Clinical trial NCT02829723
Conditions: Advanced Solid Tumors
Keywords: Phase I/II BLZ945 PDR001 CSF-1R PD-1 advanced solid tumors glioblastoma
Sponsor: Novartis Pharmaceuticals
Start date: 2016-10-21; Completion date: 2022-12-01
Enrollment: 192 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this first-in-human (FIH) study of BLZ945 given as a single agent or in combination with PDR001 was to characterize the safety, tolerability, pharmacokinetics (PK), pharmacodynamics, and anti-tumor activity of BLZ945, administered orally, as a single agent or in combination with PDR001, administered intravenously (i.v.) in adult patients with advanced solid tumors.

Detailed description:
This study was a first in human, open-label, multi-center phase I/II study which consisted of a phase I dose escalation part of BLZ945 as single agent, and of BLZ945 in combination with PDR001, where alternative dosing regimens of BLZ945 were evaluated. The escalation was guided by a Bayesian logistic regression model with overdose control. Once the maximum tolerated dose (MTD) / recommended phase 2 dose (RP2D) for BLZ945 as single agent was established, a phase II part could commence, should signs of antitumor activity had been seen during the phase I. Once the MTD/RP2D for BLZ945 in combination with PDR001 was established, a phase II part could commence.

Phase I part of the study involved patients with advanced solid tumors, including patients with recurrent glioblastoma and patients with Hodgkin's lymphoma, and phase II part patients with relapsed or refractory glioblastoma.

A separate Japanese single agent dose escalation was performed in order to ensure that the safety and pharmacokinetic profiles of BLZ945 single agent were adequately characterized in Japanese patients. The Japanese dose escalation for BLZ945 single agent run separately from the ongoing global dose escalation. No Japanese patients were enrolled in phase II part according to protocol. The enrollment of the Japanese cohort was halted per investigator letter, dated 18-Jun-2021.

Arms: arm 1: BLZ945 administered as single agent arm 2: BLZ945 administered in combination with PDR001
Interventions: intervention 1: BLZ945 intervention 2: PDR001
Intervention descriptions: intervention 1: BLZ945 administered orally as a capsule. Up to five alternative dosing schedules were evaluated: once per day (QD) 7 days on/7 days off (i.e., administer BLZ945 for 7 days and suspend for 7 days), QD 4 days on/10 days off, twice per day (BID) 4 days on/10 days off, once weekly (Q1W) QD and Q1W BID.

Each cycle consisted of 28 days. intervention 2: PDR001 400 mg administered via intravenous (i.v.) infusion every 4 weeks (Q4W)

Protocol documents:
Prot_000.pdf: 


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................7
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................11
Glossary of terms...............................................................................................................14
Protocol summary:.............................................................................................................15
Amendment 7 (05-May-2022)...........................................................................................19
Amendment 6 (20-Feb-2020)............................................................................................21
Amendment 5 (16-Nov-2018)...........................................................................................24
Amendment 4 (31-Jul-2018) .............................................................................................27
Amendment 3 (05-Feb-2018)............................................................................................28
Amendment 2 (24-Oct-2017) ............................................................................................30
Amendment 1 (04-Aug-2017)...........................................................................................31
1
Background........................................................................................................................34
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............35
1.1.1
CSF-R1 Overview.................................................................................37
1.1.2
PD-1 Overview......................................................................................39
1.2
Introduction to investigational treatment(s) and other study treatment(s).............39
1.2.1
Overview of BLZ945............................................................................39
1.2.2
Overview of PDR001............................................................................44
1.2.3
Overview of combination treatment......................................................46
2
Rationale............................................................................................................................47
2.1
Study rationale and purpose...................................................................................47
2.2
Rationale for the study design ...............................................................................48
2.3
Rationale for dose and regimen selection..............................................................49
3
Objectives and endpoints...................................................................................................51
4
Study design ......................................................................................................................53
4.1
Description of study design ...................................................................................53
4.2
Timing of interim analyses and design adaptation ................................................56
4.3
Definition of end of study......................................................................................57
4.4
Early study termination..........................................................................................57
5
Population..........................................................................................................................57
5.1
Patient population..................................................................................................57
5.2
Inclusion criteria ....................................................................................................58
5.3
Exclusion criteria...................................................................................................58


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Treatment...........................................................................................................................62
6.1
Study treatment......................................................................................................62
6.1.1
Dosing regimen.....................................................................................62
6.1.2
Ancillary treatments..............................................................................63
6.1.3
Treatment duration................................................................................63
6.2
Dose escalation guidelines.....................................................................................64
6.2.1
Starting dose rationale...........................................................................64
6.2.2
Provisional dose levels..........................................................................65
6.2.3
Guidelines for dose escalation and determination of MTD/RP2D .......67
6.2.4
Definitions of dose limiting toxicities (DLTs)......................................70
6.3
Dose modifications................................................................................................71
6.3.1
Dose modification and dose delay ........................................................71
6.3.2
Follow-up for toxicities.........................................................................72
6.3.3
Anticipated risks and safety concerns of the study drugs .....................90
6.4
Concomitant medications ......................................................................................90
6.4.1
Permitted concomitant therapy .............................................................90
6.4.2
Prohibited concomitant therapy ............................................................90
6.4.3
Permitted concomitant therapy requiring caution and/or action...........91
6.4.4
Prohibited food......................................................................................92
6.5
Patient numbering, treatment assignment or randomization .................................92
6.5.1
Patient numbering .................................................................................92
6.5.2
Treatment assignment or randomization...............................................92
6.6
Study drug preparation and dispensation...............................................................92
6.6.1
Study treatment packaging and labeling ...............................................93
6.6.2
Drug supply and storage........................................................................93
6.6.3
Study drug compliance and accountability ...........................................93
6.6.4
Disposal and destruction .......................................................................94
7
Visit schedule and assessments .........................................................................................94
7.1
Study flow and visit schedule................................................................................94
7.1.1
Screening.............................................................................................109
7.1.2
Treatment period.................................................................................109
7.1.3
Discontinuation of study treatment .....................................................111
7.1.4
Withdrawal of consent ........................................................................112
7.1.5
Follow up period .................................................................................113
7.1.6
Lost to follow-up.................................................................................113
7.2
Assessment types.................................................................................................114


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7.2.1
Efficacy assessments...........................................................................114
7.2.2
Safety and tolerability assessments.....................................................117
7.2.3
Pharmacokinetic and immunogenicity assessments............................122
7.2.4
Biomarkers..........................................................................................130
8
Safety monitoring and reporting......................................................................................135
8.1
Adverse events.....................................................................................................135
8.1.1
Definitions and reporting ....................................................................135
8.1.2
Laboratory test abnormalities..............................................................136
8.2
Serious adverse events.........................................................................................137
8.2.1
Definitions...........................................................................................137
8.2.2
Reporting.............................................................................................138
8.3
Pregnancies..........................................................................................................139
8.4
Warnings and precautions....................................................................................139
8.5
Data Monitoring Committee................................................................................139
8.6
Steering Committee .............................................................................................140
9
Data collection and management.....................................................................................140
9.1
Data confidentiality .............................................................................................140
9.2
Site monitoring ....................................................................................................140
9.3
Data collection.....................................................................................................141
9.4
Database management and quality control..........................................................142
10 Statistical methods and data analysis ..............................................................................142
10.1
Analysis sets ........................................................................................................143
10.1.1
Full Analysis Set .................................................................................143
10.1.2
Safety set .............................................................................................143
10.1.3
Per-Protocol set ...................................................................................143
10.1.4
Dose-determining analysis set.............................................................143
10.1.5
Pharmacokinetic analysis set...............................................................144
10.1.6
Other analysis sets...............................................................................144
10.2
Patient demographics/other baseline characteristics ...........................................144
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................145
10.4
Primary objective.................................................................................................145
10.4.1
Variable...............................................................................................145
10.4.2
Safety objectives .................................................................................146
10.4.3
Tolerability..........................................................................................147
10.4.4
Statistical hypothesis, model, and method of analysis........................148
10.4.5
Handling of missing values/censoring/discontinuations.....................149


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10.4.6
Supportive analyses.............................................................................149
10.5
Secondary objectives ...........................................................................................150
10.5.1
Key secondary objective(s).................................................................150
10.5.2
Other secondary efficacy objectives ...................................................150
10.5.3
Safety objectives .................................................................................150
10.5.4
Tolerability..........................................................................................151
10.5.5
Supportive analyses for secondary objectives.....................................151
10.5.6
Pharmacokinetics ................................................................................152
153
10.5.8
Resource utilization.............................................................................154
10.5.9
Patient-reported outcomes...................................................................154
10.6
Exploratory objectives.........................................................................................155
10.6.1
Biomarkers..........................................................................................155
155
10.7
Interim analysis....................................................................................................155
10.8
Sample size calculation........................................................................................156
10.9
Power for analysis of key secondary variables....................................................156
11 Ethical considerations and administrative procedures ....................................................156
11.1
Regulatory and ethical compliance......................................................................156
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................157
11.3
Informed consent procedures...............................................................................157
11.4
Discontinuation of the study................................................................................158
11.5
Publication of study protocol and results.............................................................158
11.6
Study documentation, record keeping and retention of documents.....................158
11.7
Confidentiality of study documents and patient records .....................................159
11.8
Audits and inspections.........................................................................................159
11.9
Financial disclosures............................................................................................159
12 Protocol adherence ..........................................................................................................159
12.1
Amendments to the protocol................................................................................160
13 References (available upon request)................................................................................161
14 Appendices ......................................................................................................................168
14.1
Appendix 1: Guidelines for Response, Duration of Overall Response, TTF, 
TTP, Progression-Free Survival and Overall Survival (based on RECIST 1.1) .168
14.1.1
Introduction.........................................................................................169
14.1.2
Efficacy assessments...........................................................................169
14.1.3
Efficacy definitions .............................................................................179


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14.1.4
Data handling and programming rules................................................188
14.1.5
References (available upon request) ...................................................191
14.2
Appendix 2: Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) .................................192
14.2.1
Introduction.........................................................................................192
14.2.2
New lesions and non-target lesions.....................................................192
14.2.3
Follow-up evaluation of target and non-target lesions........................192
14.2.4
Definitions of response categories and evaluation of overall lesion 
response...............................................................................................193
14.2.5
Only non-measurable disease at baseline............................................194
14.2.6
References (available upon request) ...................................................194
14.3
Appendix 3: Response assessment in neuro-oncology (RANO) criteria for 
high-grade gliomas ..............................................................................................195
14.3.1
Antitumor effect – definitions.............................................................195
14.3.2
Response/progression categories ........................................................196
14.3.3
Methods for evaluation of measurable disease ...................................198
14.3.4
Evaluation of best response.................................................................198
14.3.5
Other effect measures..........................................................................199
14.3.6
References...........................................................................................199
14.4
Appendix 4: Immunotherapy Response Assessment in Neuro-Oncology 
(iRANO) criteria for high-grade gliomas ............................................................200
14.4.1
Immunotherapy Continuation Beyond Initial Progressive Disease ....200
14.4.2
Response Assessment..........................................................................201
14.4.3
References...........................................................................................201
14.5
Appendix 5: Statistical methods..........................................................................202
14.5.1
Statistical details of Bayesian regression models, priors, design 
operating characteristics and hypothetical dose escalation scenarios.202
14.5.2
Single agent BLZ945 ..........................................................................202
14.5.3
Combination of BLZ945 (7days on/7days off) and PDR001 .............206
14.5.4
Combination BLZ945 (Q1W) and PDR001 .......................................214
14.5.5
Split dosing regimen (two doses per day)...........................................215
14.6
Sample size determination for Phase II ...............................................................215
14.6.1
Prior specifications..............................................................................215
14.6.2
Operating characteristics.....................................................................216
14.6.3
References...........................................................................................218
14.7
Appendix 6: Statistical details of Phase I Bayesian logistic regression model 
(BLRM) in Japanese patients treated with single agent of BLZ945 ...................219


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14.7.1
Statistical model..................................................................................219
14.7.2
Prior specifications..............................................................................219
14.7.3
BLRM design properties for hypothetical data scenarios...................222
14.7.4
Alternative dosing schedule................................................................225
14.7.5
References (available upon request) ...................................................225
14.8
Appendix 7: Prohibited Medication.....................................................................226
14.9
Appendix 8: Medications to be used with caution...............................................229
14.10 Appendix 9: Guidelines for efficacy evaluation in Hodgkin and non-Hodgkin 
lymphoma studies ................................................................................................230
14.10.1
Introduction.........................................................................................231
14.10.2
Methodologies.....................................................................................231
14.10.3
Definitions...........................................................................................232
14.10.4
Efficacy assessments...........................................................................234
14.10.5
Data handling and programming conventions ....................................246
14.10.6
References...........................................................................................247
14.10.7
Appendix A: Adaptation for use in maintenance/adjuvant settings....247
List of figures
Figure 1-1
BLZ945 mechanism of action...............................................................38
Figure 1-2
Efficacy data represented as Kaplan-Meier survival analysis curve 
(a) and as a tumor volume kinetic measured at the indicated times 
(b and c).................................................................................................41
Figure 4-1
Study design (effective prior to protocol amendment 6 approval) .......54
Figure 4-2
Study design (effective after approval of protocol amendment 06)......54
Figure 4-3
Study flow............................................................................................56


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List of tables
Table 3-1
Objectives and related endpoints ..........................................................51
Table 6-1
Dose and treatment schedule.................................................................62
Table 6-2
Provisional dose levels (BLZ945 single agent) ....................................66
Table 6-3
Provisional dose levels (BLZ945 in combination with PDR001).........66
Table 6-4
Criteria for defining dose-limiting toxicities.........................................70
Table 6-5
Criteria for dose modifications and interruption of BLZ945 during 
treatment with BLZ945 as single agent ................................................73
Table 6-6
Criteria for dose modifications and interruption for BLZ945 and 
PDR001 as combination treatmen.........................................................80
Table 6-7
Dose reduction steps for BLZ945 (Phase II only) ................................90
Table 7-1
Visit evaluation schedule for BLZ945 7d on / 7d off ...........................95
Table 7-2
Visit evaluation schedule for BLZ945 Q1W ........................................98
Table 7-3
Visit evaluation schedule for BLZ945 4d on / 10d off (phase I) ........102
Table 7-4
Visit evaluation schedule for phase II (BLZ945 4d on / 10d off).......105
Table 7-5
Disease assessment collection plan.....................................................116
Table 7-6
ECOG performance status...................................................................118
Table 7-7
Local/Central Clinical laboratory parameters collection plan ............119
Table 7-8
Central ECG collection plan ...............................................................120
Table 7-9
Pharmacokinetic blood collection log for BLZ945 7d on/7d off 
regimen (single agent).........................................................................122
Table 7-10
Pharmacokinetic blood collection log for BLZ945 once weekly 
(Q1W) regimen (single agent) ............................................................123
Table 7-11
Pharmacokinetic blood collection log for BLZ945 4d on/10d off 
regimen (single agent) in phase I ........................................................124
Table 7-12
Pharmacokinetic blood collection log for BLZ945 4d on/10d off 
regimen (single agent) in phase II.......................................................125
Table 7-13
Pharmacokinetic blood collection log for BLZ945 and PDR001 
and ADA (BLZ945 and PDR001 combination) 7d on/7d off 
regimen................................................................................................125
Table 7-14
Pharmacokinetic blood collection log for BLZ945 and PDR001 
and ADA (BLZ945 and PDR001 combination) once weekly 
(Q1W) regimen ...................................................................................126
Table 7-15
Pharmacokinetic blood collection log for BLZ945 and PDR001 
and ADA (BLZ945 and PDR001 combination) 4d on/10d off 
regimen in phase I...............................................................................128
Table 7-16
Pharmacokinetic blood collection log for BLZ945 and PDR001 
and ADA (BLZ945 and PDR001 combination) 4d on/10d off 
regimen in phase II..............................................................................129


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Table 7-17
Biomarker sample collection plan (tumor/blood samples) .................131
Table 10-1
Non-compartmental pharmacokinetic parameters ..............................152
Table 10-2
Operating characteristics.....................................................................156
Table 14-1
Response criteria for target lesions .....................................................175
Table 14-2
Response criteria for non-target lesions..............................................177
Table 14-3
Overall lesion response at each assessment ........................................178
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................185
Table 14-5
Options for event dates used in PFS, TTP, duration of response........186
Table 14-6
Overall response at each assessment...................................................194
Table 14-7
Summary of the RANO response criteria ...........................................198
Table 14-8
Imaging and Treatment after 1st Radiologic Evidence of PD ............201
Table 14-9
Prior distribution parameters-BLZ945 SA (7d on/ 7d off schedule) ..203
Table 14-10
Summary of prior distribution of DLT rates- BLZ945 SA (7d on/
7d off schedule)...................................................................................203
Table 14-11
Hypothetical scenarios ........................................................................203
Table 14-12
dose-DLT scenarios ............................................................................204
Table 14-13
Operating characteristics.....................................................................205
Table 14-14
Hypothetical data from single agent part ............................................207
Table 14-15
Prior distributions for the parameters of the MAP model used to 
derive the prior ....................................................................................208
Table 14-16
Data from PDR001X2101 study.........................................................208
Table 14-17
Prior distributions for the parameters of the MAP model used to 
derive the prior for the single-agent PDR001 model parameters........209
Table 14-18
Prior distribution of model parameters ...............................................210
Table 14-19
Summary of prior distribution of DLT rates- BLZ945 (7d on/ 7d 
off)+ PDR001......................................................................................211
Table 14-20
Hypothetical dose escalation scenarios for on-study decisions –
Combination of BLZ945 (7 days on/7days off) and PDR001 ............211
Table 14-21
Dose-DLT scenarios............................................................................212
Table 14-22
Operating characteristics.....................................................................213
Table 14-23
Specifications for Prior distribution....................................................216
Table 14-24
Operating Characteristics....................................................................218
Table 14-25
Operating Characteristics for TNBC group (no longer effective 
after approval of protocol amendment 06)..........................................218
Table 14-26
Hypothetical data from global patients in study CBLZ945X2101 .....221
Table 14-27
Prior distributions for the parameters of the MAP model used to 
derive the prior ....................................................................................221


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Table 14-28
Prior distribution of model parameters ...............................................221
Table 14-29
Summary of prior distribution of DLT rates.......................................222
Table 14-30
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent BLZ945...............................................................222
Table 14-31
dose-DLT scenarios ............................................................................223
Table 14-32
Operating characteristics.....................................................................224
Table 14-33
List of prohibited medications during study drug treatment...............227
Table 14-34
List of medications to be used with caution during study drug 
treatment..............................................................................................229
Table 14-35
Five Point Scale (5PS) ........................................................................232
Table 14-36
Radiological response assessment.......................................................237
Table 14-37
Overall disease response .....................................................................240
Table 14-38
Censoring reasons ...............................................................................244
Table 14-39
Options for event dates used in PFS, EFS, TTP, DOR.......................245


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List of abbreviations
Abs
Antibodies  
ADA
Anti-Drug Antibody
AE
Adverse Event
ALT
Alanine aminotransferase
ANC
Absolute Neutrophil Count
APTT
Activated Partial Thromboplastin Time
AST
Aspartate aminotransferase
AUC
Area Under the Curve
BLRM
Bayesian Logistic Regression Model
BHLRM
Bayesian Hierarchical Logistic Regression Model
BOR
Best Overall Response
BVN
Bivariate normal
CCL2
Chemokine (C-C motif) ligand 2
CNS
Central Nervous System
CLp
Plasma Clearance
CMO&PS
Chief Medical Office and Patient Safety
CR
Complete Response
CRF
Case Report/Record Form; the term CRF can be applied to either EDC or Paper
CRS
Cytokine Release Syndrome 
CSF-1
Colony-Stimulating Factor 1
CSF-1R
Colony-Stimulating Factor 1 Receptor
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CTLA-4
Cytotoxic T-Lymphocyte-Associated Protein 4
CYP
Cytochrome P450 
DCs
Dendritic Cells
DDI
Drug-Drug Interaction 
DCR
Disease Control Rate
DLT
Dose Limiting Toxicity
DOR
Duration Of Response
DFS
Disease Free Survival 
ECs
Ethic Committees
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic Case Report Form
EDC
Electronic Data Capture
ELISA
Enzyme-Linked Immunosorbent Assay
EoT
End of Treatment
EWOC
Escalation With Overdose Control 
FIH
First In Human
GBM
Glioblastoma Multiforme
GI
Gastrointestinal
GLP
Good Laboratory Practice
GM-CSF
Granulocyte Macrophage Colony-Stimulating Factor
HBV
Hepatitis B Virus
hCG
Human Chorionic Gonadotropin


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HCV
Hepatitis C Virus
hERG
Human Ether-à-go-go-Related Gene
HIV
Human Immunodeficiency Virus
HNSTD
Highest Non-Severely Toxic Dose
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IL
Interleukin
INR
International Normalized Ratio
irAE
immune Related Adverse Event
iRANO
immune Response Assessment in Neuro-Oncology Criteria
IRB
Institutional Review Board
irCR
immune-related Complete Response
irPD
immune-related Progressive Disease
irPR
immune-related Partial Response
irRC
immune-related Response Criteria
irSD
immune-related Stable Disease
i.v.
Intravenous(ly)
KD
Dissociation constant
LLOQ
Lower Limit Of Quantification
M-CSF
Macrophage Colony-Stimulating Factor
MDSCs
Myeloid-Derived Suppressor Cells
MGMT
Methylguanine-DNA MethylTransferase 
MHC
Major Histocompatibility Complex 
MOA
Mechanism Of Action
MTD
Maximum Tolerated Dose
OS
Overall Survival
PBMC
Peripheral Blood Mononuclear Cell 
PD-1
Programmed Death-1
PDAC
Pancreatic Ductal Adenocarcinoma
PD-L1
Programmed Death-Ligand 1
PD-L2
Programmed Death-Ligand 2
PFS
Progression Free Survival
PFS6
Progression free survival rate at 6 months
PPS
Per protocol set
PFSR
Progression-Free Survival Rate 
PGx
Pharmacogenetics
PK
Pharmacokinetics
p.o.
per os/by mouth/orally
PR
Partial Response
Q1W
Once a Week
Q4W
Every 4 Weeks
r/r
relapsed or refractory
RANO
Response Assessment in Neuro-Oncology Criteria
RCC 
Renal Cell Carcinoma 
RECIST
Response Evaluation Criteria In Solid Tumors


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RF
Rheumatoid Factor 
RP2D
Recommended Phase 2 Dose
SAE
Serious Adverse Event
SAP
Statistical Analysis Plan 
SD
Stable Disease
SEB
Staphylococcal Enterotoxin B
STAT3
Signal Transducer and Activator of Transcription 3
T1/2
Half-life
TAMs
Tumor Associated Macrophages
TIL
Tumor Infiltrating Lymphocytes
TNBC
Triple Negative Breast Cancer
Tregs
Regulatory T cells
ULN
Upper Limit of Normal
Vss
Volume of distribution


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Glossary of terms
Assessment
A procedure used to generate data required by the study
Biologic Samples
A biological specimen including, for example, blood (plasma, serum), saliva, 
tissue, urine, stool, etc. taken from a study subject or study patient
Cohort
A group of newly enrolled patients treated at a specific dose and regimen 
(i.e. treatment group) at the same time
Cycles
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol)
Medication number
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study
Other study treatment
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment
Personal Data
Subject information collected by the Investigator that is transferred to 
Novartis for the purpose of the clinical trial. This data includes subject 
identifier information, study information and biological samples.
Subject Number (Subject No.)
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study
Randomization number
A unique treatment identification code assigned to each randomized patient, 
corresponding to a specific treatment arm assignment
Stage in cancer
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body
Stop study participation
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later
Study treatment
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins.
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and non-investigational 
treatments in combination.
Study treatment discontinuation
Point/time when patient permanently stops taking study treatment for any 
reason
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 study consent
Withdrawal of consent from the study occurs only when a patient does not 
want to participate in the study any longer, and does not allow any further 
collection of personal data


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Protocol summary:
Title
A phase I/II, open-label, multi-center study of the safety and efficacy of 
BLZ945 as single agent and in combination with PDR001 in adults patients 
with advanced solid tumors
Brief title
Phase I/II study of BLZ945 single agent or BLZ945 in combination with 
PDR001 in advanced solid tumors
Sponsor and Clinical 
Phase
Novartis Phase I/II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this first-in-human (FIH) study of BLZ945 given as a single 
agent or in combination with PDR001 is to characterize the safety, 
tolerability, pharmacokinetics (PK), , and anti-tumor activity of BLZ945, 
administered orally, as a single agent or in combination with PDR001, 
administered intravenously (i.v.) in adult patients with advanced solid 
tumors.
Primary Objective(s) 
Phase I: To characterize the safety and tolerability of BLZ945 as a single 
agent (in non-Japanese and Japanese patients) and in combination with 
PDR001 and to identify the Maximum Tolerated Dose (MTD) / 
Recommended Phase 2 Dose (RP2D).
Phase II: To assess the anti-tumor activity of BLZ945 in combination with 
PDR001 (and as single agent if appropriate) in patients with advanced 
solid tumors.
Secondary Objectives
Phase I:. To characterize PK of BLZ945 as a single agent and in 
combination with PDR001. To assess the preliminary anti-tumor activity of 
BLZ945 as single agent and in combination with PDR001.
Phase I and II: To assess emergence of anti-PDR001 antibodies when 
BLZ945 is administered in combination with PDR001.
Study design
This study is a FIH, open-label, multi-center, phase I/II, study which 
consists of a phase I dose escalation part of BLZ945 as single agent 
(including a separate Japanese BLZ945 single agent dose escalation arm) 
and in combination with PDR001. Alternative dosing regimens of BLZ945 
may be evaluated. Once the MTD/RP2D for BLZ945 as a single agent is 
established, a phase II may commence, if signs of activity have been 
detected. Once the MTD/RP2D for BLZ945 in combination with PDR001 
is established, a phase II part of the combination will commence. 
BLZ945 will be administered orally, and PDR001 will be administered i.v. 
every four weeks until patient experiences unacceptable toxicity, 
progressive disease and/or treatment is discontinued at the discretion of 
the Investigator or the patient.


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Population
The phase I dose escalation of the study will be conducted in adult patients 
with advanced solid tumors.
The phase II part of the study will be conducted in adult patients with 
glioblastoma. 
Inclusion criteria
(Selected)
Phase I: Patients with advanced/metastatic solid tumors (including 
lymphoma), with measurable or unmeasurable disease as determined by 
Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 or 
RANO (glioblastoma) who have progressed despite standard therapy or 
are intolerant of standard therapy, or for whom no standard therapy exists.
Patients 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 treatment. Exceptions may be considered for 
glioblastoma patients after documented discussion with Novartis.
Phase II: Patients with recurrent isocitrate dehydrogenase (IDH) wild-type 
glioblastoma (GBM), with at least one measurable lesion as determined 
by Response Assessment in Neuro-Oncology Criteria (RANO)
patients 
with 
O6-methylguanine-DNA 
methyltransferase 
(MGMT) 
methylated recurrent glioblastoma that failed to respond to or progressed 
on radiotherapy and temozolomide 
patients with MGMT unmethylated recurrent gliobastoma that failed to 
respond to or progressed on radiotherapy (with or without temozolomide)
patients who received no prior treatment with a VEGFR targeting agent 
(e.g. Avastin®).
Exclusion criteria
(Selected)
History of severe hypersensitivity reactions to monoclonal antibodies.
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 electrocardiogram (ECG) or congenital 
long QT syndrome
Acute myocardial infarction or unstable angina pectoris < 3 months prior 
to study entry
Active autoimmune disease or a documented history of autoimmune 
disease, including ulcerative colitis and Crohn’s disease or any condition 
that requires systemic steroids, except vitiligo or resolved asthma/atopy 
that is treated with broncho-dilators (e.g. albuterol). Patients previously 
exposed to anti-PD-1/PD-L1 treatment who are adequately treated for skin 
rash or with replacement therapy for endocrinopathies should not be 
excluded.
Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day 
prednisone or equivalent).  Topical, inhaled, nasal and ophthalmic steroids 
are not prohibited. For glioblastoma patients only: patients must not be 
receiving more than 2 mg dexamethasone per day (or an equivalent 
amount of an alternative corticosteroid) providing the dose is stable for at 
least 2 weeks prior to the baseline tumor assessments. 




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Data analysis
The study data will be analyzed and reported based on all patients’ data 
of the dose escalation and Phase II parts up to the time when all patients 
from dose escalation part have potentially completed at least six cycles of 
treatment or discontinued the study and all patients from phase II part 
have had at least one tumor assessment after six months of treatment or 
discontinued the study.
Key words
Phase I/II, BLZ945, PDR001, PD-1, CSF-1R




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
Section 4.3: Addition of language to account for patients who would transfer into 
another study or an alternative way to provide study treatment

Section 7.1.3 and 7.1.5: Addition of language to specify that patients who transfer to 
another study or an alternative way to provide study treatment will not proceed to safety, 
disease progression and survival follow up.

Table 7-17: Removal of “(secondary endpoint)”.

Section 10.5.7: Addition of language that this section is no longer applicable, as 
biomarker assessments are considered as exploratory and hypotheses generating.

Section 10.6.1: Addition of language to clarify, that immunohistochemistry assessments 
are included in the exploratory objectives.
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 6 (20-Feb-2020)
Amendment rationale
The purpose of this amendment is as follows:
1. Update the patient population in the phase II part

The phase II part of study (both BLZ945 single agent and in combination with PDR001) 
will focus on glioblastoma due to the encouraging results observed in the phase I part of 
the study. The phase II part in advanced pancreatic cancer and triple negative breast 
cancer will be removed from the study protocol due to business considerations.

Clarification was included to refine the eligibility criteria of glioblastoma population in 
the phase II part of the study regarding the prior anti-neoplastic therapies and dosage of 
concomitantly used dexamethasone.

Based on the emerging data from phase I part of the study, the number of glioblastoma
patients to be enrolled in BLZ945 single agent phase II part is increased to better 
characterize the anti-tumor activity of BLZ945 as single agent.
2. Modify the study assessments to further characterize biological effects of BLZ945 

Elevation of liver enzymes are observed under treatment with BLZ945 both pre-clinically 
and clinically. To further characterize the biological mechanism behind these findings, 
optional research samples will be collected to look for novel biomarkers that are not yet 
clinically validated, but have received letters of support from FDA and EMEA for 
evaluation in clinical trials.

To enable comprehensive assessment of tumor tissue from patients with glioblastoma
enrolled in either phase I or phase II parts of the study, an archival tumor sample is
requested for exploratory assessments, such as:
 evaluation of predictive 
markers.

Collection of biological samples is simplified in the phase II part of the study. Only 
plasma samples will be collected for pharmacodynamic assessments. PK serum samples 
will be collected during and at the end of cycle 1 and EoT only.

Based on the preliminary results from a 13-week Good Laboratory Practice (GLP) study 
in Wistar rats (report in preparation), which showed reversible thickening of the heart 
valves in rats dosed at ≥30 mg/kg/day, Doppler echocardiography is added to monitor for 
any potential cardiac risk at baseline and day 1 of every cycle. 
Other clarifications (such as: safety objectives in the phase I and phase II parts, formal interim 
analysis in the phase II part) and editorial changes have been made to this protocol for 
consistency and/or clarity.


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Study update
The CBLZ945X2101 study started enrollment on 21-Oct-2016. As of 14-Aug-2019, 77 patients 
have been enrolled in the BLZ945 single agent dose escalation part and 69 patients have been 
enrolled in the BLZ945 and PDR001 combination dose escalation part.
The RP2D of BLZ945 single agent and BLZ945 in combination with PDR001 were declared at 
1200 mg at a 4 days on/10 days off schedule and at 700 mg at a 4 days on/10 days off schedule
with 400 mg PDR001 Q4W, respectively. The phase II part of the study will start upon the 
approval of protocol amendment 6.
The BLZ945 single agent dose escalation is ongoing for Japan arm and the MTD and/or RP2D 
in Japanese patients are not declared yet. 
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.

Protocol summary: Updated the targeted patient population in phase II and the selected 
inclusion and exclusion criteria.  

Section 1.1: Updated the treatment landscape of glioblastoma.  

Section 1.2.1.1.2: Updated the new findings from the 13-week GLP toxicology study in 
Wistar rats.

Section 1.2.1.2: Updated the clinical experiences of BLZ945 and the declared RP2Ds

Section 2.1 and Section 2.2: Updated the rationale of phase II indications for both BLZ945 
single agent and in combination with PDR001.

Section 2.2, Section 4.2 and Section 10.7: Updated the timing and design of interim 
analysis in phase II part of study.

Table 3-1: Updated the endpoints of primary and secondary objectives based on the 
updated phase II indications. Clarified the safety objectives in the phase II part.

Section 4.1: Updated the study design by increasing the number of patients in BLZ945 
single agent Phase II part. Updated the corresponding descriptions based on the modified 
indications in Phase II part of BLZ945 in combination with PDR001.

Section 4.2: Updated the timing of interim analyses and design adaptation based on the 
modified indications in Phase II part.

Section 5.1, Section 5.2 and Section 5.3: Updated patient population and some inclusion 
or exclusion criteria regarding to patients diagnosed with recurrent GBM. 

Section 6.3.1 and Table 6-7: Added the table of dose reduction steps for BLZ945 based on 
the declared RP2D and/or MTD and the tested dose regimens in the Phase I part of the 
study.

Table 6-5 and Table 6-6: Incorporated formatting changes slightly.

Section 6.4.2: Clarified the steroids used for the treatment of glioblastoma are not 
prohibited.

Section 7.1, Table 7-3 and Table 7-4: Updated Table 7-3 to include Doppler 
echocardiography. Added the Table 7-4 to outline the visit evaluation schedule in Phase II 




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Amendment 5 (16-Nov-2018) 
Amendment rationale 
The purpose of this amendment is as follows:
1. To clarify that patients with relapsed or refractory (r/r) lymphoma are eligible to enroll in 
the study and to implement the methodology for efficacy assessments that will follow the 
appropriate guidelines for these patient populations. The guidelines are to be used for all 
patients with r/r lymphoma, either previously treated or to be enrolled moving forward, as 
indicated in Appendix 9.
2. The option of twice per day dosing has been introduced to enable the exploration of higher 
doses while reducing the total number of BLZ945 capsules to be taken at each 
administration. This will also decrease steady state Cmax, potentially improving 
tolerability of study treatment. The dosing regimens defined in Section 6.1.1 remain the 
same while the total daily dose may be split into two doses per day.
3. To align with the recently published ImmunoOncology toxicity management guidelines
(Brahmer 2018, Haanen 2017). The dose modification section of the protocol and 
corresponding tables were updated. The Appendix 9 ‘Recommended management 
algorithms for suspected toxicities’ were removed for the same purpose.
4. Removal of the baseline and on treatment blood sample collections for the assessment of 
serum cytokines used for retrospective analysis of a cytokine release syndrome adverse 
event. Blood samples for serum cytokines were included due to the unknown risk of 
Cytokine Release Syndrome (CRS) with ImmunoOncology agents alone and in 
combination, and to allow an assessment of any association between cytokines and clinical 
events. These samples have been drawn at baseline and at the time of a potential CRS 
event, stored, and analyzed retrospectively. Due to this, results are not intended to be used 
to support clinical decision-making for patients with possible CRS. There were no 
unexpected clinically assessed events of CRS observed across 19 studies including more 
than 2200 patients. The risk of CRS in the current study is deemed to be low, thus 
supporting the removal of this blood sample collection.
Other changes to the protocol include:
The ‘prohibited’ and ‘to be used with caution’ medications requirements have been updated 
with recent clinical data on drug interaction information for potential co-medications.
The time points of collection of PBMC and plasma biomarker samples have been updated to 
correlate with drug exposure.
The withdrawal of consent language has been revised to differentiate sample use after a patient 
withdraws consent based on the different regulations/laws around the world.
Other clarifications and editorial changes have been made to this amendment for consistency 
and/or clarity. 


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Study update
The CBLZ945X2101 study started enrollment on 21-Oct-2016. As of 27-Aug-2018, 52 patients 
have been enrolled in the BLZ945 single agent dose escalation part and 30 patients have been 
enrolled in the BLZ945 and PDR001 combination dose escalation part.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Glossary of terms: updated the definition of Personal Data and Withdrawal of study consent
Section 2.2 and 2.3: added clarifications to study design of regimen and introduced twice per 
day administration for those dosing schedules 
Table 3-1 and Section 10.5.2: updated the secondary objective of phase I part to include tumor 
assessment for lymphoma patients
Section 5.2: added the clarification for inclusion criteria of relapsed or refractory (r/r) 
lymphoma patients in the study
Section 6.1.1, 6.2.1.1 and Table 6-1: introduced the twice per day dosing frequency and the 
corresponding dose administration requirements
Section 6.1.3, 7.1.2, 7.1.3, 7.1.5: updated the duration of treatment period and the requirements 
of follow up period for lymphoma patients
Section 6.2.3.2.2 and 10.1.4: updated the minimum dose exposure for dose escalation decisions
for twice per day dosing
Table 6-4: updated the Grade 3 electrolyte abnormalities that resolve to ≤ Grade 1 within 7 days 
after starting supplementation is not considered as dose-limiting toxicities
Table 6-5 and 6-6: updated the dose modifications and interruptions for selected toxicities to 
align with the recently published ImmunoOncology toxicity management guidelines
Section 6.4.2 and Appendix 7 and 8: added clarifications to the co-administration of moderate 
CYP3A4/5 and CYP2C8 inhibitors/inducers
Table 7-1, 7-2 and 7-3: updated the reference of tumor evaluations and corrected typos of 
BLZ945 administration frequency
Table 7-1, 7-2, 7-3, 7-6 and Section 7.2.2.5.6: removed the collection of blood samples for 
safety cytokines
Section 7.1.4: updated withdrawal of consent language and the use of samples after consent is 
withdrawn 
Section 7.2.1.3 and Table 7-4: added the efficacy assessment requirements for lymphoma 
patients
Table 7-8 to 7-13: updated the PK sampling time points for twice per day dosing 


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Section 8.1.1 and 8.2.1: updated the definition of safety reporting for lymphoma patients
Section 8.3: updated to change the follow-up of a newborn child from 3 to 12 months
Section 10.1.3: updated the details of Per-Protocol Set for lymphoma patients
Appendix 5: updated the statistical methods applied to the twice per day dose administration
Appendix 7 and 8: updated the list of prohibited and ‘to be used with caution’ medications as 
per guidelines
Appendix 9: removed to align with the recently published ImmunoOncology toxicity 
management guidelines
Newly added Appendix 9: added “Guidelines for efficacy evaluation in Hodgkin and non-
Hodgkin lymphoma studies” to standardize the response evaluations for lymphoma patients 
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 4 (31-Jul-2018)
Amendment rationale
The primary purpose of this amendment is to incorporate health authority-requested language 
requiring study treatment discontinuation in the event of Stevens-Johnson syndrome (SJS) or 
Lyell syndrome/toxic epidermal necrolysis (TEN).
After the occurrence of a case of Steven Johnson Syndrome in a study with PDR001 in 
combination with another investigational agent, the dose modification guidelines for protocols 
using PDR001 were updated to mandate permanent discontinuation of study treatment for 
patients who experience SJS or Lyell syndrome/TEN. This change has already been 
implemented as part of an urgent safety measure released on 15 June 2018. This protocol 
amendment is now finalizing these changes in the dose modification section and corresponding 
tables describing the criteria for dose modification and interruption for selected toxicities. 
Study update
The CBLZ945X2101 study started enrollment on 21-Oct-2016. As of 24-Jul-2018, 45 patients 
have been enrolled in the ongoing BLZ945 single agent dose escalation part and 26 patients 
have been enrolled in the BLZ945 and PDR001 combination dose escalation part.
Changes to the protocol
Tables 6-5 and 6-6 (Criteria for dose modifications and interruption for BLZ945 and PDR001 
as combination treatment) have been updated to include permanent discontinuation of study 
treatment for SJS or Lyell syndrome/TEN.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
This amendment is required for formalization of the changes already implemented by the USM 
issued on 15 June 2018. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 3 (05-Feb-2018)
Amendment rationale 
Analysis of pharmacodynamic changes is critical for the selection of the best dose and schedule 
for further evaluation of BLZ945. Therefore the main purpose of this amendment is to adjust 
biomarker and biochemistry sample collection time points based on information obtained 
during the study so far.

To ensure a comprehensive assessment of pharmacodynamic changes in tumor tissue the 
on-treatment biopsy will be obtained at an earlier timepoint (at the beginning of cycle 2) 
and all patients must now have a site of disease amenable to biopsy. As a biopsy is 
typically not feasible in glioblastoma patients, such patients may enroll in the study 
without biopsy following documented agreement between Investigator and Novartis.

To optimize the analysis of systemic humoral and cellular immune-modulation, the 
collection of plasma and PBMC biomarker samples will also be obtained earlier during the 
study.

Elevation of liver enzymes are proposed to be a pharmacodynamic effect of BLZ945 due 
to decreased clearance by liver macrophages and were found to have an early onset 
(typically in cycle 1) in this study. To capture these pharmacodynamic modulations and to 
correlate with exposure to BLZ945, PK and biochemistry samples will be collected more 
frequently in cycles 1 and 2.
Other minor clarifications and editorial changes have been made and are included in the list of 
changes below.
Study update
The CBLZ945X2101 study started enrollment on 21-Oct-2016. As of 29-Nov-2017, 28 patients 
have been enrolled in the ongoing BLZ945 single agent dose escalation part. In addition, 5 
patients have been enrolled in the BLZ945 and PDR001 combination dose escalation part.
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 5.2: updated inclusion criteria #4 removing the limitation that only patients in Phase 1 
part were to have tumor biopsies, hence all patients must now provide tumor samples. Inclusion 
criteria #3 was clarified where appropriate that the tumor assessment of glioblastoma patients 
will use the RANO criteria. 
Table 7-1, 7-2 and 7-3: updated the biomarker sample collection plan. 
Table 7-1, 7-2 and 7-3: updated the PK sample collection. 
Table 7-3: A typographical error regarding the on-treatment timepoint for Chest X-ray was 
corrected 
Table 7-2: updated the schedule of clinical chemistry assessments by adding Cycle 1 Day 2, 9 
and Cycle 2 Day 2.


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Table 7-3: updated the schedule of clinical chemistry assessments by adding Cycle 1 Day 2, 19 
and Cycle 2 Day 2.
Table 7-1, 7-2 and 7-3 and section 7.1.5: clarified the requirement regarding to safety follow-
up to only include 30-day, 90-day and 150-day follow-up for patients treated with BLZ945 in 
combination with PDR001.
Section 7.2.2.6: clarified the instructions for ECG assessment
Section 7.2.2.6.1: clarified the sequence of blood sample and ECG collections
Table 7-8, 7-9, 7-10, 7-11, 7-12 and 7-13: updated the PK sample collection time points and the 
corresponding analytes.
Table 7-11, 7-12 and 7-13: clarified the reference treatments of specified PK sample collection 
time points. 
Table 7-13: updated analytes to include PDR001 on Cycle 1 Day 5.
Table 7-14: updated biomarker sample collection plan for on-treatment tumor and blood 
samples 
Section 8.2.2: clarified the SAE collection period.
Appendix 9: updated Management Algorithms to include the neurological AEs.
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 2 (24-Oct-2017)
Amendment rationale 
The purpose of this amendment is to revise definitions for dose limiting toxicities (DLTs) 
regarding Grade 3 febrile neutropenia, and update the definition of Grade 3 febrile neutropenia 
in line with CTCAE version 4.03, following Health Authority feedback.
Study update
The CBLZ945X2101 study started enrollment on 21-Oct-2016. As of 05-Oct-2017, 22 patients 
with advanced solid tumors have been enrolled in the ongoing BLZ945 single agent dose 
escalation part. The BLZ945 and PDR001 combination part opened for enrollment on 6-Oct-
2017.
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.

Section 6.2.4, Table 6-4: The grade 3 febrile neutropenia should be defined as DLTs 
without exception related to the duration of fever ≥38 °C.

Section 6.3.2, Table 6-5 and Table 6-6: The grade 3 febrile neutropenia quoted for dose 
modifications and interruption is updated to be consistent with CTCAE version 4.03.
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes described 
in this amended protocol require IRB/IEC approval prior to implementation. 


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Amendment 1 (04-Aug-2017)
Amendment rationale
The purpose of this amendment is to address the inclusion of Japanese patients in the study in 
a separate dose escalation arm, to permit the exploration of alternative BLZ945 dosing 
schedules, and to clarify eligibility criteria. 
The single agent dose escalation part of this study is ongoing globally with the exception of 
Japan. At the time of this amendment patients are being treated with BLZ945 single agent at a 
dose higher than the starting dose of 150 mg QD 7d on/7d off. In order to ensure that the safety 
and pharmacokinetic profiles of single agent BLZ945 are adequately characterized in Japanese 
patients, a specific dose escalation of single-agent BLZ945 in a minimum of 12 Japanese 
patients has been included in the protocol. The Japanese dose escalation will run separately 
from the ongoing dose escalation. PDR001 has been administered as a single agent to Japanese 
patients in a separate study and no differences have been observed in either the safety profile or 
PK of PDR001 between Japanese patients and patients in the rest of the world. Therefore, if the 
recommended dose determined in the global dose escalation part of the BLZ945 phase I single 
agent is found to be the same in Japanese patients, then Japanese patients may also enter the 
combination part of study at whichever dose is being tested at that time. 
To further characterize the safety and efficacy of BLZ945 an additional dosing schedule has 
been added to the protocol. PK/PD (preclinical and preliminary clinical PK) modeling results 
have suggested that an alternative schedule (4 daily doses of BLZ945 followed by 10 days off) 
may permit recovery of observed ALT elevations. This regimen repeats every 14 days.
As preliminary PK data has become available for this first in human study, the observed 
elimination half-life of BLZ945 was longer than predicted (24 versus 10 hours) and has been 
included in section 2.3. As a consequence of this, the exclusion criteria 20 and 21 have been 
updated to amend the follow-up requirements of contraception after the last dose of single agent 
BLZ945. 
Following the request of a regulatory authority inclusion criteria 5 is modified. Previously it 
was stated that pancreatic cancer patients are eligible if they failed to respond or progressed on 
or after treatment with gemcitabine. However, in some regions the standard of care for 
pancreatic cancer may not only be gemcitabine. Therefore, gemcitabine is no longer specified, 
and has been replaced by standard of care. 
The study prohibits systemic steroid therapy, however glioblastoma patients may be receiving 
dexamethasone for symptom relief. In order not to exclude such patients who may otherwise be 
eligible for study entry, these patients may be considered if they are receiving dexamathasone 
<1 mg/day.
Asymptomatic serum enzyme elevation, including grade 2 and 3 AST and ALT elevations, have 
been observed and reported as suspected to be related to BLZ945 treatment. The events resolved 
without interruption of study treatment except for one patient with liver metastases who had 
grade 2 AST/grade 1 ALT elevation at baseline. In order to ensure patient safety, an eligibility 
criterion has been revised to exclude patients with either AST or ALT laboratory values greater 
than grade 1 at screening (it had previously be stated AST and ALT >grade 1). This criterion 
now applies to all patients irrespective of liver tumor involvement. 


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To add clarity, Table 6-5 (Criteria for dose modifications and interruption for BLZ945 and 
PDR001) has been separated into two tables, one table for single agent BLZ945 and one table 
for BLZ945 and PDR001 in combination.
To add clarity, Table 7-1 (Visit Evaluation Schedule) has been separated into three tables, one 
table for each dosing schedule. 
Other minor changes/corrections were made for consistency and/or clarification.
Study status
The current study began recruitment on 21-Oct-2016. As of 27-Jun-2017, 13 patients with 
advanced solid tumors have been enrolled and treated at dose levels of BLZ945 150 mg QD 7 
d on/7d off (Cohort 1), BLZ945 300 mg QD 7d on/7d off (Cohort 2) or BLZ945 300 mg QD 
7d on/7d off (Cohort 3).
Changes to the protocol
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions.
Section 1.2.1.2: updated BLZ945 clinical experience.
Section 2.2: updated rationale for the study design to include the Japanese dose escalation part 
and to allow exploration of an alternative BLZ945 dosing regimen.
Section 2.3: updated rationale for dose and regimen selection to include new BLZ945 regimen 
and clarify the RP2D/MTD in phase II. Updated median elimination half-life based on 
preliminary PK data.
Section 3, table 3-1: included the objective for the dose escalation in Japanese patients.
Section 4.1: updated study design to include the dose escalation in Japanese patients and the 
new BLZ945 regimen.
Section 5.2: updated inclusion criteria for Japanese only: written consent is necessary both 
from the patient and his/her legal representative if he/she is under the age of 20 years. Inclusion 
criteria 5 modified to clarify that patients with advanced pancreatic cancer who failed to respond 
or progressed on or after treatment with standard of care are eligible.
Section 5.3: updated criteria 3 to exclude patient with ALT or AST > 3 x ULN at screening. 
Clarified criteria 7 to exclude patients with ongoing symptomatic interstitial lung disease. 
Clarified criteria 9 to exclude GBM patients receiving greater than 1 mg dexamethasone per 
day (or an equivalent amount of an alternative corticosteroid). Clarified criteria 11 to include 
the washout period for prior immunotherapies. Updated criteria 20 and 21 to change the 
contraception follow-up from 3 to 14 days after last dose. 
Section 6.1: updated dosing regimen instruction for the new BLZ945 regimen.
Section 6.2: updated starting dose rationale with the new BLZ945 regimen as a single agent and 
in combination with PDR001, and the dose rationale for the dose escalation in Japanese patients. 
Section 6.3: clarified dose modifications to indicate in which circumstances immune-related 
etiology (irAE) AEs must lead to discontinuation of PDR001. 


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Section 6.3.2: Table 6-5 has been clarified by splitting it into two separate tables, one for single 
agent BLZ945 and one for the BLZ945 and PDR001 combination.
Section 6.4: clarified that not all concomitant medications which are known to increase the pH 
are prohibited. 
Section 6.6.1: Clarified the formulation of PDR001
Section 7, table 7-1: updated section and table to include new assessments specific to Japanese 
patients, and table 7-1 split into three separate tables for each dosing schedule 
Section 7.1.5: Clarified some follow up period procedures. 
Section 8.1 and 8.2: clarified the AE/SAE reporting rule after initiation of new post-treatment 
antineoplastic therapy.
Section 10: Updated as per the new requirements for the Japanese dose escalation and the new 
dosing schedule. 
Section 11.3: updated informed consent procedures for Japanese patients only: written consent 
is necessary both from the patient and his/her legal representative if he/she is under the age of 
20 years.
Section 11.5: Novartis publication policy has been updated
Section 14.7: added statistical details of Phase I Bayesian logistic regression model in Japanese 
patients treated with BLZ945 single agent.
IRB/IEC/REB 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. In addition, the 
changes herein affect the Informed Consent and sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
amended protocol.


