT)
↑
International normalized ratio (INR)
↑
ALT (SGPT)
↑
Chloride
↓
Bicarbonate
↓
Total Bilirubin
↑
Glucose 
↑↓
Alkaline Phosphatase
↑
Creatine kinase
↑
↑ Indicates that CTC grade increases as the parameter increases.
↓ Indicates that CTC grade increases as the parameter decreases.
Table 2-2
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined
Hematology and coagulation
Biochemistry
Urinalysis
Prothrombin time (PT)
Blood Urea Nitrogen (BUN) or Urea
Specific gravity
Hematocrit
T3 [free]
Glucose
Basophils (absolute or %)
T4 [free]
Blood
Eosinophils(absolute or %)
TSH
Bilirubin
Monocytes(absolute or %)
Direct bilirubin
Ketones
Indirect bilirubin
White Blood Cells
Lactate dehydrogenase (LDH )
pH
A listing will be produced for the serum pregnancy test and only patients with positive test 
results will be included.
2.8.4
Other safety data
2.8.4.1
ECG and cardiac imaging data
Baseline for ECG analysis is defined as the average of all available ECG measurements
associated with the baseline assessment. Scheduled study day 1 pre-dose ECGs will be


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considered to have been obtained prior to study drug administration if dosing time is missing.
If a scheduled pre-dose measurement actually occurred post-dose, then the corresponding 
measurement will be treated and analyzed similar to an unscheduled post-dose measurement.
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.
The following summary will be provided for each applicable ECG parameter:

Frequency counts and percentages of patients having notable ECG values according to 
Table 2-3.
Table 2-3
Criteria for notable ECG values
ECG parameter
Criteria for ECG notable values
QTcF (ms) and QD (ms)
Increase > 30 ms to ≤60 ms
Increase > 60 ms
New > 450 to ≤480 ms
New > 480 to ≤500 ms
New > 500 ms
QRS (ms)
Increase > 25% and QRS > 120 ms
New QRS > 120 ms
HR (bpm)
Increase > 25% and HR > 100 bpm
Decrease > 25% and HR < 50 bpm
PR (ms)
Increase > 25% and PR > 200 ms
New PR > 200 ms
Notable ECG values (including notable QT interval values) will be flagged in the listings.
2.8.4.2
Vital signs
Vital sign parameters collected are systolic and diastolic blood pressure (mmHg), pulse rate 
(beats per minute), body temperature (°C), and weight (kg). Vital sign values considered 
notably abnormal are defined in Table 2-4.
Table 2-4
Criteria for notable vital sign values
Vital sign
Criteria for clinically notable vital sign values
Systolic blood pressure 
[mmHg]
≥180 mmHg/≤90 mmHg with increase/decrease from baseline of 
≥20 mmHg
Diastolic blood pressure 
[mmHg]
≥105 mmHg/≤50 mmHg with increase/decrease from baseline of 
≥15 mmHg
Pulse rate [bpm]
≥100 bpm/≤50 bpm with increase/decrease from baseline of ≥25%
Body temperature [°C]
≥39.1
Weight [kg]
≥10% decrease/increase from baseline
Patients with any clinically notable vital sign value will be listed.