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1
Background 
One major challenge preventing successful tumor immunotherapy is the need to break immune 
tolerance and overcome local immunosuppression. In many cases, the tumor microenvironment 
is skewed toward an anti-inflammatory state, favoring immune-suppressive regulators, rather 
than immune effector cells (Mantovani et al 2008). Tumor cell-intrinsic mechanisms of immune 
evasion are reduced expression of major histocompatibility complex (MHC) molecules, 
increased expression of immunosuppressive molecules such as programmed death-ligand 1
(PD-L1) and cytokines such as interleukin (IL)-10 and TGF-β (Gajewski et al 2013). 
Tumor-associated macrophages (TAMs), regulatory T cells (Tregs) and myeloid-derived 
suppressor cells (MDSCs) greatly contribute to cancer-induced immune suppression 
(Bayne et al 2012). In contrast to anti-tumorigenic M1 subtype macrophages, M2 subtype 
macrophages have been shown to exert pro-tumorigenic functions (Mantovani et al 2002). 
These TAMs secrete proangiogenic and growth factors, as well as potently suppress T cell 
effector function by releasing immunosuppressive cytokines (Wynn et al 2013, 
Biswas and Mantovani 2010, Gordon and Martinez 2010). This will result in enhanced survival, 
proliferation, invasion and metastasis of tumor cells and also a supportive stroma by promoting 
tumor vascularization and suppression of the antitumor immunity (Qian and Pollard 2010). 
Additionally, increased macrophage infiltration has been identified as an independent poor 
prognostic factor in several cancer types, including breast, glioblastoma and pancreatic cancer, 
with infiltrating CD68+ or CD163+ TAMs shown to correlate with poor outcome (DeNardo et 
al 2011, Kurahara et al 2011, Shabo et al 2008). 
Not surprisingly, a tumor microenvironment rich with TAMs can impede immunotherapy, and 
approaches to specifically reduce immune suppression within the tumor microenvironment are 
gaining momentum as a companion immune-base treatment. The major survival factor for these 
macrophages is macrophage colony-stimulating factor 1 (CSF-1). CSF-1 and its colony-
stimulating factor 1 receptor (CSF-1R) regulate the migration, differentiation, and survival of 
tumor-associated macrophages and their precursors (Hume and MacDonald 2012, 
Chitu and Stanley 2006).  
CSF-1R inhibition has been shown to deplete macrophages and reduces tumor volume in 
several xenograft models (Manthey et al 2009, Patel and Player 2009). BLZ945, a high affinity 
CSF-1R inhibitor, has been shown to significantly decrease TAMs survival in vivo, alter their 
accumulation and block tumor progression in a genetic mouse model of glioblastoma 
multiforme (GBM) (Pyonteck et al 2013). Further experiments combining BLZ945 with 
checkpoint inhibitors such as anti-programmed death-1 (PD-1) and PD-L1 have shown 
considerable additive or synergistic effects and may provide more efficient therapeutic options 
for patients with solid tumors. 


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1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
TAMs and MDSCs are associated with high tumor grade and poor prognosis in many cancers, 
including gliomas, pancreatic cancer and triple negative breast cancer (Bingle et al 2002, 
Komohara et al 2008, Yuan et al 2014). A paracrine CSF-1/epidermal growth factor signaling 
loop has also been implicated in metastatic invasion (Coniglio 2012, Ruffell 2012).
Glioblastoma multiforme (GBM) is the most common and aggressive glioma, accounting for 
approximately 15% of all primary brain tumors in adults. There are numerous lines of evidence
highlighting the importance of host immunity in GBM biology. GBM patients with effector T 
cell tumor infiltration on histopathology have improved prognosis (Lohr et al 2011). High 
expression levels of PD-L1 are associated with worse prognosis in patients with GBM. Of 
interest, high PD-L1 expression in the neurons adjacent to tumor cells is correlated with low 
PD-L1 expression in tumor cells and associated with improved survival (Liu et al 2013). TAMs 
in particular are associated with high tumor grade and poor prognosis including gliomas 
(Bingle et al 2002, Hussain et al 2006, Komohara et al 2008). TAMs are the predominant 
infiltrating immune cell in GBM and can account for up to 40% of the tumor cell mass 
(Kostianovsky et al 2008, Kennedy et al 2013) and have been shown to play a major role in the 
creation of a tumor microenvironment that promotes tumor progression. Shortcomings of 
attempts at anti-glioma immunotherapy may result from a failure to adequately address these 
effects. For patients with tumor progression after first-line treatment, management options 
include repeat surgical resection, stereotactic radiotherapy and systemic therapies such as 
bevacizumab, metronomic temozolomide, carmustine and lomustine (Weller et al 2013). 
However, these approaches lack significant efficacy and median overall survival (OS) is 
generally less than 1 year and a 5-year survival rate is only 3.3% (Weller et al 2013).  Therefore, 
novel therapeutic strategies are clearly needed.
Recently, a Phase 3 trial evaluating the addition of nivolumab to the current standard of care 
(temozolomide and radiation therapy) versus the standard of care alone (CheckMate-548) did 
not meet the primary endpoint of progression-free survival (PFS), in patients with newly 
diagnosed glioblastoma multiforme (GBM) that is O6-methylguanine-DNA methyltransferase 
promoter 
(MGMT)-methylated
(Bristol-Myers 
Squibb 
Company, 
press 
release, 
[https://bit.ly/2ktBxYb]). Nivolumab also failed to meet the primary endpoint of overall 
survival in combination with radiation therapy compared with temozolomide and radiation in 
the phase III CheckMate-498 trial, which looked at patients with newly diagnosed MGMT-
unmethylated GBM (Bristol-Myers Squibb Company, press release, [https://bit.ly/2V9ceag]). 
A recent analysis from the Checkmate-143 study indicated that there are subgroups of patients 
who may derive benefit from anti-PD1 treatment, including patients requiring only low doses 
of corticosteroids (Weller et al 2019). Targeting the myeloid cells of the tumor 
microenvironment by inhibiting CSF-1R may add to the potential of immunotherapy in 
glioblastoma.
Breast cancer is one of the most frequent malignant neoplasms occurring in women in 
developed countries. Triple-negative breast cancer (TNBC) accounts for approximately 15% of 
newly diagnosed breast cancers, but due to its aggressive nature a disproportionate number 
(25%) of TNBC are reported in the metastatic setting (Carey et al 2006, Dahlberg et al 2009). 
TNBC is characterized by lack of expression of the estrogen and progesterone receptors and 


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lack of overexpression of the human epidermal growth factor receptor 2. The clinical course of 
TNBC is associated with a high probability of distant metastases, especially to the lung and 
brain (Dent et al 2007). 
The tumor microenvironment plays an important role in breast cancer progression. Among the 
many cell types associated with the tumor microenvironment, TAMs are the most influential 
for breast cancer progression by promoting angiogenesis, tumor growth and dissemination 
(Leek et al 1996, Pollard 2004, Obeid et al 2013). Furthermore, TAMs have an 
immunosuppressive effect by inhibiting the CD8+ cytotoxic T-cells (Noy and Pollard 2014). 
High tumor infiltration of TAMs is associated with poor chemotherapy response and prognosis 
in breast cancer (DeNardo et al 2011, Yuan et al 2014). In human breast tumors expressing both 
CSF-1 and CSF-1R, invasion in vivo is dependent both on a paracrine interaction with TAMs 
and an autocrine regulation of CSF-1R in the tumor cells themselves (Patsialou et al 2009). 
Recently it has been shown that autocrine CSF-1R signaling mediates switching between 
invasion and proliferation downstream of TGFβ in claudin-low breast tumor cells 
(Patsialou et al 2015). Blockade of CSF-1 signaling to the macrophages has also been shown to 
reduce primary tumor growth due to decreased angiogenesis as well as to improve 
chemotherapeutic efficacy in tumor xenografts due to increased antitumor T-cell responses 
(Aharinejad et al 2004, Paulus et al 2006).
Currently, there are no targeted therapies for TNBC and the only treatment option is 
chemotherapy, though more recent clinical trials have shown some remarkable response to anti-
PD-1/PD-L1 treatment (Emens et al 2015).  Most patients receive anthracyclines and taxanes 
in the adjuvant setting and the standard of care for patients with metastatic TNBC also mainly 
includes cytotoxic chemotherapy (NCCN 2014, Cardoso et al 2018).  For this reason, TNBC is 
considered a disease with high unmet medical need, as the median survival is approximately 1 
year (Kassam et al 2009).   
Pancreatic cancer is a very aggressive disease with dismal prognosis and expected to be the 
second deadliest malignancy in the USA by 2020. (Hidalgo 2010, Hidalgo et al 2015). 
The tumor microenvironment is characterized by a strong desmoplastic reaction, with a 
complex cross-talk between tumor cells and the stroma, which is a hallmark of disease. Kaplan–
Meier survival analyses revealed that higher numbers of tumor-infiltrating CD163 M2 
macrophages and MDSCs were significantly associated with shorter OS and disease free 
survival (DFS) in patients with pancreatic cancer.
Surgery remains the only curative treatment for pancreatic cancer, but therapeutic strategies 
based on initial resection have not substantially improved the survival of patients with 
resectable disease over the past 25 years; presently, more than 80% of patients suffer disease 
relapse after resection and the 5-year survival rate for these patients remains only 15–20% 
(Hidalgo et al 2015). In patients with advanced-stage disease, modest improvements in survival 
have recently been attained with FOLFIRINOX (folinic acid, 5-fluorouracil, irinotecan, and 
oxaliplatin) or albumin-bound paclitaxel (nab-paclitaxel) plus gemcitabine (Conroy et al 2011, 
Von Hoff et al 2013). In the metastatic setting, single-agent gemcitabine therapy has been the 
standard of care for patients desiring active treatment. Checkpoint inhibitors, such as anti-PD‑
1 or anti-CTLA ‑ 4 have failed to show activity in pancreatic cancer as single agents 
(Royal et al 2010, Topalian et al 2012).


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The common feature of these indications is the high unmet medical need and a tumor biology 
characterized by high levels of TAMs in the tumor microenvironment that may contribute to 
immune evasion and immune suppression. Novel therapeutic strategies are urgently needed. 
This study provides an opportunity to assess whether blockade of CSF-1R in conjunction with 
anti-PD-1 therapy may promote robust re-programming of TAMs and remove immune 
suppression of tumor infiltrating lymphocytes (TIL) potentially providing a new standard of 
care for these patients.
1.1.1
CSF-R1 Overview
Human macrophages are differentiated from monocytes in vitro in the presence of either CSF-
1 or granulocyte macrophage colony-stimulating factor (GM-CSF). CSF-1-differentiated 
macrophages are pro-tumorigenic, are called M2 macrophages or TAMs when present in 
malignant tissues, and are characterized by the expression of CSF-1R and CD163, whereas 
differentiation with GM-CSF resulted in M1-macrophages with undetectable CD163 and CSF-
1R, high expression of  CD80+MHC-II and high antigen processing capacity 
(Geissmann et al 2010, Martinez et al 2008). 
In cancer, CSF-1-differentiated macrophages reflect diminished tissue integrity and an adaptive 
process engaged by tumors to support growth (Noy and Pollard 2014). With the critical role for 
chemokine (C-C motif) ligand 2 (CCL2) and CSF-1 in recruiting macrophages to neoplastic 
tissue, there is growing interest in targeting these ligands and/or their respective receptors in an 
effort to ablate the pro-tumorigenic properties of macrophages. 
For many solid tumor types, high densities of cells expressing macrophage-associated markers have 
generally been found to be associated with a poor clinical outcome (Komohara et al 2014, 
Zhang et al 2012). Expression of both CD163 and CD204 are associated with activation of 
macrophages toward a tumor-promoting and immunosuppressive phenotype, and significant 
correlations between CD163/CD204 and negative outcomes have been reported across multiple 
tumor types (Komohara et al 2014). To exert their pro-tumorigenic activity, M2 macrophages 
produce an array of cytokines, chemokines, growth factors, hormones, matrix-remodeling 
proteases, and metabolites such as CSF-1 and CCL2, prostaglandin E2, and damage-associated 
molecular patterns such as high-mobility group box 1 protein, extracellular adenosine 
triphosphate, and degraded extracellular matrix components (Ruffell et al 2012, 
Zelenay and Reis e Sousa 2013).
In vivo studies have revealed that M2-macrophages also mediate chemotherapy resistance by 
providing survival factors and/or activating anti-apoptotic programs in malignant cells. 
In murine pancreatic ductal adenocarcinoma (PDAC) cells, resistance to gemcitabine is 
dependent on the macrophage-mediated activation of signal transducer and activator of 
transcription 3 (STAT3) (Mitchem et al 2013). STAT3 activation promotes neoplastic cell 
proliferation and survival, and multiple tumor cell lines exhibit IL-6- or STAT3-dependent 
chemoresistance in vitro (Taniguchi and Karin 2014, Yu et al 2014). CSF-1 neutralization 
enhances the response to chemotherapy in mammary carcinomas (DeNardo et al 2011).
TAMs are also well described regulators of tumor angiogenesis, with supporting evidence 
derived from both clinical and experimental studies (Murdoch et al 2008, Ruffell et al 2012) in 
which much of their capability is associated with vascular endothelial growth factor signaling. 


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Furthermore, M2-macrophages can also directly suppress CD8+ T cell proliferation in murine 
tumor models (DeNardo et al 2011, Doedens et al 2010, Movahedi et al 2010, 
Ruffell et al 2014). In these models, T cell suppression by immature myeloid cells is typically 
linked to nutrient depletion via the metabolism of L-arginine or production of free radicals 
(Gabrilovich and Nagaraj 2009). Hypoxia also promotes macrophage-suppressive activity via 
expression of arginase-1 (Doedens et al 2010) and L-arginine depletion (Rodriguez et al 2003). 
In humans, however, there is no evidence for a role of nutrient depletion in mediating immune 
suppression by TAMs because macrophages conditioned by ovarian carcinoma ascites suppress 
T cell proliferation independent of arginase and NOS activity (Kryczek et al 2006). Instead, 
macrophages directly suppress T cell responses through PD-L1 expression in hepatocellular 
and ovarian carcinomas (Kuang et al 2009, Kryczek et al 2006). 
It is therefore tempting to target CSF-1-derived macrophages to block tumor 
immunosuppression and thus enhance checkpoint blockade therapy. As monotherapy, CSF-1R 
inhibition alone impedes the growth of orthotopically implanted PDAC cell lines 
(Mitchem et al 2013) and induces regression of 
glioblastoma multiforme (GBM)
(Pyonteck et al 2013). Interestingly, synergism in combination with immune checkpoint 
blockade has also been shown. CSF-1R inhibition provided additive efficacy to either PD-1 or 
CTLA-4 blockade in combination with gemcitabine in an orthotopic implant model of PDAC 
(Zhu et al 2014). Importantly, in this model CSF-1R inhibition also enhanced the response to 
combined PD-1/ CTLA-4 blockade in the absence of chemotherapy (Zhu et al 2014).
Figure 1-1
BLZ945 mechanism of action






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1.2.2.1
PDR001 Non-clinical experience
PDR001 binds specifically and with high affinity to human PD-1. In Biacore assays, the 
dissociation constant (KD) of PDR001 on human PD-1 is 
 In ex vivo lymphocyte 
stimulation assays using human blood, PDR001 enhances IL-2 production by approximately 2-
fold in response to super antigen stimulation with Staphylococcal enterotoxin B (SEB). PDR001 
does not cross-react with rodent PD-1, and cannot be evaluated in murine tumor models. It does 
cross-react with cynomolgus monkey PD-1, and is functionally active, making cynomolgus 
monkey a relevant species for toxicology studies. A GLP tissue cross reactivity study using 
frozen human and cynomolgus monkey tissues was also done in support of the safety of 
PDR001. There was no unexpected binding observed.
The non-clinical toxicology of PDR001 was evaluated in a five week GLP toxicology study in 
cynomolgus monkeys with safety pharmacology endpoints and an eight week recovery. Repeat 
administration of PDR001 to monkeys was well tolerated at all doses tested in the GLP 
toxicology study. No test article-related in-life, mortality, organ weight changes, or 
macroscopic findings were noted. There were no PDR001-related effects seen in any of the 
safety pharmacology endpoints assessed (cardiovascular, neurobehavioral, and respiratory). 
Macrophage infiltrates into the splenic white pulp were observed in animals given 
100 mg/kg/week and mononuclear cell infiltrates, often associated with fibrosis, around the 
injection site blood vessel (saphenous vein) in a few animals given 25 mg/kg/week. These PDR001-
related microscopic changes were fully reversible after an eight week recovery.
The following changes were noted in main phase and recovery treated animals as well as control 
recovery animals. Mostly low grade changes were noted in several tissues in the form of 
mononuclear infiltrates in the vascular and perivascular space. In general, in most organs, 
vascular/perivascular changes were limited to one or a few blood vessels in each organ and 
sometimes involved a segment of a blood vessel with occasional vessel wall degeneration. 
No evidence of parenchymal damage was associated with the vascular/perivascular changes in 
any of the organs examined and the changes were not associated with any frank tissue injury. 
While these effects were not exclusive to treated animals, because of their nature and close 
association with the expected pharmacology of PD-1 blockade, a potential PDR001 related 
effect cannot be excluded and possibly explained by mild enhanced pharmacology of PDR001. 
There were no test article related effects seen in the cardiovascular assessments. All other 
microscopic findings were considered spontaneous or otherwise unrelated to PDR001 
administration.
Dose-dependent exposure to PDR001 in each dose group was confirmed. A pharmacodynamics 
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) 
dose in this study was 
.


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1.2.2.2
PDR001 Clinical experience
PDR001 is being tested in a first in human (FIH), multi-center, open-label study 
[CPDR001X2101] starting with a phase I dose escalation part, followed by a phase II part.
The objective of this study is to determine the safety and tolerability of PDR001, and define the 
maximum tolerated dose (MTD) and/or recommended phase 2 dose (RP2D), and PK of PDR001. 
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 every 2 weeks and 3 and 5 mg/kg every 4 weeks (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 every 3 weeks as an alternative dose 
regimen if it is more convenient for scheduling purposes, for example in combination treatment 
regimens.
Most frequent AEs observed were nausea (15 patients, 25.9%), anemia and fatigue (12 patients, 
20.7%, respectively), diarrhea and vomiting (10 patients, 17.2%, respectively). The safety 
appeared to be similar across the different dose groups.
1.2.3
Overview of combination treatment
1.2.3.1
Non-clinical experience with combination of BLZ945 and PDR001
1.2.3.1.1 Non clinical pharmacokinetics and metabolism
Specific studies to investigate drug drug interactions (DDIs) have not been conducted with 
PDR001. As an antibody, PDR001 is eliminated through protein catabolism and target-
mediated disposition. Therefore, PDR001 is not anticipated to be directly eliminated through 
hepatic/renal metabolism and excretion, to compete with the elimination of BLZ945, which is 
mainly eliminated through metabolism and renal excretion. However, immunomodulators 
which may regulate CYP enzymes may cause DDI with small molecule drugs because of the 
potential to alter CYP mediated metabolism (Lee et al 2010, Huang et al 2010, 
Girish et al 2011). Therefore, the risk of DDI between PDR001 and BLZ945 cannot be totally 
excluded, although anticipated to be low. For nivolumab, the Clinical Pharmacology and 
Biopharmaceutics Review (Nivolumab FDA application number: 125554Orig1s000) states that 
nivolumab showed a lack of CYP enzyme related cytokine modulation up to a dose of 10 mg/kg 
investigated in RCC patients. Nevertheless, PK of BLZ945 in the presence and absence of 
PDR001 will be characterized in this study to assess the DDI, if any, between PDR001and 
BLZ945 (Section 10.5.4).
1.2.3.1.2 Expected overlapping toxicities
For BLZ945, the target organ effects included: clinical chemistry parameters such as 
transaminases, bone, hypothalamic/pituitary/adrenal/gonadal axis, hematopoietic system, 


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lymphoid organs/tissues, and GI track. Additionally, minor findings were observed in liver, 
lung, and kidney.
Due to the lack of common target organ effects between BLZ945 and PDR001, the potential 
for synergistic toxicity in combination is not expected.
2
Rationale
2.1
Study rationale and purpose 
Preclinical data indicate that TAMs represent an attractive therapeutic target as they represent 
key orchestrators of various tumor-promoting processes, such as escape of immune surveillance. 
Their differentiation, migration and survival are regulated by CSF-1R upon engagement with 
the soluble CSF. CSF-1R is a member of the receptor protein tyrosine kinase family of growth 
factor receptors, which includes several known proto-oncogenes (Ries et al 2014). By 
interfering with the CSF-1R pathway, BLZ945 induced reduction and re-programming of M2-
type macrophages in animal models of glioma, providing significant antitumor efficacy by 
removing/reprogramming the immuno suppressive TAMs. 
Checkpoint inhibitors have been successfully introduced to clinical practice with the recent 
approval of the antagonist antibodies to the CTLA-4 (ipilimumab) and PD-1 (e.g nivolumab 
and pembrolizumab) checkpoints. A large proportion of patients, however, do not respond to 
checkpoint inhibitors as monotherapy, and these patients therefore represent a population with 
high unmet medical needs that might benefit from alternative approaches. Results from use of 
checkpoint inhibitors in glioblastoma have not been encouraging so far, although subsets of 
patients may still benefit from the treatment, and the use of corticosteroids may affect the
efficacy of these drugs (Weller et al 2019). The use of corticosteroids will be restricted at 
baseline and collected throughout the study for potential exploration as predictive factors.
Reasons for this limited success include immune regulation mediated by cancer cells and 
leukocyte populations through a variety of cell-expressed and secreted molecules. In many 
cases, immune regulation occurs locally within the tumor, leading to an ineffectual or 
suppressed antitumor response. Antitumor immunity within the tumor microenvironment can 
be suppressed by a variety of tumor infiltrating leukocytes, including Tregs, MDSCs and TAMs. 
TAMs and MDSCs can be found in large numbers in tumors and their immunomodulatory 
activity is often exerted locally within the tumor microenvironment. Mechanisms employed by 
these cell types to suppress effective immunity include secretion of cytokines such as IL-10 and 
TGF-β, and expression of inhibitory receptors such as CTLA-4 and PD-L1.
The removal of the TAMs and MDSCs which are so important in generative 
immunosuppression provide the basis for combination strategies with checkpoint inhibitors 
such as anti-PD-1 therapy in those malignancies in which TAMs contribute to tumor 
pathogenesis. For this reason, a CSF-1R inhibitor might enhance the clinical efficacy of a 
checkpoint inhibitor such as anti-PD-1, or induce clinical benefit in patients with tumors 
showing high expression of TAMs such as glioblastoma, TNBC and pancreatic cancer and in 
those who do not respond to anti-PD-1 as single agent.


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By the end of phase I part of study (except for Japan), treatment with BLZ945 single agent and 
in combination with PDR001 showed preliminary anti-tumor activity and was well tolerated 
with manageable safety profiles. As of 14-Aug-2019, among 18 evaluable patients with 
relapsed/refractory glioblastoma (7 patients in BLZ945 arm and 11 patients in combination 
arm), 2 partial responses were reported per RANO (1 per arm). Among all 24 treated patients 
with GBM, 7 patients (29%) were on treatment for more than 16 weeks.
The phase II part of the study will investigate both BLZ945 single agent and BLZ945 in 
combination with PDR001 in glioblastoma due to the encouraging results observed during dose 
escalation. The TNBC and pancreatic cancer which were initially part of the phase II indications 
will no longer be pursued due to the business decision to focus on glioblastoma.
2.2
Rationale for the study design 
This is an open-label, phase I/II study with BLZ945 as single agent or in combination with
PDR001. The study consists of the following parts: 

A phase I dose escalation part with BLZ945 as single agent in advanced solid tumors, with 
a schedule of 7 days on/7 days off (7d on/7d off). Other dosing schedules such as once a 
week (Q1W) or 4 days on/10 days off (4d on/10d off) dosing may also be explored if deemed 
appropriate based on emerging PK and safety assessments. For each of these dosing 
schedules, once per day (QD) or twice per day (BID) dosing may be evaluated.

A phase I dose escalation part with BLZ945 as single agent in advanced solid tumor 
Japanese patients, with the goal of informing subsequent clinical development in Japan. 
The purpose of the Japanese dose escalation is to ensure that the safety and 
pharmacokinetic profile of BLZ945 as single agent are adequately characterized in 
Japanese patients at more than one BLZ945 dose level. The Japanese dose escalation for 
BLZ945 single agent will run separately from the ongoing global dose escalation.

A phase I dose escalation part with BLZ945 in combination with PDR001 in advanced 
solid tumors. The criteria for the starting dose are described in Section 6.2.1.2. 

A phase II part to evaluate clinical efficacy of BLZ945 in combination with PDR001 at the 
RP2D in glioblastoma, as shown in Figure 4-2.

A phase II part to evaluate clinical efficacy of BLZ945 in glioblastoma as single agent at 
the RP2D based on the observed signs of anti-tumor activity and demonstrated proof of 
mechanism of action (MOA) for BLZ945.
The design of the phase I part was chosen to establish the regimen and the MTD/RP2D of BLZ945 
as a single agent and in combination with PDR001 in patients with advanced solid tumors.
The dose escalation decision making will be guided by a Bayesian logistic regression model 
(BLRM) with Escalation 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/RP2D in cancer patients. The adaptive BLRM will be guided by the EWOC 
principle to control the risk of DLT in future patients on study. The use of Bayesian response 
adaptive models for small datasets has been accepted by European Medicines Agency 


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(Guideline on clinical trials in small populations, 13-Feb-2007) and endorsed by numerous 
publications (Zacks and Hersh 1998, Neuenschwander et al 2008, Neuenschwander et al 2010), 
and its development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
In the phase II part, the anti-tumor effect of BLZ945 as single agent (if applicable) or in 
combination with PDR001 will be evaluated in terms of progression-free survival rate (PFSR) 
at 6 months. Progression status at 6 months is a strong predictor of survival, and PFSR at 
6 months is a valid endpoint for the evaluation of treatment in very aggressive diseases such as 
recurrent malignant gliomas, pancreatic cancer and TNBC (Lamborn et al 2008, 
Teague et al 2015, Yadav et al 2014). A Bayesian design will be used to estimate and provide 
inferential summaries for the PFSR at 6 months. MGMT promoter methylation status and use 
of corticosteroids will be captured for potential exploration as predictive factors. The phase II 
part of the study will initially enroll 20 glioblastoma patients and may expand to 40 patients in 
total per treatment arm. An interim futility analysis will be conducted to inform a “go/no-go” 
decision (i.e. to continue enrolling up to the maximum sample size allowed) based on disease 
control rate at the first tumor assessment per RANO. This study design for phase II part is 
aiming to potentially reduces patient exposure to futile treatment. PDR001 has been 
administered as a single agent to Japanese patients in a separate study and no differences have 
been observed in either the safety profile or PK of PDR001 between Japanese patients and 
patients in the rest of the world. Therefore, if the recommended dose determined in the global 
dose escalation part of the BLZ945 phase I single agent is found to be the same in Japanese 
patients, then Japanese patients may also enter the combination part of study at whichever dose 
is being tested at that time.
2.3
Rationale for dose and regimen selection 
The selection of the starting dose follows the International Conference Harmonization (ICH)
S9 guidelines for choosing a starting a dose for a first-in-human trial conducted in patients with 
cancer, and is shown in Table 6-2.
Preclinical data suggest that comparable antitumor activity can be achieved with non continuous 
schedules. Experiments in rats and monkeys have shown significant transaminases elevation 
with continuous daily dosing. These transaminases elevations are however transitory and 
therefore the 7d on/7d off regimen has been selected to achieve a tolerable profile and TAMs 
depletion. The starting dose for BLZ945 (7d on/7d off) in combination with PDR001 will 
depend on the available data of single agent BLZ945. Preclinical data suggest that a Q1W of 
BLZ945 performs at least as well as the daily dose in terms of TAMs depletion and anti-tumor 
activity (refer to Section 1.2.1.1). The starting dose for BLZ945 (Q1W) in combination with 
PDR001 is described in Section.6.2.1.2.
Preclinical PK/PD modelling of BLZ945 plasma concentrations and ALT elevations suggest 
that a regimen of 4 daily doses of BLZ945 followed by 10 days off BLZ945 (4d on/10d off)
could allow the recovery of elevated ALT values in most patients.


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In any combination dose escalations, PDR001 will be administered at a fixed dose of 400 mg i.v. 
infusion every 4 weeks which has been shown to be well tolerated (refer to Section 1.2.2.2).
In the BLZ945 single agent dose escalation, up to three dosing schedules will be explored in 
parallel. When a dosing schedule reaches the MTD/RP2D in phase I and signs of anti-tumor 
activity are seen, a phase II part may commence with that regimen.
In the combination dose escalation, no more than two BLZ945 dosing schedules combined with 
PDR001 will be explored in parallel. When a combination dosing schedule reaches the 
MTD/RP2D in phase I, a phase II part may commence with that regimen. 
In the dose escalation in Japanese patients, up to two dosing schedules of BLZ945 will be 
explored, for example Q1W and/or 4d on/10d off.  


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3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.
Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
Phase I: To characterize the safety and tolerability and to estimate 
the MTDs and/or  RP2Ds of BLZ945 as a single agent (in non-
Japanese and Japanese patients, separately) and in combination 
with PDR001
Safety: Incidence and severity of Adverse Events (AEs) and serious 
Adverse Events (SAEs), including changes in laboratory parameters, 
vital signs and Electrocardiogram (ECGs)
Tolerability: Dose interruptions, reductions and dose intensity
The incidence of DLTs during the first cycle of treatment with single 
agent BLZ945 and with BLZ945 in combination with PDR001
Phase II: To assess the anti-tumor activity of BLZ945 in combination 
with PDR001 (and BLZ945 as single agent if appropriate)
PFS rate at 6 months (PFS6) per response assessment in Neuro-
Oncology (RANO) Criteria for glioblastoma indication.
Secondary
Refer to Section 10.5
Phase I : To evaluate the preliminary anti-tumor activity of BLZ945 
as single agent and in combination with PDR001
PFS, Best Overall Response (BOR), Overall Response Rate (ORR), 
Disease Control Rate (DCR)  per RECIST v1.1 and immune-related 
response criteria (irRC), and RANO/iRANO Criteria for glioblastoma 
indication and the Guidelines for efficacy evaluation in lymphoma 
studies for lymphoma indication(s).
Phase II : To evaluate the preliminary anti-tumor activity of BLZ945 
as single agent (if appropriate) and in combination with PDR001
PFS per immune response assessment in Neuro-Oncology (iRANO) 
for glioblastoma indication
BOR, DOR and DCR per RANO and iRANO for glioblastoma
Phase II: 
To describe the survival distribution of patients treated with BLZ945 
as single agent (if appropriate) and in combination with PDR001 
Phase II: To further characterize the safety and tolerability of 
BLZ945 as a single agent and in combination with PDR001
Overall survival (OS)
Safety: Incidence and severity of Adverse Events (AEs) and serious 
Adverse Events (SAEs), including changes in laboratory parameters, 
vital signs and Electrocardiogram (ECGs); 
Tolerability: Dose interruptions, reductions and dose intensity
Phase I/II parts: 
BLZ945 and PDR001 PK parameters [e.g. AUC, Cmax, Tmax]


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Objective
Endpoint
Analysis
Characterize PK of BLZ945 as a single agent and in combination 
with PDR001
Phase I/II parts: 
To assess emergence of anti-PDR001 antibodies following one or 
more i.v. infusions of PDR001 in combination with BLZ945
Presence and/or concentration of anti-PDR001 antibodies
Exploratory
Refer to Section 10.6
Phase I: 
To assess the pharmacodynamics effect of BLZ945 as single agent 
and in combination with PDR001 in tumor 
Change from baseline in expression of immune-related genes. Change 
from baseline in expression of immune-oncology biomarkers including
but not restricted to CD163; CD8 by immunohistochemistry.


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4
Study design
4.1
Description of study design 
This study is a first in human, open-label, multi-center phase I/II study which consists of a phase 
I dose escalation part of BLZ945 as single agent, and of BLZ945 in combination with PDR001,
where alternative dosing regimens of BLZ945 will be evaluated. Once the MTD/RP2D for 
BLZ945 as single agent is established, a phase II part may commence, should signs of anti-
tumor activity been seen during the phase I. Once the MTD/RP2D for BLZ945 in combination 
with PDR001 is established, a phase II part will commence.
The single agent BLZ945 dose escalation may explore up to three dosing schedules in parallel, 
7d on/7d off, Q1W or 4d on/10d off, if deemed appropriate based on emerging PK and safety 
assessments.
A separate Japanese single agent dose escalation will be performed in order to ensure that the 
safety and pharmacokinetic profiles of BLZ945 single agent are adequately characterized in 
Japanese patients. The Japanese dose escalation for BLZ945 single agent will run separately 
from the ongoing global dose escalation. Up to two dosing schedules may also be explored in 
parallel, for example Q1W and/or 4d on/10d off.
The BLZ945 and PDR001 combination dose escalation may explore up to two dosing schedules 
in parallel, for example Q1W and/or 4d on/10d off.
To minimize selection bias between dosing schedules, patients will be centrally assigned 
between the dosing schedules (Section 6.5.2).
Study treatment will be administered until a patient experiences unacceptable toxicity, 
progressive disease or treatment is discontinued at the discretion of the investigator or the 
patient.
Based on the outcome of the planned interim analysis (Section 10.7 for details), no further 
patients were enrolled in part II of phase 2 according to protocol. Therefore, the enrollment of 
the Japanese cohort was halted per Investigator letter, dated 18-Jun-2021. 
The study design is summarized in Figure 4-1.


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Figure 4-1
Study design (effective prior to protocol amendment 6 approval)
1.
Optional: To be opened if signs of anti-tumor activity is seen in the phase I with BLZ945 single 
agent and upon agreement between Investigators and Novartis
2.
Best MTD/RP2D combination regimen to be selected by exploring the changes from baseline of 
CD163 and CD8/Foxp3 at Week 8
3.
To be expanded to 40 patients if anti-tumor activity is observed in the first 20 patients
4.
To be expanded to 20 patients if anti-tumor activity is observed in the first 10 patients
Figure 4-2
Study design (effective after approval of protocol amendment 06)


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*: To be expanded to 40 patients if anti-tumor activity is observed in the first 20 patients
** Japan arm was halted as communicated on 18-Jun-2021 via Investigator letter
Phase I dose escalation BLZ945 as single agent
At least 21 patients are required during the dose escalation in BLZ945 single agent to define 
MTD; however, fewer than 21 patients may be treated if the RP2D is determined prior to 
reaching the MTD (for further details see Section 6.2.3). 
Enrollment in the 7d on/7d off schedule may be stopped if early toxicity is observed, such as 
AST/ALT Grade 3 related to BLZ945 for more than 7 days in cycle 1, or AST/ALT Grade 2 
with total bilirubin Grade 2, or any other event that would lead to a dosing delay of more than 
7 days in cycle 1; then, the Q1W schedule or the 4d on/10d off schedule may be started as based 
on emerging PK and safety assessments.. 
In the Japanese dose escalation, at least 12 patients are required to be treated during dose 
escalation to define the MTD/RP2D. Dose escalation decisions will be guided by a separate 
BLRM to estimate the MTD /RP2D in Japanese patients (see Appendix 6).
Phase I dose escalation BLZ945 in combination with PDR001
The criteria for the starting dose for BLZ945 in combination with PDR001 is described in 
Section 6.2.1.2. 
A minimum of 15 patients are required during dose escalation to define the MTD; however, 
fewer than 15 patients may be treated if the RP2D is determined prior to reaching the MTD (for 
further details see Section 6.2.3).
The escalation will also be guided by an adaptive BLRM following the EWOC principle. 
Pharmacodynamics tumor changes (CD163 and CD8/foxp3) at Week 8 will assist to make a 
decision of the RP2D.
BLZ945 single agent Phase II part 
Should signs of anti-tumor activity (e.g. prolonged stable disease or PR) be seen in the phase I 
dose escalation with BLZ945 as single agent, and in agreement with the investigators, a phase
II part will be opened in order to further explore BLZ945 single agent efficacy at a
recommended dose and schedule. Patients with tumor types that have been shown to respond 
to single agent BLZ945 (maximum of two indications) will be enrolled. 
Based on the signs of anti-tumor activity observed in the phase I dose escalation with BLZ945 
as single agent in patients diagnosed with recurrent glioblastoma, this indication will be further 
explored in the phase II part (see Figure 4-2). This treatment group will initially enroll 
approximately 20 patients. If the disease control rate (DCR) is ≥ 60% (more than 12 SD or 
better at the first tumor assessment for each patient) per RANO, then the sample size may be 
expanded to approximately 40 patients. 


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Phase II part (BLZ945 in combination with PDR001)
Once the MTD and/or RP2D has been declared for BLZ945 in combination with PDR001, 
patients diagnosed with recurrent glioblastoma will be enrolled in the phase II part in order to 
assess the preliminary anti-tumor activity of the combination (see Figure 4-2).
The combination treatment group in glioblastoma will initially enroll approximately 20 patients.
If the disease control rate (DCR) is ≥ 60% (more than 12 SD or better at the first tumor 
assessment for each patient) per RANO, then the sample size may be expanded to 
approximately 40 patients. No enrollment halt is foreseen until analysis readout is available.
Details of the sample size calculations leading to the patient numbers are provided in
Section 10.8. A Bayesian design will be used in order to estimate PFS rate at 6 months for 
patients with glioblastoma (see Section 10.8 for details of sample size).
Study flow
Patients will undergo safety and efficacy assessments during screening/baseline and 
periodically during treatment as outlined in Table 7-1, Table 7-2, Table 7-3 and 
Table 7-4. Additional information for study visit flow is provided on Section 7.1.
Figure 4-3
Study flow
*30-days follow-up for BLZ945 single agent and 150-days follow-up for BLZ945 in 
combination with PDR001.
4.2
Timing of interim analyses and design adaptation
No formal interim analysis is planned for the phase I part. However, the dose-escalation design 
foresees that decisions based on the current data will be taken before the end of the study. In 
the phase II part, an interim analysis for futility based on DCR will be conducted after 
approximately 20 patients have been enrolled and have had first protocol defined post-treatment 
evaluation (or discontinue from the treatment) in each treatment arm (i.e. BLZ945 single agent 
or BLZ945 in combination with PDR001).  The purpose of the interim analysis will be to review 
the preliminary efficacy data to make decision on further expanding the enrollment. If DCR in


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either or both of the treatment arms is ≥60%, the sample size may be expanded from 20 to 
approximately 40 patients for each individual treatment arm. Please refer to Section 10.7 for 
further details.
4.3
Definition of end of study
The end of the study will be when:

at least 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 as well as the 30-days (BLZ945 single agent) or 
150-days (BLZ945 in combination with PDR001) safety follow-up period.
or

Another clinical study becomes available that can continue to provide study treatment , 
all ongoing patients on treatment are transferred to that clinical study or an alternative 
way to provide study treatment, and all discontinued patients have completed the safety 
follow-up period. Follow-up for disease progression or survival will not be performed 
or pursued.
At the end of the study, every effort will be made to continue provision of study treatment 
outside this study through an alternative option to patients who, in the opinion of the investigator, 
are still deriving clinical benefit from study treatment.
See Section 10 Statistical Methods and Data Analysis for details of timing of the primary 
analysis and final reporting of data.
4.4
Early study termination
The study 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 for discontinued or 
withdrawn patients. 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 Board (IRBs) and/or 
Ethic Committees (ECs) of the early termination of the trial.
5
Population
5.1
Patient population
In the phase I part of the study, both single and combination escalation will be conducted in all 
types of advanced solid tumors including r/r lymphoma. 
In the phase II part (both single agent and combination groups), the study will be conducted in 
patients with glioblastoma. 
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.


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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 screening procedures. 
For Japanese patients only: written consent is necessary both from the patient and his/her 
legal representative if he/she is under the age of 20 years. 
2. Age ≥ 18 years
3. Phase I part: Patients with advanced/metastatic solid tumors, with measurable or 
unmeasurable disease as determined by RECIST v1.1 (refer to Appendix 1) or RANO 
(glioblastoma) (refer to Appendix 3), who have progressed despite standard therapy or are 
intolerant of standard therapy, or for whom no standard therapy exists, including patients 
with radiographically measurable r/r lymphoma according to the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies (refer to Appendix 9) who have 
received at least two lines of available therapy and who have relapsed after transplant or 
who are not eligible for transplant.
4. Patients must have a site of disease amenable to biopsy, and be a candidate for tumor biopsy 
according to the treating institution’s guidelines. Patients must be willing to undergo a new 
tumor biopsy at screening, and during treatment. Exceptions may be considered for 
glioblastoma patients after documented discussion with Novartis.
5. Phase II part
(both single agent and 
combination groups): Patients with 
advanced/metastatic/recurrent isocitrate dehydrogenase (IDH) wild-type glioblastoma, with 
at least one measurable lesion as determined by RANO (refer to Appendix 3) 

patients with O6-methylguanine-DNA methyltransferase (MGMT)
methylated 
recurrent glioblastoma that failed to respond to or progressed on radiotherapy and 
temozolomide

patients with MGMT unmethylated recurrent glioblastoma that failed to respond to, or 
progressed on radiotherapy (with or without temozolomide)

patients who received no more than 2 prior lines of treatment (radiotherapy and 
temozolomide followed by temozolomide alone is considered one line of treatment)

patients who received no prior treatment with a VEGFR targeting agent (e.g. Avastin®).
6. Patient Eastern Cooperative Oncology Group (ECOG) performance status 0-1.
7. Life expectancy more than 12 weeks.
8. For glioblastoma patients enrolled in phase II of the study (both single agent and 
combination groups): if a newly obtained tumor sample cannot be safely collected at study 
entry, the patients must be willing to provide an archival tumor sample.
5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Presence of symptomatic CNS metastases, or CNS metastases that require local 
CNS-directed therapy (such as radiotherapy or surgery), or increasing doses of 
corticosteroids within the prior 2 weeks before start of study treatment. Patients with treated 
brain metastases should be neurologically stable (for 4 weeks post-treatment and prior to 


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study enrollment) and off of steroids for at least 2 weeks before administration of any study 
drug (this exclusion criteria does not apply for GBM patients)
2. History of severe hypersensitivity reactions to study drugs(s) and other monoclonal 
antibodies and/or their excipients.
3. Having out of range laboratory values defined as:

Creatinine clearance (calculated using Cockcroft-Gault formula, or measured) 
< 40 mL/min or serum creatinine >1.5 x Upper Limit of Normal (ULN)

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) or aspartate aminotransferase (AST) > 3 x ULN, 

Absolute neutrophil count (ANC) < 1.0 x 109/L

Platelet count < 75 x 109/L

Hemoglobin < 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 electrocardiogram (ECG) or congenital long QT 
syndrome

Acute myocardial infarction or unstable angina pectoris < 3 months prior to study entry
5. Known human immunodeficiency virus (HIV), active hepatitis B virus (HBV) or active 
hepatitis C virus (HCV) infection. No testing is required at screening. Patients whose HBV 
or HCV infection is controlled by antiviral therapy should not be excluded. 
6. Malignant disease, other than that being treated in this study. Exceptions to this exclusion 
include the following: malignancies that were treated curatively and have not recurred 
within 2 years prior to study treatment; completely resected basal cell and squamous cell 
skin cancers; any malignancy considered to be indolent and that has never required therapy; 
and completely resected carcinoma in situ of any type.
7. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns, compliance with clinical study 
procedures or interpretation of study results, including but not limited to:

ongoing symptomatic interstitial lung disease (ILD), noninfectious pneumonitis or
history of drug induced interstitial lung disease
8. Active autoimmune disease or a documented history of autoimmune disease, including 
ulcerative colitis and Crohn’s disease or any condition that requires systemic steroids, 
except vitiligo or resolved asthma/atopy that is treated with broncho-dilators (e.g. albuterol). 
Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately treated for 
skin rash or with replacement therapy for endocrinopathies should not be excluded.
9. Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day prednisone or 
equivalent). Topical, inhaled, nasal and ophthalmic steroids are not prohibited. For GBM 
patients only: patients must not be receiving greater than 1 mg dexamethasone per day (or 


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an equivalent amount of an alternative corticosteroid) (Kostaras et al 2014). For the phase 
II part, patients must not be receiving more than 2 mg dexamethasone per day (or an 
equivalent amount of an alternative corticosteroid). The doses of corticosteroids must be 
stable within 2 weeks before baseline tumor assessments.
10. Use of any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 
4 weeks of initiation of study treatment.
11. Systemic anti-cancer therapy within 2 weeks of the first dose of study treatment. 
For cytotoxic agents that have major delayed toxicity, e.g. mitomycin C and nitrosoureas, 4 
weeks is indicated as washout period. Prior antibodies or immunotherapies require a 
4 weeks washout period. 
12. Major surgery within 2 weeks of the first dose of study treatment (mediastinoscopy, 
insertion of a central venous access device, and insertion of a feeding tube are not considered 
major surgery).
13. Pre-treatment with anti-cytotoxic T-Lymphocyte-associated protein 4 (CTLA-4) antibodies 
in combination with any other antibody or drug specifically targeting T-cell co-stimulation 
or checkpoint pathway. Patients pre-treated with anti-CTLA-4 as single agent must have 
minimum 8 week washout period between the last dose of anti-CTLA-4 and the first dose 
of PDR001.
14. Participation in an interventional, investigational non-immunotherapy study within 2 weeks 
of the first dose of study treatment.
15. Presence of ≥ common terminology criteria for adverse events (CTCAE) grade 2 toxicity 
(except alopecia, peripheral neuropathy and ototoxicity, which are excluded if ≥ CTCAE 
grade 3) due to prior cancer therapy.
16. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF)
and thrombopoietin mimetics ≤2 weeks prior to start of study drug. An erythroid 
stimulating agent is allowed as long as it was initiated at least 2 weeks prior to the first dose 
of study treatment and the patient is on a stable dose.
17. Radiotherapy within 2 weeks of the first dose of study drug, except for palliative 
radiotherapy to a limited field, such as for the treatment of bone pain or a focally painful 
tumor mass. To allow evaluation for response to treatment, patients enrolled in the phase II 
part must have remaining measurable disease that has not been irradiated. For glioblastoma
patients in phase II part only: last dose of radiotherapy within 3 months of the tumor
assessment at screening.
18. Patient receiving treatment with medications that meet one of the following criteria and that 
cannot be discontinued at least 1 week prior to start of treatment and for the duration of the 
study (Appendix 6):

Strong inhibitors of CYP2C8 and of CYP3A4/5.

Strong inducers of CYP2C8 and of CYP3A4/5. 

Proton pump inhibitors

Co-administration of moderate CYP2C8 and of CYP3A4/5 inhibitors

Co-administration of moderate CYP2C8 and of CYP3A4/5 inducers


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19. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a female 
after conception and until the termination of gestation, confirmed by a positive human 
chorionic gonadotropin (hCG) laboratory test.
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 14 days after last dose of BLZ945 as a single agent and for 150 days after 
the last dose of BLZ945 in combination with PDR001. Highly effective contraception 
methods include: 

Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptom-thermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception.

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy, or tubal ligation at least six weeks before taking 
study treatment. In case of oophorectomy alone, only when the reproductive status of 
the woman has been confirmed by follow up hormone level assessment.

Male sterilization (at least 6 months prior to screening). For female patients on the study, 
the vasectomized male partner should be the sole partner for that patient.

Use of oral (estrogen and progesterone), injected or implanted combined hormonal 
methods of contraception or placement of an intrauterine device or intrauterine system, 
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 
12 months of natural (spontaneous) amenorrhea with an appropriate clinical profile (i.e. age 
appropriate [generally age from 40 to 59], history of vasomotor symptoms [e.g. hot flush]
in the absence of other medical justification) or have had surgical bilateral oophorectomy 
(with or without hysterectomy), total hysterectomy, or tubal ligation at least six weeks ago. 
In the case of oophorectomy alone, only when the reproductive status of the woman has 
been confirmed by follow up hormone level assessment is she considered not of child 
bearing potential
21. Sexually active males unless they use a condom during intercourse while taking the drug 
during treatment, for 14 days after stopping BLZ945 and 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 semen.
22. Use of non-invasive antineoplastic therapy (e.g. Optune®) within 2 weeks of the tumor
assessment at screening.


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6
Treatment 
6.1
Study treatment
For this study, the study drugs are BLZ945 and PDR001. The study treatment is defined as 
BLZ945 as a single agent or in combination with PDR001. Both study drugs will be provided 
by Novartis.
All dosages prescribed and dispensed to patients and all dose changes during the study must be 
recorded on the Dosage Administration Record electronic Case Report Form (eCRF).
6.1.1
Dosing regimen
BLZ945 dosing is being evaluated on the following schedules, 7 days on/7days off (i.e., 
administer BLZ945 for 7 days and suspend for 7 days), once weekly (Q1W), and 4 days on/10 
days off (i.e., administer BLZ945 for 4 days and suspend for 10 days).
For each of these schedules, once per day (QD) or twice per day (BID) dosing may be evaluated.  
For once daily administration, patients should take their dose at approximately the same time 
in the morning. For the twice a day dosing, the first dose should be taken in the morning and 
the second dose should be taken approximately 10 to 12 hours after the morning dose.
On days that PK samples are obtained, the patient should take BLZ945 during the clinic visit 
after the pre-dose PK samples and prior to post-dose PK samples, when instructed by the study 
staff.
Patients should take BLZ945 on an empty stomach (i.e. fast from food and drink, except water) 
at least 1 hour before or 2 hours after a meal. Each dose should be taken with a glass of water. 
Patients should be instructed to swallow whole capsules and not to chew or open them.
If vomiting occurs during the course of treatment, patients should not take the study drug 
BLZ945 again before the next scheduled dose. For the BLZ945, a missed dose is defined as a 
case when the full dose is not taken up to one day after the approximate time of the usually 
daily dosing. That day's dose should be omitted and the patient should continue treatment with 
the next scheduled dose. If a patient forgets a prescribed once daily dose administration, and 
remembers in the morning within 4h of the scheduled dose time, BLZ945 can still be taken. 
Otherwise, dose must be skipped. For the twice a day dose administration, if a patient forgets 
to take the morning dose as scheduled but takes the morning dose within 4 hours of the 
scheduled dose time, the evening dose should be taken at least 8 hours apart from the morning 
dose. If the patient forgets to take the evening dose, it should be omitted except for the patient 
receiving BLZ945 once weekly as described below. 
For the Q1W dosing, a missed once daily dose can still be taken the next morning. For the twice 
a day dose administration, a missed morning dose can still be taken the next morning 8h apart 
from the latest evening dose. A missed evening dose can still be taken the next morning at 
approximately the same time in the morning.
Table 6-1
Dose and treatment schedule
Study 
treatments
Pharmaceutical form and route of 
administration
Dose
Frequency and/or 
Regimen
PDR001
Powder for solution for i.v. infusion
400 mg
every 4 weeks


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Study 
treatments
Pharmaceutical form and route of 
administration
Dose
Frequency and/or 
Regimen
BLZ945
Capsule, per os (p.o.)
150 mg (starting dose)
Once daily or twice a day 
either for 7days on/7days off 
Or Q1W
Or 4days on/10days off
PDR001 will be administered via i.v. infusion over 30 minutes (up to 2 hours, if clinically 
indicated) once every 4 weeks. BLZ945 should be administered, whilst fasting, prior to PDR001. 
PDR001 infusion can start any time after BLZ945 intake.
Further instructions for the preparation and dispensation of PDR001 are described in the 
[BLZ945X2101 Pharmacy Manual].
The dose of PDR001 may be delayed by up to 7 days to recover from previous drug-related 
AEs. If the dose cannot be administered within the above mentioned 7-day window, then the 
dose should be skipped. Dosing will be resumed at the next scheduled dose. Dose modifications 
should be followed described in Section 6.3.1 and Section 6.3.2.
In case of study treatment interruption, visit schedule should still be followed and assessments 
performed as per Table 7-1.
6.1.2
Ancillary treatments
Patients should not receive pre-medication to prevent infusion reaction before the first infusion 
of PDR001, in order to determine if pre-medication is necessary. If a patient experiences an 
infusion reaction, he/she may receive pre-medication on subsequent dosing days. The pre-
medication should be chosen per institutional standard of care, at the discretion of the treating 
physician.
Acute allergic reactions should be treated as needed per institutional standard of care. In the 
event of anaphylactic/anaphylactoid reactions, this includes any therapy necessary to restore 
normal cardiopulmonary status. If a patient experiences a Grade 3 anaphylactic/anaphylactoid 
reaction, the patient will be discontinued from the study.
Patients should be treated in a facility equipped for cardiopulmonary resuscitation. Appropriate 
resuscitation equipment should be available at the bedside and a physician readily available.
Guidelines on management of PDR001 infusion reactions are provided in Table 6-6.
The CTCAE category of “Infusion related reaction” should be used to describe PDR001 
infusion reactions, unless the investigator considers another category, such as “Allergic 
reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
6.1.3
Treatment duration
All patients treated with either BLZ945 single agent or in combination with PDR001 will begin 
study treatment on Cycle 1 Day 1. Each cycle will consist of 28 days. 
A patient may continue treatment with BLZ945 single agent until the patient experiences 
unacceptable toxicity, confirmed disease progression per irRC (or per iRANO for glioblastoma 
patients) or progressive (metabolic) disease per the Guidelines for efficacy evaluation in 


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Hodgkin and non-Hodgkin lymphoma studies for r/r lymphoma patients and/or treatment is 
discontinued at the discretion of the investigator or the patient. 
A patient may continue treatment with BLZ945 in combination with PDR001 until the patient 
experiences unacceptable toxicity, confirmed disease progression per irRC (or per iRANO for 
glioblastoma patients) or progressive (metabolic) disease per the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies for r/r lymphoma patients, and/or 
treatment is discontinued at the discretion of the investigator or the patient. In the first 24 weeks 
of treatment, patients will not be withdrawn from the study due to progressive disease per 
RECIST v1.1 (or per RANO for glioblastoma patients or per the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies for r/r lymphoma patients). Refer to
Section 7.1.2.
If treatment with BLZ945 has been interrupted for more than 4 consecutive weeks, then study 
treatment should be permanently discontinued. Refer to Table 6-5 and Table 6-6 for dose 
modification and interruption guidelines. 
If more than 2 consecutive doses of PDR001 have to be skipped due to study treatment-related 
toxicities the study treatment should be permanently discontinued. However, if a patient who 
misses more than 2 consecutive doses due to a study treatment-related toxicity is experiencing 
clinical benefit, and in the opinion of the investigator it is in the patient’s best interest to remain 
on study, then the patient may continue treatment after discussion with Novartis.
The above rules of discontinuation do not apply to GBM patients while evaluated with the 
iRANO criteria (Appendix 4).
Patients treated with BLZ945 in combination with PDR001 who meet criteria of discontinuation 
due to AE will not be allowed to continue on either drug as a single agent.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
6.2.1.1
Starting dose of BLZ945 as a single agent 
BLZ945 safety profile was investigated in 4-week GLP toxicology studies in rats (10, 50 and 
150 mg/kg/day) and cynomolgus monkeys (10, 30 and 100 mg/kg/day). As shown below, the 
starting dose for BLZ945 of 150 mg as a single agent is estimated based on the STD10 in rat 
study, and the HNSTD from the monkey study following ICH S9 guidance:

The STD10 for the GLP 4-week rat study is 150 mg/kg/day, with HED=24 mg/kg/day; 
1/10 of STD10 HED=2.4 mg/kg/day

The HNSTD for the 4-week GLP monkey study is 100 mg/kg/day, with 
HED=32 mg/kg/day; 1/6 of HNSTD HED=5.33 mg/kg/day.

Rat is the sensitive species, thus the human starting dose will use HED calculated from 
1/10 of STD10 in rat: 2.4 mg/kg*60kg = 144 mg/day
In order to evaluate the safety, PK and antitumor activity of BLZ945 across a range of doses, 
the recommended starting dose in this study will be 150 mg on a 7d on/7 off schedule. 


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Q1W or 4d on/10d off dosing may also be explored in parallel if deemed appropriate based on 
emerging PK and safety assessments. The starting dose of new schedule(s) will be equal or 
lower than the maximum dose that have been previously tested and met the EWOC criteria for 
the BLRM model on the 7d on/7d off schedule.
The Japanese dose escalation for BLZ945 single agent will run separately from the ongoing 
non-Japanese dose escalation with a starting dose deemed appropriate based on emerging PK 
and safety assessments and meeting the EWOC criteria of both the BLRM in the global dose 
escalation arm and that for the Japan specific escalation.
Twice daily dosing schedules may also be explored if deemed appropriate. The cumulative 
starting dose (i.e., morning dose plus evening dose) will not be higher than the dose of the once 
daily administration that has been tested and shown to satisfy the EWOC criteria using the 
Bayesian Hierarchical Logistic Regression Model (BHLRM) following a discussion with 
participating Investigators during a dose escalation teleconference.
6.2.1.2
Starting dose of BLZ945 and PDR001 combination
In order to administer a safe dose of BLZ945 in the combination with PDR001, the starting
dose of BLZ945 will meet the following:

Dose has already been tested in the single agent escalation arm 

At least one dose level below the highest investigated single agent dose for BLZ945 that 
satisfied the EWOC criterion under the appropriate single agent BLRM, is deemed 
appropriate based on emerging PK and safety assessments, and meets the EWOC criteria 
based on the BLRM of the combination model.

Not less than the single agent starting dose (i.e. 150mg) unless DLT are observed at the 
starting dose. 
In both combination dose escalations, PDR001 will be administered at a fixed dose of 400 mg 
i.v. every 4 weeks, which has been shown to be well tolerated.
6.2.2
Provisional dose levels
There will be three dose escalation arms in this study; Table 6-2 and Table 6-3 describe the 
starting doses and the provisional dose levels of the single-agent BLZ945 and the combinations 
of BLZ945 and PDR001 respectively that may be evaluated during this trial. With the exception 
of starting dose level 1, actual dose levels will be determined based on available toxicity, PK 
data, guided by the BLRM, following a discussion with participating 
Investigators during dose escalation teleconference (Section 6.2.3). Dose escalation will 
continue until one or more MTDs/RP2Ds are determined.


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Table 6-2
Provisional dose levels (BLZ945 single agent)
Dose level
Proposed dose of BLZ945*
Increment from previous dose
-1**
100 mg
-33%
1 
150 mg
(starting dose)
2
300 mg
100%
3
600 mg
100%
4
900 mg
50%
*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 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.
Table 6-3
Provisional dose levels (BLZ945 in combination with PDR001)
Dose level
Proposed dose of 
BLZ945*
Increment from previous 
dose
Proposed dose of 
PDR001
-1**
100 mg
-33%
400mg 
1 
150 mg
(starting dose)
400 mg
2
300 mg
100%
400 mg
3
600 mg
100%
400 mg
4
900 mg
50%
400 mg
*It is possible for additional and/or intermediate dose levels to be added during the course of the study Cohorts 
may be added at any dose level below the MTD in order to better understand safety, PK or PD.
**Dose level -1 represents treatment doses for patients requiring a dose reduction from the starting dose level. 
No dose reduction below dose level -1 is permitted for this study.


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6.2.3
Guidelines for dose escalation and determination of MTD/RP2D
6.2.3.1
MTD definition
The maximum tolerated dose (MTD) is defined as:

BLZ945 single agent and BLZ945 in combination with PDR001: the highest drug dosage 
that is unlikely (< 25% posterior probability) to cause DLT in 33% or more of the treated 
patients in the first cycle (28 days) of study treatment. 
6.2.3.2
Dose cohort modification
6.2.3.2.1 Dose escalation cohorts
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 dose escalation will proceed as follows:
BLZ945 single agent: The first cohort enrolled in the study will be treated with the starting 
dose as specified in Table 6-2. Once this cohort is complete and the dose escalation decision 
has been determined to escalate, the second cohort for the single agent will open. 
BLZ945 in combination with PDR001: The combination dose escalation will proceed at least 
one dose level below the highest investigated single agent dose for BLZ945 shown to satisfy 
the EWOC criterion under the appropriate single agent BLRM, for more details refer to 
Section 6.2.1.2.
6.2.3.2.2 Dose escalation decisions
For the purpose of dose escalation decisions, patients can be considered evaluable after having 
met the following criteria: 
BLZ945 single agent: Patients must complete a minimum of 1 cycle of BLZ945 treatment with 
the minimum safety evaluation and drug exposure (75% of the planned dosing days during cycle 
1 as defined below) or have had a DLT within the first cycle of treatment to be considered 
evaluable for dose escalation decisions (Section 10.1.4).
BLZ945 in combination with PDR001:
Patients must complete a minimum of 1 cycle of treatment with the minimum safety evaluation 
and drug exposure (75% of the planned dosing days of BLZ945 as defined below and a dose of 
PDR001) or have had a DLT within the first cycle of treatment to be considered evaluable for 
dose escalation decisions (Section 10.1.4).
For both once and twice a day dosing schedules, the 75% of the planned dosing days of 
BLZ945 is defined as:

at least 11 days of taking planned doses in 7d on/7d off regimen

at least 3 days of taking planned doses of BLZ945 in Q1W regimen

at least 6 days of taking planned doses of BLZ945 in the 4d on/10d off regimen


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For other potential regimens, 75% of the planned dosing days of BLZ945 during cycle 1 will 
be determined using the same principle.
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 patient has experienced a treatment-
related toxicity > CTCAE grade 2, 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, PK, and PD data from evaluable patients. The recommended dose 
for the next cohort of patients will be guided by the BLRM with EWOC principle.
The adaptive Bayesian methodology provides an estimate of all dose levels of BLZ945 as a 
single agent or in combination with PDR001 that do not exceed the MTD and incorporates all 
DLT information at all dose levels for this estimation. In general, the next dose will have the 
highest chance that the DLT rate will fall in the target interval [16-33%) and will always satisfy 
the EWOC principle. In all cases, the dose for the next cohort will not exceed a 100% increase 
from the previous dose. Smaller increases in dose may be recommended by the Investigators 
and Sponsor upon consideration of all of the available clinical data. Any dose escalation 
decisions made by investigators and Novartis personnel will not exceed the dose level identified 
by the BLRM as satisfying the EWOC principle.
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 and Table 6-3) that satisfies the EWOC criteria. 
However, if 2 patients in a new cohort at a previously tested dose level experience a DLT (e.g., 
a total of 8 patients are treated on this dose level with 2 DLT observed), further enrollment to 
that cohort will stop, the BLRM will be updated with this new information and re-evaluation of 
the available safety, PK, and PD data will occur. By incorporating information gained at the 
preceding dose cohorts, additional patients may be enrolled into the current dose cohort only if 
the combination still meets the EWOC criteria and as agreed by Investigators and Novartis 
personnel. Alternatively, if recruitment to the same cohort may not resume, a new cohort of 
patients may be recruited to a lower dose combination as agreed by Investigators and Novartis 
personnel and if the BLRM predicts that the risk for this lower dose combination to exceed the 
MTD remains below 25% (EWOC). Re-escalation may then occur 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 MTD or a suitable lower dose for 
expansion.  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 
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b. a minimum of 21 patients for single agent of global patients or 12 patients for the 
Japanese single agent dose escalation or 15 patients for combination have already 
been treated on the trial. Recommendation of RP2D may be made with fewer patients, 
prior to identification of MTD, or
c. significant activity is seen early in the phase I part, in which case a recommended 
dose for expansion may be identified and the phase II groups may be initiated without 
determination of the MTD.
3. it is the 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
To better understand the safety, tolerability and PK of single-agent BLZ945 or combinations of 
BLZ945 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 cycle of treatment, then 
the BRLM will be updated with this new information before any additional patients are enrolled 
at that higher dose level. Patients ongoing will continue treatment at their assigned dose levels.
MTD of the combination would not exceed the MTD of the single agent as no DDI is expected.
6.2.3.3
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events (AE) and laboratory abnormalities that are not DLTs), the recommendations 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. Drug administration at the next higher dose level may not proceed 
until the investigator receives written confirmation from Novartis indicating that the results of 
the previous dose level were evaluated and that it is permissible to proceed to a higher dose 
level.
6.2.3.4
Intra-Patient dose escalation
Intra-patient dose escalation is not permitted at any time within the first 4 cycles of treatment. 
After the 4th cycle is completed, individual patients may be considered for treatment at a dose 
of BLZ945 higher than the dose to which they were initially assigned. In order for a patient to 
be treated at a higher dose of BLZ945, he or she must have tolerated the lower dose for at least 
2 cycles of therapy (i.e. he or she must not have experienced any BLZ945 or PDR001-related 
toxicity CTCAE grade ≥ 2 at the lower dose originally assigned). Moreover, the new, higher 
dose with which the patient is to be treated must be a dose that has completed evaluation and 
has been shown to satisfy the EWOC criterion. For any further increase after the initial intra-
patient dose escalation, the following rules apply: the patient must have experienced no CTCAE 
grade ≥ 2, BLZ945 or PDR001-related toxicity over at least two cycles of therapy at the lower 
dose, and the higher dose being considered must have been fully evaluated and shown to satisfy 
the EWOC criterion. Consultation and agreement with Novartis must occur prior to any intra-
patient dose escalation occurring. These changes must be recorded on the Dosage 
Administration Record eCRF. Data from the first cycle of treatment at the new dose level will 


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not be formally included into the statistical model describing the relationship between dose and 
occurrence of DLT. However, this data will be incorporated into the clinical assessment of 
safety within a dose escalation teleconference.
6.2.4
Definitions of dose limiting toxicities (DLTs)
A DLT is defined as an adverse event or abnormal laboratory value assessed as unrelated to 
disease, disease progression, inter-current illness, or concomitant medications that occurs 
within the first 28 days of treatment with BLZ945 as a single agent or in combination with 
PDR001 and meets any of the criteria included in Table 6-4. National Cancer Institute 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.
The observation period for DLT in phase I part for Cycle 1 may be extended to 35 days for 
patients experiencing AE onset within the first 28 days of treatment and which requires to be 
followed up for up to 7 days to determine whether the AE is considered to be a DLT.
Table 6-4
Criteria for defining dose-limiting toxicities
For the purpose of dose escalation and cohort expansion, DLT will be adjudicated as follows:
Any Grade 4 AEs will be considered DLTs with the exception of:
Neutropenia lasting <72 hours that is not associated with fever or other clinical symptoms.
Lymphopenia. 
Electrolyte abnormalities that are not associated with clinical sequelae and are corrected with 
appropriate management or supplementation within 72 hours of the onset.
Any Grade 3 AEs will be adjudicated as DLTs with the exception of:
Infusion reaction that resolves to ≤ Grade 1 within 6 hours.
Any hematologic toxicity  lasting for < 7 consecutive days
Lymphopenia
Neutropenia lasting <7 days that is not associated with fever or other clinical symptoms. 
Nausea and vomiting persisting for < 2 days after optimal anti-emetic therapy.
Thrombocytopenia without significant bleeding.
Diarrhea persisting for < 2 days after optimal anti-diarrhea treatment.
Hypertension persisting < 7 days after treatment. 
Infection or fever in the absence of neutropenia persisting < 5 days. 
Rash or photosensitivity persisting < 7 days after treatment.
Fatigue lasting < 7 days.
Immune-related adverse events persisting < 7 days after treatment with corticosteroids.
AST or ALT  for < 7 days
Electrolyte abnormalities that resolve to ≤ Grade 1 < 7 days after starting supplementation.


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For the purpose of dose escalation and cohort expansion, DLT will be adjudicated as follows:
Any Grade 4 AEs will be considered DLTs with the exception of:
The following Grade 2 AEs will be adjudicated as DLTs:
Total bilirubin ≥ CTCAE Grade 2 and AST or ALT Grade 2
Pneumonitis persisting > 7 days despite treatment with corticosteroids. 
Eye pain or reduction of visual acuity that does not respond to topical therapy and does not 
improve to grade 1 severity within 2 weeks of the initiation of topical therapy OR requires 
systemic treatment. 
Other clinically significant toxicities, including a single event or multiple occurrences of the same 
event that lead to a dosing delay of > 7 days in cycle 1.
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 (refer to Table 6-5 or 
Table 6-6 and Table 6-7). For the dose escalation part of the study, dose reductions during Cycle 
1 are only allowed if a DLT is observed and recorded. Dose reductions are not permitted for 
PDR001.
The following guidelines may be applied:

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: 
[nccn.org/professionals/physician_gls/default.aspx#immunotherapy]), the American 
Society of 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.

A decision to resume treatment following the occurrence of a DLT, grade 3 or 4 or serious 
adverse suspected immune-related events that occur after the DLT period may be taken only 
after documented discussion with the Novartis medical monitor.
Patients who discontinue the study for a study related AE or a study-related abnormal laboratory 
value must be followed as described in Section 6.3.2.
If necessary, dose reduction will be conducted as indicated in Table 6-7. Any further dose 
reduction of BLZ945 may be performed only after documented discussion with the Novartis 
medical monitor. 


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Patients treated with BLZ945 in combination with PDR001 who meet criteria of discontinuation 
due to AE will not be allowed to continue on either drug as a single agent (refer to Section 6.1.3)
These changes must be recorded on the Dosage Administration Record Case Report Form (CRF). 
6.3.2
Follow-up for toxicities
The emergence of immune-related AE (irAE) may be anticipated based on general experience 
in clinical studies with similar class of compounds that block the negative immune regulators 
or interfere with immune cell compartments.
An irAE is any clinically significant adverse event affecting any organ that is associated with 
study drug exposure, is consistent with an immune-mediated mechanism, and where alternative 
explanations have been investigated and ruled out or are considered to be unlikely. Serologic, 
histologic (tumor sample) and immunological assessments should be performed as deemed 
appropriate by the Investigator or specialist consultant to verify the immune-related nature of 
the AE. An empiric trial of corticosteroids may also contribute to understanding the etiology of 
a potential irAE. 
Consensus management algorithms for irAEs have been developed and are available to assist 
investigators in assessing and managing irAEs (refer to Section 6.3.1).
Patients whose treatment is interrupted or permanently discontinued due to an irAE, AE or 
clinically significant laboratory value, must be followed-up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
In case of a suspected irAE, the relevant immunological assessments (e.g. rheumatoid factor
(RF), anti-DNA antibody) should be performed. In case of a toxicity suspected to be a cytokine 
release syndrome, the assessments outlined in Section 7.2.2.5.6 must be performed. All patients 
must be followed up for irAEs, AEs and SAEs for 30 days following the last dose of BLZ945 
single agent and for 150 days following the last dose of BLZ945 single agent  in combination 
with PDR001. 
Table 6-5 and Table 6-6 outlines the follow-up evaluation recommended for selected toxicities. 
For any irAEs/AEs Grade 1 and/or Grade 2, treatment with BLZ945 and/or PDR001 should be 
maintained at the determined dose and schedule, unless otherwise specified in Table 6-5.and 
Table 6-6


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Table 6-5
Criteria for dose modifications and interruption of BLZ945 during treatment with BLZ945 as single agent
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Hematology
Neutropenia 
Grade 3 (ANC < 1000 -
500/mm3)
Dose delay until resolved to ≤Grade 1
Grade 4 (ANC < 500/mm3)
Dose delay until resolved to ≤Grade 1
if resolved in ≤ 7 days, then maintain dose level.
If resolved in >7 days, ↓ 1 dose level.
Thrombocytopenia
Grade 3 (PLT < 50,000 -
25,000/mm3)
Dose delay  until resolved to ≤Grade 1
if resolved in ≤ 7 days, then maintain dose level.
If resolved in >7 days, then ↓1 dose level.
Discontinue for  study treatment-related Grade 3 >21 days or associated with significant bleeding
Grade 4 (PLT < 
25,000/mm3)
Dose delay until resolved to ≤Grade 1
if resolved to ≤ Grade 1 in ≤ 21 days, then ↓1 dose level.
If resolved in >21days, then discontinue patient from study treatment.
Febrile neutropenia
Grade 3 (ANC < 1.0 x 
109/L, with a single 
temperature of > 38.3°C or 
a sustained temperature of 
≥ 38°C for more than one 
hour)
Dose delay until resolved to ≤ Grade 1.
if resolved in ≤ 21 days, then ↓1 dose level. 
If resolved in >21days, then discontinue patient from study treatment.
Grade 4 (ANC <500/mm3)
Discontinue patient from study treatment


Novartis
Confidential
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Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Lymphopenia
Grade 3 (<0.5-0.2 x 109/L)
Maintain dose level for study treatment-related ≤ Grade 3.
Grade 4 (<0.2 x 109/L)
Dose delay until resolved to ≤Grade 3.
Grade 4 lymphopenia or leukopenia does not require discontinuation, delay treatment until resolved to ≤ Grade 3 in ≤ 28 days.
Renal
Serum creatinine
Grade 2 (> 1.5 - 3.0 x ULN) 
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification after discussion with the Novartis Medical Monitor.
Grade 3 (> 3.0 - 6.0 x ULN) 
or Grade 4 (> 6.0 x ULN)
Discontinue study treatment.
Hepatic
Isolated total Bilirubin
elevation
Grade 2 (> 1.5 - 3.0 x ULN)
If baseline total bilirubin is within normal limits, dose delay until resolved to ≤Grade 1.
If baseline total bilirubin is Grade 1, patient may continue without dose delay.
Grade 3 (> 3.0 - 10.0 x 
ULN)
Dose delay until resolved to ≤Grade 1, then may consider resuming study treatment after discussion with the Novartis Medical Monitor.
Grade 3 or Grade 4 (> 10.0 
x ULN) due to the indirect 
(non-conjugated) 
component only
Firstly, rule out hemolysis as the etiology 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.  
Grade 4 (> 10.0 x ULN) due 
to other causes
Discontinue study treatment.


Novartis
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Page 75
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
AST and/or ALT
Grade 2 (> 3.0 -  5.0 x 
ULN)
Dose delay until resolved to ≤Grade 1, then continue at same dose level.
If baseline ALT/AST is Grade 1, patient may continue without dose delay if total bilirubin is less than Grade 2.
Grade 2 transaminase 
elevation with bilirubin >2 x 
ULN (unless Gilbert’s 
syndrome)
If resolved in ≤7 days, then ↓1 dose level.
If resolved in > 7 days: discontinue study treatment
Grade 3 (> 5.0 - 20.0 x 
ULN)
Dose delay until resolved to ≤Grade 1. then:
If resolved before the next scheduled administration of BLZ945 (7 days on/ 7 days off or once weekly: < 7 days; 4 days on / 10 days off: 
< 10 days), patient may continue at the same dose level. 
If resolved after the next scheduled administration of BLZ945: ↓1 dose level.
Grade 4 (> 20.0 x ULN)
Discontinue study treatment.
Asymptomatic amylase and/or lipase elevation**
Grade 3 or Grade 4, not 
associated with symptoms 
or clinical manifestations of 
pancreatitis
Continue study treatment. 
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial report, hold study treatment.
Upon resolution to ≤ Grade 2, may resume study treatment without dose modification, after discussion with the Novartis Medical Monitor.
Pancreatitis
Grade 2/radiologic 
evidence
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification, if no clinical evidence of pancreatitis and after
discussion with the Novartis Medical Monitor.
Grade 3 or Grade 4
Discontinue study treatment.


Novartis
Confidential
Page 76
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Electrolyte abnormalities
Grade 4
Isolated G4 electrolyte imbalances/abnormalities not associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72hrs of their onset do not require discontinuation. Otherwise:
If resolved to ≤Grade 1 in ≤ 7 days, maintain dose level. 
If resolved to ≤Grade 1 in > 7 days, then ↓1 dose level
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.
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.


Novartis
Confidential
Page 77
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
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.
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)
Any Grade
Permanently discontinue study treatment


Novartis
Confidential
Page 78
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
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 treatment at same dose level
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.
Grade 4
Discontinue study treatment.
Fatigue/Asthenia
Grade 3 or Grade 4
Dose delay until resolved to ≤Grade 1
If resolved in ≤ 7 days, maintain dose level.
If resolved in > 7 days, ↓1 dose level
Any neurological disorder
Grade 2
Dose delay for study ≥ Grade 2 until resolved to ≤  Grade 1
Grade 3 or Grade 4
Discontinue for Grade 3 lasting > 7 days or Grade 4


Novartis
Confidential
Page 79
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Ocular (uveitis, eye pain, blurred vision)
Grade 2 
Dose delay for ≥ Grade 2 until resolved to ≤Grade 1
If resolved in ≤ 21 days, then ↓1 dose level)
Discontinue for any study treatment-related Grade 2 uveitis, eye pain or blurred vision that does not respond to topical therapy and does 
not improve to Grade 1 severity in ≤ 21 days OR requires systemic treatment
Grade 3 or Grade 4
Discontinue for study treatment-related Grade 3 uveitis of any duration
Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Pulmonary (pneumonitis)
Grade 1
Consider study treatment hold.
Manage per institutional practice.
Consider resuming study treatment upon radiographic evidence of improvement.
Grade 2 
Hold study treatment.
Pulmonary and infection workup.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification.
Grade 3 or Grade 4
Discontinue study treatment.
Other non-laboratory toxicities
Grade 3
Dose delay until resolved to ≤ Grade 1
If resolved in ≤ 21 days, ↓1 dose level.
If resolved in >21 days, discontinue patient from study treatment.
Grade 4
Discontinue patient from study treatment.


Novartis
Confidential
Page 80
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Any other laboratory toxicities
Grade 3 or Grade 4
Dose delay until resolved to ≤  Grade 1
**Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥ Grade 3 of 
amylase and/or lipase. 
***Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.
Table 6-6
Criteria for dose modifications and interruption for BLZ945 and PDR001 as combination treatmen
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Infusion/Hypersensitivity reactions (for PDR001 only)
Grade 1
Decrease  PDR001 infusion rate until recovery of the symptoms
Grade 2
Stop PDR001 infusions immediately, and keep line open.
Follow institutional guidelines for the management and follow-up of infusion reaction.
Restart PDR001 infusion at 50% of previous rate under continuous observation. Ensure that there is a minimum observation period of 
1 hour prior to restarting the infusion(s)
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-medication, then discontinue patient from study treatment
Grade 3 or Grade 4
Discontinue PDR001 infusion immediately, and discontinue patient from study
Provide supplemental oxygen, fluids, and other resuscitative measures and/or measures for symptomatic relief (see under Grade 2, 
above) as needed. Monitor vital signs (e.g. blood pressure, pulse, respiration, and temperature) every 15 ± 5 minutes until resolution


Novartis
Confidential
Page 81
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Hematology
Neutropenia 
Grade 3 (ANC < 1000 -
500/mm3)
Dose delay until resolved to ≤Grade 1
Grade 4 (ANC < 500/mm3)
Dose delay until resolved to ≤Grade 1
If duration > 7 days, discontinue patient for BLZ945 and PDR001 
Thrombocytopenia
Grade 3 (PLT < 50,000 -
25,000/mm3)
Dose delay until resolved to ≤Grade 1 in ≤ 21 days. 
If resolved in ≤ 7 days, then maintain dose level.
If resolved in >7 days, then ↓1 dose level for BLZ945 and maintain PDR001 dose level.
Discontinue patient from study treatment for Grade 3 >21 days or associated with significant bleeding
Grade 4 (PLT < 25,000/mm3)
Discontinue study treatment
Febrile neutropenia
Grade 3 (ANC < 1.0 x 109/L, 
with a single temperature 
of > 38.3°C or a sustained 
temperature of ≥ 38°C for 
more than one hour)
Dose delay for until resolved to ≤ Grade 1. 
If resolved in ≤ 21 days, then ↓1 dose level for BLZ945 and maintain PDR001 dose level. 
If resolved in >21days, then discontinue patient from study treatment.
Grade 4 (ANC <500/mm3)
Discontinue patient from study treatment


Novartis
Confidential
Page 82
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Lymphopenia
Grade 3 (<0.5-0.2 x 109/L)
Maintain dose level for study treatment-related ≤ Grade 3
Grade 4 (<0.2 x 109/L)
Dose delay until resolved to ≤Grade 3
Study treatment-related Grade 4 lymphopenia or leukopenia does not require discontinuation, delay treatment until resolved to ≤ Grade 
3 in ≤ 28 days.
Renal
Serum creatinine
Grade 2 (> 1.5 - 3.0 x ULN) 
Hold study treatment.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification after discussion with the Novartis Medical 
Monitor.
Grade 3 (> 3.0 - 6.0 x ULN) 
or Grade 4 (> 6.0 x ULN)
Discontinue study treatment.
Hepatic
Isolated total Bilirubin
elevation
Grade 2 (> 1.5 - 3.0 x ULN)
If baseline total bilirubin is within normal limits, dose delay until resolved to ≤  Grade 1
If baseline total bilirubin is Grade 1, patient may continue without dose delay.
Grade 3 (> 3.0 - 10.0 x ULN)
Dose delay until resolved to ≤ Grade 1, then may consider resuming study treatment after discussion with the Novartis Medical 
Monitor.
Grade 3 or Grade 4 (> 10.0 x 
ULN) due to the indirect 
(non-conjugated) component 
only 
Firstly, rule out hemolysis as the etiology 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.
Grade 4 (> 10.0 x ULN) due 
to other causes
Discontinue study treatment.


Novartis
Confidential
Page 83
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
AST and/or ALT
Grade 2 (> 3.0 -  5.0 x ULN)
Dose delay until resolved to ≤Grade 1, then continue at same dose level.
If baseline ALT or AST is Grade 1, patient may continue without dose delay if total bilirubin is less than Grade 2.
Grade 2 transaminase 
elevation with bilirubin >2 x 
ULN (unless Gilbert’s 
syndrome)
If resolved in ≤ 7 days, then ↓1 dose level for BLZ945, if resolved in > 7 days, then discontinue study treatments
Grade 3 (> 5.0 - 20.0 x ULN)
Dose delay until resolved to ≤Grade 1. then:
If resolved before the next scheduled administration of BLZ845 (7 days on/ 7 days off or once weekly: < 7 days; 4 days on / 10 days 
off: < 10 days), patient may continue at the same dose level. 
If resolved after the next scheduled administration of BLZ845 ↓1 dose level for BLZ945 and maintain PDR001 dose level.
Grade 4 (> 20.0 x ULN)
Discontinue study treatments.
Asymptomatic amylase and/or lipase elevation**
Grade 3 or Grade 4, not 
associated with symptoms or 
clinical manifestations of 
pancreatitis
Continue study treatments.
If levels do not resolve to ≤ Grade 2 within ≤ 14 days after the initial report, hold study treatments.
Upon resolution to ≤ Grade 2, may resume study treatments without dose modification, after discussion with the Novartis Medical 
Monitor.
Pancreatitis
Grade 2/radiologic evidence
Hold study treatments.
Manage per institutional practice.
Upon resolution to ≤ Grade 1, may resume study treatments without dose modification, if no clinical evidence of pancreatitis and after 
discussion with the Novartis Medical Monitor.
Grade 3 or Grade 4
Discontinue study treatments.


Novartis
Confidential
Page 84
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Electrolyte abnormalities
Grade 4
Isolated G4 electrolyte imbalances/abnormalities not associated with clinical sequelae and are corrected with 
supplementation/appropriate management within 72hrs of their onset do not require discontinuation.
Otherwise:
If resolved to ≤Grade 1 in ≤ 7 days, maintain dose level. 
If resolved to ≤Grade 1 in > 7 days, then ↓1 dose level for BLZ945 and maintain PDR001 dose level.
Cardiovascular
ECG QTc-Interval prolonged; hypertension
Grade 3
Hold study treatments. 
Upon resolution to Grade ≤ 1 or baseline (hypertension, QTc) or < 30 msec difference from baseline (QTc) within ≤ 7 days, may 
resume study treatments without dose modification after discussion with the Novartis Medical Monitor. Baseline ECG refers to the 
ECG(s) collected at screening.
Grade 4
Discontinue study treatments.
Other cardiovascular disorders
Grade 2 (except myocarditis)
Hold study treatments.
Upon resolution to Grade ≤ 1 or baseline, may resume study treatments 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 treatments.


Novartis
Confidential
Page 85
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Endocrinopathy
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.


Novartis
Confidential
Page 86
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
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)
Any Grade
Permanently discontinue study treatment


Novartis
Confidential
Page 87
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
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 treatment at same dose level
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.
Grade 4
Discontinue study treatment.
Fatigue/Asthenia
Grade 3 or Grade 4
Dose delay for study treatment-related Grade 3 until resolved to ≤  Grade 1
Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4. 
Any neurological disorder
Grade 2
Dose delay for ≥ Grade 2 until resolved to ≤  Grade 1
Grade 3 or Grade 4
Discontinue for Grade 3 lasting > 7 days or Grade 4


Novartis
Confidential
Page 88
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Ocular (uveitis, eye pain, blurred vision)
Grade 2 
Dose delay for ≥ Grade 2 until resolved to ≤Grade 1 (If resolved in ≤ 21 days, then ↓1 dose level for BLZ945 and maintain PDR001 
dose level)
Discontinue for any study treatment-related Grade 2 uveitis, eye pain or blurred vision that does not respond to topical therapy and 
does not improve to Grade 1 severity in ≤ 21 days OR requires systemic treatment
Grade 3 or Grade 4
Discontinue for study treatment-related Grade 3 uveitis of any duration
Discontinue for study treatment-related Grade 3 lasting > 7 days or Grade 4
Pulmonary (pneumonitis)
Grade 1
Consider study treatment hold.
Manage per institutional practice.
Consider resuming study treatment upon radiographic evidence of improvement.
Grade 2 
Hold study treatment.
Pulmonary and infection workup.
Upon resolution to ≤ Grade 1, may resume study treatment without dose modification.
Grade 3 or Grade 4
Discontinue study treatment.
Cytokine release syndrome (CRS)
Grade 2
Stop infusion immediately, and keep line open. 
Follow institutional guidelines for the management and follow-up of infusion reaction.
Restart infusion at 50% of previous rate under continuous observation. Ensure that there is a minimum observation period of 1 hour 
prior to restarting the infusion.
If the AE recurs at the reinitiated slow rate of infusion, and despite oral pre-medication, then permanently discontinue study treatment.
Grade 3 or Grade 4
Discontinue study treatment.
Follow-up CRS as per institutional guidelines.


Novartis
Confidential
Page 89
Amended Protocol Version v07 (Clean)
Protocol No. CBLZ945X2101
Recommended Dose Modification for BLZ945 and PDR001
For BLZ945 in combination with PDR001 treatment: Dose level maintenance, dose omission, and treatment discontinuation refer to both BLZ945 and PDR001. 
Reduction of one level refers to BLZ945 only, while PDR001 dose level should be maintained, unless otherwise specified. 
Worst toxicity CTCAE 
v4.03 Grade (unless 
otherwise specified)
Recommended dose interruption, delay and discontinuation for study treatment during a cycle of treatment. These guidelines 
are recommendations only and should not obviate local Institutional Guidelines
Other non-laboratory adverse events
Grade 3
Dose delay until resolved to ≤ Grade 1
Discontinue from study treatment if lasting > 7 days.
If resolved in ≤ 7 days, ↓1 dose level for BLZ945 and maintain PDR001 dose level.
Grade 4
Discontinue patient from study treatment.
Any other laboratory toxicities
Grade 3 or Grade 4
Dose delay until resolved to ≤  Grade 1
Note: Dose reductions for PDR001 are not permitted
**Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder must be performed within 1 week of the first occurrence of any ≥ Grade 3 of 
amylase and/or lipase. 
***Note: antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools or overt diarrhea.


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Table 6-7
Dose reduction steps for BLZ945 (Phase II only)
Dose reduction (BLZ945 administered as single agent)
Starting dose level and 
schedule
Dose reduction level – 1 
and schedule
Dose reduction level – 2
and schedule#
BLZ945
1200 mg, 4 days on/10 
days off
800 mg, 4 days on/10 
days off
600 mg, 4 days on/10 
days off
Dose reduction (BLZ945 in combination with PDR001)*
BLZ945
700 mg, 4 days on/10 
days off
450 mg, 4 days on/10 
days off
300 mg, 4 days on/10 
days off
*: PDR001 dose remains fixed at 400 mg, every 4 weeks
#: Any further dose reduction beyond the Dose level -2 of BLZ945 may be performed only after 
documented discussion with the Novartis medical monitor.
6.3.3
Anticipated risks and safety concerns of the study drugs 
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 management of study-drug induced AEs are provided in Table 6-5
and Table 6-6. 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 BLZ945 and PDR001 treatment which could be serious.  Refer to the 
[BLZ945 Investigator’s Brochure] and [PDR001 Investigator’s Brochure] respectively.
6.4
Concomitant medications 
6.4.1
Permitted concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care 
(e.g. such as anti-emetics, anti-diarrhea) and safety of the patient are allowed.
The patient must be told to notify the investigational site about any new medications, herbal 
remedies and dietary supplements he/she takes after the start of the study treatment. 
All medications (other than study treatment) and significant non-drug therapies (including 
physical therapy, herbal/natural medications and blood transfusions) administered during the 
study must be listed on the Prior/Concomitant Medications or the Surgical and Medical 
Procedures eCRFs.
6.4.2
Prohibited concomitant therapy
Preclinical data suggest that BLZ945 is metabolized in human via CYP3A4/5 and CYP2C8. 
The following medications are prohibited in this study:

Strong inhibitors or inducers of CYP3A4/5 or CYP2C8 are prohibited (refer to 
Appendix 7).

Co-administration of moderate CYP3A4/5 and CYP2C8 inhibitors

Co-administration of moderate CYP3A4/5 and CYP2C8 inducers


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
Furthermore, concomitant medications with known QT risk or possible risk to prolong the 
QT interval are also prohibited.

The use of proton pump inhibitors is not allowed since they alter the pH of the upper GI 
tract with a long duration of action of 48 to 72 hours.
BLZ945 shows pH dependent solubility (refer to Section 1.2.1.1.1). Concomitant medications 
which are known to increase the pH in the GI tract will have an impact on the solubility of 
BLZ945. Concomitant use of long-acting proton pump inhibitors is prohibited. Examples of 
this class of drugs include: omeprazole, pantoprazole, and lansoprazole. If patients are using 
proton pump inhibitors at the time of screening, these drugs must be discontinued at least 7 days
prior to the first dose of study treatment.  
Treatment with hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-
CSF) and thrombopoietin mimetics should not be taken during the study.
During the course of the study, patients must not receive other additional study drugs, devices, 
chemotherapy, or any other therapies that may be active against cancer or modulate the immune 
responses. 
Additionally, 
no 
other 
therapeutic 
monoclonal 
antibodies 
and 
no 
immunosuppressive medication should be administered while on this study.
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed, with 
the only exclusion of steroids for the treatment of an infusion reaction, irAEs, replacement-dose 
steroids in the setting of adrenal insufficiency (providing this is ≤ 10mg/day prednisone or 
equivalent) or treatment of glioblastoma. Systemic corticosteroids required for the control of 
infusion reactions or irAEs must be tapered and be at non-immunosuppressive doses 
(≤10 mg/day of prednisone or equivalent) before the next study drug administration. If more 
than 10 mg/day prednisone is used, study treatment should be suspended (Topical, inhaled, 
nasal and ophthalmic steroids for any purpose or steroids for the treatment of glioblastoma are 
not prohibited).
The use of live vaccines is not allowed through the whole duration of the study. Other vaccines 
are excluded, except inactivated seasonal influenza vaccines. 
Refer to Appendix 7 for a list of prohibited medications.  If a patient must use a drug in
Appendix 7, the patient must be discontinued from the study.
6.4.3
Permitted concomitant therapy requiring caution and/or action
The following medications are to be used with caution in this study:
Concomitant medications which are known to be moderate inhibitors or inducers of CYP3A4/5 
or CYP2C8 are permitted to be used with caution but not in combination.
Refer to Appendix 8 for permitted medications that require caution when concomitantly used 
with study treatment. 
Drugs that alter the pH of the upper GI tract (e.g., H2-receptor antagonists, antacids) may alter 
the solubility of BLZ945 and reduce its bioavailability. Short acting gastric acid modulators 
containing aluminum hydroxide and magnesium hydroxide, (e.g., Maalox®) or calcium 
carbonate (e.g., TUMS®) can be taken. However, it is recommended to take these drugs at least 
1 hour before or 2 hours after administration of BLZ945. H2 receptor antagonists should be 


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avoided. If patients are using H2 receptor antagonists (e.g. ranitidine) during the course of this 
study, patients should take BLZ945 at least 3 hours before H2 receptor antagonists. In addition, 
next dose schedule of BLZ945 administration should be at least 6 hours after taking H2 receptor 
antagonists.
If a patient is using erythropoiesis stimulating agents prior to enrollment (at least 2 weeks before 
start of study treatment), he/she may continue at the same dose.
Anticoagulation therapy is permitted if the patients are already at stable doses of warfarin or 
stable doses of low molecular weight heparin for > 2 weeks at time of first dose and 
International Normalized Ratio (INR) should be monitored as clinically indicated per 
investigator’s discretion. However, ongoing anticoagulant therapy should be temporarily 
discontinued to allow tumor sample according to the institutional guidelines.
Anti-hypertensive therapy is allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with PDR001.
A brief (< 24 hours) course of steroids for prophylaxis against contrast dye allergy is permitted 
for patients undergoing tumor assessments with exposure to the allergen.
6.4.4
Prohibited food
Patients must avoid consumption of Seville orange (and juice), grapefruit or grapefruit juice, 
grapefruit hybrids, pomelos and star citrus fruits at least 7 days prior to the first dose of study 
treatment and during the entire study treatment period due to potential CYP3A interaction. 
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 enrolled for screening and 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 patient 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 
Patient No. must not be reused for any other patient and the Patient No. for that individual must 
not be changed, even if the patient is re-screened. If the patient fails to start treatment for any 
reason, the reason will be entered into the Screening Disposition eCRF page.
6.5.2
Treatment assignment or randomization
The assignment of a patient to a particular cohort will be coordinated by the Sponsor. No 
randomization will be performed in this study.
6.6
Study drug preparation and dispensation
The Investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 


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personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF.
BLZ945
BLZ945 capsules including instructions for administration are dispensed by study personnel on 
an outpatient basis. Patients will be provided with adequate supply of study treatment for self-
administration at home until at least their next scheduled visit.
PDR001
PDR001 will be administered intravenously as an infusion (Section 6.1.1). Further instructions 
for the preparation and dispensation of PDR001 are described in the [BLZ945X2101 Pharmacy 
Manual].
6.6.1
Study treatment packaging and labeling
Study treatment will be provided as global clinical open supply and will be packed and labeled 
under the responsibility of Novartis, Drug Supply Management.
PDR001 100 mg powder for solution for infusion will be supplied by Novartis to Investigators
as open label bulk medication.
BLZ945 (50 mg and 200 mg strengths capsules) will be prepared by Novartis and supplied to 
investigator in blister packs or high density polyethylene bottles.
Study treatment labels will be in the local language and comply with the legal requirements of 
each country and will include storage conditions for the drug and a unique medication number. 
If the label has 2-parts (base plus tear-off label), immediately before dispensing the package to 
the patient, site personnel will detach the outer part of the label from the package and affix it to 
the patient‘s source document.
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, BLZ945 and/or PDR001 should be stored according 
to the instructions specified on the drug labels and in the [Investigator’s Brochure].
6.6.3
Study drug compliance and accountability
6.6.3.1
Study drug compliance
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit.
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 


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monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging on a regular basis, at the end of the study or at the time 
of study treatment discontinuation.
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site.
6.6.4
Disposal and destruction
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate.
7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1, Table 7-2, Table 7-3 and Table 7-4 list all of the assessments and indicates with an 
“X”, the visits when they are performed. For Japan only: patients are required to be 
hospitalized in Cycle 1 of the dose escalation part. All data obtained from these assessments 
must be supported in the patient’s source documentation. 
No CRF will be used as a source document. 
Screening evaluations must be performed ≤ 28 days of Cycle 1 Day 1 (except for the pregnancy 
test which has to be performed within 72 hours before first dose). Assessments performed as 
part of the screening evaluations and within 3 days prior to the first dose of study treatment, are 
not required to be repeated on Cycle 1 Day 1. Laboratory and radiological assessments
performed as part of standard of care prior to signing informed consent may be used if 
performed ≤ 28 days 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 ± 3 days is allowed. On PK collection days the windows are 
provided in Section 7.2.3.
Radiological assessments must be performed ±7 days of the scheduled date of the assessment.