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2.8.4.3
Tolerability 
Tolerability of study treatments will be assessed by summarizing the number of dose 
interruptions and dose reductions (see Section 2.4.1 for more details) by treatment group in the 
phase Ib part and by patient group in the phase II part. The reasons for dose interruption and 
dose reductions will be listed by patient and treatment group in the dose escalation part and by 
patient group in the dose expansion part; they will be summarized for each investigational drug 
by treatment group in the dose escalation part, and by patient group in dose expansion part. 
Cumulative dose, dose intensity and relative dose intensity will be summarized. Categories for 
relative dose intensity 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. 
2.9
Pharmacokinetics Analyses
The pharmacokinetic parameters will be determined by profiles using noncompartmental 
method(s) for both MCS110 and PDR001 as presented in Table 2-5, and PAS will be used in 
all pharmacokinetic data analysis and PK summary statistics. Patients will 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 the analyses.
Table 2-5
Pharmacokinetic parameters to be analyzed
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass × time × volume-1)
AUCinf
The AUC from time zero to infinity (mass × time × volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass × 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 terminal half-life associated with the terminal slope (z) of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL
The total body clearance of drug from the plasma (volume × time-1)
Vz
The apparent volume of distribution during terminal phase (associated with z) 
(volume)
Clast
Last observed quantifiable concentration (mass × volume-1)
AR
Accumulation Ratio=AUClast (multiple Dose)/AUClast (single dose) (for cycle 4 
only)
For phase Ib part, descriptive statistics of all pharmacokinetic parameters in the Table 2-5 for 
both cycle 1 and cycle 4 will include arithmetic and geometric mean, median, SD, and CV, 
geometric CV, minimum and maximum, by treatment group. For phase II part, descriptive 
statistics will be conducted for the pararmeters, including AUClast, AUCinf, Cmax, Clast, 
Tmax for both cycle 1 and cycle 4 and AR only for cycle 4 by patient group.
Summary statistics will be presented for MCS110 and PDR001 serum concentrations at each 
scheduled time point. Descriptive graphical plots of individual and mean serum/plasma
concentration versus time profiles of free MCS110, PDR001 will be generated by treatment or 
patient group and cycle.


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2.9.1
Data handling principles
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.
Missing concentration values will be reported as is in data listings. Concentration values below 
Lower limit of quantitation will be handled as zero in summary statistics, and reported as is in 
data listings. Any missing pharmacokinetic parameter data will not be imputed. 
2.9.2
Immunogenicity
The presence and/or concentration of anti-MCS110 and/or anti-PDR001 antibodies, at each 
scheduled time point, will be listed by treatment group, disease and patient. Overall 
immunogenicity will be summarized when sample size is sufficient. Anti-MCS110 and/or anti-
PDR001 antibody data will also be summarized. Number (%) of patients with positive 
immunogenicity will be calculated.
2.10
Patient-reported outcomes
Not applicable.


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2.13
Interim analysis
Not applicable.
3
Sample size calculation
Phase Ib
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation phase including at 
least six patients at the MTD/RP2D level, as described in [CLSZ102X2101-CSP-Section 6.2.3]. 
Multiple cohorts may be sequentially enrolled to the same dose level. Additional cohorts of 3 
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 15 patients are 
expected to be treated in the dose escalation phase for the model to have reasonable operating 
characteristics relating to its estimation of MTD.
Phase II
Approximately 20 patients will initially be enrolled to each of groups 1, 3 and 4. Enrollment 
may be expanded up to approximately 40 patients in these groups if objective responses (CR or 
PR) per RECIST v1.1 or irRC are observed (≥ 3 of 20 patients in each of the PD-1/PD-L1 
therapy naïve groups or ≥ 2 of 20 patients in the PD-1/PD-L1 therapy resistant group) 


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([CMCS110Z2102-CSP-Section 2.2]). In Group 2, 20 patients will be enrolled at RP2D, and 
enrolment may be expanded up to approximately 40 patients if at least 3 pts with CR, PR or 
SD > 4 months per RECIST v1.1 or irRC are observed. In addition, an exploratory group of 20 
patients at a lower dose (1 mg/kg MCS110 in combination with PDR001 300 mg) may be 
opened if the above mentioned gating criterion is met (Group 2b). The operating characteristics 
of the designs are provided in Table 3-1 (for Group 1, 3), Table 3-2 (for Group 4), and Table 3-
3 (for Group 2 at RP2D), Table 3-4 (for Group 2b).
Table 3-1
Operating characteristics of the design (Group 1, 3)
True ORR
Probability to observe >=3 
responses in first 20 
patients
Group 1: TNBC
Group 3: Endometrial cancer
probability to observe an ORR ≥ 30% with 40 patients
(Overall success rate)
15%
59.5%
1.2%
20%
79.4%
8.7%
25%
90.9%
28.4%
30%
96.5%
55.8%
40%
99.6%
92.8%
50%
100.0%
99.7%
Table 3-2
Operating characteristics of the design (Group 4)
True ORR
Probability to observe >=2 
responses in first 20 
patients
Groups 4: resistant melanoma
probability to observe an ORR ≥ 15% with 40 patients
(Overall success rate)
7.5%
44.9%
7.1%
15%
82.4%
54.2%
20%
93.1%
81.5%
30%
99.2%
98.6%
40%
99.9%
99.9%
50%
100.0%
100%