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Table 7-1
Visit evaluation schedule for BLZ945 7d on / 7d off
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
7
8
11
15
1
2
15
1
8
15
1
Obtain Informed Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and extent of 
cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, surgery and 
medical procedures
D
7.1.1.2
X
Continuous
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Chest X-ray+
D
7.2.2.7
X
X
Vital signs
D
7.2.2.2
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
ECOG status
D
7.2.2.4
X
X
X
X
X
X
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5
X
X
X
X
X
X
Urinalysis
D
7.2.2.5
X
If clinically indicated
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
7
8
11
15
1
2
15
1
8
15
1
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
Serum Pregnancy test
D
7.2.2.5
X
X
X
X
X
Urine pregnancy test
S
7.2.2.5
X
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation 
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and then every 3 cycles until 
progression of disease or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until progression of disease or lost 
to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
Additional assessments may be performed to confirm progressive disease as described in Section 7.2.1
12-Lead ECG
D
7.2.2.6
X
X
X
X
X 
(Cycle 
6 only)
X
Adverse events
D
8
Continuous
Collection of new tumor 
sample
D
7.2.4
X
X
(day 
2-3)
Blood collection for 
biomarker analyses
(plasma & PBMC)
D
7.2.4
X
X
(day 
2-3)
X
(day 
2-3)
X
X
(Cycle 
5 only)
X
PDR001 infusion (only in 
combination)
D
6.1.1
i.v. every 4 weeks
BLZ945  administration
D
6.1.1
7d on /7d off


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
7
8
11
15
1
2
15
1
8
15
1
Blood sample for PK 
analysis (for  BLZ945 
single agent)
D
7.2.3
X
X
X
X
X+
X
X
X
Blood sample for PK 
analysis (for BLZ945 + 
PDR001)
D
7.2.3
X
X
X
X
X+
X
X
X
X
X
X
(up to 
Cycle 
6)
X
X
Blood sample for ADA 
analysis(for BLZ945 +
PDR001)
D
7.2.3
X
X
X
X
(up to 
Cycle 
6)
X
X
Survival contact (every 3 
months)
D
7.1.5
X
* 30-day safety follow-up for patients treated with BLZ945 single agent. 150 days safety follow-up for patients treated with BLZ945 in combination with PDR001 with safety 
evaluations (i.e. 30-day, 90-day and 150-day follow-up )
+ Only for patients in Japan during dose escalation
Patients in Japan enrolled in dose escalation are required to be hospitalized during cycle 1


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Table 7-2
Visit evaluation schedule for BLZ945 Q1W
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
S f
*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
8
9
11
15
1
2
15
1
2
8
11
15
1
Obtain Informed 
Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and 
extent of cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, surgery 
and medical 
procedures
D
7.1.1.2
X
Continuous
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Chest X-ray+
D
7.2.2.7
X
X
Vital signs
D
7.2.2.2
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
ECOG status
D
7.2.2.4
X
X
X
X
X
X
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5
X
X
X
X
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
S f
*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
8
9
11
15
1
2
15
1
2
8
11
15
1
Urinalysis
D
7.2.2.5
X
If clinically indicated
X
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
Serum Pregnancy 
test
D
7.2.2.5
X
X
X
X
X
Urine pregnancy test
S
7.2.2.5
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation 
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and then every 3 cycles 
until progression of disease or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until progression of disease or 
lost to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
Additional assessments may be performed to confirm progressive disease as described in Section 7.2.1
12-Lead ECG
D
7.2.2.6
X
X
X
X
X 
(Cycle 
6 
only)
X
Adverse events
D
8
Continuous
Collection of new 
tumor sample
D
7.2.4
X
X
(day 
2-3)


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
S f
*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
8
9
11
15
1
2
15
1
2
8
11
15
1
Collection of archival 
tumor sample & 
associated de-
identified pathology 
report
D
7.2.4
X#
Blood collection for 
biomarker analyses 
(plasma & PBMC)
D
7.2.4
X
X
(day 
2-3)
X
(day 
2-3)
X
(day
2-4)
X 
(Cycle 
5 
only)
X
PDR001 infusion 
(only in combination)
D
6.1.1
i.v. every 4 weeks
BLZ945  
administration
D
6.1.1
Q1W
Blood sample for PK 
analysis (for  
BLZ945 single 
agent)
D
7.2.3
X
X
X
X
X+
X
X
X
X
X
Blood sample for PK 
analysis (for BLZ945 
+ PDR001)
D
7.2.3
X
X
X
X
X+
X
X
X
X
X
X
X
X
X
(up to 
Cycle 
6)
X
X
Blood sample for 
ADA analysis(for 
BLZ945 + PDR001)
D
7.2.3
X
X
X
X
(up to 
Cycle 
6)
X
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
S f
*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
8
9
11
15
1
2
15
1
2
8
11
15
1
Survival contact 
(every 3 months)
D
7.1.5
X
* 30-day safety follow-up for patients treated with BLZ945 single agent. 150 days safety follow-up for patients treated with BLZ945 in combination with PDR001 with safety 
evaluations (i.e. 30-day, 90-day and 150-day follow-up)
# For glioblastoma patients for whom the newly obtained tumor samples were not collected at study entry only. For any glioblastoma patients who completed the screening 
phase and are ongoing at the time of protocol amendment 6 approval, if a newly obtained tumor sample was not collected at study entry, retrospective submission of an 
archival tumor sample is required. The associated de-identified pathology report is also requested.
+ Only for patients in Japan during dose escalation
Patients in Japan enrolled in dose escalation are required to be hospitalized during cycle 1


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Table 7-3
Visit evaluation schedule for BLZ945 4d on / 10d off (phase I)
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
11
15
19
1
2
15
1
2
8
15
1
Obtain Informed 
Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion 
criteria
D
5.2
5.3
X
Medical History
D
7.1.1.2
X
Diagnosis and 
extent of cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, 
surgery and medical 
procedures
D
7.1.1.2
X
Continuous
Physical 
examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Chest X-ray+
D
7.2.2.7
X
X
Vital signs
D
7.2.2.2
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
ECOG status
D
7.2.2.4
X
X
X
X
X
X
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5
X
X
X
X
X
X


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Protocol No. CBLZ945X2101
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
11
15
19
1
2
15
1
2
8
15
1
Urinalysis
D
7.2.2.5
X
If clinically indicated
X
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Doppler 
echocardiography
D
7.2.2.6
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
Serum Pregnancy 
test
D
7.2.2.5
X
X
X
X
X
Urine pregnancy 
test
S
7.2.2.5
X
Antineoplastic 
therapies since 
discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation 
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and then every 3 cycles until 
progression of disease or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until progression of disease or 
lost to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
Additional assessments may be performed to confirm progressive disease as described in Section 7.2.1
12-Lead ECG
D
7.2.2.6
X
X
X
X
X 
(Cycle 
6 
only)
X
Adverse events
D
8
Continuous


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Protocol No. CBLZ945X2101
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
11
15
19
1
2
15
1
2
8
15
1
Collection of new 
tumor sample
D
7.2.4
X
X 
(day 
2-3)
Collection of 
archival tumor 
sample & 
associated de-
identified pathology 
report
D
7.2.4
X#
Blood collection for 
biomarker analyses 
(plasma & PBMC)
D
7.2.4
X
X
(day 
2-3)
X 
(day 
2-3
X 
(day 
2-4)
X 
(Cycle 
5 
only)
X
PDR001 infusion 
(only in 
combination)
D
6.1.1
i.v. every 4 weeks
BLZ945  
administration
D
6.1.1
4d on/10d off
Blood sample for PK 
analysis (for  
BLZ945 single 
agent)
D
7.2.3
X
X
X
X
X+
X
X
X
X
X
X
Blood sample for PK 
analysis (for 
BLZ945 + PDR001)
D
7.2.3
X
X
X
X
X
X+
X
X
X
X
X
X
X
X
X
X
(up to 
Cycle 
6)
X
X


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Protocol No. CBLZ945X2101
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
11
15
19
1
2
15
1
2
8
15
1
Blood sample for 
ADA analysis(for 
BLZ945 + PDR001)
D
7.2.3
X
X
X
X
(up to 
Cycle 
6)
X
X
Survival contact 
(every 3 months)
D
7.1.5
X
* 30-day safety follow-up for patients treated with BLZ945 single agent. 150 days safety follow-up for patients treated with BLZ945 in combination with PDR001 with safety 
evaluations (i.e. 30-day, 90-day and 150-day follow-up )
# For glioblastoma patients for whom the newly obtained tumor samples were not collected at study entry only. For any glioblastoma patients who completed the 
screening phase and are ongoing at the time of protocol amendment 6 approval, if a newly obtained tumor sample was not collected at study entry, retrospective 
submission of an archival tumor sample is required. The associated de-identified pathology report is also requested.
+ Only for patients in Japan during dose escalation
Patients in Japan enrolled in dose escalation are required to be hospitalized during cycle 1
Table 7-4
Visit evaluation schedule for phase II (BLZ945 4d on / 10d off)
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
15
19
1
2
15
1
2
1
Obtain Informed Consent
D
7.1.1
X
Demography
D
7.1.1.2
X
Inclusion/ exclusion criteria
D
5.2
X


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Protocol No. CBLZ945X2101
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
15
19
1
2
15
1
2
1
5.3
Medical History (including 
MGMT and IDH status for 
GBM patients)
D
7.1.1.2
X
Diagnosis and extent of 
cancer
D
7.1.1.2
X
Prior antineoplastic 
therapies
D
7.1.1.2
X
Prior/concomitant 
medications, surgery and 
medical procedures
D
7.1.1.2
X
Continuous
Physical examination
S
7.2.2.1
X
X
X
X
X
X
X
X
X
Vital signs
D
7.2.2.2
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
ECOG status
D
7.2.2.4
X
X
X
X
X
X
Hematology
D
7.2.2.5
X
X
X
X
X
X
X
X
X
Chemistry
D
7.2.2.5
X
X
X
X
X
X
X
X
X
X
Coagulation
D
7.2.2.5
X
X
X
X
X
X
Urinalysis
D
7.2.2.5
X
If clinically indicated
X
Thyroid function
D
7.2.2.5
X
X
X
X
X
X
Serology exam
D
7.2.2.5
X
X
X
X
X
X
Doppler echocardiography
D
7.2.2.6
X
X
X
X
X
Serum Pregnancy test
D
7.2.2.5
X
X
X
X
X
Urine pregnancy test
S
7.2.2.5
X


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Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
15
19
1
2
15
1
2
1
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.5
X
X
X
Tumor evaluation**
D
7.2.1
X
During treatment: starting on Cycle 3 Day 1, every 2 cycles until Cycle 11 Day 1, and then every 3 
cycles until progression of disease or patient withdrawal.
Follow-up for progression: every 8 weeks until week 40, then every 12 weeks until progression of 
disease or lost to follow-up.
EOT: if a scan was not conducted within 30 days prior to end of study treatment.
Additional assessments may be performed to confirm progressive disease as described in 
Section 7.2.1
12-Lead ECG
D
7.2.2.6
X
X
X
X
X 
(Cycle 
6 only)
X
Adverse events
D
8
Continuous
Collection of new tumor 
sample
D
7.2.4
X
X 
(day 
2-3)
Collection of archival tumor 
sample & associated de-
identified pathology report
X#
Blood collection for 
biomarker analyses 
(plasma)
D
7.2.4
X
X
X
X
X
X
(Cycle 
5 only)
X
PDR001 infusion (only in 
combination)
D
6.1.1
i.v. every 4 weeks


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Protocol No. CBLZ945X2101
Visit Name
Category
Protocol 
Section
Screening
Cycle 1
Cycle 2
Cycle 3
Subsequent 
cycles
EoT
30 days or 
150 days 
Safety*
Disease 
progression
Survival
Day of cycle
-28 to -1
1
2
4
5
8
15
19
1
2
15
1
2
1
BLZ945  administration
D
6.1.1
4d on/10d off
Blood sample for PK 
analysis (for  BLZ945 single 
agent)
D
7.2.3
X
X
X
X
X
Blood sample for PK 
analysis (for BLZ945 + 
PDR001)
D
7.2.3
X
X
X
X
X
X
X
X
X
Blood sample for ADA 
analysis(for BLZ945 + 
PDR001)
D
7.2.3
X
X
X
X
Survival contact (every 3 
months)
D
7.1.5
X
* 30-day safety follow-up for patients treated with BLZ945 single agent. 150 days safety follow-up for patients treated with BLZ945 in combination with PDR001 with safety 
evaluations (i.e. 30-day, 90-day and 150-day follow-up )
** MRI or CT scans obtained prior to study baseline evaluation and used for determination of disease progression from prior line of anti-neoplastic treatments might be 
requested for central review of response assessment and/or baseline characterization.
# For glioblastoma patients enrolled in the phase II part of study, if a newly obtained tumor sample cannot be safely collected at study entry, submission of an archival 
tumor sample is required. The associated de-identified pathology report is also requested.


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7.1.1
Screening
The study IRB/ Independent Ethics Committee (IEC) informed consent form must be signed 
and dated before any screening procedures are performed, except for evaluations performed as 
part of standard of care.
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1, Table 7-2, Table 7-3 and Table 7-4. Screening 
assessments must be repeated if performed outside of the specified screening window.
Submission of a newly (up to 3 months prior to study treatment and after completion of the last 
therapy) obtained tumor sample (formalin fixed, or in ethanol, please refer to [CBLZ945X2101 
Laboratory Manual] for details) at screening is requested from all patients. For details refer to 
Section 7.2.4
For the glioblastoma patients for whom a newly obtained tumor was not collected at screening, 
submission of an available archival tumor sample is required (refer to Section 7.2.4 for details). 
7.1.1.1
Information to be collected on screening failures
Patients who sign an informed consent but fail to be started on treatment for any reason will be 
considered a screen failure. The reason for not being started on treatment 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 Serious Adverse Event during the Screening Phase (see Section 8 for SAE 
reporting details) or died (Death eCRF should be completed) or withdrew consent (Withdrawal 
of consent eCRF should be completed).
7.1.1.2
Patient demographics and other baseline characteristics
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, diagnosis and extent of tumor, details of prior anti-neoplastic 
treatments, prior medication, procedures, significant non-drug therapies and any other 
assessments that are done for the purpose of determining eligibility for inclusion in the study.
7.1.2
Treatment period
For the purpose of scheduling and evaluations, a treatment cycle will consist of 28 days for 
patients treated with BLZ945 as a single agent or in combination with PDR001.
For Japan only, patients enrolled in dose escalation are required to be hospitalized during the 
DLT evaluation period (Cycle 1).
Patients who meet the following criteria will continue treatment in additional cycles:

Patients with SD, PR, CR, and unconfirmed progressive disease (PD) who do not show 
signs of clinical deterioration or toxicity (according to RECIST v1.1, irRC and iRANO).
Patients who meet the following criteria may continue treatment in additional cycles (after 
discussion Novartis):


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Protocol No. CBLZ945X2101

Patients with confirmed PD (according to RECIST v1.1, irRC and iRANO) or progressive 
(metabolic) disease (according to the Guidelines for efficacy evaluation in Hodgkin and
non-Hodgkin lymphoma studies), if the Investigator considers it to be in the patient’s best 
interest to remain on the study, and after discussion with Novartis.
Patients who meet the following criteria will NOT continue treatment in additional cycles:

Patients who experience unacceptable toxicity

Patients with confirmed PD (according to RECIST v1.1, irRC and iRANO). These 
patients will then enter the Safety follow-up period.

Patients with progressive (metabolic) disease (according to the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies). These patients will then 
enter the Safety follow-up period.  

Patients with an unconfirmed PD (according to RECIST v1.1, irRC and iRANO) who 
show signs of clinical deterioration or toxicity will enter the Safety follow-up period (see
Section 7.1.5), and will be continued to be followed up until confirmed PD or initiation of 
a new treatment. Patients will then enter the Survival Follow-up period.
Patients with confirmed progressive disease/ immune-related Progressive Disease (irPD) in 
stable or improved clinical status can remain under treatment 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.
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 et al 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 and iRANO. An outline of the irRC and 
iRANO are provided in Appendix 2 and Appendix 4 respectively. 
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.
Please refer to Table 7-1, Table 7-2, Table 7-3 and Table 7-4 for details of the timing of required 
assessments and Section 7.1 for visit windows.


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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 eCRF. They may be 
considered discontinued if they state an intention to withdraw or fail to return for visits.
The i nvestigator should discontinue study treatment for a given patient if, on balance, he/she
believes that continuation would be detrimental to the patient’s well-being.
Study treatment may be discontinued under the following circumstances:

Adverse event

Lost to follow-up

Physician’s decision

Progressive disease as per confirmed irRC (not as per RECIST v1.1) 

For glioblastoma patients, progressive disease as per confirmed iRANO (not as per 
RANO)

For lymphoma patients, progressive (metabolic) disease as per the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies

Confirmed Complete response (CR) (as per RECIST v1.1)

Patient/guardian decision

Protocol deviation
Patients must be discontinued if any of the following occur:

Death

Pregnancy
Patients who discontinue study treatment should not be considered discontinued from the study. 
They should return for the EoT assessments as soon as possible and within 14 days of the last 
dose of study treatment or within 14 days of the decision to discontinue study treatment, and 
then enter the follow-up period as indicated in Section 7.1.5. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone calls, e-mail, letter) should be 
made to contact them as specified in Section 7.1.6. If a patient discontinues study treatment, but 
continues study assessments, the patient remains on study until such time as he/she completes 
protocol criteria for ending study assessments.
Patients who transfer into another study or an alternative way to provide study treatment will 
perform the end of treatment procedures only. The follow-up for safety, disease progression
and survival visits will not be performed.
If the decision to discontinue the patient occurs at a regular scheduled visit, that visit may 
become the EoT visit rather than having the patient return for an additional visit. An End of 
Treatment Phase Disposition eCRF should be completed, giving the reason for stopping the 
study treatment. End of treatment/Premature withdrawal visit is not considered as the end of the 
study.


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7.1.3.1
Replacement policy 
Escalation part:
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
the dose determining set (DDS), enrollment of a new patient to the current cohort will be 
considered if there is less than the required number of evaluable patients. Enrollment of new 
patients may be considered until at least the minimum number (3) or at most the maximum 
number (6) of evaluable patients is achieved within the cohort. A minimum of 2 patients is 
acceptable as long as neither patient has experienced a treatment-related toxicity > CTCAE 
grade 2. Minimum and maximum numbers of evaluable patient per cohort are defined in 
Section 6.2.3.
Phase II part:
During the phase II part no replacements will be considered.
7.1.4
Withdrawal of consent
Patients may voluntarily withdraw consent to participate in the study for any reason at any 
time. Withdrawal of consent occurs only when a patient:

Does not want to participate in the study any longer, and

Does not allow further collection of personal data
In this situation, the investigator should make 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 
communication or follow up.
All efforts should be made to complete the assessments prior to study withdrawal. A final 
evaluation at the time of the patient’s study withdrawal should be made as detailed in the 
assessment table. 
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a patient’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form. 
For EU and Rest of World: All biological samples not yet analyzed at the time of withdrawal 
will no longer be used, unless permitted by applicable law. They will be stored according to 
applicable legal requirements.


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7.1.5
Follow up period
Patients treated with BLZ945 single agent must have a safety evaluation 30 days after last dose 
and patients treated with BLZ945 in combination with PDR001 must have safety evaluations 
for 150 days after the last study treatment dose. The evaluations can be done either by telephone 
call or visit for the 30-, 90- and 150- days safety follow up visits.
Data collected should be added to the Adverse Events CRF and the Concomitant Medications 
CRF until the safety follow-up has been completed or the start of a new antineoplastic therapy. 
Only study treatment related AEs should be reported after initiation of new antineoplastic 
therapy.
Antineoplastic therapies since discontinuation of study drug will be collected during this 
follow-up period in the appropriate eCRF page.A PK and immunogenicity sample should be
collected at 150 days as described in Section 7.2.3 (Pharmacokinetics and Immunogenicity
assessments). If the 150-day safety evaluation is conducted by phone, samples do not need to 
be collected.
Patients who discontinue study treatment for any reason other than death, disease progression 
per confirmed irRC (per iRANO for glioblastoma patients; per Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies for lymphoma patients), clinical 
deterioration, lost to follow-up, consent withdrawal or study termination, also should return for 
tumor evaluation assessments and should not be considered withdrawn from the study until at 
least 80% of the patients enrolled had completed the survival follow-up period (minimum 18 
months after the first dose of treatment) or discontinued the study for any reason. 
If patients refuse to return for these visits or are unable to do so, every effort should be made to 
contact them or a knowledgeable informant by telephone to determine if the patient had disease 
progression.
Upon completion of the 30- day or 150-day safety follow up or disease progression follow up, 
patients will be followed for survival every 3 months (can be done by telephone call) until death 
or until the end of the study is reached, unless they withdraw consent or are lost to follow-up.
For patients who transfer to another clinical study or an alternative way to provide study 
treatment as described in Section 4.3, the safety follow up, disease progression or survival 
follow up visits 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.


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7.2
Assessment types
7.2.1
Efficacy assessments
7.2.1.1
Solid tumors (except glioblastoma)
Tumor response will be determined locally according to two sets of criteria:

RECIST v1.1 (Appendix 1)

irRC (Appendix 2)
The local investigator’s assessment will be used for the analysis of response according to both 
RECIST v1.1 and irRC, and for treatment decision making (study discontinuation due to PD as 
per irRC). During the course of the study, Novartis may decide to have a central review of the 
radiological assessments performed. In such case, the investigator’s staff will be instructed on 
how to send data from these radiological assessments to a Contract Research Organization 
(CRO) for central review when needed.
At screening, all patients will undergo CT with i.v. contrast of the brain, chest, abdomen and 
pelvis. If there is clinical evidence of disease in the neck, a CT with i.v. contrast of the neck 
will also be performed. MRI should only be used to evaluate sites of disease that are not 
adequately imaged by CT. If a patient is intolerant of iodine-based contrast agents, CTs may be 
performed without contrast. MRI may be used to evaluate sites of disease where a CT without 
i.v. contrast is not adequate. Visible skin lesions and easily palpable subcutaneous tumors may 
be measured by physical examination using a ruler or calipers. Ultrasound should not be used 
to measure sites of disease.
Tumor assessments will be performed at the time points as described in Table 7-5. PR or CR, 
per both RECIST v1.1 and irRC, will be confirmed by a new assessment after at least 4 weeks. 
Also PD, as per irRC, will be confirmed after at least 4 weeks. Disease progression follow-up 
should be performed as described in Section 7.1.5.
7.2.1.2
Glioblastoma
Tumor response will be determined locally according to two sets of criteria for glioblastoma 
patients:

RANO (Appendix 3) 

iRANO (Appendix 4) 
Tumor response and progression will be assessed using the Response Assessment in Neuro-
Oncology (RANO) Working Group updated response assessment criteria for high-grade 
gliomas (Wen et al 2010b) as detailed in Appendix 3. Since Standard RANO criteria may not 
be adequate in case of immunotherapy treatment, a new assessment criteria (iRANO) will be 
used to deal with pseudoprogression in the first 24 weeks of treatment (Okada et al 2015).
Novartis may decide to collect and store MRI or CT scans for central review of response 
assessment and/or baseline characterization. Novartis may decide to collect, store and review
MRI or CT scans obtained prior to study baseline evaluation and used for determination of 
disease progression from prior lines of anti-neoplastic treatments. 


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Throughout the study, RANO (Appendix 3) or iRANO criteria (Appendix 4) must be applied 
when assessing any responses to the study treatment. All CRs and PRs must be confirmed by a 
second assessment at least 4 weeks later.
To distinguish pseudoprogression from progressive disease and minimize premature 
discontinuation of study treatment, patients meeting RANO criteria for disease progression may 
continue receiving study medication until confirmation of progression with an MRI performed 
approximately 12 weeks later, unless they experience significant clinical decline. Whenever 
possible, patients discontinuing from the study for progressive disease must have their disease 
progression documented by radiological and clinical evaluations following RANO criteria.
Tumor assessments will be performed at the time points as described in Table 7-5.
Note: in case a patient cannot tolerate MRI, the patient may still participate in the study 
following discussion between Novartis and the investigator. In this case, all efficacy 
assessments will be made by CT scans for that patient. Efficacy assessments should be 
performed by using the same technique throughout the study for each patient.
7.2.1.3
Relapsed or refractory lymphoma
For all patients with r/r lymphoma, the tumor response will be determined locally according to 
the Guidelines for efficacy evaluation in Hodgkin and non-Hodgkin lymphoma studies
(Appendix 9). The local investigator’s assessment will be used for treatment decision making 
as well as analyses of primary and secondary endpoints.
In order to understand the disease stage, documentation of status of bone marrow involvement 
by lymphoma based on prior bone marrow biopsy/aspirate is required. If no such documentation 
is available then a bone marrow biopsy/aspirate is required at screening.
At screening, all patients will undergo FDG PET-CT scan. For patients with FDG avid tumors, 
all subsequent disease assessments will be performed with FDG-PET CT, using the 5-point 
scale (Barrington et al 2014). The avidity of up to six representative index lesions must be 
documented and the rest as non-index lesions. For patients with non-avid or variably FDG-avid 
tumors, CT scan with IV contrast of chest/abdomen/pelvis/additional known lesions will be 
performed. If at screening, a patient has a medical contraindication to CT IV contrast or 
develops a contraindication during the trial, a non-contrast chest CT and a contrast 
abdomen/pelvis Magnetic Resonance Imaging (MRI) will be performed.
Tumor assessments will be performed at the time points as described in Table 7-5. Depending 
on regulatory requirements it is allowed to have the EOT PET-CT scan performed within an 
extended time frame but no later than 8 weeks from the last PET-CT scan. Imaging evaluations 
subsequent to an off-schedule confirmatory scan should be performed according to the original 
assessment schedule. The same method of assessment and the same technique should be used 
to characterize each individual and reported lesion at screening and during follow-up.
Bone marrow biopsy should be performed to confirm complete responses in patients with bone 
marrow involvement prior to study treatment.
Skin lesions present at screening should be documented using color photography, including a 
ruler, so that the size of the lesion(s) can be determined from the photograph. Skin photographs 


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should be continued at subsequent tumor assessments for any lesions that were photographed 
at screening.
All patients discontinuing from the study for progressive disease must have their disease 
progression documented by radiologic evaluation. In cases of clinically-evident disease 
progression, all efforts should be made to perform a radiologic evaluation.Tumor assessments 
will be performed at the time points as described in Table 7-5.
Table 7-5
Disease assessment collection plan
Procedure
Screening
During Treatment/Follow-up
Solid tumors
CT or MRI
with contrast enhancement
(Chest, Abdomen, Pelvis)
Mandated
During treatment: starting on Cycle 3 
Day 1, every 2 cycles until Cycle 11 Day 
1, and then every 3 cycles until 
progression of disease as per irRC or 
patient withdrawal.
Follow-up for progression: every 8 
weeks until week 40, then every 12 
weeks until progression of disease per 
irRC or lost to follow-up.
If progressive disease is detected: 
confirmatory CT or MRI at least 4 weeks 
after first progressive disease 
assessment.
EOT: if a scan was not conducted within 
30 days prior to end of study treatment.
Brain CT or MRI with contrast
Mandated
If disease was detected at baseline, or if 
clinically indicated
Glioblastoma
Brain CT or MRI
with contrast 
Mandated
During treatment: starting on Cycle 3 
Day 1, every 2 cycles until Cycle 11 Day 
1, and then every 3 cycles until 
progression of disease as per iRANO 
for glioblastoma or patient withdrawal.
Follow-up for progression: every 8 
weeks until week 40, then every 12 
weeks until progression of disease per 
iRANO for glioblastoma or lost to follow-
up.
If progressive disease is detected: 
confirmatory CT or MRI 12 weeks after 
first progressive disease assessment
EoT: if a scan was not conducted within 
30 days prior to end of study treatment.
CT or MRI 
with contrast enhancement
(Chest, Abdomen, Pelvis)
Mandated
If disease was detected at baseline, or if 
clinically indicated
Lymphoma


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Procedure
Screening
During Treatment/Follow-up
Solid tumors
PET-CT or CT 
chest/abdomen/pelvis/
additional known lesions
PET-CT is mandated at 
screening
During treatment: starting on Cycle 3 
Day 1, every 2 cycles until Cycle 11 Day 
1, and then every 3 cycles until
progression of disease as per the 
Guidelines for efficacy evaluation in 
Hodgkin and non-Hodgkin lymphoma 
studies or patient withdrawal.
If FDG avid: use PET-CT, and if non-
avid/mixed avidity: CT
Follow-up for progression: every 8 
weeks until week 40, then every 12 
weeks until progression of disease as 
per the Guidelines for efficacy 
evaluation in lymphoma studies or lost 
to follow-up.
EOT: if a scan was not conducted within 
30 days prior to end of study treatment.
Bone marrow biopsy
Mandated except for Hodgkin 
lymphoma patients
To confirm complete responses in 
patients with bone marrow tumor 
involvement prior to study treatment
Skin color photography with 
ruler (skin lesions only)
Mandated if skin lesions at 
screening
If skin lesions at screening, Cycle 3 
During treatment: starting on Cycle 3 
Day 1, every 2 cycles until Cycle 11 Day 
1, and then every 3 cycles until
progression of disease as per the 
Guidelines for efficacy evaluation in 
Hodgkin and non-Hodgkin lymphoma 
studies or patient withdrawal.
Follow-up for progression: every 8 
weeks until week 40, then every 12 
weeks until progression of disease as 
per the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin 
lymphoma studies or lost to follow-up.
EOT: if a scan was not conducted within 
30 days prior to end of study treatment.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessing physical examination, vital signs, body height and weight, 
performance status, hematology, chemistry, coagulation, thyroid function, pregnancy, ECG as 
well as collecting of the adverse events at every visit. For details on AE collection and reporting, 
refer to Section 8.
7.2.2.1
Physical examination
At screening and Cycle 1 Day 1 prior to treatment administration, a complete physical 
examination will include the examination of general appearance, skin, neck (including thyroid), 
eyes, ears, nose, throat, lungs, heart, abdomen, back, lymph nodes, extremities, vascular and 
neurological. If indicated based on medical history and/or symptoms, rectal, external genitalia, 
breast, and pelvic exams will be performed.


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From Cycle 1 Day 8 onwards (or from Cycle 1 Day 5 for patients treated with the 4d on/10d off 
schedule), a short physical exam will include the examination of general appearance and vital 
signs (blood pressure and pulse) (refer to Table 7-1, Table 7-2, Table 7-3 and Table 7-4). 
Significant findings that were present prior to the signing of informed consent must be included 
in the Medical History page on the patient’s CRF. Significant new findings that begin or worsen 
after informed consent must be recorded on the Adverse Event page of the patient’s CRF.
For Japanese patients in phase I 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, Table 7-2 and Table 7-3.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure in supine position when ECG is 
collected) must be performed prior to treatment administration and as indicated in Table 7-1, 
Table 7-2, Table 7-3 and Table 7-4 as per institutional standards. Vital signs should be assessed 
in the same position through the study.
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 and body weight will be measured as indicated in Table 7-1, Table 7-2, Table 7-3 and 
Table 7-4 as per institutional standards.
7.2.2.4
Performance status
ECOG performance status will be assessed according to Table 7-6 and as indicated in Table 7-1, 
Table 7-2, Table 7-3 and Table 7-4.
Table 7-6
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
Note: Grade 5 (death) was removed from this table. This information will be collected on a separate eCRF.


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7.2.2.5
Laboratory evaluations
All laboratory parameters assessed for safety purposes will be evaluated locally (except 
serology examinations that will be evaluated centrally). Refer to Table 7-7 for a summary of 
the parameters to be evaluated.
More frequent evaluations may be performed at the investigator’s discretion if medically 
indicated; results should be recorded as unscheduled laboratory assessments.
Novartis will be provided with a copy of the laboratory certification and tabulation of the normal 
ranges for each parameter required. In addition, if at any time a patient has laboratory 
parameters obtained from a different outside laboratory, Novartis must be provided with a copy 
of the certification and a tabulation of the normal ranges for that laboratory.
Table 7-7
Local/Central Clinical laboratory parameters collection plan
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells with Differential (Basophils, 
Eosinophils, Lymphocytes, Monocytes, Neutrophils)
Chemistry
Amylase, Lipase, Albumin, Alkaline phosphatase, ALT, AST, Bicarbonate, Calcium, 
Chloride, Sodium, Potassium, Creatinine, Glucose, Magnesium, Inorganic Phosphate, 
Total Bilirubin (also measure direct and indirect bilirubin if total bilirubin is > grade 1), 
Blood Urea Nitrogen or Urea, creatine phosphokinase, troponin and, uric acid
Coagulation
Prothrombin time or INR, Activated partial thromboplastin time (APTT)
Urinalysis
Bilirubin, Blood, Glucose, Ketones, pH, Protein, Specific Gravity, White Blood Cells
Thyroid
Free T4,Thyroid Stimulation Hormone
Serology exam*
Anti-DNA antibodies (Abs), Anti-nuclear Abs, Anti-mitochondrial Abs, c-Reactive protein, 
RF
Pregnancy
Serum or urine samples only for women of childbearing potential
* To be performed by a Central laboratory. Details will be provided in the [CBLZ945X2101 Laboratory Manual]
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-7 will be performed as per the assessment schedule in 
Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-7 will be performed as per the assessment schedule 
in Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
It should be noted in the patient’s eCRF if the patient was fasting at the time of blood sampling.
7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-7 will be performed as per the assessment schedule in 
Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
7.2.2.5.4 Urinalysis
Dipstick measurements for specific gravity, protein, glucose and blood will be performed. Any 
significant findings on dipstick will be followed up with a microscopic evaluation where WBC 
and RBC sediments will also be measured. 


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Urinalysis panel outlined in Table 7-7 will be performed as per the assessment schedule in 
Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
7.2.2.5.5 Thyroid function and Serology exam
Thyroid and Serology panels outlined in Table 7-7 will be performed as per the assessment 
schedule in Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
7.2.2.5.6 Pregnancy and assessments of fertility
All females of childbearing potential will have a serum pregnancy test at screening within ≤72 
hours before first dose of study treatment. During the study, a serum pregnancy test should be 
done at day 1 of each cycle from cycle 2 onwards, and at EOT visit.
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). 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.
A positive pregnancy test requires immediate discontinuation of study treatment and 
discontinuation from study. See Section 8.3 for pregnancy reporting.
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, 
Table 7-2, Table 7-3, Table 7-4 and Table 7-8. For patients receiving BLZ945 twice per day, 
the ECG will be collected following the morning dose of BLZ945, and 1-2 hours after the evening 
dose, if feasible. Blood samples scheduled at the same clock time point should be taken after the 
ECGs are completed. The ECGs must be performed in triplicate in supine position during study 
treatment as indicated in Table 7-1, Table 7-2, Table 7-3 and Table 7-4.
The post-infusion ECGs in the combination part will be collected after the completion of the 
infusion. The next meal can be taken after the 4 hours ECG assessments.
Table 7-8
Central ECG collection plan
Cycle
Day
Time
ECG type
Screening
-28 to -1
Anytime
Single
1
1
Pre-dose (fasting, baseline ECG)
Triplicate
1
1
0.5 h post-dose (± 10 min)
Triplicate
1
1
1 h post-dose (± 10 min) 
Triplicate
1
1
2 h post-dose (± 10 min) 
Triplicate
1
1
4 h post-dose (± 15 min) 
Triplicate
1
1
6 h post-dose (± 1 h) 
Triplicate
1
1
8 h post-dose (± 1 h) 
Triplicate
1
1
1-2 h post-evening dose#
Triplicate
1
4*
Pre-dose (fasting)
Triplicate
1
4*
0.5 h post-dose (± 10 min)
Triplicate


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Cycle
Day
Time
ECG type
1
4*
1 h post-dose (± 10 min) 
Triplicate
1
4*
2 h post-dose (± 10 min) 
Triplicate
1
4*
4 h post-dose (± 15 min) 
Triplicate
1
4*
1-2 h post-evening dose#
Triplicate
1
7†
Pre-dose (fasting)
Triplicate
1
7†
0.5 h post-dose (± 10 min)
Triplicate
1
7†
1 h post-dose (± 10 min) 
Triplicate
1
7†
2 h post-dose (± 10 min) 
Triplicate
1
7†
4 h post-dose (± 15 min) 
Triplicate
1
7†
1-2 h post-evening dose#
Triplicate
1
8‡
Pre-dose (fasting)
Triplicate
1
8‡
0.5 h post-dose (± 10 min)
Triplicate
1
8‡
1 h post-dose (± 10 min) 
Triplicate
1
8‡
2 h post-dose (± 10 min) 
Triplicate
1
8‡
4 h post-dose (± 15 min) 
Triplicate
1
8‡
1-2 h post-evening dose#
Triplicate
3
1
Pre-dose
Triplicate
3
1
1h (±10 min) hour post dose
Triplicate
6
1
Pre-dose
Triplicate
6
1
1h (±10 min) hour post dose
Triplicate
EoT
-
Anytime
Single
Unscheduled*
-
Anytime
Single
*A PK sample should be collected just after an ECG performed due to an unexpected cardiac signal.
* When BLZ945 4d on/10d off regimen
† When BLZ945 7d on/7d off regimen
‡ When BLZ945 Q1W regimen
# Only for twice a day dosing and if deemed logistically feasible
All ECGs will be independently reviewed by a central laboratory. Instructions for the collection 
and transmission of ECGs to the central ECG laboratory will be provided in the ECG Manual.
Interpretation of the tracing must be made by a qualified physician and documented on the ECG. 
Each ECG tracing should be labeled with the study number, patient initials (where regulations 
permit), patient number, and date, and kept in the source documents at the study site. Clinically 
significant abnormalities present at screening should be reported on the Medical History eCRF. 
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 eCRF. All eligibility and patient management decisions 
should be made based on the local reading of the ECG.
7.2.2.6.2 Doppler echocardiography
Doppler echocardiography will be performed as outlined in Table 7-3 and Table 7-4. Additional 
assessments may be performed if clinically indicated. When possible, the same cardiologist 
should read and report the outcome to minimize the variability in results. 




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Cycle
Day
Scheduled Time Point (h)
Analytes
1
7
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
7
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
7
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
7
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
7
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
7
10-12 h post-C1D7 morning dose and pre-C1D7 
evening dose#
BLZ945, LEL284
1
7
1-2 h post-C1D7 evening dose†
BLZ945, LEL284
1
8
24 h post-C1D7 dose / 12 h post-C1D7 evening dose#
BLZ945, LEL284
1
11+
96 h post-dose
BLZ945, LEL284
2
1
Pre-dose of Cycle 2 
BLZ945, LEL284
3
1
Pre-dose of Cycle 3
BLZ945, LEL284
EoT
Anytime
BLZ945, LEL284
Unscheduled
Anytime
BLZ945, LEL284
+Only for Japanese patients
#Only for twice a day dosing
†Only for twice a day dosing and if deemed logistically feasible
Table 7-10
Pharmacokinetic blood collection log for BLZ945 once weekly (Q1W)
regimen (single agent)
Cycle
Day
Scheduled Time Point (h)
Analytes
1
1
Pre-dose of Cycle 1
BLZ945, LEL284 
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
10-12 h post-C1D1 morning dose and pre-C1D1 evening 
dose#
BLZ945, LEL284
1
1
1-2 h post-C1D1 evening dose†
BLZ945, LEL284
1
2
24 h post-C1D1 dose / 12 h post-C1D1 evening dose#
BLZ945, LEL284
1
8
Pre-dose C1D8
BLZ945, LEL284
1
8
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
8
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
8
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
8
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
8
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
8
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
8
10-12 h post-C1D8 morning dose and pre-C1D8 evening 
dose#
BLZ945, LEL284
1
8
1-2 h post-C1D8 evening dose†
BLZ945, LEL284
1
9
24 h post-C1D8 dose / 12 h post-C1D8 evening dose#
BLZ945, LEL284
1
11+
72 h post-dose
BLZ945, LEL286
2
1
Pre-dose of Cycle 2 
BLZ945, LEL284
2
2
24 h post-C2D1 dose
BLZ945, LEL284
3
1
Pre-dose of Cycle 3
BLZ945, LEL284


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Cycle
Day
Scheduled Time Point (h)
Analytes
3
2
24 h post-C3D1 dose
BLZ945, LEL284
EoT
Anytime
BLZ945, LEL284
Unscheduled
Anytime
BLZ945, LEL284
+Only for Japanese patients
#Only for twice a day dosing
†Only for twice a day dosing and if deemed logistically feasible
Table 7-11
Pharmacokinetic blood collection log for BLZ945 4d on/10d off 
regimen (single agent) in phase I
Cycle
Day
Scheduled Time Point (h)
Analytes
1
1
Pre-dose of Cycle 1
BLZ945, LEL284 
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
10-12 h post-C1D1 morning dose and pre-C1D1 evening 
dose#
BLZ945, LEL284
1
1
1-2 h post-C1D1 evening dose†
BLZ945, LEL284
1
2
24 h post-dose / 12 h post-C1D1 evening dose# and pre-dose 
C1D2
BLZ945, LEL284
1
4
Pre-dose 
BLZ945, LEL284 
1
4
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
4
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
4
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
10-12 h post-C1D4 morning dose and pre-C1D4 evening 
dose#
BLZ945, LEL284
1
4
1-2 h post-C1D4 evening dose†
BLZ945, LEL284
1
5
24 h post-dose / 12 h post-C1D4 evening dose#
BLZ945, LEL284
1
11+
168 h post-dose
BLZ945, LEL284
1
19
24 h post-C1D18 dose
BLZ945, LEL284
2
1
Pre-dose of Cycle 2 
BLZ945, LEL284
2
2
24 h post-C2D1 dose
BLZ945, LEL284
3
1
Pre-dose of Cycle 3
BLZ945, LEL284
3
2
24 h post-C3D1 dose
BLZ945, LEL284
EoT
Anytime
BLZ945, LEL284
Unscheduled
Anytime
BLZ945, LEL284
+Only for Japanese patients
#Only for twice a day dosing frequency
†Only for twice a day dosing and if deemed logistically feasible 


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Table 7-12
Pharmacokinetic blood collection log for BLZ945 4d on/10d off 
regimen (single agent) in phase II
Cycle
Day
Scheduled Time Point (h)
Analytes
1
1
Pre-dose of Cycle 1
BLZ945, LEL284 
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
2
24 h post-dose (± 2 h) and pre-C1D2 dose
BLZ945, LEL284
1
4
Pre-dose 
BLZ945, LEL284 
1
4
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
4
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
4
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
5
24 h post-dose (± 2 h)
BLZ945, LEL284
EoT
Anytime
BLZ945, LEL284
Unscheduled
Anytime
BLZ945, LEL284
Table 7-13
Pharmacokinetic blood collection log for BLZ945 and PDR001 and 
ADA (BLZ945 and PDR001 combination) 7d on/7d off regimen
Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
1
Pre-dose of Cycle 1
BLZ945, LEL284,  PDR001 
ADA
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h (± 10 min) post-PDR001 dose 
BLZ945, LEL284, PDR001
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
10-12 h post-C1D1 morning dose 
and pre-C1D1 evening dose#
BLZ945, LEL284
1
1
1-2 h post-C1D1 evening dose†
BLZ945, LEL284
1
2
24 h (± 2h) post-BLZ945 C1D1 
dose / 12 h post-C1D1 evening 
dose# and pre-dose C1D2
BLZ945, LEL284, PDR001
1
7
Pre-dose 
BLZ945, LEL284, 
1
7
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
7
1 h post-dose (± 10 min) 
BLZ945, LEL284 
1
7
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
7
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
7
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
7
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
7
10-12 h post-C1D7 morning dose 
and pre-C1D7 evening dose#
BLZ945, LEL284
1
7
1-2 h post-C1D7 evening dose†
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Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
8
24 h (± 2h) post-BLZ945 C1D7 
dose / 12 h post-C1D7 evening 
dose# and 168h (± 8h) post-
PDR001 C1D1 dose 
BLZ945, LEL284, PDR001
1
11+
96 h post-dose
BLZ945, LEL284
1
15
Pre-dose / 336h post dose 
BLZ945, LEL284, PDR001
2
1
Pre-dose of cycle 2 
BLZ945, LEL284, PDR001 
ADA
2
1
1 h (± 10 min) post-PDR001 
C2D1 dose 
PDR001
3
1
Pre-dose of Cycle 3
BLZ945, LEL284, PDR001 
ADA
3
1
1 h (± 10 min) post-PDR001 
C3D1 dose 
PDR001
3
8
24 h (± 2h) post-BLZ945 C3D7 
dose/ 168 h (± 8h) post-PDR001 
C3D1 dose 
BLZ945, LEL284, PDR001
3
15
336h (±24h) post-PDR001 C3D1 
dose 
PDR001
4
1
Pre-dose of cycle 4 
BLZ945, LEL284, PDR001 
ADA
4
1
1 h (± 10 min) post-PDR001 
C4D1 dose 
PDR001
5
1
Pre-dose of Cycle 5
BLZ945, LEL284 PDR001 
ADA
5
1
1h (± 10 min) post-PDR001 
C5D1 dose 
PDR001
6
1
Pre-dose of Cycle 6
BLZ945, LEL284, PDR001 
ADA
6
1
1h (± 10 min) post-PDR001 
C6D1 dose 
PDR001
EoT
Anytime
BLZ945, LEL284, PDR001 
ADA
150 day safety 
FUc
Anytime
PDR001
ADA
Unscheduled
Anytime
BLZ945, LEL284, PDR001 
ADA
a ADA samples associated with PDR001 are to be collected together with PK samples. 
c Only for patients who come to the site for the 150-day safety FU
PK samples will be collected from the arm opposite of infusion site. 
+Only for Japanese patients 
#Only for twice a day dosing frequency
†Only for twice a day dosing and if deemed logistically feasible 
Table 7-14
Pharmacokinetic blood collection log for BLZ945 and PDR001 and 
ADA (BLZ945 and PDR001 combination) once weekly (Q1W) regimen
Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
1
Pre-dose of Cycle 1
BLZ945, LEL284,  PDR001 
ADA
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h (± 10 min) post-PDR001 dose 
BLZ945, LEL284, PDR001
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
10-12 h post-C1D1 morning dose 
and pre-C1D1 evening dose#
BLZ945, LEL284


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Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
1
1-2 h post-C1D1 evening dose†
BLZ945, LEL284
1
2
24 h (± 2h) post-BLZ945 C1D1 
dose / 12 h post-C1D1 evening 
dose#
BLZ945, LEL284, PDR001
1
8
Pre-dose C1D8 / 168h post dose
BLZ945, LEL284, PDR001
1
8
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
8
1 h post-dose (± 10 min) 
BLZ945, LEL284
1
8
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
8
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
8
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
8
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
8
10-12 h post-C1D8 morning dose 
and pre-C1D8 evening dose#
BLZ945, LEL284
1
8
1-2 h post-C1D8 evening dose†
BLZ945, LEL284
1
9
24 h post-dose / 12 h post-C1D8 
evening dose#
BLZ945, LEL284
1
11+
72 h post-dose
BLZ945, LEL284
1
15
Pre-dose / 336h post dose 
BLZ945, LEL284, PDR001
2
1
Pre-dose of cycle 2 
BLZ945, LEL284, PDR001 
ADA
2
1
1 h (± 10 min) post-PDR001 
C2D1 dose 
PDR001
2
2
24 h (± 2h) post-BLZ945 C2D1 
dose/ PDR001 C2D1 dose
BLZ945, LEL284, PDR001
2
15
336 h post-dose (± 24h) of 
PDR001 C2D1 dose
PDR001
3
1
Pre-dose of Cycle 3
BLZ945, LEL284, PDR001 
ADA
3
1
1 h (± 10 min) post-PDR001 dose 
PDR001
3
2
24 h (± 2h) post-BLZ945 C3D1 
dose/ PDR001 C3D1 dose
BLZ945, LEL284, PDR001
3
8
168 h (± 8h) post-PDR001 C3D1 
dose
PDR001
3
15
336h (±24h) post-PDR001 C3D1 
dose 
PDR001
4
1
Pre-dose of cycle 4 
BLZ945, LEL284, PDR001 
ADA
4
1
1 h (± 10 min) post-PDR001 dose 
PDR001
5
1
Pre-dose of Cycle 5
BLZ945, LEL284, PDR001 
ADA
5
1
1h (± 10 min) post-PDR001 dose 
PDR001
6
1
Pre-dose of Cycle 6
BLZ945, LEL284, PDR001 
ADA
6
1
1h (± 10 min) post-PDR001 dose  
PDR001
EoT
Anytime
BLZ945, LEL284, PDR001 
ADA
150 day safety 
FUc
Anytime
PDR001
ADA
Unscheduled
Anytime
BLZ945, LEL284, PDR001 
ADA
a ADA samples associated with PDR001 are to be collected together with PK samples. 
c Only for patients who come to the site for the 150-day safety FU
+Only for patients in Japan
#Only for twice a day dosing frequency
†Only for twice a day dosing and if deemed logistically feasible 
PK samples will be collected from the arm opposite of infusion site. 


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Table 7-15
Pharmacokinetic blood collection log for BLZ945 and PDR001 and 
ADA (BLZ945 and PDR001 combination) 4d on/10d off regimen in 
phase I
Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
1
Pre-dose of Cycle 1
BLZ945, LEL284,  PDR001 
ADA
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h post-PDR001 dose (± 10 min) 
BLZ945, LEL284, PDR001
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
10-12 h post-C1D1 morning dose 
and pre-C1D1 evening dose#
BLZ945, LEL284
1
1
1-2 h post-C1D1 evening dose†
BLZ945, LEL284
1
2
24 h (± 2h) post-BLZ945 C1D1 
dose / 12 h post-C1D1 evening 
dose# and pre-dose C1D2
BLZ945, LEL284, PDR001
1
4
Pre-dose 
BLZ945, LEL284, 
1
4
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
4
1 h post-dose (± 10 min) 
BLZ945, LEL284 
1
4
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
4
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
10-12 h post-C1D4 morning dose 
and pre-C1D4 evening dose#
BLZ945, LEL284
1
4
1-2 h post-C1D4 evening dose†
BLZ945, LEL284
1
5
24 h post-dose / 12 h post-C1D4
evening dose#
BLZ945, LEL284, PDR001
1
8
168 h post-PDR001 C1D1 dose
PDR001
1
11+
168 h post-dose
BLZ945, LEL284
1
15
336h post-dose 
PDR001
1
19
24 h post-C1D18 dose
BLZ945, LEL284
2
1
Pre-dose of cycle 2 
BLZ945, LEL284, PDR001 
ADA
2
1
1 h post-PDR001 dose (± 10 min)
PDR001
2
2
24 h (± 2h) post-PDR001 C2D1 
dose
BLZ945, LEL284, PDR001
2
15
336 h (± 24h) post-PDR001 
C2D1 dose
PDR001
3
1
Pre-dose of Cycle 3
BLZ945, LEL284, PDR001 
ADA
3
1
1 h (± 10 min) post-PDR001
C3D1 dose (± 10 min) 
PDR001
3
2
24 h (± 2h) post-PDR001 C3D1 
dose
BLZ945, LEL284, PDR001
3
8
168 h (± 8h) post-PDR001 C3D1 
dose 
PDR001
3
15
336h (±24h) post-PDR001 C3D1 
dose 
PDR001
4
1
Pre-dose of cycle 4 
BLZ945, LEL284, PDR001 
ADA


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Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
4
1
1 h (± 10 min) post- PDR001 
C4D1 dose 
PDR001
5
1
Pre-dose of Cycle 5
BLZ945, LEL284, PDR001 
ADA
5
1
1h (± 10 min) post-PDR001 dose  
PDR001
6
1
Pre-dose of Cycle 6
BLZ945, LEL284, PDR001 
ADA
6
1
1h (± 10 min) post-PDR001 dose 
PDR001
EoT
Anytime
BLZ945, LEL284, PDR001 
ADA
150 day safety 
FUc
Anytime
PDR001
ADA
Unscheduled
Anytime
BLZ945, LEL284, PDR001 
ADA
a ADA samples associated with PDR001 are to be collected together with PK samples. 
c Only for patients who come to the site for the 150-day safety FU
+Only for Japanese patients
#Only for twice a day dosing frequency
†Only for twice a day dosing and if deemed logistically feasible 
PK samples will be collected from the arm opposite of infusion site. 
Table 7-16
Pharmacokinetic blood collection log for BLZ945 and PDR001 and 
ADA (BLZ945 and PDR001 combination) 4d on/10d off regimen in 
phase II
Cycle
Day
Scheduled Time Point (h)
Analytes
ADA analysis a
1
1
Pre-dose of Cycle 1
BLZ945, LEL284,  PDR001 
ADA
1
1
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
1
1 h post-PDR001 dose (± 10 min) 
BLZ945, LEL284, PDR001
1
1
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
1
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
1
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
1
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
2
24 h (± 2h) post-BLZ945 C1D1 
dose and pre-C1D2 dose
BLZ945, LEL284, PDR001
1
4
Pre-dose 
BLZ945, LEL284, 
1
4
0.5 h post-dose (± 10 min)
BLZ945, LEL284
1
4
1 h post-dose (± 10 min) 
BLZ945, LEL284 
1
4
2 h post-dose (± 10 min) 
BLZ945, LEL284
1
4
4 h post-dose (± 15 min) 
BLZ945, LEL284
1
4
6 h post-dose (± 1 h) 
BLZ945, LEL284
1
4
8 h post-dose (± 1 h) 
BLZ945, LEL284
1
5
24 h (± 2 h) post-dose
BLZ945, LEL284, PDR001
1
8
168 h post-PDR001 C1D1 dose
PDR001
1
15
336h post-PDR001 C1D1 dose 
PDR001
2
1
Pre-dose of cycle 2 
PDR001 
ADA
EoT
Anytime
BLZ945, LEL284, PDR001 
ADA
150 day safety 
FUc
Anytime
PDR001
ADA
Unscheduled
Anytime
BLZ945, LEL284, PDR001 
ADA
a ADA samples associated with PDR001 are to be collected together with PK samples. 
c Only for patients who come to the site for the 150-day safety FU






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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. For additional details about irAE, please refer to Section 6.3.2.
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 eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s eCRF. Adverse event monitoring should 
be continued for at least 30 days for BLZ945 single agent and 150 days for BLZ945 in 
combination with PDR001 following the last dose of study treatment. 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 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 though 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:


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
The severity grade (CTCAE Grade 1-4)

The duration (Start and end dates)

The relationship to the study treatment (Reasonable possibility that AE is related: No, 
Yes)

The action taken with respect to study treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable)

Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)

Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown)

Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1, 
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 eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per irRC, RECIST v1.1, RANO or iRANO, the Guidelines for efficacy 
evaluation in Hodgkin and non-Hodgkin lymphoma studies) 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.
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.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.


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Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 

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 irRC, RECIST 
v1.1, RANO or iRANO, the Guidelines for efficacy evaluation in Hodgkin and non-Hodgkin 
lymphoma studies. 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.


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If there is any uncertainty about an adverse event being due only to the disease under study, it 
should be reported as an AE or SAE.
8.2.2
Reporting
SAE collection will start upon signing the informed consent whether the patient is a screen 
failure or not. SAEs will be followed until resolution or until clinically relevant improvement 
or stabilization.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 30 days after the patient has 
stopped BLZ945 single agent and 150 days after the patient has stopped BLZ945 in combination
with PDR001 must be reported to Novartis within 24 hours of learning of its occurrence. If a 
patient starts a post treatment antineoplastic therapy, then only SAEs suspected to be related to 
study treatment will be reported.
Any additional information for the SAE including complications, progression of the initial SAE, 
and recurrent episodes must be reported as follow-up to the original episode within 24 hours of 
the investigator receiving the follow-up information. An SAE occurring at a different time 
interval or otherwise considered completely unrelated to a previously reported one should be 
reported separately as a new event.
Any SAEs experienced after the safety evaluation follow-up period should only be reported to 
Novartis if the investigator suspects a causal relationship to the study treatment.
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, and submit
the completed form within 24 hours to Novartis.
Detailed instructions regarding the submission process and requirements for signature are to be 
found in the Investigator folder provided to each site.
Follow-up information is submitted in the same way as 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 BLZ945 or PDR001 Investigator’s Brochures
or Package Insert (new occurrence) and is thought to be related to the Novartis study treatment, 
an oncology Novartis 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.


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8.3
Pregnancies
To ensure patient safety, each pregnancy occurring while the patient is on study treatment or 
for the female partners of male participants in the study, must be reported to Novartis within 24 
hours of learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. After 
the mother has provided consent, the newborn will be followed-up for 12 months.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety (CMO&PS). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational any pregnancy outcome. Any SAE 
experienced during pregnancy must be reported on the SAE Report Form.
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother.
8.4
Warnings and precautions
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided Investigator 
Brochure. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed.
8.5
Data Monitoring Committee
A data monitoring board will not be used for this study. This is an open-label, Phase I-II study 
in which all patients receive either BLZ945 or the combination of BLZ945 with PDR001. 
Novartis will have access to the Safety Data on a regular basis. Novartis will host investigator 
teleconferences on a regular basis during the study. Further, during the phase I part of the study 
Novartis and the investigators will meet at the end of each treatment cohort to discuss and 
evaluate all of the gathered safety data. At the dose escalation teleconference the clinical course 
(safety information including both DLTs and all CTCAE Grade 2 or higher toxicity data during 
the first cycle of treatment, and PK data) for each patient in the current dose cohort will be 
described in detail. Updated safety data on other ongoing patients, including data in later cycles, 
will be discussed as well.
Dose escalation decisions will be based on a clinical synthesis of all relevant available data and 
not solely on DLT information. Selection of the actual dose for the next cohort of patients will 
be guided by the BLRM with EWOC, and a medical review of relevant clinical, PK and 
laboratory data. Novartis and the investigator parties must reach a consensus on whether to 
declare MTD, escalate the dose any further, or whether to de-escalate and/or recruit an 
additional cohort of patients at the current dose level Section 10.4.4, and Section 10.7.
During the phase II part of the study, individual patient data will be reviewed on an ongoing 
basis. Aggregate safety data will be monitored quarterly by the study team across the duration 


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of the trial. The data review and analysis will be based on the available investigator reported 
data in the clinical database at that time Section 10.7. 
8.6
Steering Committee 
A Steering Committee constituted of members of the Translational Clinical Oncology 
Leadership Team will be formed for this study. If the monitoring of the study data requires a 
decision to be taken on the continuation of the study, then the relevant data (e.g., safety data or 
primary analysis and predictive probability of success) will be communicated to the Steering 
Committee for decision making purposes.
9
Data collection and management
9.1
Data confidentiality
Information about study patients will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 


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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 and biomarker (blood, serum, plasma and/or tissue) samples obtained during the course of 
the study will be collected from the Investigator sites and analyzed by a Novartis designated 
laboratory, contracted central laboratories, or local laboratories. 
ECG data collected during the study will be reviewed and processed centrally by a specialist CRO. 
During the course of the study, Novartis may decide to have a central review of the radiological 
assessments performed. In such case, the investigator’s staff will be instructed on how to send data 
from these radiological assessments to a CRO for central review when needed.
Designated investigational site staff will enter the information required by the protocol into the 
appropriate eCRF and/or designated laboratory requisition forms. Field monitors will review 
the eCRFs and laboratory paper requisition forms for accuracy and completeness and instruct 
site personnel to make any required corrections or additions. One copy of the requisition form 
will be forwarded to each analytical laboratory with the respective sample(s) by the field 
monitor or by the designated investigational site staff; and one copy will be retained at the 
investigational site.


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9.4
Database management and quality control
For studies using eCRFs, Novartis personnel (or designated CRO) will review the data entered 
by investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing values 
and sent to the investigational site via the EDC system. Designated investigator site staff 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 (Biomarker sampling, PK sampling, ECG data) will be processed centrally 
and the results will be sent electronically to Novartis (or a designated CRO).
For EDC studies, after database lock, the investigator will receive a CD-ROM or paper copies 
of the patient data for archiving at the investigational site.
10
Statistical methods and data analysis
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized using 
descriptive statistics (continuous data) and/or contingency table (categorical data) for 
demographic and screening characteristics, efficacy measurements, safety measurements and 
all relevant PK and PD measurements. Categorical data will be presented as frequencies and 
percentages. For continuous data, mean, standard deviation, median, minimum, and maximum 
will be presented.
The study data will be analyzed and reported based on all patients’ data of the dose escalation 
and Phase II parts up to the time when all patients from dose escalation part have potentially 
completed at least six cycles of treatment or discontinued the study and all patients from Phase 
II part have had at least one tumor assessment after six months 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:

For the phase I part, cohorts treated with the same dose or dose combination (dose levels 
and schedules) will be pooled into a single treatment group. All summaries, listings, figures 
and analyses will be performed by treatment group.

For the phase II part, all summaries, listings, figures for primary efficacy analysis and 
safety analyses for glioblastoma patients will be presented by treatment arms (i.e., BLZ945 as 
single agent at the RP2D, and BLZ945 at the RP2D in combination with PDR001).
Note: patients from the phase I dose escalation part and the phase II part will not be pooled in 
any analyses unless otherwise specified.
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.


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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 study 
treatment. Patients will be analyzed according to the planned treatment. The FAS will be used 
for all listings of raw data. Unless otherwise specified, the FAS will be the default analysis set 
used for all analyses.
10.1.2
Safety set
The Safety Set includes all patients who received at least one dose of BLZ945 or PDR001. 
Patients will be analyzed according to the study treatment (regimen) they actually received, 
where treatment received is defined as:
The treatment assigned if it was received at least once, or the first treatment received when 
starting therapy with study treatment if the assigned treatment was never received. The safety 
set will be used for the safety summary of the study.
10.1.3
Per-Protocol set
The Per-Protocol Set (PPS) consists of a subset of the patients in the FAS in the phase II part 
who meet the following criteria: 

Presence of at least one measurable lesion according to RANO as per Appendix 3;

Evaluable per RANO, or have discontinued due to clinical progression

Have received the planned treatment
All major protocol deviations leading to exclusion from the PPS will be detailed in the statistical 
analysis plan (SAP). Patients will be classified according to planned treatment.
The PPS will be used in the phase II part of the study only and will define the patients used in 
the sensitivity analysis of the primary endpoint (Section 10.4). If the PPS and the FAS are 
identical, then analyses described by the PPS below will not be performed.
10.1.4
Dose-determining analysis set
Single agent BLZ945 dose escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during Cycle 1.
A patient is considered to have met the minimum exposure criterion if having received BLZ945 
on at least 75% of the planned dosing days during Cycle 1 (as defined below). Patients who do 
not experience a DLT during the first cycle are considered to have sufficient safety evaluations 
if they have been observed for ≥ 28 days following the first dose and are considered by both the 
Sponsor and Investigators to have enough safety data to conclude that a DLT did not occur.


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Combination of BLZ945 and PDR001 dose escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during the first cycle.
A patient is considered to have met the minimum exposure criterion if having received BLZ945 
on at least 75% of the planned dosing days during Cycle 1 (as defined below) and at least one 
dose of PDR001 during Cycle 1. Patients who do not experience a DLT during the first cycle 
are considered to have sufficient safety evaluations if they have been observed for ≥28 days 
following the first dose, and are considered by both the Sponsor and Investigators to have 
enough safety data to conclude that a DLT did not occur.
For both once and twice a day dosing schedules, the 75% of the planned dosing days of 
BLZ945 is defined as:

at least 11 days of taking planned doses in 7d on/7d off regimen

at least 3 days of taking planned doses of BLZ945 in Q1W regimen

at least 6 days of taking planned doses of BLZ945 in the 4d on/10d off regimen
For other schedules, 75% of the planned dosing days of BLZ945 during cycle 1 will be 
determined following the same principle.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) includes all patients who provide an evaluable PK 
profile. A profile is considered evaluable if all the following conditions are satisfied:

Patient receives one of the planned treatments

Patient provides at least one primary PK parameter

Patient does not vomit within 4 hours after dosing of BLZ945
10.1.6
Other analysis sets 
Not applicable
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data (including disease characteristics) will be summarized 
descriptively by treatment group for both phase I and phase II with the FAS.


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10.3
Treatments (study treatment, concomitant therapies, 
compliance)
For each of BLZ945 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 BLZ945 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 
in phase I and phase II.
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 anatomical therapeutic chemical 
(ATC) term and treatment group in phase I and phase II.
The reason for discontinuation from treatment will be summarized and listed, along with dates 
of first and last dose of BLZ945 and PDR001 (if applicable), duration of exposure to BLZ945
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 I part
To characterize the safety and tolerability and to estimate the MTD or RP2D of BLZ945 as a 
single agent and in combination with PDR001.
To characterize the safety and tolerability and to estimate the MTD or RP2D of BLZ945 as a 
single agent for Japanese patients
Phase II part
To assess the anti-tumor activity of BLZ945 as single agent and in combination with PDR001
among patients with GBM.
10.4.1
Variable
Phase I part

Safety: Frequency and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs

Tolerability: dose interruptions, reductions and dose intensity.
See Section 10.5.3 for details of analysis.

The DLT rate during the first cycle of treatment with single agent BLZ945 and with 
BLZ945 in combination with PDR001


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Estimation of the MTD(s)/RP2D(s) will be based upon the estimation by the BLRM of the 
probability of a DLT in the first cycle of treatment for patients in the DDS. 
Phase II part 
The primary variable is the PFS rate at 6 months, defined as the time from the date of start of 
treatment to the date of the first documented progression or death due to any cause. Disease 
progression is defined as per RANO for glioblastoma.
10.4.2
Safety objectives
10.4.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used. All listings and tables will be presented by 
treatment group in phase I.
The overall observation period will be divided into three mutually exclusive segments:

pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication

on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study treatment

post-treatment period: starting at day 31 after last dose 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.
10.4.2.2 Adverse events (AEs)
Summary tables for adverse events (AEs) have to include only AEs that started or worsened 
during the on-treatment period, the treatment-emergent AEs. However, all safety data 
(including those from the pre and post-treatment periods) will be listed and those collected 
during the pre-treatment and post-treatment period are to be flagged.
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment by treatment group in phase I.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and by treatment group in phase I.
Specific safety event categories (SEC) will be considered. Such categories consist of one or 
more well-defined safety events which are similar in nature and for which there is a specific 
clinical interest in connection with the study treatment(s).
For each specified SEC, number and percentage of patients with at least one event part of the 
SEC will be reported.




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10.4.4
Statistical hypothesis, model, and method of analysis
Phase I
An adaptive BLRM guided by the escalation with overdose control (EWOC) principle will be 
used to make dose recommendations and estimate the MTD(s) for each regimen considered. 
The BLRM will be fitted on the dose-limiting toxicity data (i.e. absence or presence of DLT) 
during the DLT window accumulated throughout the dose escalation to model the dose-toxicity 
relationship.
In the single-agent BLZ945 dose escalation part, the dose-toxicity (DLT) relationship is 
modeled by a 2-parameter BLRM.
In the dose escalation for the combinations, the dose-toxicity (DLT) relationship is modeled by 
a 5-parameter BLRM. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
For BLZ945 component a weakly informative prior will be derived based on vague knowledge 
from pre-clinical studies. Available PDR001 single agent data will be used to derive Meta-
Analytic-Predictive (MAP) priors for PDR001 component of the model based on available 
clinical data from [CPDR001X2101], the FIH PDR001 oncology study. At the time of each 
BLZ945 in combination with PDR001 dose escalation analysis, DLT data up to, and including, 
the last completed cohort from the single agent dose escalation will be included in the BLZ945
in combination with PDR001 BLRM. Single agent BLZ945 data will be incorporated directly 
into the BLRM since this data comes from the same study. For further details on the BLRM 
models including the prior specification for the model parameters, and examples of hypothetical 
decisions that may be followed during the dose escalation, refer to Appendix 5.
For Japanese patients, separate single-agent BLRM model will be applied to guide single agent 
dose escalation decisions. Currently available information about the dose-DLT relationships of 
single agent from global patients will be used to derive informative priors for the BLRM 
parameters describing the dose-DLT relationships of this agent taking into consideration the 
heterogeneity between the global population and Japanese patients. For further details on the 
statistical model including the prior specification for the model parameters refer to in 
Appendix 6.
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels (or combinations) will be obtained. Dose recommendation will be based 
on posterior summaries including the mean, median, standard deviation, 95%-credible interval, 
and the probability that the true DLT rate for each dose lies in one of the following categories:

[0,16%) under-dosing

[16%,33%) targeted toxicity

[33%,100%] excessive toxicity
Dose recommendation will also be guided by the EWOC principle, which mandates the dose 
for the next cohort to have less than 25% chance of excessive toxicity. The final estimate of the 
MTD(s)/ RP2D(s) will also satisfy this condition.


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Phase II
The primary analysis will be based on the estimation of the progression free survival rate at 6 
months (PFS6).
The efficacy in glioblastoma for both treatment arms of BLZ945 as single agent and in 
combination with PDR001 will be concluded if both of the following criteria are met for that 
specific group:
1. The posterior mean of PFS6 ≥  40%
2. The posterior probability that PFS6 is ≥ 20% is at least 90%.
A Bayesian design will be used to estimate and provide inferential summaries of the PFS rate 
at 6 months. The PFS will be modeled using a Weibull distribution. A weakly informative prior 
distribution for the PFS at 6 months will be assumed. For further details, refer to Appendix 5. 
At the time of the primary analysis, the model will be updated with all available data of patients 
in the FAS by treatment arm (i.e. RP2D of BLZ945 as single agent and RP2D of BLZ945 in 
combination with PDR001, both in glioblastoma patients), and the posterior distribution for the 
PFS at 6 months will be estimated. Inferential summaries based on the posterior distribution 
and posterior probabilities for activity interval below will be presented. 
Categories for anti-tumor activity
The following classification of clinical relevance of the antitumor activity based on PFS rate at 
6 months will be applied for both treatment groups:
- [0, 20%) unacceptable anti-tumor activity
- [20%, 30%) limited anti-tumor activity
- [30%, 40%) moderate anti-tumor activity
- [40%, 100%] strong anti-tumor activity
If the estimated posterior mean of PFS rate at 6 months is at least 40% and the posterior risk of 
being in the unacceptable anti-tumor activity interval is less than 10%, then preliminary 
antitumor activity can be declared. 
10.4.5
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.
In the phase II part, when a patient discontinued treatment for ‘disease progression’, but without 
documentation of radiological evidence of progression, it will not be counted as a PFS event. 
Patients who discontinue the study and are lost to follow-up without a known date of 
progression or death due to any cause on or before the data cut-off date or when he/she receives 
any further anti-cancer therapy will be censored for PFS at the date of their last available tumor 
evaluation before the cut-off date or the anti-cancer therapy start date.
10.4.6
Supportive analyses
For the phase I part, a method that takes into account both toxicity and PD markers response in 
order to further guide the estimation of the recommended phase II dose(s) by finding an optimal 
dose or range of doses that maximizes the PD response while safety is controlled may be used. 


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First of all, two independent models to assess dose-toxicity and dose-PD response relationships 
will be presented. The toxicity model is a BLRM model and the PD response model is a 
polynomial logistic regression model describing the PD markers response and dose levels 
relationships. This model generalizes the monotonic relationships and allow for different dose-
response shapes. In addition, a bivariate modelling of both PD parameters and safety may be 
explored if appropriate. Details of the analyses will be described in the SAP. For the phase II 
part, the proportion of patients with PFS rate at 6 months will be estimated using the Kaplan-
Meier method along with the two-sided 90% confidence interval, using the FAS. In addition, 
the primary analysis on PFS may be repeated using PPS. Additional supportive 
analyses will be conducted if appropriate and will be defined in the SAP.
10.5
Secondary objectives
10.5.1
Key secondary objective(s)
Not applicable
10.5.2
Other secondary efficacy objectives
For all efficacy parameters, data will be listed, summarized, and/or analyzed by treatment group 
for the phase I and phase II.
Tumor response will be determined per local investigators’ assessment, according to RECIST 
v1.1, RANO, irRC and iRANO and the Guidelines for efficacy evaluation in Hodgkin and non-
Hodgkin lymphoma studies as appropriate. Response related efficacy assessments will be 
defined and analyzed based on RECIST v1.1, RANO, irRC, iRANO or the Guidelines for 
efficacy evaluation in Hodgkin and non-Hodgkin lymphoma studies as appropriate.
ORR, DCR and PFS will be listed and summarized with accompanying 90% confidence interval.
DOR for patients who experience a CR or PR at any time on study will be listed by patient. PFS 
will be presented graphically using Kaplan Meier plots including all patients in phase II by 
treatment group. Median PFS time and the proportion of patients who are progression-free at 3, 
6, 9, and 12 months will be estimated for each group. If there are a large number of patients 
achieving response, the Kaplan-Meier plots for DOR will also be produced and the median 
DOR will be estimated.
Individual lesion measurements and overall response assessments will be listed by patient and 
assessment date. Best overall response per RECIST v1.1, RANO, irRC, iRANO or the 
Guidelines for efficacy evaluation in Hodgkin and non-Hodgkin lymphoma studies will be 
listed and tabulated.
OS will be presented graphically using Kaplan Meier plots including all patients in phase II by 
treatment group. Median OS time and the proportion of patients who are alive at 3, 6, 9, and 12 
months will be estimated for each group.
10.5.3
Safety objectives
Phase II part of the study will further characterize the safety and tolerability of BLZ945 as a 
single agent and in combination with PDR001 in glioblastoma patients. For all safety analyses, 


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the safety set will be used. All listings and tables will be presented by treatment arm in phase 
II. The analysis plan follows the same as indicated in Section 10.4.2.
10.5.4
Tolerability
Phase II part of the study will continue evaluating tolerability of study treatment in glioblastoma
patients (refer to Section 10.4.3 and Section 10.3).
10.5.5
Supportive analyses for secondary objectives 
Not applicable.
10.5.5.1 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).


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10.5.6
Pharmacokinetics
All subjects who have evaluable PK data will be included in the PK data analysis.  The 
pharmacokinetic parameters listed in Table 10-1 will be estimated when feasible. The 
parameters that require terminal phase determination (T1/2 and AUCinf) may not be adequately 
calculated by non-compartmental methods. 
Table 10-1
Non-compartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) 
(mass x time x volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
Cmax
The maximum (peak) observed plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma, blood, serum, or other body fluid drug 
concentration after single dose administration (time)
T1/2
The elimination half-life associated with the terminal slope (z) of a semi 
logarithmic concentration-time curve (time). Use qualifier for other half-lives
CLp/F
The total body clearance of drug from the plasma (volume x time-1)
Vz/F
The apparent volume of distribution during terminal phase (associated with z) 
(volume)
AR
Accumulation Ratio = AUC (multiple Dose)/AUC (single dose)
PAS will be used in all pharmacokinetic data analysis and PK summary statistics. PK data from 
Japanese patients treated on the single agent Japanese dose escalation will be analyzed 
separately.
10.5.6.1 Data handling principles
Only PK blood samples with the date and time and for which the last prior dose dates and times 
are adequately recorded will be included in the PK analyses. Missing concentration values will 
be reported as is in data listings. Concentration values below LLOQ will be handled as zero in 
summary statistics, and reported as is in data listings. Any missing pharmacokinetic parameter 
data will not be imputed.
10.5.6.2 Basic Tables, Figures and Listings
Descriptive statistics (mean, standard deviation, CV% or median (range)) will be presented for 
all pharmacokinetic parameters. When a geometric mean is presented, it will be stated as such. 
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 presented for 
this parameter. Summary statistics will be presented for BLZ945, LEL284 and PDR001 serum 
concentrations at each scheduled time point. Anti-PDR001 antibody data will also be 
summarized. Descriptive graphical plots of individual serum concentration versus time profiles 
and mean concentration versus time profiles will be generated. 
 


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10.5.8
Resource utilization
Not applicable
10.5.9
Patient-reported outcomes
Not applicable




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Table 10-2
Operating characteristics
True PFSR6
Complete success 
rate
Complete failure rate
Probability of stop at 
interim
20
0.004
0.996
0.71
30
0.09
0.91
0.43
40
0.57
0.43
0.21
50
0.90
0.10
0.08
60
0.97
0.03
0.03
The Investigators and Novartis study personnel will make the decision based on a synthesis of 
all relevant data available including safety, PK 
information.
10.8
Sample size calculation
Dose escalation part 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD/RP2D level, as described in Section 6.2.3. Multiple cohorts may be 
sequentially enrolled to the same dose level. At least 21 patients are expected to be treated in 
the in the single agent BLZ945 dose escalation part, at least 12 patients are required to be treated 
in the Japanese single agent dose escalation and at least 15 patients are required to be treated in 
each combo dose escalation, for the models to have reasonable operating characteristics relating 
to its MTD recommendation.
Phase II
Approximately 20 glioblastoma patients will be initially enrolled at the RP2D of BLZ945 as 
single agent and at the RP2D of BLZ945 in combination with PDR001, with the possibility of 
expanding to 40 patients for each treatment arm. Based on the operating characteristics as 
described in Appendix 5, with a sample size of 40 patients when the true PFS6 is 60%, there is 
97% chance to conclude clinically relevant efficacy, and when the true PFS6 is 20% there is 
less than 1% chance to wrongly conclude clinically relevant efficacy.
10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.




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11.4
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), 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 ...novartis.com.
11.6
Study documentation, record keeping and retention of 
documents
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress.
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 


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at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The electronic study case report form (eCRF) is the primary data 
collection instrument for the study. The investigator should ensure the accuracy, completeness, 
legibility, and timeliness of the data reported in the eCRFs and all other required reports. Data 
reported on the eCRF, that are derived from source documents, should be consistent with the
source documents or the discrepancies should be explained. All data requested on the eCRF
must be recorded. Any missing data must be explained. Any change or correction to a paper 
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.
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.


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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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Wen PY, Macdonald DR, Reardon DA, et al (2010b) Updated Response Assessment Criteria 
for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin 
Oncol; 28:1963-1972
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(23):7412-20
Wynn TA, Chawla A, Pollard JW (2013) Macrophage biology in development, homeostasis 
and disease. Nature; 496(7446):445-55
Yadav BS, Sharma SC, Chanana P, et al (2014) Systemic treatment strategies for triple-
negative breast cancer.World J Clin Oncol; 10;5(2):125-33
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new and unexpected biological functions. Nat Rev Cancer; 14(11):736-46
Yuan ZY, Luo RZ, Peng RJ, et al. (2014) High infiltration of tumor-associated macrophages 
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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown
14.1.1
Introduction
The purpose of this document is to provide the working definitions and rules necessary for a 
consistent and efficient analysis of efficacy for oncology studies in solid tumors. This document 
is based on the RECIST criteria for tumor responses (Therasse et al 2000) and the revised 
RECIST 1.1 guidelines (Eisenhauer et al 2009).
The efficacy assessments described in Section 14.1.2 and the definition of best response in 
Section 14.1.3.1 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.3.2 is summarizing the “time to event” 
variables and rules which are mainly derived from internal discussions and regulatory 
consultations, as the RECIST criteria do not define these variables in detail. Section 14.1.4 of 
this guideline describes data handling and programming rules. This section is to be referred to 
in the RAP (Reporting and Analysis Plan) to provide further details needed for programming.
14.1.2
Efficacy assessments
Tumor evaluations are made based on RECIST criteria (Therasse et al 2000), New Guidelines 
to Evaluate the Response to Treatment in Solid Tumors, Journal of National Cancer Institute, 
Vol. 92; 205-16 and revised RECIST guidelines (version 1.1) (Eisenhauer et al 2009) European 
Journal of Cancer; 45:228-247.


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


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14.1.2.1.2
Eligibility based on measurable disease
If no measurable lesions are identified at baseline, the patient may be allowed to enter the study 
in some situations (e.g. in Phase III studies where PFS is the primary endpoint). However, it is 
recommended that patients be excluded from trials where the main focus is on the Overall 
Response Rate (ORR). Guidance on how patients with just non-measurable disease at baseline 
will be evaluated for response and also handled in the statistical analyses is given in 
Section 14.1.3.2.8.
14.1.2.2 Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to i.v. contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the anti-tumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.

A change in methodology can be defined as either a change in contrast use (e.g. keeping 
the same technique, like CT, but switching from with to without contrast use or vice-versa, 
regardless of the justification for the change) or a change in technique (e.g. from CT to 
MRI, or vice-versa), or a change in any other imaging modality. A change in methodology 
will result by default in a UNK overall lesion response assessment. However, another 
response assessment than the Novartis calculated UNK response may be accepted from the 
investigator or the central blinded reviewer if a definitive response assessment can be 
justified, based on the available information.

FDG-PET: can complement CT scans in assessing progression (particularly possible for 
‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified according 
to the following algorithm:

Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD 
based on a new lesion.

No FDG-PET at baseline with a positive FDG-PET at follow-up:

If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed by 
CT, this is PD.


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


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


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Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement.  This default value is derived from the 5 mm CT slice
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
Nodal lesions
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes are not 
expected to disappear completely, so a “non-zero size” will always persist.
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to be 
non-reproducible. Therefore, it is recommended to report a default value of 5 mm, instead of 
the actual measurement.  This default value is derived from the 5 mm CT slice thickness (but 
should not be changed with varying CT slice thickness). Actual measurement should be given 
for all lesions larger than 5 mm in short axis irrespective of slice thickness/reconstruction 
interval.
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements will 
continue to be recorded to allow the values to be included in the sum of diameters for target 
lesions, which may be required subsequently for response determination.


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14.1.2.4.2
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response 
(CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph nodes 
assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as reference 
the baseline sum of diameters.
Progressive Disease 
(PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking as 
reference the smallest sum of diameter of all target lesions recorded at or after baseline. 
In addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
SOD for CR may not be zero when nodal lesions are part of target lesions
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
Methodology change See Section 14.1.2.2.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the eCRF and the tumor assessment will remain 
based on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will 
be determined if there is at least 20% increase in the sum of diameters of all measured 
target lesions, taking as reference the smallest sum of diameters of all target lesions 
recorded at or after baseline with at least 5 mm increase in the absolute sum of the 
diameters). Proper documentation should be available to support this decision. This applies 
to patients who have not achieved target response of CR. For patients who have achieved 
CR, please refer to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.


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Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 
in other cases where a PD cannot definitely be attributed, the target lesion response would 
be UNK.
Nodal lesion decrease to normal size: When nodal disease is included in the sum of target 
lesions and the nodes decrease to “normal” size they should still have a measurement 
recorded on scans. This measurement should be reported even when the nodes are normal 
in order not to overstate progression should it be based on increase in the size of nodes.
Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub-lesions. 
When this occurs, the diameters (long axis - non-nodal lesion, short axis - nodal lesions) of 
the two split lesions should be added together and the sum recorded in the diameter field on 
the case report form under the original lesion number. This value will be included in the 
sum of diameters when deriving target lesion response. The individual split lesions will not 
be considered as new lesions, and will not automatically trigger a PD designation.
Lesions coalesced: Conversely, it is also possible that two or more lesions which were 
distinctly separate at baseline become confluent at subsequent visits. When this occurs a 
plane between the original lesions may be maintained that would aid in obtaining diameter 
measurements of each individual lesion. If the lesions have truly coalesced such that they 
are no longer separable, the maximal diameters (long axis - non-nodal lesion, short axis -
nodal lesions) of the “merged lesion” should be used when calculating the sum of 
diameters for target lesions. On the case report form, the diameter of the “merged lesion” 
should be recorded for the size of one of the original lesions while a size of “0”mm should 
be entered for the remaining lesion numbers which have coalesced.

The measurements for nodal lesions, even if less than 10 mm in size, will contribute to 
the calculation of target lesion response in the usual way with slight modifications.

Since lesions less than 10 mm are considered normal, a CR for target lesion response 
should be assigned when all nodal target lesions shrink to less than 10 mm and all non-
nodal target lesions have disappeared.

Once a CR target lesion response has been assigned a CR will continue to be appropriate 
(in the absence of missing data) until progression of target lesions.

Following a CR, a PD can subsequently only be assigned for target lesion response if 
either a non-nodal target lesion “reappears” or if any single nodal lesion is at least 10 mm 
and there is at least 20% increase in sum of the diameters of all nodal target lesions 
relative to nadir with at least 5 mm increase in the absolute sum of the diameters. 


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14.1.2.4.3
Determination of non-target lesion response
Table 14-2
Response criteria for non-target lesions
Response Criteria
Evaluation of non-target lesions
Complete Response (CR):
Disappearance of all non-target lesions. In addition, all lymph nodes assigned a non-
target lesions must be non-pathological in size (< 10 mm short axis)
Progressive Disease (PD):
Unequivocal progression of existing non-target lesions.1
Non-CR/Non-PD:
Neither CR nor PD
Unknown (UNK)
Progression has not been documented and one or more non-target lesions have not 
been assessed or have been assessed using a different method than baseline.
1 Although a clear progression of non-target lesions only is exceptional, in such circumstances, the opinion of the 
treating physician does prevail and the progression status should be confirmed later on by the review panel (or 
study chair).
Notes on non-target lesion response

The response for non-target lesions is CR only if all non-target non-nodal lesions which 
were evaluated at baseline are now all absent and with all non-target nodal lesions 
returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still present, or 
there are any abnormal nodal lesions (i.e. 10 mm) the response can only be ‘Non-
CR/Non-PD’ unless any of the lesions was not assessed (in which case response is UNK) 
or there is unequivocal progression of the non-target lesions (in which case response is 
PD).

Unequivocal progression: To achieve “unequivocal progression” on the basis of non-target 
disease there must be an overall level of substantial worsening in non-target disease such 
that, even in presence of CR, PR or SD in target disease, the overall tumor burden has 
increased sufficiently to merit discontinuation of therapy. A modest “increase” in the size 
of one or more non-target lesions is usually not sufficient to qualify for unequivocal 
progression status. The designation of overall progression solely on the basis of change in 
non-target disease in the face of CR, PR or SD of target disease is therefore expected to be 
rare. In order for a PD to be assigned on the basis of non-target lesions, the increase in the 
extent of the disease must be substantial even in cases where there is no measurable 
disease at baseline. If there is unequivocal progression of non-target lesion(s), then at least 
one of the non-target lesions must be assigned a status of “Worsened”. Where possible, 
similar rules to those described in Section 14.1.2.4.2 for assigning PD following a CR for 
the non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.


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14.1.2.4.4
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion eCRF.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
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
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.


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In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of CR 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.

For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.


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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.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.


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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 endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.


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14.1.3.2.2
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 
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by
Morgan (1988).


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It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
Duration of overall response (CR or PR): For patients with a CR or PR (which may have to 
be confirmed the start date is the date of first documented response (CR or PR) and the end date 
and censoring is defined the same as that for time to progression.
The following two durations might be calculated in addition for a large Phase III study in which 
a reasonable number of responders is seen.
Duration of overall complete response (CR): For patients with a CR (which may have to be 
confirmed) the start date is the date of first documented CR and the end date and censoring is 
defined the same as that for time to progression.
Duration of stable disease (CR/PR/SD): For patients with a CR or PR (which may have to be 
confirmed) or SD the start and end date as well as censoring is defined the same as that for time 
to progression.
14.1.3.2.6
Time to response
Time to overall response (CR or PR) is the time between date of randomization/start of 
treatment until first documented response (CR or PR). The response may need to be confirmed 
depending on the type of study and its importance. Where the response needs to be confirmed 
then time to response is the time to the first CR or PR observed.
Although an analysis on the full population is preferred a descriptive analysis may be performed 
on the “responders” subset only, in which case the results should be interpreted with caution 
and in the context of the overall response rates, since the same kind of selection bias may be 
introduced as described for duration of response in Section 14.1.3.2.5. It is recommended that 
an analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 


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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 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 CR) or CR / PR (for duration of overall response) 
respectively, when this status is later confirmed.
End dates
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (during treatment as recorded on the treatment completion page or during 
follow-up as recorded on the study evaluation completion page or the survival follow-up 
page).

Date of progression is the first assessment date at which the overall lesion response was 
recorded as progressive disease.

Date of last adequate tumor assessment is the date the last tumor assessment with overall 
lesion response of CR, PR or SD which was made before an event or a censoring reason 
occurred. In this case the last tumor evaluation date at that assessment is used. If no post-
baseline assessments are available (before an event or a censoring reason occurred) the 
date of randomization/start of treatment is used.

Date of next scheduled assessment is the date of the last adequate tumor assessment plus 
the protocol specified time interval for assessments. This date may be used if back-dating 
is considered when the event occurred beyond the acceptable time window for the next 
tumor assessment as per protocol (see Section 14.1.3.2.8).


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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


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Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
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)
= Definitions can be found in Section 14.1.3.2.7
=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.3.2.7
=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. 
Clearly define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: 
The primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.
Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the 
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:


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Date of previous scheduled assessment (from baseline) is the date when a tumor assessment 
would have taken place, if the protocol assessment scheme was strictly followed from baseline, 
immediately before or on the date of the last adequate tumor assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.4
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

Patient/guardian decision

Death

Progressive disease per irRC (not per RECIST)

Study terminated by Novartis
14.1.4.3 End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment 
and post-treatment evaluations but prior to collecting survival follow-up.


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Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Patient/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by Novartis
14.1.4.4 Medical validation of programmed overall lesion response
As RECIST is very strict regarding measurement methods (i.e. any assessment with more or 
less sensitive method than the one used to assess the lesion at baseline is considered UNK) and 
not available evaluations (i.e. if any target or non-target lesion was not evaluated the whole 
overall lesion response is UNK unless remaining lesions qualified for PD), these UNK 
assessments may be re-evaluated by clinicians at Novartis or external experts. In addition, data 
review reports will be available to identify assessments for which the investigators’ or central 
reader’s opinion does not match the programmed calculated response based on RECIST criteria. 
This may be queried for clarification. However, the investigator or central reader’s response 
assessment will never be overruled.
If Novartis elect to invalidate an overall lesion response as evaluated by the investigator or 
central reader upon internal or external review of the data, the calculated overall lesion response 
at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.


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14.1.4.5 Programming rules
The following should be used for programming of efficacy results:
14.1.4.5.1
Calculation of ‘time to event’ variables
Time to event = end date - start date + 1 (in days)
When no post-baseline tumor assessments are available, the date of randomization/start of 
treatment will be used as end date (duration = 1 day) when time is to be censored at last tumor 
assessment, i.e. time to event variables can never be negative.
14.1.4.5.2
Incomplete assessment dates
All investigation dates (e.g. X-ray, CT scan) must be completed with day, month and year.
If one or more investigation dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date (and 
assessment date is calculated as outlined in Section 14.1.3.2.7). If all measurement dates have 
no day recorded, the 1st of the month is used.
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


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For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (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:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Novartis decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.
14.1.5
References (available upon request)
Dent S, et al (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791.
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer; Vol.45: 228-47.
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465.
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005.
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007.
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18.
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16.


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14.2
Appendix 2: Guidelines for immune-related Response Criteria 
(irRC) using one-dimensional measurements (simulating RECIST 
1.1)
14.2.1
Introduction
The currently used immune-related response criteria (irRC) uses unidimensional measurements 
to assess tumor response and it is an adaptation of the original irRC published by Wolchok 
(Wolchok et al. 2009, Nishino 2013).
The purpose of this document is to summarize the irRC guidelines in details focusing on 
differences in tumor response assessments between irRC and RECIST v1.1. 
The primary difference between irRC and RECIST 1.1 is the definition of progressive disease. 
The definitions of baseline target/non target lesions, number of lesions selected at baseline,  the criteria 
for lesion measurement method of evaluation of response and definition of response are the same for 
irRC and RECIST 1.1 and are available in the RECIST 1.1 guidelines (Appendix 1). 
14.2.2
New lesions and non-target lesions
In irRC a new lesion does not automatically indicate progressive disease. 
New measurable lesions are added to the sum of longest diameters of the previously existing target 
lesions, and the sum of longest diameters is followed at each subsequent tumor assessment.
New measureable lesions are defined using the same criteria as for baseline target lesions in 
RECIST v1.1. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions. Up to five new measurable lesions (and a 
maximum of two per organ) are allowed in total and will be included in the overall tumor 
assessment.
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 
at baseline and any new non-measurable lesions that have appeared during the study). If after 
worsening a non-target lesion becomes measurable, it should still be followed as a non-target lesion. 
Worsening of non-target lesions and new non-measurable lesions only indicate disease progression 
if there is unequivocal evidence of disease progression (Table 14-6). 
14.2.3
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of longest diameters for all target lesions is calculated 
(at baseline and throughout the study). The longest diameters of any new measurable lesions 
are included in the sum of longest diameters at each assessment to provide the total tumor 
burden. At each assessment, percent change in the sum of longest 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 immune-related partial response (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 immune-related Complete Response
(irCR), and irPD in the case of unequivocal progression, as shown below in Table 14-6. 
Like in RECIST v1.1, irCR and irPR must be confirmed at a new assessment after at least 4 
weeks. Unlike RECIST v1.1, irPD also requires confirmation at a new assessment after at least 
4 weeks.
The response categories are defined as follows:

irCR: Disappearance of all non-nodal target lesions and non-target lesions in two 
consecutive observations not less than 4 weeks apart. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm. (Sum of
diameters may be greater than zero at the time of CR, if nodal lesions are included as 
target lesions).

irPR: At least a 30% decrease in the sum of diameters of all target lesions including new 
target lesions in two consecutive observations not less than 4 weeks apart, taking as 
reference the baseline sum of diameters. 

irPD: At least a 20% increase in the sum of diameters of all measured target lesions 
including new measurable lesions. The irPD must be confirmed in a second evaluation not 
less than 4 weeks later, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline (nadir). In addition to the relative increase of 20%, the 
sum must also demonstrate an absolute increase of at least 5 mm. Worsening of non-target
lesions (existing or new) only indicate PD when there is unequivocal evidence of 
progression, confirmed in a second evaluation not less than 4 weeks later. 

immune-related stable disease (irSD): Neither a sufficient shrinkage to qualify for irPR or 
irCR, nor an increase in lesions which would qualify for irPD. 

Unknown (UNK):  Progression has not been documented and one or more target lesions or 
new measurable lesions observed at earlier assessment have not/could not be assessed, or 
have been assessed using a method significantly different from baseline (target lesions) or 
assessment of first occurrence (for new measurable lesions) that prevents reasonable 
comparison to the prior assessments.


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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
≤-30b
Absent/Stable/not evaluated
irPRa
>-30b and<+20c
Absent/Stable/not evaluated
irSD
≥+20c
Any
irPDa
Any
Unequivocal progression
irPDa
*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 adjust the section number as needed) 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)
Wolchok JD, Hoos A, O'Day S et al (2009) Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res; 15:7412-20.
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013) Developing a Common Language for 
Tumor Response to Immunotherapy: Immune-Related Response Criteria Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-3943.


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14.3
Appendix 3: Response assessment in neuro-oncology (RANO) 
criteria for high-grade gliomas
Antitumor response will be primarily evaluated by the Response Assessment in Neuro-
Oncology (RANO) working group (Wen et al 2010) criteria in this study. The RANO Criteria 
updates its established predecessor, the modified Macdonald Criteria (Macdonald et al 1990), 
by adding assessment of non-enhancing lesions.
Patients will undergo MRI assessments for response evaluation on an every 8 weeks interval from the 
start of the study until disease progression, as outlined in the Visit schedule Table 7-1, 
Table 7-2 and Table 7-3.
The following components will be taken into account when assessing a patient’s overall 
response at an individual evaluation.

Tumor evaluation eCRF for measureable enhancing lesions (T1-Gd+)

Tumor evaluation eCRF for non-enhancing lesions (T2/FLAIR)

Tumor evaluation eCRF for new lesion

Concomitant medication eCRF for steroid usage

Clinical status eCRF for ECOG and other clinical evaluation finding

Overall response eCRF for response category (CR/PR/PD/SD/NA)
14.3.1
Antitumor effect – definitions
Evaluable for toxicity
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment.
Evaluable for objective response
Only those participants who have measurable disease present at screening (Day -28 to -1 scan) 
and have received at least one dose of therapy will be considered evaluable for response. These 
participants will have their response classified according to the definitions stated below. (Note: 
Participants who exhibit objective disease progression or die prior to the end of Cycle 1 will 
also be considered evaluable.)
Measurable disease
Bi-dimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT 
or MRI scan, with a minimal diameter of 1 cm, and visible on 2 axial slices which are at least 5 
mm apart with 0 mm skip. Measurement of tumor around a cyst or surgical cavity, if necessary, 
requires a minimum thickness of 3 mm. If there are too many measurable lesions to measure at 
each evaluation, the investigator must choose the largest two to be followed before a participant 
is entered on study. The remaining lesions will be considered non-measureable for the purpose 
of objective response determination. Unless progression is observed, objective response can 
only be determined when all measurable and non-measurable lesions are assessed.


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Non-measurable evaluable disease
Uni-dimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 1 cm.
14.3.2
Response/progression categories
Complete response (CR)
All of the following criteria must be met:
a. Complete disappearance of all enhancing measurable and non-measurable disease 
sustained for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan 
will be considered only stable disease.
b. No new lesions.
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.
d. Participants must be on no steroids or on physiologic replacement doses only.
e. Stable or improved non-enhancing (T2/FLAIR) lesions.
f.
Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related.
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease.
Partial response (PR)
All of the following criteria must be met:
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease.
b. No progression of non-measurable disease.
c. No new lesions.
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline.
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at 
time of baseline scan.
f.
Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan.
g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically.
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease.


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Progressive disease (PD)
The following criterion must be met:
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids
and/or one or more of the following:
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects).
c. Any new lesion
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g. 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the Easter cooperative Oncology 
Group (ECOG) performance scores from 0 or 1 to 2 or 2 to 3 would be considered 
neurologic deterioration, unless attributable to co-morbid events or changes in 
corticosteroid dose.
e. Failure to return for evaluation due to death or deteriorating condition
Stable disease (SD)
All of the following criteria must be met:
a.
Does not qualify for CR, PR, or progression.
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline.
c.
Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the 
corticosteroid dose was equivalent to the baseline dose.
d. Stable clinically.


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Unknown response status
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed.
These RANO Response Criteria are also summarized in Table 14-7.
Table 14-7
Summary of the RANO response criteria
CR
PR
SD
PD
T1-Gd +
None
≥50% decrease
<50% decrease but
<25% increase
≥25% increase*
T2/FLAIR
Stable or decrease
Stable or decrease
Stable or decrease
Increase*
New Lesion
None
None
None
Present*
Corticosteroids
None
Stable or decrease
Stable or decrease
NA**
Clinical Status
Stable or improve
Stable or improve
Stable or improve
Deterioration*
Requirement for 
Response
All
All
All
Any*
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into account in 
determining progression in the absence of persistent clinical deterioration
14.3.3
Methods for evaluation of measurable disease
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 14 days before the beginning of the treatment.
The same method of assessment and the same technique should be used to characterize each 
identified and reported lesion at baseline and during follow-up.
14.3.4
Evaluation of best response
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response. If the response is sustained, i.e. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time 
of tumor progression. Participants without measurable disease may only achieve SD or PD as 
their best “response.”


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14.3.5
Other effect measures
14.3.5.1 Neurological exam
Although not used for determining response, it is useful to evaluate changes in the neurological 
exam compared to the previous exam. The following scale may be used:
+2
Definitely better
+1
Possibly better
0
Unchanged
-1
Possibly worse
-2
Definitely worse
14.3.5.2 Performance status
Participants will be graded according to ECOG score.
14.3.5.3 Overall survival time
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) to 
date of death due to any cause.
14.3.5.4 Progression-free survival time
From date of first dose (date of first post-surgery treatment for participants in Dose Level 1) to 
date of progression or death. Participants who stop treatment for causes other than progression 
may be censored if other therapy is initiated or if regular assessments for assessing progression 
are no longer available.
14.3.6
References
Macdonald DR, Cascino TL, Schold SC Jr, et al (1990) Response criteria for phase II studies 
of supratentorial malignant glioma. J Clin Oncol; 8: 1277-80. In appendix 3
Wen PY, Prados M, Schiff D, et al (2010a) Phase II study of XL184 (BMS 907351), an 
inhibitor of MET, VEGFR2, and RET, in patients (pts) with progressive glioblastoma (GB). 
J.Clin Oncol; 28:15s (suppl, abstr 2006)
Wen PY, Macdonald DR, Reardon DA, et al (2010b) Updated Response Assessment Criteria 
for High-Grade Gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin 
Oncol; 28:1963-1972


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14.4
Appendix 4: Immunotherapy Response Assessment in Neuro-
Oncology (iRANO) criteria for high-grade gliomas
The iRANO criteria, provide special considerations for the development of pseudoprogression, 
given that the treatment is designed to evoke an immune/inflammatory response. This appendix 
is based on the report of the RANO working group (Okada et al 2015). 
14.4.1
Immunotherapy Continuation Beyond Initial Progressive Disease
Correct interpretation of progressive imaging findings after administration of immunotherapy 
is essential because early progressive radiographic changes (i.e. pseudoprogression) not always
preclude subsequent therapeutic benefit.
Pseudoprogression occurring within the first 24 weeks after the start of immunotherapy may be 
difficult to differentiate from true tumor progression and may have important implications for 
patient management. 
In order to distinguish between pseudoprogression and true tumor progression, and therefore 
minimize premature discontinuation of study treatment, the iRANO working committee 
recommends that for patients with early progressive imaging findings, including patients who 
develop new lesions but who do not have significant neurological decline, confirmation of 
radiographic progression by follow-up imaging should be sought 12 weeks after initial 
radiographic evidence of progressive disease to decrease the likelihood of prematurely 
declaring progressive disease in patients with pseudoprogression or delayed response.
In such patients, those with confirmation of further radiographic progression based on a 
comparison with the scan that first showed evidence of disease progression, or who develop 
significant clinical decline at any time, should be classified as having progressive disease with
the date of disease progression back-dated to the first date that the patient met criteria for 
radiographic progression. For these patients, immunotherapy should be discontinued and 
patients will enter the survival follow up phase. In the event that follow-up imaging does not 
confirm further disease progression compared with the scan of the tumor that first showed initial
progressive changes, but instead there is stabilization or reduction in tumor burden, treatment 
should be continued or resumed in the absence of increased corticosteroid dosing (i.e. > 4mg of 
dexamethasone or equivalent per day). A treatment algorithm to summarize guidance for 
follow-up imaging after initial progressive changes is provided in Table 14-8. 
In those cases in which radiologic progression cannot be differentiated from pseudoprogression 
and which acquisition of tumor histopathology by biopsy or resection is thought to be feasible, 
pathological assessment might be considered to clarify the cause of progressive imaging 
findings. If pathology confirms a predominance of recurrent tumor, the cause should be 
considered to be true progression. For cases where there is no evidence of a viable tumor, or 
where a prominence of gliosis or inflammation with restricted viable tumor is reported, the 
cause should be deemed consistent with treatment effect, and such patients should be classified 
as stable and allowed to continue therapy.


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14.4.2
Response Assessment
Standard RANO criteria may not provide an accurate response assessment of
immunotherapeutic agents. Therefore, the following adaptations of the RANO criteria will be 
used to assess response for patients treated with immunotherapeutics (Table 14-8):
Table 14-8
Imaging and Treatment after 1st Radiologic Evidence of PD
First radiologic evidence of PD within 24 weeks
and
patient does not have new or significant neurological 
decline
patient has new or significant neurological decline
perform scan at week 12 
Continue study treatment
perform scan at week 12 whenever possible
Interrupt study treatment
The scan performed at week 12 confirms PD
Yes
No
Yes
NO
No additional imaging  
assessments 
Discontinue 
Study treatment
Continue imaging  
assessments as per 
protocol
Continue study treatment 
at the clinician’s 
discretion
No additional imaging  
assessments
Discontinue study 
treatment
Continue imaging 
assessments as per 
protocol
Resume study treatment
14.4.3
References
Okada H, Weller M, Huang R,et al. (2015) Immunotherapy response assessment in neuro-
oncology: a report of the RANO working group. Lancet Oncol. 16(15): 534-542.


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14.5
Appendix 5: Statistical methods
14.5.1
Statistical details of Bayesian regression models, priors, design 
operating characteristics and hypothetical dose escalation scenarios
An adaptive Bayesian design using escalations with overdose control (EWOC) will guide the 
dose escalation of single agent and combination treatment to its MTD(s)/RP2D(s). The use of 
Bayesian response adaptive designs for Phase I studies has been advocated by the 
EMEA guideline on small populations (2007) and by Rogatko (2007), and is one of the key 
elements of the FDA’s Critical Path Initiative. 
The BLRMs will study the dose-toxicity relationship of BLZ945 when given alone and in 
combination with PDR001. This Bayesian analysis will be based on the dose limiting toxicity 
data (absence or presence of DLT) of the first 28 days of the single agent as well as the 
combination treatment, accumulated throughout the dose escalation. This appendix provides 
details of the statistical models and the derivation of prior distributions for the model parameters.
To check the performance of the model, some hypothetical dose escalation scenarios and 
operation characteristics for the single agent and the combination models are presented.
14.5.2
Single agent BLZ945
14.5.2.1 Statistical model
In the single-agent BLZ945 dose escalation part, the dose-toxicity (DLT) relationship will be 
described by a 2-parameter BLRM formulated in the following way:
logit(π(d)) = log(α) + β log(d/d∗)
Where, π(d) is the probability that a patient has a DLT during the first 28 days when BLZ945 
is given as single agent at the 7 days on/7 days off dose d, where d is the planned total dose (mg) 
in cycle 1, and d*=900x14mg is the reference dose.
α, β > 0 are the parameters of the model.
14.5.2.2 Prior specification
Pre-clinical toxicology data showed no definitive BLZ945 related toxicity, thereby making it 
impossible to predict the MTD in human. For this reason the priors of model parameter 
distributions are defined based on a weakly informative prior. A vague bivariate normal prior 
distribution for the model parameters, (log(α), log(β)), was elicited based on a plausible mean 
values but allowing for considerable uncertainty, essentially making sure that the a-priori range 
for the parameters cover a wide range of plausible values.
Assuming a median prior probability of DLT equal to 0.15 at the dose reference results in a 
mean of log(α) equal to logit(0.15) = -1.735.
Assuming the odds is doubled when doubling the dose results in a mean of log(β) equal to 0.
The standard deviations of log(α) and log(β) are set respectively to 2 and 1, and the correlation 
is assumed to be 0.