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Table 3-3
Operating characteristics of the design (Group 2 at RP2D)
True 
CBR
Probability to observe >=3 
responses (CR, PR or SD > 4 
months) in first 20 patients
Group 2: Pancreatic cancer 
probability to observe a CBR ≥ 15% with 40 patients
7.5%
18.6%
5.5%
15%
59.5%
46.1%
20%
79.4%
73.4%
30%
96.5%
96.1%
Table 3-4
Operating characteristics of the design (Group 2b)
True CBR
Groups 2b: Pancreatic cancer 
probability to observe a CBR ≥ 15% with 20 patients
7.5%
18.6%
15%
59.5%
20%
79.4%
30%
96.5%
4
Change to protocol specified analyses
The following section have been updated in comparison to first SAP
Section 1.1 Study design
Section 1.2 Study objectives and endpoints
Section 2.1 Data analysis general information
Section 2.1.1 General definitions
Section 2.2 Analysis sets/Withdrawal of ICF/Subgroups
Section 2.4.1 Study treatment/compliance
Section 2.5.1 Primary endpoints
Section 2.5.2 Phase II part (Secondary endpoint)
Section 2.5.4 Supportive analyses
Section 2.7.1 Secondary endpoints
Section 2.8 Safety analyses
Section 2.8.3 Laboratory data
Section 3 Sample size calculation
Section 5.5 Rule of exclusion criteria of analysis sets
Section 1.1 Study design

Updated the study design for Phase II part per protocol amendment version 5
Section 1.2 Study objectives and endpoints


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
Secondary objectives, Phase II part: changed endpoint for Group 2 (Pancreatic cancer) to 
CBR instead of ORR
Section 2.1 Data analysis general information

Add R version which will be used for Bayesain anayses for Phase II part.
Section 2.1.1 General definitions

Definition of on-treatment and post-treatment assessment/event
Section 2.2 Analysis sets/Withdrawal of ICF/Subgroups

Per-protocol Set was planned as per the protocol, but outputs were not generated because 
no analyses were conducted based on per-protocol set

Add section 2.2.5 Withdrawal of Informed Consent
Section 2.4.1 Study treatment/compliance

Definition of last date of exposure of study drug/treatment (+ 20 days instead of + 21)
Section 2.5.1 Phase II part (Primary endpoint)

Change of group 2 (Pancreatic cancer) endpoint to CBR instead of ORR
Section 2.5.2 Phase II part (Secondary endpoint)

Change of group 2 prior distribution

Update design of group 2 per protocol amendment version 5
Section 2.5.4 Supportive analyses

Change to be not applicable cause supportive analyses were not conducted.
Section 2.7.1.2 Phase II (Secondary efficacy objectives)

Group 2 (pancreatic cancer) secondary endpoint chnaged to CBR
Section 2.8 Safety analyses

Definition of on-treatment period changed from including 90 days to 30 days after last 
dose in line with all other IO studies and reporting standards. 

Definition of post-treatment period changed from starting at day 91 after last dose of study 
medication to 31 days after last administration of study treatment in line with all other IO 
studies and reporting standards.
Section 2.8.3 Laboratory data

Both fasting glucose and non-fasting glucose will be summarized and listed for information 
integrity. Both of glucoses will be combined and reported based on CTCAE v4.03. Fasting 
glucose values will be flagged in the listing.