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The prior distribution parameters of the BLRM for single agent are provided in Table 14-9 and 
summary of prior distribution of DLT rates in Table 14-10. 
Table 14-9
Prior distribution parameters-BLZ945 SA (7d on/ 7d off schedule)
(log(α) , log(β))
Means
SDs
Correlation
(-1.735 , 0)
(2 , 1)
0
Table 14-10
Summary of prior distribution of DLT rates- BLZ945 SA (7d on/ 7d off
schedule)
Dose 
level 
(mg)
Prior probabilities that P(DLT) is in 
interval:
Mean
SD
Quantiles
0-0.16
0.16-0.33
0.33-1
0.025
Median
0.975
100
0.843    
0.077  
0.080 
0.083 
0.164 
0.000 
0.012 
0.644
150*
0.816     
0.088  
0.096 
0.097 
0.176 
0.000 
0.018 
0.686
300
0.748     
0.115  
0.137 
0.132 
0.202 
0.000 
0.038 
0.764
600
0.630     
0.155  
0.215 
0.193 
0.236 
0.001 
0.087 
0.846
900
0.515     
0.182  
0.302 
0.255 
0.263 
0.003 
0.149 
0.898
* Starting dose
14.5.2.3 Hypothetical dose escalation scenarios
In order to show how the proposed approach works, hypothetical dose escalation scenarios are 
investigated. The model will be used to assess risk to future patients during the clinical trial 
based on the observed DLTs. This assessment of risk is then used to guide future dosing 
decisions. In choosing a dose to explore, the clinical team will also consider all available clinical, 
safety, PK and PD, but will not consider a dose for use unless it satisfies the EWOC criterion.
Table 14-11 illustrates a selection of possible dose escalation scenarios.
Table 14-11
Hypothetical scenarios
Scenario
Cohort
Dose level 
(mg)
Ntox / Npat
Next dose 
level (NDL) 
(mg)
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
1
1
150
0/3
300
0.084
0.032
0.021
2
1
150
1/3
150
0.297
0.240
0.177
3
1
150
2/3
STOP
4
1
150
0/3
4
2
300
2/3
150
0.356
0.183
0.174
5
1
150
1/5
5
2
300
2/6
150
0.445
0.107
0.174
6
1
150
1/5
6
2
300
1/4
300
0.432
0.208
0.206
7
1
150
0/3
7
2
300
0/3
600
0.116
0.054
0.040
8
1
150
0/3
8
2
300
0/3
8
3
600
1/3
600
0.306
0.124
0.134


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Scenario
Cohort
Dose level 
(mg)
Ntox / Npat
Next dose 
level (NDL) 
(mg)
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
9
1
150
0/3
9
2
300
0/3
9
3
600
2/4
300
0.249
0.046
0.101
10
1
150
0/3
10
2
300
0/3
10
3
600
0/4
10
4
900
2/3
600
0.285
0.054
0.113
14.5.2.4 Operating characteristics
In order to show how the proposed design performs under different true dose- DLT profiles, 
various hypothetical scenarios were investigated.
14.5.2.5 Simulation setup
Table 14-12 shows 5 dose-DLT scenarios, taking scenario 1 (true DLT rates equal to median
prior DLT rates) as the basis. Scenario 2 has decreased DLT rates compared to scenario 1. 
Scenarios 3, 4 and 5 have increased DLT rates compared to scenario 1:
The following table presents the true underlying probabilities of DLT for each scenario
Table 14-12
dose-DLT scenarios
Test 
scenarios
Assigning DLT probabilities to each dose level
Note
100 mg
150 mg
300 mg
600 mg
900 mg
1
0.012
0.018
0.038
0.087
0.149
Scenario1: Median DLT probabilities
2
0.006
0.009
0.019
0.045
0.08
Scenario2: the odds of DLTs are 50% 
smaller than the ones of scenario 1
3
0.024
0.035
0.073
0.16
0.259
Scenario3: 2-fold odds inflation from  
scenario 1
4
0.057
0.084
0.165
0.323
0.467
Scenario4: 5-fold odds inflation from 
scenario 1
5
0.108
0.155
0.283
0.488
0.636
Scenario5: 10-fold odds inflation from 
scenario 1
For each scenario, data for 1000 trials were generated, with randomly chosen cohorts of size 3 
to 6. The starting dose is 150 mg for BLZ945. 
The following metrics were assessed in the simulations:

percentage of patients receiving a dose that is in the target toxicity (TT) interval (metric I)

percentage of patients receiving an overdose (OD) (metric II)

percentage of patients receiving an underdose (UD) (metric III)

probability that recommended MTD at the end of the trial is in the target toxicity interval 
(metric IV)

probability that recommended MTD is an overdose (metric V)


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
probability that recommended MTD is an underdose (metric VI)

percentage of trials stopped without MTD declaration  (metric VII)

average sample size

average number of DLT
The maximum number of patients per trial was set to 60. The trial was stopped using the rules 
defined in the protocol in Section 6.2.3.2.
Table 14-13
Operating characteristics
Metric
Scenario 1
Scenario 2
Scenario 3 
Scenario 4
Scenario 5
I
0.0
0.0
54.1
58.5
40.4
II
0.0
0.0
0.0
14.1
13.4
III
100
100
45.9
27.4
46.2
IV
0.0
0.0
85.0
76.7
48.1
V
0.0
0.0
0.0
7.0
4.2
VI
99.4
99.7
11.6
6.5
30.9
VII
0.6
0.3
3.4
9.8
16.8
Average sample size
24
23
24
23
20
Average number of DLT 
2.2
1.2
3.5
4.9
5.1
The simulated operating characteristics presented show that the BLRM performs well under the 
hypothetical profiles investigated. Indeed, the simulations performed illustrate that the model 
has reasonable operating characteristics and the number of patients with DLT was limited 
through a trial.
In scenario 1, the probability of DLT by dose is aligned with the prior with all the doses lie 
within the underdose interval. The simulations show that there is 99.4% of chance for 
identifying the MTD at underdose interval. The chance to stop the trial at overly toxic dose is 
very low (0.6%).
While in scenario 4, with 5-fold odds inflation from test scenario 1 where the underlying P 
(DLT) is above 33% for only 900 mg, there is about 77% of chance for selecting MTD within 
the target toxicity interval. Finally, in scenario 5, with 10-fold odds inflation from test scenario 
1, the simulations show that there is about 4.2% of chance for identifying the MTD within the 
over dose toxicity interval. The chance to stop the trial due to high toxicity of all dose levels is 
high (16.8%).
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics under the 5 hypothetical profiles investigated.


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14.5.3
Combination of BLZ945 (7days on/7days off) and PDR001
14.5.3.1 Statistical model
In the combination BLZ945 and PDR001 dose escalation part, the dose-toxicity (DLT) 
relationship will be described by a 5-parameter BLRM formulated in the following way:
The respective single agent dose-DLT relationships are defined as:
BLZ945:
logit(π(d)) = log(α) + β log(d/d
∗)
PDR001:
logit(π(d)) = log(α) + β log(d/d
∗)
Where, π1(d1) and π2(d2) are respectively the probability that a patient has a DLT when BLZ945 
and PDR001 are given as single agent at the dose d1 and d2, and 
∗=900x14mg and 
∗=400mg
at Q4W are respectively the BLZ945 and PDR001 reference doses. α., β. > 0 are the parameters 
of the model.
Then, the dose-DLT relationship of the dual combinations of BLZ945 with PDR001 is defined 
as:
Oddsπ(d, d) =
(,)
(,) = exp(η

∗

∗) $
()%()()()
(())(())
&, 
Where η is the interaction term. 
14.5.3.2 Prior specification
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single-agent parameters for BLZ945 and PDR001, and the interaction 
parameter: (log(α1),log(β1)), (log(α2),log(β2)) and η respectively. A meta-analytic-predictive 
(MAP) approach was used to derive the prior distribution for the single-agent model parameters.
The derivation of the prior distributions is provided in the following subsections.
14.5.3.2.1
Prior distribution for the logistic parameters
The mixture prior distributions for the single-agent PDR001 model parameters and BLZ945 
model parameters will be derived separately as follows.  
It consists of a mixture of:
-
a meta-analytic-predictive (MAP) prior derived using the available historical  dose-DLT 
data (which is approximated by a mixture of bivariate normal (BVN) distributions)
-
and a weakly informative prior corresponding to high toxicity to make the prior more 
robust. 
To obtain the mixture prior, 50% weight was assigned to the MAP prior, and 50% weight was 
assigned to the weakly informative prior of BLZ945 whereas 80% weight was assigned to the 
MAP prior, and 20% weight was assigned to the weakly informative prior of PDR001. 
14.5.3.2.2
Description of the MAP approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters 
log(α∗), log(β∗) of the new trial using DLT data from historical studies. 


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Let r( and n( be the number of patients with a DLT, and the total number of patients at dose 
d in historical trial s (s = 1, … , S).  The corresponding probability of a DLT is π(.  The model 
specifications for the derivation of the MAP prior are as follows:
r( | π( ~ Bin(π(, n()
logit(π() = log(α() + β( log(d/d∗)
log(α(), log(β() / μ, ψ ~ BVN(μ, ψ),
s = 1, … , S
log(α∗), log(β∗) / μ, ψ ~ BVN(μ, ψ)
The parameters μ = (μ, μ) and ψ are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations t, t, and correlation r.  The parameters 
t and t quantify the degree of between trial heterogeneity.  The following priors will be used 
for these parameters:  

normal priors for μ and μ, 

log-normal priors for t and t, and 

a uniform prior for r.
The MAP prior for single-agent model parameters in the new trial, log(α∗), log(β∗), is the 
predictive distribution 
log(α∗), log(β∗) / (r(, n( ∶s = 1, … , S)
Since the predictive distribution is not available analytically, MCMC is used to simulate values 
from this distribution.  This is implemented using JAGS version 3.4.0. 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).
14.5.3.2.3
Implementation of the MAP approach for BLZ945
For the MAP model, data from the available data from the SA arms in the current study (as per 
protocol, the combination part will only start after at least two cohorts of BLZ945 as single 
agent have been completed, and safety data suggests acceptable toxicity for patients to begin 
treatment in combination). The details of the derivation of the priors using available data from 
single agent BLZ945 arm will be given in the SAP. For illustrative purpose, it is assumed that 
there are 3 evaluable patients in each of the first two cohorts (doses 150mg and 300mg at 7days 
on/7 days off regimen) and 0 DLTs are observed as described in Table 14-14. 
Table 14-14
Hypothetical data from single agent part
BLZ945 dose level (mg 7days on/7days off)
N DLTs / N patients in first 28 days
150
0/3
300
0/3
Note: These data are hypothetical and the real current available data from single agent part will be incorporated 
directly in the combination part during the DETCs 


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Weakly informative priors are assumed for μand μ, with means corresponding to a risk of 
DLT at the reference dose of 9%, and a doubling in dose leading to a doubling in the odds of 
the risk of a DLT, respectively.  Priors for t and t are assigned such that (1) their medians 
correspond to moderate between trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations (Neuenschwander 2014). The prior 
distributions for the model used for deriving the MAP priors are specified in Table 14-15. 
Table 14-15
Prior distributions for the parameters of the MAP model used to derive 
the prior
Parameter
Prior distribution
6
N(mean = logit(0.09), sd = 2)
6
N(mean = 0, sd=1)
7
log-normal(mean = 0.25, sd = log(2)/1.96)
7
log-normal(mean = 0.125, sd = log(2)/1.96)
8
uniform(-1,1)
14.5.3.2.4
Derivation of the weakly informative prior
A weakly informative BVN prior to allow higher toxicity than MAP prior is derived by 
assuming median probability of DLT at 900x14 mg to be 24%, as well as a log-linear 
relationship between dose and the odds of DLT as defined in Section 14.5.2. This results in 
setting the mean of log(α) equal to -1.153. The mean of log(β) is set to 0. Furthermore, setting 
standard deviation of log(α) = 2 and log(β) = 1, and setting the correlation between log(α) and 
log(β) = 0 to complete the determination of this prior. See Table 14-18.
14.5.3.2.5
Weight in the mixture prior 
To obtain the mixture prior, 50% weight is assigned to the MAP prior, and 50% weight is 
assigned to the weakly informative prior
14.5.3.2.6
Implementation of the MAP approach for PDR001
For PDR001, currently available historical data of PDR001 from study [CPDR001X2101] has 
been used in order to derive the prior distribution for the BLRM parameters (log(α2),log(β2))
using MAP approach. 
Table 14-16
Data from PDR001X2101 study
PDR001 dose level (mg/kg)
PDR001 dose in first 28 days 
(mg)
N DLTs / N patients in first 28 
days
3 q4w
240
0/6
5 q4w
400
0/10
*A weight of 80kg is considered to convert weight adjusted dose to a flat dose
Note:  Data cut-off date: 17 December 2015.
Weakly informative priors are assumed for 6 and 6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 7 and 7 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).  


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The prior distributions for the model used for deriving the MAP priors are specified in 
Table 14-17.
Table 14-17
Prior distributions for the parameters of the MAP model used to derive
the prior for the single-agent PDR001 model parameters
Parameter
Prior distribution
6
N(mean = logit(0.10), sd = 2)
6
N(mean = 0, sd=1)
7
log-normal(mean = 0.5, sd = log(2)/1.96)
7
log-normal(mean = 0.25, sd = log(2)/1.96)
8
uniform(-1,1)
14.5.3.2.7
Derivation of the weakly informative prior
A weakly informative BVN prior to allow higher toxicity than MAP prior is derived by 
assuming median probability of DLT at 400 mg to be 25%, as well as a log-linear relationship 
between dose and the odds of DLT as defined in Section 14.5.2. This results in setting the mean 
of log(9) equal to -1.099. The mean of log(:) is set to 0. Furthermore, setting standard 
deviation of log(9) = 2 and log(:) = 1, and setting the correlation between log(9) and log(:)
= 0 to complete the determination of this prior. See Table 14-18.
14.5.3.2.8
Weight in the mixture prior 
To obtain the mixture prior, 80% weight is assigned to the MAP prior, and 20% weight is 
assigned to the weakly informative prior
14.5.3.2.9
Prior for the interaction parameter
Although no interaction is expected, considerable uncertainty remains. A normal prior 
distribution for the interaction parameter η is to be derived to reflect the current uncertainty 
about the toxicity profile of the combination of PDR001 and BLZ945. The risk of significant 
positive interaction between PDR001 and BLZ945 cannot be totally excluded. The interaction 
parameter η was chosen accordingly but with a degree of uncertainty in order to allow for the 
possibility that the interaction may be positive or negative. Therefore the following assumption 
is made for the interaction parameter:
η is normally distributed, with mean 0 and standard deviation 3.363
At the starting dose of 150 mg BLZ945 and 400 mg PDR001 of the corresponding distribution 
for the odds ratio has mean 1 and a 97.5th percentile of 3, i.e. 3-fold increase in odds of DLT 
due to interaction compared to no interaction.
14.5.3.3 Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 14-18.
Prior summaries for DLT rates are summarized at each provisional dose level in Table 14-19.


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Table 14-18
Prior distribution of model parameters
Parameter
Mean
Standard deviations
Correlation
Weight
PDR001 MAP prior, BVN mixture ?@A(BC), ?@A(DC), weight = 80%
BVN mixture 1
(-4.545, 0.014)
(1.528 , 1.039)
-0.013
0.445
BVN mixture 2
(-3.235 , 0.103  )
(1.074 , 1.046 )
0.094
0.355
Weakly informative prior?@A(BC), ?@A(DC), weight = 20%
Weakly informative
(-1.099, 0)
(2, 1)
0
0.200
BLZ945 MAP prior, BVN mixture ?@A(BE), ?@A(DE), weight = 50%
BVN mixture 1
(-2.632, -0.020)
(1.181, 1.060)
0.156
0.206
BVN mixture 2
(-4.096 , 0.216  )
(1.586 , 0.989 )
0.129
0.203
BVN mixture 3
(-1.066,0.580)
(1.305, 0.759)
0.437
0.091
Weakly informative prior?@A(BE), ?@A(DE), weight = 50%
Weakly informative
(-1.153, 0)
(2, 1)
0
0.500
Interaction BLZ945-PDR001
0
3.363


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Table 14-19
Summary of prior distribution of DLT rates- BLZ945 (7d on/ 7d off)+ 
PDR001
BLZ945  + 
PDR001(400 
mg)
Prior probabilities that P(DLT) 
is in interval:
Mean
SD
Quantiles
0-0.16
0.16-
0.33
0.33-1
0.025
Median
0.975
100
0.698
0.130
0.172
0.169
0.230
0.002
0.066
0.864
150*
0.671
0.139
0.190
0.183
0.239
0.003
0.073
0.885
300
0.600
0.147
0.254
0.226
0.270
0.002
0.100
0.934
600
0.498
0.131
0.371
0.316
0.336
0.001
0.162
0.987
900
0.449
0.101
0.450
0.390
0.384
0.000
0.233
0.998
*Starting dose
14.5.3.4 Hypothetical dose escalation scenarios
Table 14-20 shows on-study dosing recommendations for some hypothetical data scenarios.
Note that the next dose is selected in concordance with the provisional dose levels specified in 
Section 6.2.2 of the protocol wherever it is allowed, to mimic possible on study escalation steps.
Table 14-20
Hypothetical dose escalation scenarios for on-study decisions –
Combination of BLZ945 (7 days on/7days off) and PDR001
Scenario
Cohort
Dose level (mg)
BLZ945/PDR001
Ntox / 
Npat
Next dose 
level (NDL) 
(mg)
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
1
1
150/400
0/4
300/400
0.122
0.055
0.045
2
1
150/400
1/4
150/400
0.286
0.168
0.143
3
1
150/400
2/3
STOP
4
1
150/400
0/4
4
2
300/400
0/3
600/400
0.113
0.119
0.036
5
1
150/400
1/4
5
2
150/400
0/5
300/400
0.237
0.105
0.103
6
1
150/400
0/3
6
2
300/400
2/3
150/400
0.378
0.193
0.184
7
1
150/400
1/3
7
2
150/400
0/3
300/400
0.266
0.190
0.143
8
1
150/400
1/6
8
2
300/400
0/4
600/400
0.165
0.190
0.085
9
1
150/400
1/6
9
2
300/400
2/5
150/400
0.450
0.123
0.179
10
1
150/400
1/6
10
2
300/400
1/4
300/400
0.389
0.182
0.183
11
1
150/400
0/4
11
2
300/400
0/3
11
2
600/400
0/6
900/400
0.069
0.051
0.012
12
1
150/400
0/4
12
2
300/400
0/3
12
3
600/400
1/5
600/400
0.273
0.107
0.119
13
1
150/400
0/3


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Scenario
Cohort
Dose level (mg)
BLZ945/PDR001
Ntox / 
Npat
Next dose 
level (NDL) 
(mg)
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
13
2
300/400
0/4
13
3
600/400
2/3
300/400
0.315
0.053
0.126
Within Table 14-20, it can be seen that the model generally leads to decisions that are in 
agreement with clinical sense: progressive increase of the provisional doses if no DLT is 
observed, enrolling of a new cohort at the same provisional dose level when 1 DLT is reported, 
and de-escalate when more than 1 DLT is reported in a cohort. 
14.5.3.5 Operating characteristics
In order to show how the proposed design performs under different true dose- DLT profiles, 
various hypothetical scenarios were investigated. 
Simulation Setup
Table 14-21 shows 3 dose-DLT scenarios, taking scenario 1 (true DLT rates equal to median 
prior DTL rates) as the basis. Scenarios 2 and 3 have increased DLT rates compared to scenario 
1:
-
Scenario 2: the odds of DLTs are 50% larger than the ones of scenario 1 
-
Scenario 3: the odds of DLTs are 100% larger than the ones of scenario 1 
The following table presents the true underlying probabilities of DLT for each scenario
Table 14-21
Dose-DLT scenarios
BLZ945/PDR001 (mg)
Scenario 1
Scenario 2
Scenario 3
100/400
0.066
0.096
0.124
150/400
0.073
0.106
0.136
300/400
0.100
0.143
0.182
600/400
0.162
0.225
0.279
900/400
0.233
0.313
0.378
For each scenario data for 1000 trials were generated, with randomly chosen cohorts of size 3 
to 6. The starting dose is 400 mg for PDR001 and 150 mg for BLZ945. 


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The following metrics were assessed in the simulations:

percentage of patients receiving a dose combination that is in the target toxicity (TT) 
interval (metric I)

percentage of patients receiving an overdose (OD) (metric II)

percentage of patients receiving an underdose (UD) (metric III)

probability that recommended MTD at the end of the trial is in the target toxicity interval 
(metric IV)

probability that recommended MTD is an overdose (metric V)

probability that recommended MTD is an underdose (metric VI)

percentage of trials stopped without MTD declaration (metric VII)

average sample size

average number of DLT
The maximum number of patients per trial was set to 60. The trial was stopped using the rules 
defined in the protocol in Section 6.2.3.2.
14.5.3.5.1
Simulation Results
Operating characteristics are presented in Table 14-22. 
Table 14-22
Operating characteristics
Scenario 1
Scenario 2
Scenario 3
Average proportion of patients in target dose (metric I)
38.2
28.1
56.8
Average proportion of patients in over dose(metric II)
0.0
0.0
4.3
Average proportion of patients in under dose(metric II)
61.8
71.9
39.0
Proportion of trials with MTD within target dose region(metric IV)
54.6
34.3
68.7
Proportion of trials with MTD within over dose region(metric V)
0.0
0.0
2.5
Proportion of trials with MTD within under doses  region(metric 
VI)
42.3
59.1
15.7
Proportion of trials stopped before declaring MTD, when all dose 
combinations were considered too toxic(metric VII)
3.1
6.6
13.1
Average sample size
22
20
19
Average number of DLT
2.8
3.1
3.5
In scenario 1, since there is no dose combination which has median DLT rate fall into the over 
toxicity interval, it is expected that there is no patient receive over-toxic dose combination 
(metric II) on study, and no trial was recommended with over-toxic dose as MTD (metric V). 
Under this scenario, the proportion of trials with MTD within target dose region is about 55%
In scenario 2, the proportion of patients receiving target dose is low (28.1%) and so does the 
proportion of trial with target dose as recommended dose (34.3%). This is due to the fact that 
only the 600/400 mg dose level is in the target interval and the 900/400 mg dose level lies in 
the boundary of the over toxicity interval. 


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In scenario 3, the proportion of patients receiving target dose is 56.8% and proportion of trial 
with target dose as recommended dose is 68.7%. 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: 4.3% and metric V: 
2.5%). 
In all scenarios, the average sample sizes are between 19 and 22, and the percentages of trials 
that were stopped when all dose combinations were considered too toxic are low (3.1%) in 
scenario 1 but relatively high in scenario 3 (13.1%). However, in this scenario, the average 
number of DLTs is comparable to the other scenarios.
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics.
14.5.4
Combination BLZ945 (Q1W) and PDR001
14.5.4.1 Statistical model and prior specification
In the combination BLZ945 and PDR001 dose escalation part, the dose-toxicity (DLT) 
relationship will be described by a 5-parameter BLRM formulated in the following way:
The respective single agent dose-DLT relationships are defined as:
BLZ945:
logit(π(d)) = log(α) + β log(d/d
∗)
PDR001:
logit(π(d)) = log(α) + β log(d/d
∗)
Where, π1(d1) and π2(d2) are respectively the probability that a patient has a DLT when BLZ945 
and PDR001 are given as single agent at the dose d1  and d2, and 
∗=3600mg and 
∗=400mg 
are respectively the BLZ945 and PDR001 reference doses. α., β. > 0 are the parameters of the 
model.
Then, the dose-DLT relationship of the dual combinations of BLZ945 with PDR001 is defined 
as:
Oddsπ(d, d) =
(,)
(,) = exp(η

∗

∗) $
()%()()()
(())(())
&, 
Where η is the interaction term. 
The methodology to derive prior for this combination is similar to the combination with 7d on/ 
7d off. As per protocol, the combination part will only start after at least two cohorts of BLZ945 
as single agent have been completed, and safety data suggests acceptable toxicity for patients 
to begin treatment in combination. The derivation of the priors will be based on several 
assumptions (either safe data from with 7days on/7days off or from Q1W data if early toxicity 
was observed with the former schedule), and therefore the details of the derivation of the prior 
will not be given in this appendix, but will be detailed in the SAP before the first dose escalation 
of this schedule.


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14.5.5
Split dosing regimen (two doses per day)
In case of exploring split dosing regimen (two doses per day) during dose escalation, separate 
adaptive Bayesian hierarchical logistic regression models (BHLRM) for all single agent dosing
schedules (i.e. 7dOn/7dOff, Q1W and 4dOn/10dOff) and appropriate BLRM for the 
combination dosing regimens will be used to guide the dose escalation by the EWOC principle.
For each single agent regimen, the BHLRM estimates the relationship between dose and the 
probability of a patient experiencing a DLT in the same original one-dose (per day) regimen 
(stratum 1), and the split dosing regimen (two doses per day, stratum 2). The BHLRM will 
allow for both full exchangeability between the strata parameters and non-exchangeability 
between strata parameters, which introduces more flexibility and potentially improve the 
estimation of dose-toxicity relationship.
When in combination with PDR001, the dose escalation of the split dosing regimen will be 
guided by a meta-analytic-combined (MAC) model based on the first Cycle DLT data of the 
study treatment. The model will integrate both single agent and combination toxicity parts with 
either the same original one-dose per day dosing or split dosing regimen. Both historical data 
and concurrent data are incorporated into the model. For different dosing regimens, once or 
twice per day, a plausible between-cohorts heterogeneity will be assumed, allowing for non-
exchangeability across trial parameters.
A full description including parameter specification, operating characteristics and hypothetical 
dose scenarios of each model will be given in a standalone document, prior to the first patient 
treated on the respective schedule.
14.6
Sample size determination for Phase II
As described in Section 10.8, a Bayesian approach will be used to analyze glioblastoma patients 
treated with BLZ945 single agent or in combination with PDR001 separately. The number of 
patients expected to be treated in each treatment arm are estimated such that the model would 
have reasonable characteristics.  
14.6.1
Prior specifications
The PFS time will be modeled using a Weibull distribution, which is a flexible distribution 
allowing for time varying hazard rate. The Weibull probability density function is given by 
F(G) = HIGJKGL(−N GJ),
G ≥0
where γ is a shape parameter and λ a scale parameter. The corresponding survival function is
P(G) = KGL[−N GJ]
and the median PFS can be calculated as
GSTUVWX = Ylog(2)
N
[
/J


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and the PFS rate at 6 month, which will be denoted PFSR6,  can be calculated as
G\ = ]^P_6 = KGL(−N 6J)
For the shape parameter, an exponential prior distribution will be used
H~exp(8)
and for the log-scale parameter, a normal prior distribution will be used
log(N) ~`(a, b)
A weakly-informative prior distribution for γ and log(λ) will be assumed, such that the mean 
PFS rate at 6 months (PFSR6) is approximately equal to the indifference point (i.e., close to 
40%). 
The prior distributions are then derived as follows:
The rate r of the exponential prior distribution for γ is set to 0.2, which allows a wide range of 
values for γ.
The mean m of the normal distribution for log(λ) is set to 0.
The standard deviation s of the normal distribution for log(λ) is chosen such that E(S(6)) 
≈ 0.40 This results in the prior distributions shown in Table 14-23.
Table 14-23
Specifications for Prior distribution
Prior parameter
Prior distribution of PFS rate  at 6 months
Rate for γ
log(λ)
(mean, SD)
Mean
Probability of
unacceptable
activity
Probability of
clinical relevant activity
0.2
(0, 9)
0.40
0.556
in [0%, 20%)
0.418
in [40%, 100%]
14.6.2
Operating characteristics
The posterior distribution of PFS is not available in closed form. Therefore, the operating 
characteristics for the Bayesian analysis described above are evaluated by performing 
simulations. The operating characteristics for this Bayesian design are obtained by performing 
extensive simulations using R software (JAGS is used for the posterior computations involving 
MCMC).
Different scenarios assuming different possible values for the true PFS rate at 6 months varying 
from 0.20 to 0.60 have been evaluated. For each scenario, 1000 simulations were run. In each 
of these simulation run, a sample of size 40 is generated with the PFSR6 corresponding to the 
true PFSR6 for that scenario assuming PFS times follow an exponential distribution. Accrual 
time of the patients is assumed to follow an exponential distribution with rate of 3 patients per 
month. In addition, censoring occurs following an exponential distribution with rate of 0.03
corresponding to a median censoring of about 23 months. Taking the priors as mentioned above, 
the interim analysis is performed based on 20 first patients. The trial will expand to 40 patients 
if the DCR ≥60% after performing the first tumor assessment for the first 20 patients (at month 
2). The complete success rate (i.e. the probability of concluding clinically relevant efficacy) 


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under different scenarios is calculated using simulated data. It is obtained according to the 
following Bayesian rules:
a) At interim analysis, the disease control rate is ≥ 60% 
b) At final analysis, the estimated posterior mean of PFSR6 ≥ 0.4 
c) At final analysis, the posterior probability that PFSR6 is ≥ 0.2 is at least 90%).
Table 14-24 and Table 14-25 show the operating characteristics under different scenarios.
14.6.2.1 Simulation of datasets
This section defines the variables used for the simulations of datasets:

Accrual waiting time: It is expected that 3 patients will be enrolled in each month; hence, 
the average accrual rate is about 0.3 month per patient. The accrual waiting time is in unit 
of months and set to 0 for the first patient.

Accrual calendar time: This is the cumulative sum of the accrual waiting times. The origin 
is set to 0 at Cycle 1 Day 1 of the first patient. The interval from the origin to Cycle 1 Day 1 
of the last patient is the accrual duration.

PFS time: It is assumed that PFS time follows an exponential distribution to get the desired 
PFSR at 6 months. 

PFS calendar time: This is the sum of the accrual calendar time and PFS time.

Censoring time: It is assumed that the censoring time follows an exponential distribution 
with a rate of 0.03.

Censoring calendar time: This is the sum of the accrual calendar time and censoring time

Cut-off date: is defined as the sum of accrual calendar time and 6 months.

Event indicator: For non-censored patients, if PFS calendar time is smaller than cut-off date, 
then the PFS event is observed; otherwise PFS is censored.

Interim event indicator: DCR≥60%. This rate is assessed at the first scan for all patients in 
the interim population.
Several possible values for true PFSR6 are specified. For each scenario with one of the specified 
values for true PFSR6, the hypothetical PFS dataset is generated by the following steps:

Set accrual waiting time to zero for the first patient. Generate a random sample of accrual 
waiting times for the remaining patients from an exponential distribution with the accrual 
waiting time rate defined above.  

Generate a random sample of 40 PFS times from an exponential distribution 
corresponding to the true PFSR6.

Generate censoring time from an exponential distribution 
14.6.2.2 Posterior analysis

Perform an interim analysis for the first 20 patients.  
-
If the DCR ≥ 60% then expand to 40 patients, otherwise stop the trial.
Perform final analysis using the 40 patients and provide posterior final analysis
These steps are repeated to simulate 1000 datasets for each scenario. For each of the 1000 
simulated datasets, the posterior distribution of PFSR6 is obtained by performing MCMC 


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simulations. Complete success rate, complete failure rate and the probability to stop at interim 
(proportion of trials stopped at interim) are given below for each disease group: 
Table 14-24
Operating Characteristics 
True PFSR6
Complete success rate
Complete failure rate
Probability of stop at interim
20
0.004
0.996
0.71
30
0.09
0.91
0.43
40
0.57
0.43
0.21
50
0.90
0.10
0.08
60
0.97
0.03
0.03
Table 14-25
Operating Characteristics for TNBC group (no longer effective after 
approval of protocol amendment 06)
True PFSR6
Complete success rate
Complete failure rate
Probability of stop at interim
20
0.03
0.97
0.55
30
0.20
0.80
0.35
40
0.58
0.42
0.22
50
0.84
0.16
0.12
60
0.94
0.06
0.05
Table 14-24 show that the Bayesian design has good operating characteristics. The probability 
of wrongly declaring the study as a success is very low when true PFSR6 is 20% (probability 
of success is less than 0.01). The probability of declaring success when the true PFSR6 is 40% 
months is close to 50% as desired. Finally, when the true efficacy is highly significant there is 
a very high probability for the study to be declared a success (when true PFSR6 is 60%, the 
probability of declaring success is larger than 0.94).
14.6.3
References
Akaike H (1974). A new look at the statistical model identification. IEEE Transactions on 
Automatic Control; 19(6):716–23.
EMEA (2007) Guideline on Clinical Trials in Small Populations. Committee for Medicinal 
Products for Human Use (CHMP).
Dempster AP, Laird NM, Rubin DB (1977). Maximum Likelihood from Incomplete Data via 
the EM Algorithm. Journal of the Royal Statistical Society; Series B 39(1):1–38.
Neuenschwander B, Matano A, Tang Z, et al (2014). 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.
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25:4982-6.


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14.7
Appendix 6: Statistical details of Phase I Bayesian logistic 
regression model (BLRM) in Japanese patients treated with 
single agent of BLZ945
This appendix provides details of the statistical model, the derivation of prior distributions from 
historical data of BLZ945 from global patients, and the results of the Bayesian analyses and 
respective dosing decisions for some hypothetical data scenarios.
14.7.1
Statistical model
An adaptive Bayesian logistic regression model (BLRM) guided by the escalation with 
overdose control (EWOC) principle will be used to make dose recommendations and estimate 
the maximum tolerated dose (MTD) and/or identify the recommended dose for phase II(RP2D)
during the dose escalation part of the study. The use of Bayesian response adaptive models for 
Phase I studies has been advocated by the EMEA guideline on small populations (2007) and by 
Rogatko (2007) and is one of the key elements of the FDA’s Critical Path Initiative.
Single agent BLZ945 for Japanese patients: In the single-agent BLZ945 dose escalation part, 
the dose-toxicity (DLT) relationship is described by the following 2-parameter BLRM:
logit((d)) = log(α) + β log(d /d*), α>0, β>0
Where  
, and (d) is the probability of a DLT at dose d.
Doses are rescaled as d/d* with reference dose d*=900x14mg of BLZ945. As a consequence α 
is equal to the odds of DLT rate at d*, and β (>0) is the increase in the log-odds of a DLT by a 
unit increase in log-dose. Note that for a dose equal to zero, the probability of toxicity is zero.
The Bayesian approach requires the specification of prior distributions for all model parameters. 
This section provides details of the statistical model, the derivation of prior distributions for the 
model parameters, and the properties of the adaptive design (dosing recommendations for 
hypothetical data scenarios and operating characteristics).
14.7.2
Prior specifications
The Bayesian approach requires the specification of prior distributions for all model parameters. 
A meta-analytic-predictive (MAP) approach was used to derive the prior distribution for the 
model parameters.
14.7.2.1 Prior distribution for the logistic parameters
A mixture prior distribution for the single-agent BLZ945 model parameters was derived. It 
consists of a mixture of a meta-analytic-predictive (MAP) prior and a weakly informative prior 
corresponding to high toxicity to make the prior more robust. To obtain the mixture prior, 50% 
weight was assigned to the MAP prior, and 50% weight was assigned to the weakly informative 
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14.7.2.1.1
Description of the MAP approach
The aim of the MAP approach is to derive a prior distribution for the logistic parameters (log(α*), 
log(β*)) of the new trial (eg., Japanese sub-population in the BLZ945x2101 study) using DLT 
data from the ongoing dose-escalation in global patients (BLZ945x2101 study).
Let rds and nds be the number of patients with a DLT, and the total number of patients at dose d
in historical trial s (s = 1, … , S). The corresponding probability of a DLT is ds. The model 
specifications for the derivation of the MAP prior are as follows:
rds | ds ~ Bin (ds, nds)
logit(ds) = log(αs) + βs log(d /d*)
(log(αs), log(βs)) | µ, ѱ ~ BVN (µ, ψ),
s = 1, … , S
(log(α*), log(β*)) | µ, ѱ ~ BVN (µ, ψ)
Where d* = 900*14mg and S = 1 in this study and refers to the global patients. The parameters 
µ = (µ1, µ2) and ѱ are the mean and between-trial covariance matrix for the logistic parameters, 
the latter with standard deviations τ1, τ2, and correlation p. The parameters τ1 and τ2 quantify the 
degree of between trial heterogeneity. The main objective is to estimate the predictive 
distribution
(log(α*), log(β*)) | (rds, nds : s = 1, … , S)
based on DLT data from arm A. To do that, it is assumed:

normal priors for µ1 and µ2,

log-normal priors for τ1 and τ2, and

a uniform prior for p.
Since the predictive distribution is not available analytically, the Markov Chain Monte Carlo 
(MCMC) method is used to simulate values from this distribution. This is implemented using 
WinBUGS 14.1.3. The sample from this distribution is approximated by a mixture of bivariate 
normal (BVN) distributions. BVN mixtures with increasing numbers of mixture components 
are fitted to the sample using the expectation-maximization (EM) algorithm (Dempster 1977). 
The optimal number of components of the mixture is then identified using the Akaike 
information criterion (AIC) (Akaike 1974).
14.7.2.1.2
Implementation of the MAP approach
For the MAP model, data from global patients treated the global study [CBLZ945X2101] was 
used (Table 14-26). The details of the derivation of the priors using available data from single 
agent global patients will be finalized and documented prior to the first patient being treated in 
Japanese dose escalation. For illustrative purpose, assuming the following hypothetical global 
patients’ data was observed. 


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Table 14-26
Hypothetical data from global patients in study CBLZ945X2101
Dose of BLZ945 
No of DLTs/No of evaluable patients
150mg 7d on/7d off
0/5
300mg 7d on/7d off
1/10
600mg 7d on/7d off
2/6
Note: These data are hypothetical and the real current available data from single agent global patients will be 
incorporated directly in the Japanese patient dose escalation during the DETCs.
Weakly informative priors are assumed for µ1 and µ2, with means corresponding to a risk of 
DLT at the reference dose of 9%, and a doubling in dose leading to a doubling in the odds of 
the risk of a DLT, respectively. Priors for τ1 and τ2 are assigned such that (1) their medians 
correspond to moderate between trial heterogeneity, and (2) their uncertainty (95% prior 
interval) cover plausible between-trial standard deviations (Neuenschwander 2014). The prior 
distributions for the model used for deriving the MAP priors are specified in Table 14-27.
Table 14-27
Prior distributions for the parameters of the MAP model used to derive 
the prior
Parameter
Prior distribution
µ1
N(mean = logit(0.09), sd = 2)
µ2
N(mean = 0, sd=1)
τ1
log-normal(mean = 0.25, sd = log(2)/1.96)
τ2
log-normal(mean = 0.125, sd = log(2)/1.96)
p
uniform(-1,1)
14.7.2.1.3
Derivation of the weakly informative prior
A weakly informative BVN prior to allow higher toxicity than MAP prior is derived by 
assuming median probability of DLT at 900x14 mg to be 24%, as well as a log-linear 
relationship between dose and the odds of DLT as defined in Section 14.5.2. This results in 
setting the mean of log(α) equal to -1.153. The mean of log(β) is set to 0. Furthermore, setting 
standard deviation of log(α) = 2 and log(β) = 1, and setting the correlation between log(α) and 
log(β) = 0 to complete the determination of this prior. See Table 14-24.
14.7.2.1.4
Summary of prior distributions
The prior distributions of the model parameters are summarized in Table 14-28.
Prior summaries for DLT rates are summarized at each provisional dose level in Table 14-29.
Table 14-28
Prior distribution of model parameters
Parameter
Mean
Standard deviations
Correlation
Weight
BLZ945 MAP prior, BVN mixture (log(α), log(β)), weight = 50%
BVN mixture 1
(-0.625, 0.528)
(1.052 , 0.490)
0.618
0.213
BVN mixture 2
(-0.868 , -0.195)
(0.780 , 0.555)
0.534
0.172
BVN mixture 2
(-1.700, -0.844)
(0.746, 0.780)
0.074
0.115
Weakly informative prior (log(α), log(β)), weight = 50%
Weakly informative
(-1.153, 0)
(2, 1)
0
0.5


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Table 14-29
Summary of prior distribution of DLT rates
BLZ945 
dose(mg), 7d 
on/7d off
Prior probabilities that
P(DLT) is in interval:
Mean
SD
Quantiles
[0, 0.16)
[0.16, 0.33)
[0.33, 1]
2.5%
50.0%
97.5%
100
0.864
0.073
0.063
0.083
0.150
0.000
0.028
0.605
150
0.830
0.094
0.076
0.100
0.160
0.000
0.042
0.657
300
0.716
0.170
0.115
0.146
0.182
0.000
0.085
0.744
600
0.464
0.294
0.242
0.236
0.212
0.000
0.175
0.837
900
0.321
0.277
0.402
0.320
0.244
0.004
0.261
0.896
SD = standard deviation.
Bold values indicate dose(s) not meeting the EWOC principle with the prior information only.
14.7.3
BLRM design properties for hypothetical data scenarios
Table 14-30 shows on-study dosing recommendations for some hypothetical data scenarios.
Note that the next dose is selected in concordance with the provisional dose levels specified in 
Section 6.2.2 of the protocol wherever it is allowed, to mimic possible on study escalation steps.
Table 14-30
Hypothetical dose escalation scenarios for on-study decisions –
phase I single agent BLZ945
Scenario
Cohort
Dose level 
(mg)
Ntox / Npat
Next dose 
level (NDL) 
(mg)
P(target) 
at NDL
P(over) 
at NDL
Median 
at NDL
1
1
150
0/3
300
0.138
0.032
0.062
2
1
150
1/3
150
0.256
0.140
0.127
3
1
150
2/3
STOP
4
1
150
0/3
4
2
300
2/3
150
0.286
0.113
0.130
5
1
150
1/5
5
2
300
2/6
150
0.350
0.063
0.143
6
1
150
1/5
6
2
300
1/4
300
0.456
0.122
0.179
7
1
150
0/3
7
2
300
0/3
600
0.264
0.096
0.111
8
1
150
0/3
8
2
300
0/3
8
3
600
1/3
600
0.441
0.146
0.184
9
1
150
0/3
9
2
300
0/3
9
3
600
2/4
300
0.226
0.026
0.103
10
1
150
0/3
10
2
300
0/3
10
3
600
0/4
10
4
900
2/3
600
0.431
0.085
0.165
Within Table 14-30, it can be seen that the model generally leads to decisions that are in 
agreement with clinical sense: progressive increase of the doses if no DLT is observed, enrolling 
of a new cohort at the same dose level when 1 DLT is reported, and de-escalation when more 


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than 1 DLT is reported in a cohort. It is expected that the dose-DLT relationship in Japanese 
patients will be very similar to that observed outside Japan. 
14.7.3.1 Operating characteristics
In order to show how the proposed design performs under different true dose- DLT profiles, 
various hypothetical scenarios were investigated.
Table 14-31 shows 5 dose-DLT scenarios, taking scenario 1 (true DLT rates equal to median
prior DLT rates) as the basis. Scenario 2 has decreased DLT rates compared to scenario 1. 
Scenarios 3, and 4 have increased DLT rates compared to scenario 1, scenario 5 have toxicity 
>33% at all dose levels.
The following table presents the true underlying probabilities of DLT for each scenario
Table 14-31
dose-DLT scenarios
Test 
scenarios
Assigning DLT probabilities to each dose level
Note
100 mg
150 mg
300 mg
600 mg
900 mg
1
0.028
0.042
0.085
0.175
0.261
Scenario1: Median DLT probabilities
2
0.014
0.021
0.044
0.096
0.15
Scenario2: the odds of DLTs are 50% 
smaller than the ones of scenario 1
3
0.054
0.081
0.157
0.298
0.414
Scenario3: 2-fold odds inflation from  
scenario 1
4
0.126
0.180
0.317
0.515
0.638
Scenario4: 5-fold odds inflation from 
scenario 1
5
0.419
0.523
0.699
0.841
0.898
Scenario5: toxicity>33% at all dose levels
For each scenario, data for 1000 trials were generated, with randomly chosen cohorts of size 3 
to 6. The starting dose is 150 mg for BLZ945. 


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The following metrics were assessed in the simulations:

percentage of patients receiving a dose that is in the target toxicity (TT) interval (metric I)

percentage of patients receiving an overdose (OD) (metric II)

percentage of patients receiving an underdose (UD) (metric III)

probability that recommended MTD at the end of the trial is in the target toxicity interval 
(metric IV)

probability that recommended MTD is an overdose (metric V)

probability that recommended MTD is an underdose (metric VI)

percentage of trials stopped without MTD declaration  (metric VII)

percentage of trials stopped due to toxicity (metric VIII)

average sample size

average number of DLT
The maximum number of patients per trial was set to 60. The trial was stopped using the rules 
defined in the protocol in Section 6.2.3.2.
Table 14-32
Operating characteristics
Metric
Scenario 1
Scenario 2
Scenario 3 
Scenario 4
Scenario 5
I
52.7
0.0
26.5
85.5
0
II
0.0
0.0
9.3
11.3
100
III
47.3
100.0
64.2
3.2
0.0
IV
81.7
0.0
37.1
78.4
0
V
0.0
0.0
7.3
3.9
6
VI
14.7
97.9
50.9
0.8
0
VII
3.3
2.0
2.7
1.7
0
VIII
0.3
0.1
2.0
15.2
94.0
Average sample size
23.5
23.7
21.7
18.0
7.7
Average number of DLT 
3.3
2.1
4.3
4.9
4.0
14.7.3.2 Results
The simulated operating characteristics presented show that the BLRM performs well under the 
hypothetical profiles investigated. Indeed, the simulations performed illustrate that the model 
has reasonable operating characteristics and the number of patients with DLT was limited 
through a trial. 
In scenario 1, the probabilities of DLT are aligned with the median prior information. In this 
scenario, the simulations show that there is 14.7% of chance for identifying the MTD at 
underdose interval, and 81.7% of chance identifying the MTD at target toxicity interval.
In scenario 2, the probabilities for all doses lie within the underdose interval. The simulations 
show that there is 97.9% of chance for identifying the MTD at underdose interval. The chance 
to stop the trial without identifying a recommended dose because all doses are estimated to be 
too toxic is very low (0.1%).


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In scenario 4, with 5-fold odds inflation from test scenario 1, the simulations show that there is 
78.4% of chance to select the MTD at target toxicity interval. 
Although the dose 300 mg has acceptable toxicity, it towards the upper bound of the target 
interval, this leads to the high chance to stop the trial due to high toxicity of all dose levels
(15.2%) 
Finally in scenario 5, with the probabilities of DLT are all within the excessive toxicity interval. 
The simulations show that the chance to stop the trial without identifying an MTD due to doses 
being estimated as too toxic is very high (94%).
In conclusion, the simulations performed illustrate that the model has good operating 
characteristics under the 5 hypothetical profiles investigated.
14.7.4
Alternative dosing schedule
If the alternative Q1W or other dosing schedule have been explored when the enrollment of 
Japanese patients starts, the dose escalation for Japanese patients will start with the same dosing 
schedule at a dose deemed same at global dose escalation. The BLRM model will be updated 
for that dosing schedule, and the prior construction will follow the similar way introduced 
previously, using a mixture of a MAP prior and weekly informative prior corresponding to high
toxicity to make the prior more robust. 
For the MAP model, data from global patient on the same dosing schedule will be used.
14.7.5
References (available upon request)
EMEA (2007) Guideline on Clinical Trials in Small Populations. Committee for Medicinal 
Products for Human Use (CHMP).
Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J Clin Oncol; 25:4982-6.
Spiegelhalter DJ, Abrams KR, Myles JP (2004) Bayesian Approaches to Clinical Trials and 
Health-Care Evaluation.


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14.8
Appendix 7: Prohibited Medication
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited in Section 6.4.2 and in Table 14-33
below. Combination administration of study drugs could result in drug-drug interactions (DDI) 
that could potentially lead to reduced activity or enhanced toxicity of the concomitant 
medication and/or BLZ945. Refer to the BLZ945 IB for more information on possible 
interactions with other drugs.
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
Database (release date: January 2018), which was compiled from the Indiana University School 
of Medicine’s “Clinically Relevant” Table and supplemented with the FDA Draft Guidance for 
Industry, Drug Interaction Studies – Study Design, Data Analysis, and Implications for Dosing 
and Labeling (February 2012), and the University of Washington’s Drug Interaction Database 
(February 2015) and QTdrugs lists from qtdrugs.org (November 2015). These lists are not 
comprehensive and are only meant to be used as a guide. Please contact the medical monitor 
with any questions. If a medication appears on both the list of prohibited and the list of 
medications to be used with caution, the medication is prohibited.


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Table 14-33
List of prohibited medications during study drug treatment
Strong inhibitors of CYP2C8 and CYP3A are prohibited
Moderate inhibitors of CYP2C8 and CYP3A are prohibited only when used in combination 
with other moderate CYP3A or CYP2C8 inhibitors.
Mechanism of Interaction
Drug Name
Strong inhibitors1 of CYP2C8
clopidogrel, gemfibrozil9
Moderate inhibitors2 of CYP2C85
(NOTE: only when combined with moderate or 
strong CYP2C8 inhibitor and/or CYP3A inhibitor)
deferasirox, teriflunomide, 
Strong inhibitors1 of CYP3A
boceprevir, clarithromycin, cobicistat, conivaptan, 
danoprevir/ritonavir, eltegravir/ritonavir grapefruit juice6a, 
indinavir, itraconazole, ketoconazole,  lopinavir/ritonavir, 
mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, 
saquinavir, sequinavir/ritonavir,  telaprevir, telithromycin, 
voriconazole, indinavir/ritonavir, tipranoavir/ritonavir, 
troleandomycin,  
Moderate inhibitors2 of CYP3A5
(NOTE: only when combined with moderate or 
strong CYP3A inhibitor and/or CYP2C8 inhibitor)
amprenavir, aprepitant, atazanavir, casopitant, cimetidine, 
ciprofloxacin, crizotinib, cyclosporin, darunavir, diltiazem, 
dronedarone, erythromycin, fluconazole8, fosamprenavir, 
grapefruit juice6a, imatinib, lomitapide, netupitant, nilotinib, 
schisandra sphenanthera6, tofisopam, verapamil
Moderate inducers4 of CYP2C8 
(NOTE: only when combined with moderate or 
strong CYP2C8 inducer and/or CYP3A inducer)
rifampin5a
Strong inducers3 of CYP3A
avasimibe, carbamazepine, enzalutamide, mitotane, 
phenobarbital, phenytoin, rifampin, St. John’s wort6, 
rifabutin
Moderate inducers4 of CYP3A
(NOTE: only when combined with moderate or 
strong CYP3A inducer and/or Rifampin)
bosentan, efavirenz, etravirine, genistein7, lersivirine, 
lopinavir, modafinil, nafcillin, ritonavir, semagacestat10, 
talviraline10, thioridazine, tipranavir
PPI10
dexlansoprazole, esomeprazole, ilaprazole, lansoprazole, 
omeprazole, pantoprazole, rabeprazole
Medications with a known risk to prolong the QT 
interval and/or known to cause Torsades de 
Pointe TdP
amiodarone, anagrelide, arsenic trioxide, astemizole, 
azithromycin, chloroquine, chlorpromazine, cilostazol, 
ciprofloxacin, cisapride, citalopram, clarithromycin, 
disopyramide, dofetilide, domperidone, donepezil, 
dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, fluconazole, gatifloxacin, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomepromazine, 
levosulpiride, methadone, moxifloxacin, ondansetron, 
oxaliplatin, papaverine HCl (intra-coronary), pentamidine, 
pimozide, procainamide, propofol, quinidine, roxithromycin, 
sevoflurane, sotalol, sulpiride, sultopride, terlipressin, 
terodiline, thioridazine, vandetanib


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Mechanism of Interaction
Drug Name
Medications with ‘possible’ risk to prolong the QT 
interval
alfuzosin, apomorphine, aripiprazole, 
artenimol+piperaquine, asenapine, atomoxetine, 
bedaquiline, bendamustine, bortezomib, bosutinib, 
buprenorphine, cabozantinib, capecitabine, ceritinib, 
clomipramine, clozapine, crizotinib, cyamemazine 
(cyamepromazine), dabrafenib, dasatinib, degarilix, 
delamanid, desipramine, dexmedetomidine, dolasetron, 
efavirenz, eliglustat, epirubicin, eribulin mesylate, 
ezogabine (retigabine), famotidine, felbamate, fingolimod, 
flupentixol, gemifloxacin, granisetron, hydrocodone-ER, 
iloperidone, imipramine (melipramine), isradipine, 
ketanserin, lapatinib, lenvatinib, leuprolide, lithium, 
melperone, midostaurin, mifepristone, mirabegron, 
mirtazapine, moexipril/HCTZ, necitumumab, nicardipine, 
nilotinib, norfloxacin, nortriptyline, nusinersen, ofloxacin, 
osimertinib, oxytocin, paliperidone, palonosetron, 
panobinostat, pasireotide, pazopanib, perflutren lipid 
microspheres, perphenazine, pilsicainide, pimavanserin, 
pipamperone, promethazine, prothipendyl, ribociclib, 
rilpivirine, risperidone, romidepsin, saquinavir, sertindole, 
sorafenib, sunitinib, tacrolimus, tamoxifen, telavancin, 
telithromycin, tetrabenazine, tiapride, tipiracil/trifluridine, 
tizanidine, tolterodine, toremifene, trimipramine, tropisetron, 
vardenafil, vemurafenib, venlafaxine, vorinostat, zotepine
Hematopoietic colony- stimulating growth factors
sargramostim , filgrastim, filgrastim-sndz, lenograstim, 
pegfilgrastim, molgramostim
1 a strong inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive substrate 
for that CYP by equal or more than 5-fold 
2 a moderate inhibitor for a specific CYP is defined as an inhibitor that increases the AUC of a sensitive 
substrate for that CYP by less than 5-fold but equal to or more than 2-fold
3 a strong inducer for a specific CYP is defined as an inducer that decreases the AUC of a sensitive substrate 
for that CYP by equal or more than 80% 
4 a moderate inducer for a specific CYP is defined as an inducer that decreases the AUC of a substrate for that 
CYP by 50-80%
5 combined treatment of a moderate CYP2C8 or CYP3A and a moderate CYP2C8 or CYP3A inhibitor will 
increase the exposure to BLZ945
5a combined use of rifampin and of an additional moderate CYP3A inducer will reduce exposure to BLZ945 and 
interfere with efficacy
6 herbal product
6a the effect of grapefruit juice varies widely among brands and is concentration-, dose-, and preparation-
dependent. Studies have shown that it can be classified as a “strong CYP3A inhibitor” when a certain 
preparation was used
7 food product
8 fluconazole is listed as a strong CYP2C19 inhibitor based on the AUC ratio of omeprazole, which is also 
metabolized by CYP3A
9 gemfibrozil also inhibits OATP1B1
10 co-administration of a PPI with BLZ945 will reduce the systemic exposure to BLZ945. Due to the pH shift in 
the stomach caused  by the PPI, BLZ945 is expected to precipitate and it will be less efficiently absorbed
11 Medications with a known risk to prolong the QT interval and/or known to cause Torsades de Pointe TdP


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14.9
Appendix 8: Medications to be used with caution
Table 14-34
List of medications to be used with caution during study drug 
treatment
Mechanism of Interaction
Drug Name
H2 antagonists1 (refer to Section 6.4.3)
nizatidine, ranitidine
Antacids1
aluminum hydroxide, aluminum carbonate, calcium hydroxide, 
calcium carbonate, bismuth subsalicylate
Medications with ‘conditional’ risk to 
prolong the QT interval
amantadine, amisulpride, amitriptyline, amphotericin B, 
bendroflumethiazide (bendrofluazide), chloral hydrate, 
diphenhydramine, doxepin, fluoxetine, fluvoxamine, furosemide, 
galantamine, garenoxacin, hydrochlorothiazide, 
hydroxychloroquine, hydroxyzine, indapamide, ivabradine, 
loperamide, metoclopramide, metronidazole, olanzapine, 
paroxetine, piperacillin/tazobactam, quetiapine, quinine sulfate, 
ranolazine, sertraline, solifenacin, torsemide, trazodone, 
ziprasidone
1 co-administration could lower the exposure to BLZ945 and have an impact on efficacy


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14.10
Appendix 9: Guidelines for efficacy evaluation in Hodgkin and 
non-Hodgkin lymphoma studies
Author(s):
Document type:
TA Specific Guideline
Development 
phase
Modified from Final Version 04: 20-Apr-2018
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis
Template version 4.0 (effective 20 Apr 2018)


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14.10.1
Introduction
The purpose of this guideline is to provide working definitions and rules to evaluate efficacy in 
non-Hodgkin lymphoma (NHL) studies conducted by Novartis. This document is based on the 
International Working Group response criteria (Cheson et al 1999), the International 
Harmonization Project revised response criteria (Cheson et al 2007), and the revised Consensus 
of the International Conference on Malignant Imaging Working Group and the Lugano 
Classification (Barrington et al 2014; Cheson et al 2014), and it is intended for studies of 
radiographically measurable disease. For studies without measurable disease, e.g., studies of 
consolidation of complete response, maintenance treatment, or autologous stem cell 
transplantation, see Appendix A.
14.10.2
Methodologies
14.10.2.1 Computed tomography (CT)
The same method of assessment and technique should be used to characterize each identified 
and reported lesion throughout the study. Contrast-enhanced CT of neck, chest, abdomen and 
pelvis, from skull base through lesser trochanters ensuring complete coverage of the pelvis and 
inguinal areas, should be performed using a ≤ 5 mm slice thickness with a contiguous 
reconstruction algorithm. If a patient has a CT contrast allergy or develops it during the trial, 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis are acceptable 
for a follow up. Chest MRI is not recommended due to respiratory artifacts.
14.10.2.2 Positron emission tomography (PET)
Studies of FDG-avid histologies require PET using the radiotracer 18F-fluorodeoxyglucose 
(FDG) to confirm any new CR determined by CT. PET will not be required to confirm 
progression or relapse.
PET scans should cover the whole body from base of skull to mid-thigh. Examinations should 
be consistent across all time points including amount of tracer, location of injection, arm 
location, and scan delay. Information of height, weight, gender, administered dose, time 
between dose administration and imaging, duration of fasting and glucose level are required for 
each time point. PET images should be converted to SUV maps to support comparison across 
time points and to standardize viewing conditions.
14.10.2.3 PET-CT
Hybrid PET-CT may be used to acquire PET and CT images if CT images produced by the 
scanner are of diagnostic quality and include intravenous contrast. Non-diagnostic CT images 
acquired for attenuation purposes during PET-CT are NOT acceptable as the only images for 
the time point.
If diagnostic CT and PET are to be acquired on the same day, PET must be performed prior to 
CT with IV contrast to avoid compromising PET results.


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Thus, any of the three following imaging methodologies are possible in a lymphoma study:

PET-CT with diagnostic

PET-CT with non-diagnostic CT and dedicated diagnostic CT

Dedicated diagnostic CT and dedicated FDG PET
14.10.2.4 Magnetic resonance imaging (MRI) and PET-MRI
MRI or PET-MRI is an acceptable method of imaging if CT is contraindicated e.g., due to CT 
contrast allergy. If at baseline a patient is known to be allergic to CT contrast or develops allergy 
during the trial, the following change in imaging modality will be accepted for follow up: a 
non-contrast CT of the chest plus contrast-enhanced MRI of abdomen and pelvis (MRI of the 
chest is not recommended due to respiratory artifacts).
14.10.2.5 Five point scale (5PS)
To standardize PET interpretation, a simple reproducible scoring method called the five point 
scale (5PS) or the Deauville criteria has been implemented for initial staging and assessment of 
interim and end of treatment responses (Barrington et al 2014). The 5PS assesses the most 
intense uptake in a site of disease (Table 14-35).
Table 14-35
Five Point Scale (5PS)
Score
Findings
Score 1
No uptake above background
Score 2
Uptake ≤mediastinum
Score 3*
Uptake > mediastinum, but ≤liver
Score 4**
Uptake moderately > liver
Score 5**
Uptake markedly higher than liver and/or new lesions
●
Score 3 will be considered PET negative unless otherwise specified in the protocol (e.g. de-escalation 
studies), in which case CMR will be based on 5PS of 1 or 2 only, and PMR/NMR/PMD will be based on 5PS of 
3,4 or 5)
●
** Score 4 should be applied to uptake greater than the maximum standard uptake value (SUV) in a large 
region \ of normal liver and score 5 to uptake 2 times greater than the maximum SUV in the liver. PET images 
should be converted to SUV maps to support comparison across time points and to standardize viewing 
conditions. 
(New) areas of uptake unlikely to be related to lymphoma will be marked as “X” (Barrington et al. 2014).
14.10.3
Definitions
14.10.3.1 Disease stage
Extent and involvement by lymphoma is described by the disease stage and is an important 
prognostic factor. Stage can also influence treatment decisions.
14.10.3.2 Baseline
Baseline examination should be as close as possible to the randomization/start of treatment (e.g., 
within 4 weeks prior to randomization/start of treatment). Longer periods may be allowed 
depending on the disease studied and the study design.


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14.10.3.3 Nodal vs. extranodal lesion
A lesion can be categorized as:

Nodal lesion (a lymph node or a nodal mass)

Extranodal lesion (a lesion located in other organs, including spleen and liver)
14.10.3.4 Measurable disease
All anatomic measurements should be taken in two perpendicular dimensions and recorded in 
metric notation, using a ruler or calipers.
Throughout this document, a lesion will be called measurable if:

It can be measured accurately in two perpendicular dimensions: longest diameter (LDi) 
(also known as transverse diameter), and short diameter (SDi), which is the longest 
diameter perpendicular to LDi (also known as perpendicular diameter). The LDi and SDi 
must be measured on the same slice.

For a nodal lesion, LDi is greater than 15 mm, regardless of SDi

For an extranodal lesion, if both LDi and SDi are greater than 10 mm
A lymph node not meeting the measurability criteria but with LDi greater than 15 mm (e.g. SDi 
cannot be measured accurately) will constitute a non-measurable nodal lesion if FDG-avid (for 
FDG-avid histologies).
A lymph node not meeting the measurability criteria but with LDi ranging from 11 mm to 15 
mm and with SDi greater than 10 mm will be checked for relationship to disease as follows:

If it is related to lymphoma, it will constitute a non-measurable nodal lesion (referred to as 
“involved node” in Cheson et al 2007)

If not related to lymphoma and not FDG-avid, it will constitute an abnormal lymph node 
but neither a measurable nor a non-measurable nodal lesion for FDG-avid histologies
All lesions visible on PET but not on CT/MRI will be treated as non-measurable.
Bulky disease
Bulky disease is captured by means of the longest measurement by CT scan. The definition of 
bulky disease (a minimum size) should be included in the study protocol.
14.10.3.5 Assessable disease
Assessable disease refers to disease presentations that are consistent with lymphoma but are not 
suitable for measurement, e.g., pleural effusion, ascites, etc. Assessable disease will be followed 
qualitatively.
14.10.3.6 Index lesion

Up to 6 of the largest nodes, nodal masses or other lymphomatous lesions, including 
extranodal lesions, measurable in two diameters (LDi and SDi)

Should represent overall disease burden and include mediastinal and retroperitoneal 
disease, if involved


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14.10.3.7 Non-index lesion

All other lesions which are not selected as index lesions but are consistent with lymphoma

Abnormal nodes and extranodal lesions, both measurable and non-measurable, such as 
cutaneous, gastrointestinal, and bone lesions, pleural or pericardial effusions, and ascites
14.10.3.8 New lesions

Regrowth of previously resolved lesions

A new nodal lesion > 15 mm in any axis

A new extranodal lesion > 10 mm in any axis

A new extranodal lesion ≤ 10 mm in any axis that is unequivocal and attributable to 
lymphoma

A new assessable lesion attributable to lymphoma (e.g., ascites, pleural effusion)
14.10.4
Efficacy assessments
14.10.4.1 Eligibility
In general, patients should have at least one measurable nodal lesion (greater than 15 mm in the 
long axis) or at least one measurable extranodal lesion (with both LDi and SDi greater than 10 
mm).
14.10.4.2 Methods of disease assessment
14.10.4.2.1
PET combined with diagnostic CT
The integration of PET into more frequently acquired CT evaluation does present a challenge 
to the way response is assessed in a clinical trial. The study protocol must clearly define the 
imaging intervals and imaging methods to be used at each imaging visit. PET scans should be 
performed at pre-specified times for example at randomization before treatment and at clearly 
defined times during and/or after the end of treatment. PET may also be acquired to confirm 
CT results.
The same CT imaging modality should be used at baseline and all post-baseline assessments in 
order to reduce the risk of false responses or progressions based on measurement error. 
A change in modality can be either a change in contrast use (i.e., with contrast versus without 
contrast) or a change in technique (e.g. from CT to MRI). Response assessments made after a 
change in imaging modality should be queried, and if the investigator or blinded central 
reviewer can provide sufficient justification, then the response can be accepted.
In order to calculate the sum of the product of the perpendicular diameters (SPD) of all index 
lesions, their size must be recorded throughout the study. Actual lesion measurements should 
be entered on the corresponding CRFs. If, during the course of the study, either of the 
perpendicular diameters of a lesion cannot be reliably measured because of its small size, it is 
recommended to enter the minimum limit of detection as the diameter size (e.g., 5 mm for spiral 
CT). In other cases when, during the course of the study, the diameter cannot be reliably 
measured for reasons other than its size (i.e., borders of the lesion are confounded by 


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neighboring anatomical structures), no measurement should be entered and the lesion cannot be 
evaluated.
If lesions become confluent over time, it is recommended to measure them as one lesion, report 
the overall diameters to one of the lesions and assign 0 mm × 0 mm to each of the other 
previously measured lesions. The PPD of the current confluent mass should be used to measure 
response, with more than 50% increase in the PPD of the confluent mass compared with nadir 
of the sum of individual nodes necessary to indicate progressive disease.
If a lesion splits into several discrete lesions, the individual product of the perpendicular 
diameters (PPDs) of each lesion should be summed together to represent the PPD of the split 
lesion; this PPD is added to the sum of the PPDs of the remaining lesions to measure response. 
If subsequent growth of any or all of these discrete nodes occurs, the nadir of each individual 
node is used to determine progression (as if each individual node was selected as an index lesion 
at baseline).
14.10.4.2.2
Bone marrow assessment
Bone marrow should be evaluated by biopsy or aspirate in all patients at baseline. If lymphoma 
involvement in bone marrow is observed at baseline, then biopsy or aspirate should be 
performed post-baseline to confirm radiological CR. Any deviation from this approach should 
be justified in the study protocol.
14.10.4.2.3
Physical examination
Skin lesions must be histologically confirmed for lymphoma involvement (the investigational 
site must document the histological confirmation (yes or no) on the corresponding CRF) and 
photographed including a ruler (color photography using digital camera). Response assessment 
of skin lesions will be performed and results will be recorded on the corresponding CRF at 
baseline and at the time of each radiological assessment.
14.10.4.3 Documentation of disease
For the evaluation of disease at baseline and throughout the study, the following will be 
recorded.
14.10.4.3.1
FGD uptake
FDG uptake in a nodal or extranodal site that is suggestive of lymphoma will be assessed using 
5PS.
14.10.4.3.2
Index lesions
A minimum of one measurable index lesion and a maximum of six of the largest dominant 
nodal and extranodal lesions must be documented at baseline and assessed throughout the study 
in two dimensions. The lesions should come from different body regions representative of the 
patient’s overall disease burden and should include mediastinal and retroperitoneal disease, if 
involved. Two perpendicular dimensions (LDi, SDi) must be recorded on the corresponding 
CRF at each assessment of a measurable lesion selected to be an index lesion.


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Index nodal lesions
Index nodal lesions are selected from the measurable nodal lesions and should be documented 
at baseline and assessed throughout the study. Index nodal lesions should be from disparate 
regions of the body including mediastinal and retroperitoneal areas of disease whenever these 
sites are involved.
Index extranodal lesions
Other organs such as breast and lung can be occasionally involved by lymphoma. 
Such extranodal lesions (e.g. hepatic nodules) may be included (if measurable) in the six index 
lesions to be assessed throughout the study. In some cases histological examination may be 
necessary to confirm that these lesions represent lymphoma involvement (e.g. skin lesions).
14.10.4.3.3
Non-index lesions
Non-index nodal lesions
Nodal lesions not selected as index lesions (both measurable and non-measurable) are 
considered as non-index lesions. Non-index lesions should be documented at baseline and 
assessed throughout the study. Measurements of these lesions are not required to be documented 
on the CRF.
Non-index extranodal lesions
Measurable extranodal lesions not selected as index lesions and all non-measurable extranodal 
lesions (including non-measurable but assessable disease e.g. pleural effusion) will be 
documented at baseline and assessed throughout the study as non-index lesions. Measurements 
of these lesions are not required to be documented on the CRF.
14.10.4.3.4
Spleen involvement
Splenic involvement is determined by imaging: vertical (cranial to caudal) length > 13 cm is 
considered as involved, and spleen length must be assessed at each imaging time point. 
Intrasplenic lesions should be followed as index, non-index and new extranodal lesions.
14.10.4.3.5
Liver involvement
Given variability in physical habitus and the impact of numerous medical conditions, 
assessment of liver size is not considered a reliable measure of hepatic involvement and 
therefore liver assessment is not included in the Lugano 2014 classification. Intrahepatic lesions 
should be followed as index, non-index and new extranodal lesions.
14.10.4.3.6
Bone marrow involvement
Lymphoma involvement in bone marrow should be documented in the CRF as “Yes” or “No” 
at each bone marrow biopsy and/or aspiration.


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14.10.4.4 Response evaluation
The efficacy variables in the statistical analysis are based on overall disease response, which 
is a combined evaluation of response based on both radiological and clinical findings, and is 
determined at each post-baseline assessment. The radiological response is first obtained from 
CT and PET studies according to the Lugano criteria (Table 14-36) and overall disease response 
is then determined by taking into account results of bone marrow biopsies and other clinical 
information (Table 14-37).
14.10.4.4.1
Radiological response
There are three separate components to radiological response, all of which should be collected 
on the CRF at each post-baseline assessment:
1. CT response based on anatomical measurements of index/non-index/new lesions and 
spleen length. The possible response outcomes are complete response (CR), partial 
response (PR), stable disease (SD), or progressive disease (PD) as defined in Table 14-36.
2. PET response based on 5PS, changes in intensity or extent of standard uptake values 
(SUVs) and bone marrow assessments directly from the PET scan. The possible outcomes 
for PET response are complete metabolic response (CMR), partial metabolic response 
(PMR), no metabolic response (NMR), or progressive metabolic disease (PMD) as defined 
in Table14-36.
3. Overall radiological response combines CT response with PET response. The outcomes 
include CR, PR, SD, and PD. For time points when both CT and PET are available, PET 
response overrules CT response. Overall radiological response at a time point with CT 
only may also be affected by PET response obtained at a different time point.
Example 
A CT response of PR at the same assessment as a PET response of CMR will constitute an 
overall radiological response of CR, and (i) a subsequent time point with CT only and CT 
response of PR will still constitute an overall radiological response of CR, (ii) a previous 
time point with CT only and CT response of PR may be upgraded to CR at the discretion 
of the investigator or blinded central reviewer.
Table 14-36
Radiological response assessment
PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
Complete 
Response
Index 
5PS† of 1, 2, or 3* with or without 
residual mass on 5PS
Nodal lesion: ≤ 15 mm in Ldi
Extranodal lesion: Absent (0 mm x 
0 mm)
Non-index
Absent
Spleen
Return to normal (≤ 13 cm)
New lesions
None
None
Bone 
marrow
No FDG-avid disease
Not applicable
Partial Metabolic Response (PMR)
(all of the following)
Partial Response (PR)
(all of the following)


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PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
Partial 
Response
Index 
5PS of 4 or 5 with reduced uptake 
compared to baseline with respect to 
SUV intensity or extent. This may apply 
to the specific hot spot and/ or overall 
the subject. It is expected that there will 
be residual mass(es) present.
≥ 50% decrease from baseline in 
SPD across all index lesions
Non-index
No increase
Spleen
≥ 50% decrease from baseline in 
enlarged portion of spleen 
Example: If 16 cm, then enlarged 
portion is 3 cm. A decrease by 2 cm 
gives a 66.6% decrease
New lesions
None
None
Bone 
marrow
●
Residual uptake higher than uptake 
in normal marrow but reduced 
compared with baseline
●
Persistent focal changes in the 
marrow with nodal response
Not applicable
No Metabolic Response (NMR)
(all of the following)
Stable Disease (SD)
(all of the following)
Stable 
Disease
Index 
5PS of 4 or 5 with no significant change 
in FDG uptake from baseline
●
<50% decrease from baseline in 
SPD across all index lesions
●
No criteria for PD are met
Non-index
No progression
Spleen
No progression
New lesions
None
None
Bone 
marrow
No change in FDG uptake from 
baseline
Not applicable
Progressive Metabolic Disease (PMD
(At least one of the following)
Progressive Disease (PD)
(At least one of the following)
Progressive 
Disease
Index 
5PS of  4 or 5 with increased uptake 
compared to the visually determined 
nadir with respect to SUV intensity or 
extent. This may apply to the specific 
hot spot and/ or overall the subject.
and/or
●
New FDG-avid foci consistent with 
lymphoma
●
Consider biopsy or interval scan if 
etiology of new lesions uncertain
PPD Progression#:
An individual node/lesion must be 
abnormal with:
●
LDi > 15 mm AND
●
Increase by >= 50% from PPD  
      nadir AND
●
An increase in LDi or SDi from  
      nadir:
●
≥5 mm for lesions with LDi ≤ 20 
mm at current assessment
●
≥ 10 mm for lesions with LDi > 
20 mm at current assessment
Non-index
Unequivocal Progression
Spleen
●  Progression (increase from 
    baseline by >50% in enlarged 
    portion). Example: If 15 cm at 
    baseline then enlarged portion is 
2 
    cm and an increase by >1 cm 
    would be progression  
●  New splenomegaly (> 13 cm and 


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PET-based response
CT-based response
Complete Metabolic Response 
(CMR)
(All of the following)
Complete Response (CR)
(All of the following)
    increase by > 2 cm from normal 
at   
    baseline)
●  Recurrent splenomegaly 
    (normalization followed by 
    increase by > 2 cm from nadir 
    reaching > 13 cm)
New lesions
●   Regrowth of previously resolved    
      lesions
●
New node > 15 mm in any axis
●
New extranodal site > 10 mm in    
      any axis
●
New extranodal site ≤ 10 mm in 
      LDi, unequivocal and 
      attributable to lymphoma
●
Assessable disease of any size 
      Unequivocally attributable to 
      Lymphoma
Bone 
marrow
New/recurrent FDG-avid foci
Not applicable
Abbreviations: LDi Longest diameter; SDi Shortest diameter; PPD Product of perpendicular diameters; SPD 
Sum of the product of the perpendicular diameters.
* Score 3 will be considered PET negative unless otherwise specified in the protocol (e.g. de-escalation 
studies, in which case CMR will be based on 5PS of 1 or 2 only, and PMR/NMR/PMD will be based on 5PS of 
3,4 or 5)
# In the context of an agent associated with a flare reaction, caution must be exercised not to confuse 
   the possible tumor flare with progressive disease. It is recommended that either a biopsy be  
   performed or the lesion be reassessed in at least 2 weeks, and if there is continued evidence of 
   tumor progression, the date of progressive disease is the previous evaluation.
† PET 5PS 1: no uptake > background; 2: uptake ≤ mediastinum; 3: uptake > mediastinum but ≤ liver; 
   4: uptake moderately > liver; 5: uptake markedly > liver and/or new lesions; X: new areas of uptake 
    unlikely to be related to lymphoma.
14.10.4.4.2
Overall disease response
Overall disease response is determined by assessing whether the combined radiological responses at 
each time point are appropriate, based on bone marrow biopsies and other clinical findings that may 
be available, such as cytology results, physical examination results of palpable lesions or skin 
lesions, and biopsies of lymph nodes or extra-nodal lesions (Table 14-37). The possible 
outcomes for overall disease response are CR, PR, SD, and PD.
For example, suppose there was lymphoma involvement in the baseline bone marrow biopsy, 
and the month 3 combined radiological response was CR (implying that PET-based bone 
marrow involvement at month 3 was negative). In that case, overall disease response could only 
be CR if there was a negative bone marrow biopsy otherwise overall disease response would be 
downgraded to PR. This is a case where the bone marrow biopsy results overrule the bone 
marrow findings on PET. Another example is when the combined radiological response is SD, 


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but cytology results of a pleural effusion show lymphoma involvement: this could lead to an 
overall disease response of PD.
Overall disease response at each post-baseline assessment should be captured on the CRF, along 
with the date of response. In addition, the source of any clinical data that affected the overall 
disease response should be documented.
Table 14-37
Overall disease response
Overall radiological 
response
Bone marrow 
biopsy/aspirate
Clinical findings
Overall disease 
response
CR/PR/SD
Negative at baseline or 
negative ± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
CR/PR/SD
CR
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
PR
PR/SD
Positive at baseline and 
either positive (without 
new or recurrent 
involvement) or not done 
± 28 days from 
assessment
Any except new or 
recurrent lymphoma 
involvement
PR/SD
PD
Any
Any
PD
Any
New or recurrent 
involvement
Any
PD
Any
Any
New or recurrent 
lymphoma involvement
PD
14.10.4.5 Efficacy analysis definitions
14.10.4.5.1
Best overall response
The best overall response (BOR) is the best overall disease response recorded from 
randomization/start of treatment until progressive disease or start of new anticancer therapy, 
whichever comes first. The definition of new anticancer therapy may need to be defined in the 
study protocol (e.g., high-dose chemotherapy with autologous stem cell transplantation).
A patient will have a best overall response of CR if they have CR as overall disease response 
for at least one of the assessments.
A patient will have a best overall response of PR if at least one overall disease response of PR 
is available (and the patient does not qualify for CR).
A best overall response of SD will be declared when at least one overall disease response of SD 
is available at least 6 weeks after randomization/start of treatment (and the patient does not 
qualify for CR or PR). If SD is observed before this minimum follow-up period, and the patient 
does not qualify for CR, PR or PD, then the best overall response would be unknown (UNK). 
If a different minimum follow-up period for SD is more appropriate (e.g., if first post-baseline 
visit is at 28 days) then this must be specified in the Study Protocol.


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A patient will have a best overall response of PD if overall disease response is PD between 
randomization/start of treatment and the second scheduled post-baseline assessment (and the 
patient does not qualify for CR, PR or SD).
For example, assuming 12 weeks between assessments and a permitted variation in visit timing 
of ± 1 week, this would mean during the first 25 weeks after randomization/start of treatment. 
If PD is observed after this maximum follow-up period, and the patient does not qualify for CR, 
PR or SD, then the best overall response would be UNK. If a different maximum follow-up 
period for PD is more appropriate then this must be specified in the Study Protocol.
A patient will have a best overall response of UNK if the patient does not qualify for CR, PR, 
SD or PD.
Overall disease response at a given assessment may be provided from different sources:

Per Investigator: overall disease response based on local radiological assessments, using 
investigator choice of index lesions, measurements and assessments of lesion status and 
5PS along with clinical findings

Per Central Blinded Review, with or without blinded adjudication: based on central review 
of local radiological assessments, using central reviewer choice of index lesions, 
measurements and assessments of lesion status and 5PS, along with clinical findings
In studies that include a central blinded review, the Study Protocol should state which source 
will be used for the primary analysis.
Best overall response is summarized by calculating the overall response rate (ORR), which is 
defined as the proportion of patients with a best overall response of CR or PR.
Similarly, the complete response rate is the proportion of patients with a best overall response 
of CR.
14.10.4.5.2
Time to event variables
Most of the time to event variables are defined in this section according to the revised 
International Working Group response criteria (Cheson et al 2007). Further details on dates and 
censoring rules are provided respectively in Section 14.10.4.5.3 and Section 14.10.4.5.4.
Overall survival
Overall survival (OS) is defined as the time from the date of randomization/start of treatment 
to the date of death due to any cause. If a patient is not known to have died, OS will be censored 
at the date of last contact.
Progression-free survival
Progression-free survival (PFS) is defined as the time from the date of randomization/start of 
treatment to the date of event defined as the first documented progression (overall disease 
response = PD) or death due to any cause. If a patient has not had an event, PFS is censored at 
the date of the last adequate assessment as defined in Section 14.10.4.5.3.


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Time to progression
Time to progression (TTP) is defined as the time from the date of randomization/start of 
treatment to the date of first documented progression (overall disease response = PD) or death 
due to lymphoma. If a patient has not had an event, TTP is censored at the date of the last 
adequate assessment.
Duration of response
Duration of response (DOR) applies only to patients with best overall disease response of CR 
or PR. It is defined as the time from the date of the first documented overall disease response 
of CR or PR to the date of first documented progression or death due to lymphoma. If a patient 
has not had an event, DOR is censored at the date of the last adequate assessment. It should be 
stated that this analysis might introduce a bias as it includes only responders.
Duration of complete response applies only to patients with best overall disease response of CR. 
It is defined as the time from the date of the first documented overall disease response of CR to 
the date of first documented progression or death due to lymphoma. If a patient has not had an 
event, duration of CR is censored at the date of the last adequate assessment. Duration of CR 
might be calculated in addition for studies in which a reasonable number of complete responders 
are seen.
The analysis of DOR should only be used as a descriptive analysis. If used as an inferential 
comparison between treatments, clear justification must be given in the study protocol.
Time to response
Time to response (TTR) is defined as the time from the date of randomization/start of treatment 
to the date of first documented overall disease response of PR or CR. Depending on the study 
design, this analysis could be based on all patients only, or on responders only, or both of these 
analysis populations may be used. The choice of analysis population for TTR should be stated 
in the study protocol.
For analysis using all patients, TTR will be censored for patients who did not achieve a PR or 
CR:

At maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. either progressed or died due to any cause)

At the date of the last adequate assessment otherwise
Time to complete response (TTCR) is defined similarly to TTR except using CR only instead 
of either PR or CR, and with this difference, the above rules and definitions for TTR also apply 
to TTCR.
Lymphoma specific survival
Lymphoma specific survival (LSS) is defined as the time from the date of randomization/start 
of treatment to the date of death documented as a result of lymphoma. If a patient has not had 
an event, LSS will be censored:

at the date of last contact if the patient is not known to have died

at the date of death if the patient died for reason other than lymphoma


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Event-free survival
Event-free survival (EFS) may be appropriate in studies of advanced disease where early 
discontinuation is typically related to intolerance of the study drug. In some protocols, EFS may 
be considered as a sensitivity analysis for TTP. If a patient has not had an event, EFS is censored 
at the date of the last adequate assessment as defined in Section 14.10.4.5.3. The definition of 
event needs to be defined in the Study Protocol according to study design.
14.10.4.5.3
Definition of start and end dates for time to event variables
Assessment date
For each assessment, the assessment date is calculated as:

the latest date of all radiological measurements (e.g. PET-CT, CT, or MRI), excluding 
bone marrow biopsy, if overall disease response at that assessment is CR/PR/SD/UNK

the earliest date of all measurements (e.g. PET-CT, CT, or MRI), including bone marrow 
biopsy if overall disease response at that assessment is PD
Start date
For all “time to event” variables other than the duration of response variables, the date of 
randomization/start of treatment will be used as the start date.
For the calculation of duration of response variables the following start date should be used:

Date of first documented response is the assessment date of the first overall disease 
response of CR for duration of complete response or CR/PR for duration of response
End date
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death as reported on the disposition CRF

Date of last contact is defined as the last date the patient was known to be alive as derived 
from different CRF pages (see details in Section 14.10.5.2)

Date of progression is the first assessment date at which the overall disease response was 
recorded as PD

Date of last adequate assessment is the date of the last assessment with overall disease 
response of CR, PR or SD which was made before an event or a censoring reason 
occurred. 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 assessment plus the 
protocol specified time interval between assessments. This date may be used if back-
dating is considered when the event occurred beyond the acceptable time window for the 
next radiological assessment as per protocol.


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Example (if protocol defined schedule of assessments is 3 months): response assessments at 
baseline - 3 months - 6 months - missing - missing - PD. Date of next scheduled assessment 
would then correspond to 9 months.

Date of treatment discontinuation is the last known date subject took study drug (to be 
used, if applicable)

Date of new anti-cancer therapy is defined as the start date of first new antineoplastic 
therapy (including medication, radiotherapy, surgery or HSCT)
14.10.4.5.4
Censoring and sensitivity analyses
Censoring reasons
This section outlines the possible censoring reasons for each time to event variables. In order 
to summarize the various reasons for censoring, the following categories (Table 14-38) will be 
calculated for each time to event variable based on the information reported.
Table 14-38
Censoring reasons
Time to event variables
Possible censoring reasons
OS
●
Alive
●
Lost to follow-up
PFS, EFS, TTP and DOR
●
Ongoing without event
●
Lost to follow-up
●
Withdrew consent
●
Death due to reason other than lymphoma (only used for TTP and DOR)
●
New anti-cancer therapy added (except for EFS optional, see Table 14-39)
●
Event documented after two or more missing response assessments 
(optional, 
see Table 14-39)
●
Adequate assessment no longer available1
LSS
●
Alive
●
Lost to follow-up
●
Death due to reason other than lymphoma
1Adequate assessment is defined in Section 14.10.4.5.3. This reason corresponds to any censoring reasons 
after two or more missing response assessments. This reason will also be used for censor in case of no 
baseline assessment
Event date, censoring date and sensitivity analyses
This section outlines the possible event and censoring dates for progression (Table 14-39), as 
well as addressing the issues of missing response assessments during the study. It is important 
that the protocol and analysis plan 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 14.10.4.5.2, and using the draft FDA guideline on 
endpoints (FDA 2007) as a reference, the following analyses can be considered:


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Table 14-39
Options for event dates used in PFS, EFS, TTP, DOR
Situation
Options for end-date (progression)1
(1) = default unless specified differently in 
the protocol or analysis plan
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment2
Censor
B
Progression at or before next 
scheduled assessment
(1) Date of progression
(2) Date of next scheduled assessment1
Event
Event
C1
Progression or death due to any 
reason after exactly one missing 
assessments
(1) Date of progression (or death)
(2) Date of next scheduled assessment1
Event
Event
C2
Progression or death due to any 
reason after two or more missing 
assessments
(1) Date of last adequate assessment1
(2) Date of next scheduled assessment1
(3) Date of progression (or death)
Censor
Event
Event
D
No progression
(1) Date of last adequate assessment
Censor
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
Event
F
New anticancer therapy given 
(except for EFS, in which this is 
always an event)
(1) Date of last adequate assessment
(2) Date of new anticancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censor
Censor
Event
Ignored
G
Death due to reason other than 
lymphoma
(1) Date of last adequate assessment
Censor
(only TTP and 
DOR)
1 = Definitions can be found in Section 14.10.4.5.3
2 = 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 Study 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 response assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the response due to clinical deterioration.


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Situation F: New cancer therapy given (except for EFS): 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 response 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 14-39 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 response 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 assessment.
The need for these types of sensitivity analyses will depend on the requirements for a specific 
study and disease area and have to be specified in the Study Protocol or RAP documentation.
14.10.5
Data handling and programming conventions
The following rules should be used and specified in the RAP documentation:
14.10.5.1 Calculation of ‘time to event’ variables
Time to event = enddate - startdate + 1 (in days)
When no post-baseline assessments are available, the date of randomization/start of treatment 
will be used as enddate (duration = 1 day) when time is to be censored at last assessment, i.e. 
time to event variables can never be negative.
14.10.5.2 Date of last contact
The date of last contact will be derived for patients alive using the latest complete date among 
the following:

Assessment dates (e.g., vital signs assessment, performance status assessment, efficacy 
assessment, laboratory, pharmacokinetics assessment)

Medication dates including study medication and antineoplastic therapies administered 
after study treatment discontinuation

Adverse events dates

Last known date subject alive collected on the ‘Survival information’ eCRF

Randomization date
14.10.5.3 Date of new anti-cancer therapy
The date of new anti-cancer therapy is the date of the first antineoplastic therapy (including 
medicine, radiotherapy and surgery) reported on the post-treatment antineoplastic therapy CRF 
or from other sources (e.g., HSCT CRF).


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14.10.5.4 Incomplete assessment dates
All investigation dates (e.g., PET-CT scan) must be completed with day, month and year. If one 
or more investigation dates are incomplete but other investigation dates are available, this/these 
incomplete date(s) are not considered for calculation of the assessment date (and assessment 
date is calculated as outlined in Section 14.10.4.5.3). 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.
14.10.5.5 Incomplete dates for last contact 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.
14.10.6
References
Barrington SF, Mikhaeel NG, Kostakoglu L, et al (2014) Role of imaging in the staging and 
response assessment of lymphoma: Consensus of the International Conference on Malignant 
Lymphomas Imaging Working Group. J Clin Oncol 32 :3048-3058.
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an international workshop to 
standardize response criteria for non-Hodgkin’s lymphomas. J Clin Oncol 17:1244-1253.
Cheson BD, Pfistner B, Juweid ME, et al (2007) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586.
Cheson BD, Fisher RI, Barrington SF, et al (2014) Recommendations for initial evaluation, 
staging, and response assessment of Hodgkin and Non-Hodgkin lymphoma: The Lugano 
Classification. J Clin Oncol 32:3059-3067.
FDA Guideline (2007) Clinical trial endpoints for the approval of cancer drugs and biologics, 
May 2007.
14.10.7
Appendix A: Adaptation for use in maintenance/adjuvant settings
For study populations without measurable disease at baseline (e.g., maintenance), the event of 
interest is no longer progression but relapse, and the main endpoint is no longer progression-
free survival but disease-free survival (see below).
Relapsed disease
Any of the following meets the definition of relapsed disease (RD):

Any new nodal lesion > 15 mm in any axis (i.e. previously normal lymph node becoming 
>1.5 cm in any axis) on CT (or MRI) after baseline

Any discrete extranodal lesion (including liver or spleen) reliably appearing on CT (or 
MRI) after baseline

≥ 50% increase in long axis from baseline of any residual lymph node or mass. A residual 
lymph node or mass is defined as a previously lymphoma-involved lymph node or mass 


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(>10 mm in short axis (without any upper limit)) that was PET negative at baseline and 
only reliably detected by baseline CT (or MRI). Note: If a residual lymph node or mass at 
baseline decreases in size during treatment and becomes normal (i.e. complete 
disappearance of extranodal mass or ≤ 10 mm in short axis and ≤ 15 mm long axis for 
nodal mass), then reappearance of an extranodal lesion at the same site or increase of the 
same nodal mass to > 15 mm in the long axis, will be considered RD and will be recorded 
as a new lesion.

Any new bone marrow involvement

Any new malignant effusion
Disease-free survival
Disease-free survival (DFS) is the time from date of randomization / start of treatment to the 
date of event defined as the first documented relapse of the disease or death due to any cause. 
If a patient has not had an event, DFS is censored at the date of the last adequate assessment. 
Similar censoring rules and reasons as the ones used for PFS can be applied.

SAP_001.pdf: 
Clinical Development
BLZ945, PDR001
CBLZ945X2101 / NCT02829723
A phase I/II, open-label, multi-center study of the safety and 
efficacy of BLZ945 as single agent and in combination with 
PDR001 in adult patients with advanced solid tumors
Statistical Analysis Plan (SAP)
Author:
, Trial Statistician
Document type:
SAP Documentation
Document status:
Addendum
Release date:
17-July-2023
Number of pages:
34
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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SAP
CBLZ945X2101
Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for 
update
Section and title impacted
(Current)
12-
Oct-
2016
Prior to 
FPFV
Creation of initial 
version
N/A - First version
N/A
13-
May-
2020
Prior to 
start of 
Phase II 
part
Document 
that  
patients who were 
not appropriately 
consented will be 
removed from all 
analysis 
activities. 
Amendment 1.0
1. Section 
2.1 
Data 
analysis 
general 
information
2. Section 2.4 Protocol 
deviations
7-
April-
2021
Prior to 
IA 
of 
Phase II 
part
Update 
the 
analysis 
plan 
based on PA06
Amendment 2.0
1. Section 1.1, 1.2
2. Section 2.1, 2.2, 2.3, 
2.5, 2.6, 2.7, 2.8, 
2.10, 2.12 
3. Section 3
4. Section 4
21-
Dec-
2022
Prior to 
DBL
Update 
the 
analysis 
plan 
ready for dry-run
Amendment 3.0
1. Section 2.1, 2.2, 2.3, 
2.5.1.2, 2.7, 2.7, 2.8, 
2.9, 2.10, 2.11
17-
Jan-
2023
Prior to 
DBL
Update of LLOQ 
values
Amendment 4.0
1. Section 2.9
17-
July-
2023
Post-
DBL
Inclusion 
of 
Japan 
vs 
non-
Japan 
safety 
analysis
along 
with requirements 
of 
clinicaltrials.gov 
and EudraCT.gov 
disclosure
Addendum
1. 2.5.1.2, 2.8.1, 2.6.1


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Table of contents
Table of contents .................................................................................................................3
List of tables ........................................................................................................................4
List of figures..............................................................................................................................4
1
Introduction .........................................................................................................................5
1.1
Study design.............................................................................................................5
1.2
Study objectives and endpoints ...............................................................................6
2
Statistical Methods ..............................................................................................................7
2.1
Data analysis general information ...........................................................................7
2.1.1
General defintions...................................................................................8
2.2
Analysis sets ............................................................................................................9
2.3
Patient disposition, demographics and other baseline characteristics ...................11
2.3.1
Patient disposition.................................................................................11
2.3.2
Basic demographic and background data..............................................12
2.3.3
Medical History.....................................................................................12
2.3.4
Prior antineoplastic therapy...................................................................12
2.3.5
Diagnosis and extent of cancer .............................................................12
2.4
Protocol deviations ................................................................................................12
2.5
Treatments (study treatment, rescue medication, other concomitant therapies, 
compliance)............................................................................................................13
2.5.1
Study treatment .....................................................................................14
2.5.2
Concomitant therapies...........................................................................15
2.5.3
Compliance ...........................................................................................16
2.6
Analysis of the primary variable(s) .......................................................................16
2.6.1
Phase I part............................................................................................16
2.6.2
Phase II part...........................................................................................17
2.6.3
Handling of missing values/censoring/discontinuations.......................18
2.6.4
Supportive analyses...............................................................................18
2.7
Analysis of the secondary efficacy variable(s)......................................................18
2.7.1
Best overall response (BOR).................................................................18
2.7.2
Overall response rate (ORR), Disease control rate (DCR) and 
duration of response (DOR)..................................................................18
2.7.3
Progression free survival (PFS) ............................................................19
2.7.4
Overall survival (OS)............................................................................19
2.8
Safety analysis .......................................................................................................20
2.8.1
Adverse events ......................................................................................20
2.8.2
Laboratory data .....................................................................................22


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2.8.3
Vital signs, weight and physical examinations .....................................24
2.8.4
Electrocardiograms ...............................................................................25
2.8.5
Doppler Echocardiography ...................................................................25
2.9
Pharmacokinetic data.............................................................................................26
2.10
Immunogenicity.....................................................................................................26
2.10.1
Sample ADA status...............................................................................26
2.10.2
Subject ADA status...............................................................................27
28
2.12
Interim analyses.....................................................................................................28
3
Sample size calculation .....................................................................................................29
4
Change to protocol specified analyses ..............................................................................29
5
Appendix ...........................................................................................................................29
5.1
Baseline..................................................................................................................29
5.2
Handling of missing and partial dates ...................................................................30
5.3
Construction of waterfall graphs ...........................................................................30
5.4
CTC grades for laboratory values in Novartis Oncology (based on CTCAE 
v4.03 – June 2010).................................................................................................31
6
References .........................................................................................................................34
List of tables
Table 1-1
Objectives and related endpoints ............................................................6
Table 2-1
Major protocol deviations .....................................................................12
Table 2-2
Imputation rules for a partially missing AE start date ..........................21
Table 2-3
Imputation legend and AE/treatment start date relationship.................21
Table 2-4
Laboratory parameters for which CTCAE grades are defined..............23
Table 2-5
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined..................................................................23
Table 2-6
Criteria for notable vital sign values .....................................................24
Table 2-7
Criteria for notable ECG values............................................................25
Table 2-8
PK parameters – descriptive statistics...................................................26
List of figures
Figure 1-1
Study design (effective after approval of PA06).....................................5


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study BLZ945X2101 that will be presented in the Clinical Study Report (CSR)
based on Protocol amendment 06 (PA06). The output shells (in-text and post-text)
accompanying this document can be found in the 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/RDE declaration, IB updates, abstracts, posters,
presentations, manuscripts and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance.
1.1
Study design
Figure 1-1
Study design (effective after approval of PA06)
*: To be expanded to 40 patients if anti-tumor activity is observed in the first 20 patients


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1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
Phase I: To characterize the safety and tolerability 
and to estimate the MTDs and/or  RP2Ds of BLZ945 
as a single agent (in non-Japanese and Japanese 
patients, separately) and in combination with 
PDR001
Safety: Incidence and severity of Adverse Events 
(AEs) and serious Adverse Events (SAEs), including 
changes in laboratory parameters, vital signs and 
Electrocardiogram (ECGs)
Tolerability: Dose interruptions, reductions and dose 
intensity
The incidence of DLTs during the first cycle of 
treatment with single agent BLZ945 and with BLZ945 
in combination with PDR001
Phase II: To assess the anti-tumor activity of BLZ945 
in combination with PDR001 (and BLZ945 as single 
agent if appropriate)
PFS rate at 6 months (PFS6) per response 
assessment in Neuro-Oncology (RANO) Criteria for 
glioblastoma indication.
Secondary
Phase I : To evaluate the preliminary anti-tumor 
activity of BLZ945 as single agent and in combination 
with PDR001
PFS, Best Overall Response (BOR), Overall Response 
Rate (ORR), Disease Control Rate (DCR)  per RECIST 
v1.1 and immune-related response criteria (irRC), and 
RANO/iRANO Criteria for glioblastoma indication and 
the Guidelines for efficacy evaluation in lymphoma 
studies for lymphoma indication(s).
Phase II : To evaluate the preliminary anti-tumor 
activity of BLZ945 as single agent (if appropriate) 
and in combination with PDR001
PFS per immune response assessment in Neuro-
Oncology (iRANO) for glioblastoma indication
BOR, DOR and DCR per RANO and iRANO for 
glioblastoma
Phase II: 
To describe the survival distribution of patients 
treated with BLZ945 as single agent (if appropriate) 
and in combination with PDR001 
Phase II: To further characterize the safety and 
tolerability of BLZ945 as a single agent and in 
combination with PDR001
Overall survival (OS)
Safety: Incidence and severity of Adverse Events 
(AEs) and serious Adverse Events (SAEs), including 
changes in laboratory parameters, vital signs and 
Electrocardiogram (ECGs); 
Tolerability: Dose interruptions, reductions and dose 
intensity
Phase I/II parts: 
Characterize PK of BLZ945 as a single agent and in 
combination with PDR001
BLZ945 and PDR001 PK parameters [e.g. AUC, 
Cmax, Tmax]
Phase I/II parts: 
To assess emergence of anti-PDR001 antibodies
following one or more i.v. infusions of PDR001 in 
combination with BLZ945
Presence and/or concentration of anti-PDR001 
antibodies
Exploratory
Phase I: 
To assess the pharmacodynamics effect of BLZ945 
as single agent and in combination with PDR001 in 
tumor 
Change from baseline in expression of immune-related 
genes. Change from baseline in expression of 
immune-oncology biomarkers including but not 
restricted to CD163; CD8 by immunohistochemistry.


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2
Statistical Methods
2.1
Data analysis general information
The data will be analyzed by Novartis personnel and/or designated CRO(s) using SAS version 
9.4 or higher, and for Bayesian modeling, R version 3.2.3 or higher and WinBUGS version 
1.4.3 or higher. PK parameters will be calculated using non-compartmental methods available 
in Phoenix WinNonlin version 5.2.
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred)
based on all patients’ data of the dose escalation and phase II parts up to the time when all 
patients have potentially completed at least six cycles of treatment or discontinued the study
and all patients from Phase II part have had at least one tumor assessment after six months of 
treatment or discontinued the study. The primary CSR will include all outputs planned within 
the TFL shells document. Additional data for patients continuing to receive study treatment past 
the data cutoff date of the primary CSR, as allowed by the protocol, will be reported once all 
patients have discontinued the study. However, only a selection of key outputs (indicated in the 
TFL shells document) for which additional data was collected will be provided for the final 
report.
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data 
will be summarized with respect to demographic and baseline characteristics, efficacy 
observations and measurements, safety observations and measurements, and all relevant 
pharmacokinetic (PK) using descriptive statistics (n, mean, standard deviation, median, 
minimum, and maximum) for quantitative data and contingency tables (frequencies and 
percentages) for qualitative data.
Both pre and post intra-patient dose escalation data will be listed and summarized together 
under the one dose level/treatment group.
The following rules will be followed for reporting results unless stated otherwise:


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
For the Phase I part, cohorts treated with the same dose or dose combination (dose levels 
and schedules) will be pooled into a single treatment group. All summaries, listings, figures 
and analyses will be performed by treatment group.

For the Phase II part, all summaries, listings, figures for primary efficacy analysis and safety 
analyses will be presented by treatment group (S.A BLZ945 and BLZ945 in combination 
with PDR001). Patients from the Phase II part will be classified according to the treatment 
group to which they were assigned at baseline.
Note: patients from the dose escalation and the expansion will not be pooled in any analyses 
unless otherwise specified.
Patients who sign a non-Ethics Committee approved ICF prior to starting study procedures will 
not be included in any of the reporting activities. 
Screen failure patients are those who signed the informed consent, but never started the study 
treatment for any reason. For these patients, the eCRF data collected will not be included in 
analyses, but will be reported in the CSR as separate listings.
Treatment group is defined by the dose level and regimen of the study treatment (e.g. BLZ945
150 mg 7 days on/7 days off + PDR001 Q4W is one treatment group). A cohort is defined as a 
group of newly enrolled patients treated at a specific regimen and dose level (i.e. treatment 
group) at the same time. Therefore, a treatment group may consist of more than one cohort.
2.1.1
General defintions
Study drug and study treatment
For Single agent:
Study drug and study treatment both refer to BLZ945 and are used interchangeably.
For the combinations:
Study drug refers to the individual compound i.e. BLZ945, PDR001. Study treatment refers to 
combination of BLZ945 and PDR001. 
Date of first/last administration of study drug and study treatment
The date of first (last) administration of study treatment is derived as the first (last) date when 
a non-zero dose of any component of study treatment was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. For the sake of simplicity, the date of first (last) 
administration of study treatment will also be referred as start (last) date of study treatment.
Study day
The study day for all assessments/events will be calculated using the start date of study 
treatment as reference. For assessments/events occurring on or after the start date of study 
treatment, study day will be calculated as:
Study day (days) = Event date – Start date of study treatment + 1
Therefore, the first day of study treatment is study day 1.