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Section 3 Sample size calculation

Update study design for phase II part per protocol amendment version 5
Section 5.5 Rule of exclusion criteria of analysis sets

Table for protocol deviations leading to exclusion from analysis set was removed due to 
no such PDs were collected
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
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
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.


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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.
No imputation will be performed for AE end dates.
5.1.3
Concomitant medication date imputation
Please refer to Section 5.1.2.
5.1.4
Prior therapies date imputation
Consider specific imputation rules for patial dates.
Start date: 
The same rule which is applied to the imputation of AE/concomitant medication (Section 5.1.2)
start date will be used with the exception that scenario (B) will be replaced to be ‘start date of 
study treatment - 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.
5.1.5
Post therapies date imputation
If the day of the medication date is missing the following imputation rules will be followed:
-
If the treatment end month and year and medication month and year are the same, then 
the day of the medication date is set to treatment end day + 1.
-
If the month or year of the medication date is after the treatment end month/year then 
the day of the medication date set to the first of the month.
If the month of the medication date is missing the following imputation rules will be followed:
-
If day is also missing,


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o
If the treatment end year and medication year are the same, then the month of 
the medication date is set to treatment end date + 1.
o
If the year of the medication date is after the treatment end year then the month 
of medication date set to be 01-JAN.
-
If day is not missing, 
o
If the treatment end year and medication year are the same and if medication day 
is before the day of treatment end date, then the month of medication date is set 
to month of treatment end date + 1.
o
If the treatment end year and medication year are the same and if medication day 
is after the day of treatment end date, then the month of medication date is set to 
month of treatment end date.
o
If the year of the medication date is after the treatment end year then medication 
date set to be JAN.
If the year of the medication date is missing there is no imputation.
5.1.6
Other imputations
For partially missing date of first recurrence/progression, date of initial diagnosis or date of 
most recent relapse/progression the following imputation rules will be applied:
o
If Month and Day missing, set to 01-Jul of the year 
o
If Day missing, set to 15 of the month
5.2
Laboratory parameters derivations
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula:
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived
corrected calcium is set to the same limits (in mg/dL) as for calcium.


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CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium as defined in the previous section.
5.3
Rule of exclusion criteria of analysis sets
Patients will be excluded from the analysis sets based on the protocol deviations entered in the 
database and specific non-protocol deviations. All protocol deviations and non-protocol 
deviations leading to exclusion from specific analysis sets will be finalized before database lock.
Table 5-3 displays non-protocol deviations leading to exclusion from analysis set definitions 
These table will be updated before database lock.
Table 5-3
Non-protocol deviations leading to exclusion from analysis set 
definitions
Summary of non PD
Analysis set(s) to 
be excluded
No post-baseline safety assessment
SS
1. Patient, who has not experienced DLT, was not observed for ≥ 42 days 
following the first dose or had not completed the required safety evaluations for 
Cycle 1 and Cycle 2 or 
2. Patient who has not experienced DLT, didn’t receive two doses in the first 
two cycles.
DDS
Patient did not have at least one primary PK parameter
PAS
6
Reference
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approach to phase I cancer trials. Statistics in Medicine 27: 2420-2439.
Spiegelhalter DJ, Abrams KR, Myles JP. Bayesian Approaches to Clinical Trials and Health-
Care Evaluation. John Wiley & Sons, New York, 2004.
Neuenschwander B, Capkun-Niggli G, Branson M, Spiegelhalter D (2010) Summarizing 
historical information on controls in clinical trials. Clin Trials 2010 7: 5.
Neuenschwander B, Matano A, Tang Z, Roychoudhury S, Wandel S and Bailey S: A 
Bayesian Industry Approach to Phase I Combination Trials in Oncology in Zhao W and Yang 
H. Statistical Methods in Drug Combination Studies. Chapman & Hall/CRC, 2014.
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25(31): 4982-6.