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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 result of an investigation describing the “true” state of the subject before start 
of study treatment administration.
The last available assessment on or before the date of the start of study treatment will be taken 
as the “baseline” assessment. In case time of assessment and time of treatment start is captured, 
the last available assessment before the treatment start date/time is used for baseline.
On-treatment assessment/event
For both single agent and the combination the overall observation period will be divided into 
three mutually exclusive segments:
pre-treatment period: 
from day of subject’s first informed consent to the day before first administration of study 
treatment
on-treatment period: 
from date of first administration of study treatment to 30 days after date of last non-zero 
actual administration of any study treatment (including start and stop date).
Post-treatment period:
starting at day 31 after last administration of study treatment.
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for on treatment deaths will be provided.  
In particular, summary tables for adverse events (AEs) will summarize only on-treatment events,
with a start date during the on-treatment period (treatment-emergent AEs).
2.2
Analysis sets 
The number (%) of patients in each of the defined analysis set will be summarized using the 
FAS.
Full Analysis Set
The Full Analysis Set (FAS) comprises all patients who received at least one dose of study 
treatment. Patients will be analyzed according to the planned treatment. The FAS will be used
for all listings of raw data. Unless otherwise specified, the FAS will be the default analysis set 
used for all analyses.


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Safety Set
The Safety Set includes all patients who received at least one dose of BLZ945 or PDR001. 
Patients will be analyzed according to the study treatment (regimen) they actually received, 
where treatment received is defined as:
The treatment assigned if it was received at least once, or the first treatment received when 
starting therapy with study treatment if the assigned treatment was never received. The safety 
set will be used for the safety summary of the study.
Dose-determining Set
Single agent BLZ945 dose escalation cohort
The dose-determining analysis set (DDS) consists of all patients from the safety set in the dose 
escalation part who either meet the minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during Cycle 1.
A patient is considered to have met the minimum exposure criterion if having received BLZ945 
on at least 75% of the planned dosing days during Cycle 1 (as defined below). Patients who do 
not experience a DLT during the first cycle are considered to have sufficient safety evaluations 
if they have been observed for ≥ 28 days following the first dose and are considered by both the 
Sponsor and Investigators to have enough safety data to conclude that a DLT did not occur.
Combination of BLZ945 and PDR001 dose escalation cohort
The DDS consists of all patients from the safety set in the dose escalation part who either meet 
the minimum exposure criterion and have sufficient safety evaluations, or have experienced a 
DLT during the first cycle.
A patient is considered to have met the minimum exposure criterion if having received BLZ945 
on at least 75% of the planned dosing days during Cycle 1 (as defined below) and at least one 
dose of PDR001 during Cycle 1. Patients who do not experience a DLT during the first cycle 
are considered to have sufficient safety evaluations if they have been observed for ≥28 days 
following the first dose, and are considered by both the Sponsor and Investigators to have 
enough safety data to conclude that a DLT did not occur.
For both once and twice a day dosing schedules, the 75% of the planned dosing days of 
BLZ945 is defined as:

at least 11 days of taking planned doses in 7d on/7d off regimen

at least 3 days of taking planned doses of BLZ945 in Q1W regimen

at least 6 days of taking planned doses of BLZ945 in the 4d on/10d off regimen
Pharmacokinetic analysis Set
The pharmacokinetic analysis set (PAS) includes all patients who provide an evaluable PK 
profile. A profile is considered evaluable if all the following conditions are satisfied:

Patient receives one of the planned treatments


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
Patient provides at least one primary PK parameter

Patient does not vomit within 4 hours after dosing of BLZ945
Immunogenicity (IG) analysis Set
The Immunogenicity Prevalence Set (IGPS) includes all patients in the FAS with a determinant 
baseline IG sample or at least one determinant post-baseline IG sample.
The Immunogenicity Incidence Set (IGIS) includes all patients in the IGPS with a determinant 
baseline IG sample and at least one determinant post-baseline IG sample.
See Section 2.10 for the definintion of determinant.
Withdrawal of informed consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the eCRF.  
Additional data for which there is a separate informed consent, e.g. PK, biomarker etc., 
collected in the clinical database without having obtained that consent will not be included in 
the analysis. These data will be excluded by the presence of the appropriate protocol deviation 
criterion.
2.3
Patient
disposition, 
demographics
and 
other 
baseline
characteristics
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 and reason entered),

Primary reasons for study treatment discontinuation (based on discontinuation reason 
entered in the ‘End of Treatment’ page),

Number (%) of patients who discontinued from the post-treatment follow-up (based on 
completion of the ‘End of Post-Treatment’ page with discontinuation date and reason 
entered),

Primary reasons for post-treatment follow-up discontinuation (based on discontinuation 
reason entered in the ‘End of Post-Treatment’ page).


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2.3.2
Basic demographic and background data
-
Demographic data including age, sex, race,  baseline weight, and ECOG performance 
status will be listed and summarized. In addition, age category (18 - <65 years, 65 -
<85 years, >=85 years) will be summarized.
BMI is calculated using the following formula:

BMI [kg/m2] = weight[kg] / (height[m]**2)
2.3.3
Medical History
Medical history and current medical conditions will be coded using the latest Medical 
Dictionary for Regulatory Activities (MedDRA) terminology available at the time of reporting. 
Medical history and current (ongoing) medical conditions, including cancer-related conditions 
and symptoms will be listed. 
2.3.4
Prior antineoplastic therapy
Prior anti-neoplastic therapy overall will be summarized. In addition these will be listed for 
medication, radiotherapy and surgery.
The summary of prior anti-neoplastic therapy overall will include the total number patients 
received medications, surgery and radiotherapy. IT will also include the total number of 
regimens (note: there can be more than one medication per regimen) Prior antineoplastic 
medications will also be summarized for Temozolomide, Lomustine and other medications for 
phase II part of study.
2.3.5
Diagnosis and extent of cancer
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, types of lesions at baseline and current extent of disease (metastatic sites).
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listings. The number (%) 
of patients with any CSR-reportable protocol deviation will be tabulated by the deviation 
category (entry criteria not satisfied; wrong treatment or incorrect dose; developed withdrawal 
criteria, but not withdrawn; took an excluded concomitant medication; others). The full list of 
protocol deviations are documented in the Study Specification Document (SSD).
Patients who sign a non-Ethics Committee approved ICF prior to starting study procedures 
(PDID = OTH14) will be excluded from all analysis sets and not included in any of the reporting 
activities. 
Major protocol deviations leading to exclusion from the PPS are given below: 
Table 2-1
Major protocol deviations
PD Criterion
Protocol Deviation 
ID 
Major PDs 
The use of other investigational therapies while the patient is on the study
COMD01
Yes
Use of anticancer therapy (chemotherapy, biologic or radiation therapy, and 
surgery) other than the study treatment while the patient is on the study
COMD02
Yes


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patient received pre-medication to prevent infusion reaction before first 
PDR001 infusion
COMD03
Yes
use of live vaccines while patient was on study treatment. 
COMD04
Yes
consumption of Seville orange (and juice), grapefruit or grapefruit juice, 
grapefruit hybrids, pomelos and star citrus fruits at least 7 days prior to the first 
dose of study treatment and during the entire study treatment period 
COMD05
Yes
Phase II only: patient  without advanced/metastatic tumors in pancreatic 
cancer, triple breast negative breast cancer, recurrent glioblastoma and who 
did not fail to respond to standard treatment
INCL07
Yes
Systemic steroid therapy or any immunosuppressive therapy (≥10mg/day 
prednisone or equivalent). 
EXCL19
Yes
Any vaccines against infectious diseases (e.g. varicella, pneumococcus) within 4 
weeks of initiation of study treatment.
EXCL20
Yes
Systemic anti-cancer therapy within 2 weeks of the first dose of study 
treatment. For cytotoxic agents that have major delayed toxicity, e.g.
mitomycin C and nitrosoureas, 4 weeks is indicated as washout period.
EXCL21
Yes
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).
EXCL22
Yes
Pre-treatment with anti- cytotoxic T-Lymphocyte-associated protein 4 (CTLA4) 
antibodies in combination with any other antibody or drug specifically targeting 
T-cell co-stimulation or checkpoint pathway. Patients pre-treated with anti-
CTLA4 as single agent must have minimum 8 week washout period between 
the last dose of anti-CTLA4 and the first dose of PDR001
EXCL23
Yes
Participation in an interventional, investigational non-immunotherapy study 
within 2 weeks of the first dose of study treatment
EXCL24
Yes
Radiotherapy within 2 weeks of the first dose of study drug, except for 
palliative radiotherapy to a limited field, such as for the treatment of bone pain 
or a focally painful tumor mass.  To allow evaluation for response to treatment, 
patients enrolled in the phase II part must have remaining measurable disease 
that has not been irradiated.
EXCL27
Yes
Phase II only: Patient treated with BLZ945 in combination with PDR001 who 
changes BLZ945 regimen
TRT07
Yes
Phase II: Patient did not receive planned treatment
TRT14
Yes
Patient was not fasted when BLZ945 was taken
TRT17
Yes
PDR001 infusion more than 2h
TRT01
Yes
PDR001 infusion less than 30 minutes
TRT02
Yes
PDR001 dose reduced
TRT04
Yes
PDR001 regimen changed
TRT05
Yes
2.5
Treatments 
(study 
treatment, 
rescue 
medication, 
other 
concomitant therapies, compliance)
Unless otherwise noted, the Safety set will be used for all medication data summaries and 
listings.


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2.5.1
Study treatment
2.5.1.1
Last date of exposure to study treatment
The last date of exposure to study treatment is the latest of the last dates of exposure to 
investigational drug, and any combination partner.

For single agent, last date of exposure to study treatment is the last date of administration 
of BLZ945 + X where X is the number of days from date of last administration until 
date of the next protocol planned dose administration.

For the BLZ945 and PDR001 combination, last date of exposure to study treatment = 
max(last date of exposure to BLZ945, last date of exposure to PDR001).
The last date of exposure to study drug corresponds to the last date of exposure to 
PDR001,
or BLZ945, and is defined as the last date of administration of the study drug + X, where 
X is the number of days from date of last administration until date of the next protocol 
planned dose administration.
For PDR001 given Q4W, the last date of exposure is defined as the last day of administration
+ 27 days.
For BLZ945 given Q1W, the last date of exposure is defined as the last day of administration + 
6 days.
For BLZ945 given 7 days on/7 days off, the last date of exposure is defined as the last day of 
administration + number of days within the “7 days on week” with missing treatment + 7 days.
For BlZ945 given 4 days on/10 days off, the last date of exposure is defined as the last day of 
administration + number of days within the “4 days on week” with missing treatment + 10 days.
If a patient dies or lost to follow-up within last date of treatment administration + X, then the 
last date of exposure is the death date or last contact date respectively. Similarly, if cut-off date 
falls within last date of treatment administration + X, then the last date of exposure is the cut-
off date.
2.5.1.2
Other study treatment definitions
The below analyses will be summarized by on treatment period and overall.
Definitions of duration of exposure, cumulative dose, actual dose intensity (DI), planned dose 
intensity (PDI), relative dose intensity (RDI), percentage of days dosed, percentage of days the 
planned/intended dose was received, as well as intermediate calculations, are as follows:

Duration of exposure (days)= last date of exposure to study treatment − first date of study 
treatment + 1 (periods of interruption are not excluded)

Cumulative dose (mg): sum of all doses of study drug taken by a patient. The off-dosing 
days as per protocol will be considered as zero doses. For BID schedule, two doses will be 
considered for a day (if taken).

Cumulative planned dose (mg): sum of all doses of study drug that was intended to have 
been taken during the treated period by a patient. 

Actual cumulative dose (mg): sum of all doses of study drug that was actually been taken 
during the treated period by a patient


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
DI (mg/day): actual cumulative dose (mg) ⁄ number of dose days scheduled per protocol
during treatment period

PDI (mg/day): cumulative planned dose (mg) ⁄ number of dose days scheduled per protocol
during treatment period

RDI (%): 100 × DI (mg/day) ⁄ PDI (mg/day)
It is required to find the adjusted exposure duration to calculate the number of dose days 
scheduled per protocol during treatment period in the denominator of dose intensity (DI). Let 
D1 represent the duration of exposure, then the adjusted exposre duration (D) will be defined 
as:
-
For 4 days on 10 days off regimen: D=4*[D1/14]+min(4, D1-14*[D1/14]) days, where 
[x] is integral part of x 
-
For 7 days on 7 days off regimen: D=7*[D1/14]+min(7, D1-14*[D1/14]) days, where 
[x] is integral part of x 
-
For Q1W regimen: D= [((last dosing date+X) – first dosing date)/7] , X=7. where [x] is 
integral part of x
-
For Q4W regimen: D= [((last dosing date +X) – first dosing date)/28] , X=28. where [x] 
is integral part of x
The duration of exposure to study treatment (including categories: <4, 4-<8, 8-<24, 24-<52,  
≥52 weeks) will be summarized. In addition, DI, and RDI  will be summarized for each study 
drug using the duration of exposure to study drug. These will also be summarized for Japan vs 
non-Japan subgroup.
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 
(and/or delays) per patient and the duration of dose reductions/interruptions/delays (days) will 
be summarized for each study drug.
All doses of the study treatment along with reasons for any dose change will be listed.
Dose interruption: CRF field “dose interrupted” is selected as yes and dose administered equal 
to zero, between the first and last non-zero doses, following a non-zero dose administered.   
Reason “as per protocol” is not considered as interruption. A patient with multiple occurrences 
of a reason is only counted once in that category.
Dose reduction: CRF field “dose changed” is selected as yes and a non-zero actual dose (i.e. 
dose administered to the patient as defined above) that is less than the immediate previous non-
zero actual dose (if not the first dose) and below the treatment received dose as per safety set
definition.
2.5.2
Concomitant therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study that are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 


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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.
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 2.8.1 Adverse events). No imputation will be performed for 
concomitant medication end dates.
2.5.3
Compliance
Compliance is presented as the percentage of patients who took a predefined percentage (RDI 
categories: <0.5, 0.5-<0.75, 0.75- <0.9, 0.9-<1.1, ≥1.1) of the number of prescribed doses of 
study treatment. Details are provided in Section 2.5.1.
2.6
Analysis of the primary variable(s)
2.6.1
Phase I part
The primary objective of the Phase I part is to to characterize the safety and tolerability and to 
estimate the MTD or RP2D of BLZ945 as a single agent and in combination with PDR001.
The primary variable is :
Safety: Frequency and severity of AEs and SAEs, including changes in laboratory 
parameters, vital signs and ECGs
Tolerability: dose interruptions, reductions and dose intensity.
See Section 2.8 for details of analysis for safety and tolerability.
The DLT rate during the first cycle of treatment with single agent BLZ945 and with 
BLZ945 in combination with PDR001
DLTs will be listed and their incidence summarized by primary system organ class, worst grade 
based on the CTCAE version 4.03, type of adverse event, and by treatment. The dose 
determining set will be used for these summaries. DLTs will also be summarized for Japan vs 
non-Japan subgroup.
Estimation of the MTD(s)/RP2D(s) will be based upon the estimation by the BLRM of the 
probability of a DLT in the first cycle of treatment for patients in the DDS. 
An adaptive BLRM guided by the escalation with overdose control (EWOC) principle will be 
used to make dose recommendations and estimate the MTD(s) for each regimen considered.
The use of Bayesian response adaptive designs for Phase I studies has been advocated by the 
EMEA guideline on small populations (2006) and by Rogatko (2007), and and endorsed by
numerous publications (Neuenschwander et al 2008, Neuenschwander et al 2010), and its 
development and appropriate use is one aspect of the FDA’s Critical Path Initiative.
The BLRM will be fitted on the dose-limiting toxicity data (i.e. absence or presence of DLT) 
during the DLT window accumulated throughout the dose escalation to model the dose-toxicity 
relationship.
In the single-agent BLZ945 dose escalation part, the dose-toxicity (DLT) relationship is 
modeled by a 2-parameter BLRM.


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In the dose escalation for the combinations, the dose-toxicity (DLT) relationship is modeled by 
a 5-parameter BLRM. 
The Bayesian approach requires the specification of prior distributions for the model parameters. 
For BLZ945 component a weakly informative prior will be derived based on vague knowledge 
from pre-clinical studies. Available PDR001 single agent data will be used to derive Meta-
Analytic-Predictive (MAP) priors for PDR001 component of the model based on available 
clinical data from [CPDR001X2101], the FIH PDR001 oncology study. At the time of each 
BLZ945 in combination with PDR001 dose escalation analysis, DLT data up to, and including, 
the last completed cohort from the single agent dose escalation will be included in the BLZ945 
in combination with PDR001 BLRM. Single agent BLZ945 data will be incorporated directly 
into the BLRM since this data comes from the same study. For further details on the BLRM 
models including the prior specification for the model parameters, and examples of hypothetical 
decisions that may be followed during the dose escalation, refer to Appendix 5 in the protocol.
2.6.2
Phase II part
The primary analysis will be based on the estimation of the progression free survival rate at 
6 months (PFS6).
The efficacy will be concluded if both of the following criteria are met for that specific group:
1. The posterior mean of PFS6 ≥40%
2. The posterior probability that PFS6 is ≥20% is at least 90%.
A Bayesian design will be used to estimate and provide inferential summaries of the PFS rate 
at 6 months. The PFS will be modeled using a Weibull distribution. A weakly informative prior 
distribution for the PFS at 6 months will be assumed. For further details, refer to Appendix 5 in 
the protocol. At the time of the primary analysis, the model will be updated with all available 
data of patients in the FAS for the relevant disease group, and the posterior distribution for the 
PFS at 6 months will be estimated. Inferential summaries based on the posterior distribution 
and posterior probabilities for activity interval below will be presented. 
Categories for anti-tumor activity
The following classification of clinical relevance of the antitumor activity based on PFS rate at 
6 months will be applied for all disease groups:
- [0, 20%) unacceptable anti-tumor activity
- [20%, 30%) limited anti-tumor activity
- [30%, 40%) moderate anti-tumor activity
- [40%, 100%] strong anti-tumor activity
If the estimated posterior mean of PFS rate at 6 months is at least 40% and the posterior risk of 
being in the unacceptable anti-tumor activity interval is less than 10%, then preliminary 
antitumor activity of the combination can be declared. 


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2.6.3
Handling of missing values/censoring/discontinuations
Patients in the dose escalation part who are ineligible for the DDS will be excluded from the 
primary analysis, although their data will be used for all remaining analyses.
In the Phase II part, patients who discontinue the study and are lost to follow-up without a 
known date of progression or death due to any cause on or before the data cut-off date or when 
he/she receives any further anti-cancer therapy will be censored for PFS at the date of their last 
available tumor evaluation before the cut-off date or the anti-cancer therapy start date.
2.6.4
Supportive analyses
For the Phase II part, the proportion of patients with PFS rate at 6 months will be estimated 
using the Kaplan-Meier method along with the two-sided 90% confidence interval, using the 
FAS. 
2.7
Analysis of the secondary efficacy variable(s)
Evaluation of anti-tumor activity will be based on investigator assessment according to RECIST 
v1.1 (solid tumor), irRC (solid tumor), RANO (glioblustoma), iRANO (glioblustoma) and 
guidelines for efficacy evaluation in lymphoma studies as appropriate. The variables used to 
evaluate anti-tumor activity are BOR, ORR, DOR, PFS and OS using the FAS (iBOR, iORR, 
iDOR in case of irRC). Unless otherwise specified, all the efficacy analyses will be performed 
by treatment group for both the Phase I part and Phase II part.
2.7.1
Best overall response (BOR)
The best overall response (BOR) is the best response recorded from the start of the treatment 
until disease progression/recurrence. However, any assessments taken more than 30 days after 
the last dose of study therapy will not be included in the best overall response derivation. 
Moreover, if any alternative cancer therapy is taken while on study, any subsequent assessments 
will be excluded from the best overall response determination.
As per RANO criteria, clear clinical deterioration not attributable to other causes apart from 
tumor also qualifies for the progressive disease (PD). Such PDs may be considered from 
disposition page. The best response for “PD from tumor assessment” and “PD as per clinical 
assessment” will be provided in table of best overall response. “PD from tumor assessment” 
will not form a part of “PD as per clinical assessment”.
2.7.2
Overall response rate (ORR), Disease control rate (DCR) and duration 
of response (DOR)
Overall response rate (ORR) is the proportion of patients with a best overall response of 
complete response (CR) or partial response (PR). CR and PRs must be confirmed by repeat 
assessments that should be performed not less than 4 weeks after the criteria for response are 
first met. Additionally, for iRano and irRC, progressive disease should be confirmed.
ORR and corresponding 90% confidence intervals (CIs) based on the exact binomial 
distribution will be presented.


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Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD. CR and PRs must be confirmed by repeat assessments that should be performed not 
less than 4 weeks after the criteria for response are first met. DCR and corresponding 90% 
confidence intervals (CIs) based on the exact binomial distribution will be presented.
DOR for patients who experience a CR or PR at any time on study will be listed by patient. 
Details of responses par RECIST v1.1, irRC, RANO, iRANO and guidelines for efficacy 
evaluation in lymphoma studies can be found in the appendix 14.1, 14.2, 14.3, 14.4 and 14.10 
respectively of study protocol.
For iRANO, the key difference from RANO in the assessment of progressive disease (PD) is 
the recommendation that progressive disease occurring within the first 24 weeks after the start 
of immunotherapy be confirmed by follow-up imaging 12 weeks after initial progression. When 
a such progressive disease is confirmed by a subsequent assessment, the date of the first of these 
assessments is then the date of progression. If initial PD is not confirmed by follow-up imaging 
post 12 weeks, then the initial PD will no longer be a PD as per iRANO and the previous best 
response will be considered to find the BOR, if available. In the absence of a response prior to 
initial PD, the BOR will be unknown in such cases. Few case are given below for better 
explanation:
-
If there is only one assessment with overall response as PD then the the overall response 
will be unknown as per iRANO.
-
If there are only two assessments with PD at both the assessments and that both the 
assessment are not 12 weeks apart then the overall response will be unknown as per 
iRANO.
-
If there are only two assessments with SD at first assessment and PD at second assement. 
Then the overall response as per iRANO will be SD and SD respectively.
-
Similarly, if there are only two assessments with PR at first assessment and PD at second 
assement. Then the overall response as per iRANO will be PR and PR respectively.
2.7.3
Progression free survival (PFS)
A Kaplan-Meier plot for PFS will be presented. Median PFS (in months) with corresponding 
95% CI, 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 
1997) and Kaplan-Meier estimated probabilities (PFS rate) with corresponding 95% CIs 
(Greenwood’s formula, Kalbfleisch and Prentice 1980) at several time points (3, 6, 9 and 12 
months) will be presented. The number (%) of progressions, deaths and patients censored will 
also be summarized.
PFS will be presented graphically using Kaplan Meier plots including all patients in Phase II 
by treatment group. 
2.7.4
Overall survival (OS)
Overall survival (OS) is defined as the time from start of treatment to date of death due to any 
cause. If a patient is not known to have died, OS time will be censored at the date of last contact. 
OS will only be summarized by treatment groups for patients enrolled in phase II part. A 


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Kaplan-Meier plot for OS will be presented. Median OS (in months) with corresponding 95% 
CI, 25th and 75th percentiles (Brookmeyer and Crowley 1982, Klein and Moeschberger 1997) 
and Kaplan-Meier estimated probabilities (OS rate) with corresponding 95% CIs (Greenwood’s 
formula, Kalbfleisch and Prentice 1980) at several time points (3, 6, 9 and 12 months) will be 
presented. The number (%) of deaths and patients censored will also be summarized.
Handling missign month/day in date of death
For rare cases when either day is missing or both month and day are missing for the date of 
death, the following imputation rule will be implemented:
-
If only day is missing, then date of death is imputed as max[(1 mmm-yyyy), min(last 
contact date+1, cutoff date)].
-
If both day and month are missing, then date of death is imputed as max[(1 Jan-yyyy), 
min(last contact date+1, cutoff date)].
2.8
Safety analysis
The assessment of safety is based on the type and frequency of adverse events (AEs) as well as 
on the number of laboratory values that fall outside of pre-determined ranges (Common 
Toxicity Criteria for Adverse Events (CTCAE) grading limits or normal ranges as appropriate). 
Other safety data include electrocardiogram and vital signs.
The Safety set will be used for summaries and listings of safety data with the exception of dose 
limiting toxicities (DLTs) for which the DDS will be used.
The safety summary tables will include on-treatment assessments collected no later than 30
days both BLZ945 as single agent and for the combination of BLZ945 in and PDR001after 
study treatment discontinuation.
2.8.1
Adverse events
AEs 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 “End of Treatment” or “Survival Information” eCRF pages.
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.
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 suspected to be study drug related leading to discontinuation of study drug

AEs regardless of study drug relationship requiring dose adjustment or study drug 
interruption


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
AEs which are not SAEs regardless of study drug relationship

SAEs regardless of study drug relationship

SAEs suspected to be study drug related

On-treatment deaths with cause of death by preferred term

All deaths with cause of death by primary system organ class and preferred term
The following AE summaries will be produced for Japan vs non-Japan subgroup:

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

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).
A missing AE start date will be imputed using the following logic matrix described in Table 2-
2.
Table 2-2
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 2-3 is the legend to the logic matrix shown in Table 2-2 and details the relationship of 
AE start date to study treatment start date.
Table 2-3
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.


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No imputation will be performed for AE end dates.
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on treatment-
emergent adverse events which are not serious adverse events with an incidence greater than 5% 
and on treatment emergent SAEs and SAEs suspected to be related to study treatment will be 
provided by SOC and PT on the safety set population. These summaries will include any event 
starting or worsening in the on-treatment period. For combincation arm, the reporting period 
will be 150 days after last dose of study treatment.
If for the same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2
Laboratory data
Laboratory data will be converted into SI units and classified (by Novartis statistical 
programming) into CTC grades according to CTCAE  version 4.0.3. The calculation of 
laboratory CTC grades will be based on the observed laboratory values only, clinical 
assessments will not be taken into account. The criteria to assign CTC grades are given in 
Novartis internal criteria for CTC grading of laboratory parameters (Section 5.4). 
For laboratory tests where grades are not defined by CTCAE version 4.0.3., results will be 
graded by the low/normal/high (or other project-specific ranges, if more suitable) classifications 
based on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 is not applicable. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labeled by direction.
The following summaries will be produced for hematology, biochemistry parameters and 
urinary laboratory tests:

Shift tables using CTC grades to compare baseline to the worst on-treatment value; 

For laboratory tests where CTC grades are not defined, shift tables using the  
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
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The following listings will be produced:

Listing of all CTC grade 3 or 4 laboratory toxicities 
Table 2-4 and Table 2-5 list all laboratory parameters that will be summarized.
Table 2-4
Laboratory parameters for which CTCAE grades are defined
Hematology and 
coagulation
Biochemistry
Urinalysis
White Blood Cells (WBC)
↑↓
Creatinine
↑
Protein
↓
Hemoglobin
↓
Sodium
↑↓
Platelets counts
↓
Potassium 
↑↓
Absolute Neutrophils
↓
Calcium
↑↓
Absolute Lymphocytes
↑↓
Magnesium 
↑↓
INR
↑
Albumin
↓
AST (SGOT)
↑
ALT (SGPT)
↑
Bicarbonate
↓
Total Bilirubin
↑
Glucose
↑↓
Amylase
↑
Lipase
↑
Alkaline Phosphatase
↑
Inorganic Phosphate
↓
Troponin
↑
↑ Indicates that CTC grade increases as the parameter increases.
↓ Indicates that CTC grade increases as the parameter decreases.
Table 2-5
Laboratory parameters (without CTCAE grades) for which lab 
reference ranges are defined
Hematology and 
coagulation
Biochemistry
Urinalysis
Prothrombin time (PT)
Blood urea nitrogen (BUN)
Specific gravity
Absolute Basophils
Urea
Glucose
Absolute Eosinophils
Direct bilirubin
Blood
Absolute Monocytes
Indirect bilirubin
pH
Hematocrit
Creatine phosphokinase
Protein
TSH
Ketones
Uric acid
WBC
T4 Free
Bilirubin


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Chloride
Liver function parameters
Liver function parameters of interest are total bilirubin (TBL), ALT and AST. 
The number (%) of subjects with worst post-baseline values will be summarized:

ALT or AST > 3xULN 

ALT or AST > 5xULN 

ALT or AST > 8xULN 

ALT or AST > 10xULN 

ALT or AST > 20xULN 

TBL > 2xULN 

TBL > 3xULN 

ALT or AST > 3xULN & TBL > 2xULN 

ALT or AST > 3xULN & TBL > 2xULN & ALP < 2xULN (potential Hy’s law)
Potential Hy’s Law events are defined as those subjects with concurrent occurrence of AST or 
ALT > 3xULN and TBL > 2xULN and ALP < 2xULN in the same assessment sample during 
the on-treatment period. Further medical review has to be conducted to assess potential 
confounding factor such as liver metastases, liver function at baseline, etc.
2.8.3
Vital signs, weight and physical examinations
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 2-6.
Table 2-6
Criteria for notable vital sign values
Vital sign (unit) 
Notable high value 
Notable low value 
Weight (kg) 
increase >= 10% from 
baseline 
decrease >= 10% from 
baseline 
Systolic blood pressure 
(mmHg) 
>=180 and increase from 
baseline of >=20 
<=90 and decrease from 
baseline of >=20 
Diastolic blood pressure 
(mmHg) 
>=105 and increase from 
baseline of >=15 
<=50 and decrease from 
baseline of >=15 
Pulse rate (bpm) 
>=100 and increase from 
baseline of >25% 
<=50 and decrease from 
baseline of >25% 
Body temperature ( °C) 
>= 39.1 
--
Subjects with notable vital sign values (high/low) will be summarized and listed by treatment 
group.


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2.8.4
Electrocardiograms
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
considered to have been obtained prior to study drug administration if dosing time is missing.
If a patient has more than one post-baseline measurement at a specific time point, the average 
of all available measurements associated with the nominal time point will be used for the 
analyses.
The following summaries will be provided for each applicable ECG parameter:

Number (%) of patients having notable ECG values according to Table 2-7.
Table 2-7
Criteria for notable ECG values
ECG parameter
Criteria for notable ECG values
QT, QTcF (ms)
New value of > 450 and ≤ 480 ms 
New value of > 480 and ≤ 500 ms 
New value of > 500 ms 
Increase from baseline >30 ms to ≤60 ms, >60 ms
HR (bpm)
Increase from baseline >25% and value >100 bpm
Decrease from baseline >25% and value <50 bpm
PR (ms)
Increase from baseline >25% and value >200 ms
New PR >200 ms
QRS (ms)
Increase from baseline >25% and value >120 ms
New QRS >120 ms
A listing of notable ECG assessments will be produced by treatment group and notable values 
will be flagged. In the listing, the assessments collected during the post-treatment period will 
be flagged.
2.8.5
Doppler Echocardiography
For patients enrolled in the phase II part, Doppler echocardiography data will be reported. Any 
assessment conducted before or on the study day 1 will be considered as baseline.
The following summaries and listings will be provided:

Parameters including left atrium volume, left atrium volume index, LV end-systolic 
dimension, LV end-diastolic dimension, posterior wall thickness and LVEF with the 
maximum change from baseline (both increase and/or decrease) will be summarized. 

Number (%) of patients having new apperance of abnormality by valve types and type 
of abnormality;

The area of the valves with the maximum reduction due to stenosis will be summarized 
by valve types among patients who develop stenosis during the study;

All Doppler Echocardiography assessments will be listed by treatment group
For patients enrolled in the phase I part, all Doppler Echocardiography assessments will be 
listed. Tolerability of study treatment will be assessed by summarizing the number of dose 


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interruptions and dose reductions by treatment group. Reasons for dose interruption and dose 
reductions will be listed by patient and treatment group and summarized by treatment group. 
Cumulative dose, dose intensity and relative dose intensity of study treatment (see Section 2.5.1)
will be also be used to assess tolerability.
2.9
Pharmacokinetic data
All PK analyses will be performed based on the PAS. Patient data may be removed on an 
individual basis.
Concentration values below the lower limit of quantitation (LLOQ) (<10 ng/mL for BLZ945 
and <0.25 ug/mL for PDR001) will be displayed in listings as zero with a flag and handled as 
zero in the calculations for mean, CV for mean, standard deviation, minimum, median, 
maximum, but handled as missing for the calculation of the geometric means and their CV.
PK parameters will be calculated using non-compartmental methods and summarized as 
described in Table 2-8 by treatment group. All PK parameters will be listed.
Table 2-8
PK parameters – descriptive statistics
Parameters
Descriptive statistics
AUCinf, AUClast, Cmax, Tmax*, T1/2, 
RACC, AUC0-24hr/dose, Cmax/dose
Mean, standard deviation, CV% mean, geometric mean, 
CV% geometric mean, median, minimum and maximum
CV% = coefficient of variation (%) = sd/mean*100
CV% geometic mean = sqrt (exp (variance for log transformed data)-1)*100
* Only median and rangles will be presented for this parameter
Anti-PDR001 antibody data will also be summarized. Descriptive graphical plots of mean 
concentration versus time  profiles will be generated.
2.10
Immunogenicity
To assess the immunogenicity of PDR001, the incidence of Anti-Drug Antibodies (ADA) anti-
PDR001 ADA will be summarized by treatment group.
2.10.1
Sample ADA status
Each anti-drug anti-body (ADA) sample is assessed in a three-tiered ADA testing approach. All 
ADA samples are analyzed in the initial screening assay (first tier). Samples testing negative in 
the screening assay are not subject to a confirmatory assay. Samples testing positive in the 
screening assay are then subjected to the confirmatory assay to demonstrate that ADA are 
specific for the therapeutic protein product (second tier). The titer of confirmatory positive 
samples will be subsequently determined in the titration assay (third tier). 
Samples can test negative in either the screening or confirmatory assay but for statistical 
analysis purposes they are not differentiated. The following properties of each sample will be 
provided in the source data (i.e. the third party data output (e.g. WLIMS) processed by 
PreAdvance): 


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Result of assay according to pre-specified confirmatory cut point: ‘POSITIVE’, 
‘NEGATIVE’, or ‘NOT REPORTABLE’
Titer: numerical representation of the magnitude of ADA response 
Threshold for determining treatment-boosted (titer fold change (i.e. x-fold)) 
The following definitions apply only to non-missing samples:
o ADA-negative sample: Sample where assay result is ‘NEGATIVE’ 
o ADA-positive sample: Sample where assay result is ‘POSITIVE’
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding non-missing baseline sample. To be classified as treatment-boosted or treatment-
unaffected, both the post-baseline and baseline titer must be non-missing.
o
treatment-induced ADA-positive sample: ADA-positive sample post-baseline with 
ADA-negative sample at baseline
o
treatment-boosted ADA-positive sample: ADA-positive sample post-baseline with titer 
that is at least the titer fold (i.e. x-fold) change greater than the ADA-positive baseline 
titer
o
treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline with 
titer that is less than the titer fold (i.e. x-fold) change greater than the ADA-positive 
baseline titer
The following summaries of ADA sample status (n and %) will be provided using the 
Immunogenicity prevalence set: 

ADA-positive samples (i.e. ADA prevalence), both overall and by time point (including 
baseline). For summaries by time point, the denominator is the number of subjects at 
that time point with a non-missing sample.
Listings will be provided of ADA sample status.
2.10.2
Subject ADA status
Subject ADA status is defined as follows:

Treatment-induced ADA-positive subject: subject with ADA-negative sample at 
baseline and at least one treatment-induced ADA-positive sample

Treatment-boosted ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one treatment-boosted ADA-positive sample

Treatment-unaffected ADA-positive subject: subject with ADA-positive sample at 
baseline, no treatment-boosted ADA-positive samples, and at least one treatment-
unaffected ADA-positive sample


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
Treatment-reduced ADA-positive subject: subject with ADA-positive sample at baseline 
and at least one non-missing post baseline sample, all of which are ADA-negative 
samples

ADA-negative subject: subject with ADA-negative sample at baseline and at least one 
non-missing post baseline sample, all of which are ADA-negative samples

Inconclusive subject: subject who does not qualify for any of the above definitions or a 
subject for which the baseline sample is missing
The following summaries of ADA subject status (n and %) will be provided using the 
Immunogenicity incidence set (for % the denominator is the number of subjects in the 
Immunogenicity incidence set unless otherwise specified): 

Subjects with ADA-negative sample at baseline

Subjects with ADA-positive sample at baseline

ADA-negative subjects

Treatment-induced ADA-positive subjects; for % the denominator is the number of 
subjects with ADA-negative sample at baseline. 

Treatment-boosted ADA-positive subjects; for % the denominator is the number of 
subjects with ADA-positive sample at baseline. 

ADA-positive subjects (i.e. ADA incidence): calculated as the number of treatment-
boosted ADA-positive and treatment-induced ADA-positive subjects. 
Listings of ADA subject status will be provided.
 
2.12
Interim analyses
However, in Phase I, the dose-escalation design foresees that decisions based on the current 
data are taken before the end of the study. More precisely, after each cohort in the dose 
escalation part, the next dose will be chosen depending on the observed data (based on safety, 
tolerability, PK, 
 efficacy data, guided by the recommendations from 
the BLRM of DLT using EWOC, and recommendations from participating investigators). 
Details of this procedure and the process for communication with Investigators are provided in 
Section 6.2.3 of the protocol.
Data from patients in the Phase II part will be reviewed on an ongoing basis to monitor the 
safety and tolerability of the RP2D in that part of the study. An interim analysis for futility will 
be conducted after 20 patients have been enrolled and completed the first post-treatment tumor 
assessment or have discontinued from the treatment as per protocol in each individual treatment 
arm. The interim analysis for futility will be based on DCR according to RANO criteria as 
determined by local assessment. The sample size of  glioblastoma groups (both RP2D of 
BLZ945 as single agent and RP2D of BLZ945 in combination with PDR001) may be extended 


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to approximately 40 patients if the disease control rate is ≥ 60% (at least 60% of the first 20 
patients have SD or better at their first tumor assessment). The Investigators and Novartis study 
personnel will make the decision based on a synthesis of all relevant data available including 
safety, PK and pharmacodynamics information.
3
Sample size calculation
Dose-escalation part 
Cohorts of 3 to 6 evaluable patients will be enrolled in the dose-escalation part including at least 
six patients at the MTD/RP2D level, as described in Section 6.2.3 of the protocol. Multiple 
cohorts may be sequentially enrolled to the same dose level. At least 21 patients are expected 
to be treated in the in the single agent BLZ945 dose escalation part and at least 15 patients are 
required to be treated in each combo dose escalation, for the models to have reasonable 
operating characteristics relating to its MTD recommendation.
Phase II
Approximately 20 patients in GBM will be initially enrolled for each treatment group. . The
sample size may be extended to approximately 40 patients per treatment group. In total, 
approximately 40-80 patients will be enrolled in the Phase II part. Based on the operating 
characteristics as described in Appendix 6 of the protocol, with a sample size of 40 patients 
when the true PFS6 is 60%, there is 97% chance to conclude clinically relevant efficacy, and 
when the true PFS6 is 20% there is less than 1% chance to wrongly conclude clinically relevant 
efficacy.
4
Change to protocol specified analyses
The analysis described in the supportive analysis section for phase I part will not be conducted.
5
Appendix
5.1
Baseline
Baseline is the last available and valid assessment performed or value measured within 28 days 
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, samples for biomarkers).
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times.
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to protocol, it should be performed before the first dose.


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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.
Computation of baseline for ECG, biomarker and other endpoints are described in each specific 
section.
5.2
Handling of missing and partial dates
For patients not known to have died prior to the cut-off date:
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will be reported as continuing at the cut-off 
date. For these events, the end date will not be imputed.
For patients known to have died prior to or on the cut-off date:
All events (e.g. AEs and concomitant medications) that started before or on the cut-off date, 
and with end date missing or after the cut-off date will have the end date imputed to the date of 
death. For these events, the imputed end date will not appear in the listings.
If imputation of an end date is required for a specific analysis (e.g. a dose administration record 
with missing end date, or last date of study treatment is after the cut-off date), the end date will 
be imputed to the cut-off date in order to calculate e.g., the duration of exposure to study 
treatment. The imputed date will be displayed and flagged in the listings.
For rare cases, when either day is missing or both month and day are missing for the date of 
death, the following imputation rule will be implemented:
-
If only day is missing, then date of death is imputed as max[(1 mmm-yyyy), min(last 
contact date+1, cutoff date)].
-
If both day and month are missing, then date of death is imputed as max[(1 Jan-yyyy), 
min(last contact date+1, cutoff date)].
When either day is missing or both month and day are missing for the date of start of post 
antineoplastic therapy, the following imputation rule will be implemented:
-
If day is missing, then impute to the max(reference start date, first date of the month)
-
If day and month are missing then impute to the max(reference start date, Jan 1)
-
Reference start date will be the last date of study treatment administration+1
End dates for post antineoplastic therapies will not be imputed.
In the listnigs of prior antineoplastic therapies, the partial dates will not be imputed.
5.3
Construction of waterfall graphs
Waterfall graphs will be used to depict anti-tumor activity. These plots will display the best 
percentage change from baseline in the sum of diameters of target lesions for each patient. 
Note: Patients without any valid assessments to calculate a percentage change from baseline 
value will be excluded from the graphs. Assessments with an unknown overall response will be 
included as long as the sum of diameters of target lesions is correctly computed on the same 
lesions assessed at baseline.
Patients will be ordered in the graph from left (worst change) to right (best change).


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1. Bars above the horizontal axis (0%) representing tumor growth,
2. Bars under the horizontal axis (0%) representing tumor shrinkage.
A special symbol (e.g. ∗) will be added below the bottom of respective bars for confirmed 
RECIST response (CR or PR), with corresponding specificatons in footnote. The total number 
of patients displayed in the graph (n) over the total number of patients in the FAS (N) will be 
shown. The best overall response (BOR) will be shown above each of the displayed bars in the 
graph. Symbols will be used to differentiate groups of interest, i.e. treatment group. A horizontal 
threshold line at -30% will be shown. 
5.4
CTC grades for laboratory values in Novartis Oncology (based on 
CTCAE v4.03 – June 2010) 
   
CTC Grades(1)
Lab test (toxicity) SI 
uni
t 
Lab 
test 
(NCDS
)  
Normal ranges (Merck 
manual, 
July 2015) and 
conversion factors
0 
1 
2 
3 
4 
Hematology
WBC ↓
109/
L
WBC 
3.9 – 10.7 x 109/L

LLN 
< LLN - 3.0 x 
109 /L 
< 3.0 – 2.0 x 109 
/L 
< 2.0 – 1.0 x 
109 /L 
< 1.0 x 
109 /L 
WBC (2)    
(Leukocytosis) 
109/
L
WBC 
-
-
> 100 x 109 
/L 
-
Hemoglobin (2)  
(Anemia) 
g/L 
HGB 
120 - 160 g/L or 7.4 - 9.9 
mmol/L (F)  
140 - 170 g/L or 8.7 – 10.6 
mmol/L (M) 

LLN 
< LLN - 100 
g/L 
< LLN - 6.2 
mmol/L 
< 100 - 80 g/L 
< 6.2 - 4.9 
mmol/L 
< 80 g/L 
< 4.9 
mmol/L 
-
Hemoglobin ↑
g/L 
HGB 
(16.113 x mmol/L = g/L)
Increase >0-
20 g/L above 
ULN 
Increase >20-40 
g/L above ULN 
Increase 
>40 g/L 
above ULN 
-
Platelets ↓
109/
L 
PLAT 
150 - 350 x 109/L

LLN 
< LLN - 75.0 
x 109/L 
< 75.0 - 50.0 x 109 
L 
< 50.0 -
25.0 x 109/L 
< 25.0 x 
109 /L 
Neutrophils (3)↓
109/
L
NEUT 
2x1
09 /L 
< 2.0 - 1.5 x 
109 /L 
< 1.5 - 1.0 x 109 /L < 1.0 - 0.5 x 
109 /L 
< 0.5 x 
109 /L 
Lymphocytes (3)↓
109/
L
LYM 
  
1.5x
109 /L
< 1.5 - 0.8 x 
109 /L 
< 0.8 - 0.5 x 109 /L < 0.5 - 0.2 x 
109 /L 
< 0.2 x 
109 /L 
Lymphocytes ↑
109/
L
LYM 
-
> 4 - 20 x 109 /L 
> 20 x 109 /L 
-
Biochemistry
AST ↑
U/L 
AST 
0 - 35 U/L or  0 –
0.58 ukat/L (60 x 
ukat/L = U/L)

ULN 
> ULN – 3.0 
x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
ALT ↑
U/L 
ALT 
0 - 35 U/L or  0 – 0.58 
ukat/L 
(60 x ukat/L = U/L)

ULN 
> ULN – 3.0 
x ULN 
> 3.0 - 5.0 x ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 


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Total bilirubin ↑
umo
l/L 
BILI 
5.1 – 20.5 umol/L or 0.3 –
1.2 mg/dL  
(17.1 x mg/dL = umol/L)  

ULN 
> ULN - 1.5 x 
ULN 
> 1.5 - 3.0 x ULN 
> 3.0 - 10.0 
x ULN 
> 10.0 x 
ULN 
Alk. 
Phosphatase ↑
U/L 
ALP 
36 - 92 U/L or  0.5 - 1.5 
ukat/L    
(60 x ukat/L = U/L)

ULN 
> ULN - 2.5 x 
ULN 
> 2.5 - 5.0 x ULN 
> 5.0 - 20.0 
x ULN 
> 20.0 x 
ULN 
Creatinine (4)↑
umo
l/L 
CREAT 
61.9 - 115 umol/L or 0.7 –
1.3 mg/dL   (88.4 x mg/dL = 
umol/L)

ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 3.0 x ULN 
> 3.0 - 6.0 x 
ULN 
> 6.0 x 
ULN 
Creatinine 
kinase (4)↑
U/L 
CK 
30 - 170 U/L or 0.5 
– 2.83 ukat/L (60 x 
ukat/L = U/L)

ULN 
> ULN - 2.5 x 
ULN 
> 2.5 - 5.0 x ULN 
> 5.0 - 10.0 
x ULN 
> 10.0 x 
ULN 
Albumin (2)  
(Hypoalbumine
mia) 
g/L 
ALB 
35 - 55 g/L or 3.5 to 5.5 
g/dL 
  

LLN 
< LLN - 30 
g/L 
< 30 - 20 g/L 
< 20 g/L 
-
Total 
Cholesterol ↑
mm
ol/L 
CHOL 
3.88 – 5.15 mmol/L or 150 
- 199 mg/dL  
(38.67 x mg/dL = mmol/L)

ULN 
> ULN - 7.75 
mmol/L
> ULN - 300 
mg/dL 
> 7.75 -10.34 
mmol/L > 
300 – 400 mg/dL 
>10.34-
12.92 
mmol/L
> 400 – 500 
mg/dL 
>12.92 
mmol
/L
> 500 
mg/dL 
Lipase ↑
U/L 
LIPASE 
<95 U/L or 
<1.58 ukat/L   
(60 x ukat/L 
= U/L)

ULN 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x 
ULN 
Amylase ↑  
U/L 
AMYLASE 0 - 130 U/L or 0 – 2.17 
ukat/L
(60 x ukat/L = U/L)

ULN 
> ULN - 1.5 
x ULN 
> 1.5 - 2.0 x ULN 
> 2.0 - 5.0 x 
ULN 
> 5.0 x 
ULN 
Uric acid (2)   
(Hyperuricemia) 
umo
l/L 
URATE 
150 - 470 umol/L or 2.5 – 8 
mg/dL  
(59.48 x mg/dL = umol/L)

ULN 
> ULN – 10 
mg/dL  
> ULN – 595 
umol/L 
-
-
> 10 
mg/dL 
> 595 
umol/L 
Phosphorus(2)    
(Hypophosphate
mia) 
mm
ol/L 
PHOS 
0.97 – 1.45 mmol/L or 3.0 -
4.5 mg/dL
(0.32 x mg/dL = mmol/L)
 LLN < LLN - 2.5 
mg/dL 
< LLN - 0.8 
mmol/L 
< 2.5 - 2.0 mg/dL 
< 0.8 - 0.6 
mmol/L 
< 2.0 - 1.0 
mg/dL 
< 0.6 - 0.3 
mmol/L 
< 1.0 
mg/dL 
< 0.3 
mmol/L 
Calcium 
(corrected) (2) 
(Hypercalcemia) 
mm
ol/L 
CACALC 
2.2 - 2.6 mmol/L or 9 - 10.5 
mg/dL  
(0.2495 x mg/dL = mmol/L)

ULN 
> ULN - 11.5 
mg/dL 
> ULN - 2.9 
mmol/L 
> 11.5  - 12.5 
mg/dL
> 2.9 - 3.1 
mmol/L 
> 12.5 -
13.5 mg/dL 
> 3.1 - 3.4 
mmol/L 
> 13.5 
mg/dL 
> 3.4 
mmol/L 
Calcium 
(corrected) (2)
(Hypocalcemia) 
mm
ol/L 
CACALC 

LLN 
< LLN - 8.0 
mg/dL 
< LLN - 2.0 
mmol/L 
< 8.0 - 7.0 mg/dL 
< 2.0 - 1.75 
mmol/L 
< 7.0 - 6.0 
mg/dL 
< 1.75 - 1.5 
mmol/L 
< 6.0 
mg/dL 
< 1.5 
mmol/L 
Magnesium (2)
(Hypermagnese
mia) 
mm
ol/L 
MG 
0.62 – 0.99 mmol/L or 1.5 
– 2.4 mg/dL  
(0.4114 x mg/dL = mmol/L)

ULN 
> ULN - 3.0 
mg/dL 
> ULN - 1.23 
mmol/L
-
> 3.0 – 8.0 
mg/dL 
> 1.23 – 3.3 
mmol/L 
> 8.0 
mg/dL 
> 3.3 
mmol/L 
Magnesium (2)
mm
ol/L 
MG 

LLN 
< LLN - 1.2 
mg/dL 
< 1.2 - 0.9 mg/dL 
< 0.5 - 0.4 
mmol/L 
< 0.9 - 0.7 
mg/dL 
< 0.7 
mg/dL 


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(Hypomagnese
mia) 
< LLN - 0.5 
mmol/L 
< 0.4 - 0.3 
mmol/L 
< 0.3 
mmol/L 
Glucose (non-
fasting) (2)
(Hyperglycemia) 
mm
ol/L 
GLUCSN 
<7.8 mmol/L or <140 mg/dL  
(0.05551 x mg/dL = 
mmol/L)

ULN 
-
> ULN - 250 
mg/dL 
> ULN - 13.9
mmol/L 
> 250 - 500 
mg/dL 
> 13.9 -
27.8 
mmol/L 
> 500 
mg/dL 
> 27.8 
mmol/L 
Glucose 
(fasting) (2)
(Hyperglycemia) 
mm
ol/L 
GLUCSF 
3.9 – 5.8 mmol/L or 70 -
105 mg/dL  (0.05551 x 
mg/dL = mmol/L)

ULN 
> ULN - 160 
mg/dL 
> ULN - 8.9 
mmol/L 
> 160 - 250 
mg/dL 
> 8.9 - 13.9 
mmol/L 
> 250 - 500 
mg/dL 
> 13.9 -
27.8 
mmol/L 
> 500 
mg/dL 
> 27.8 
mmol/L 
Glucose (2)
(Hypoglycemia) 
mm
ol/L 
GLUCSN/ 
GLUCSF 

LLN 
< LLN - 55 
mg/dL 
< LLN - 3.0 
mmol/L 
< 55 - 40 mg/dL 
< 3.0 - 2.2 
mmol/L 
< 40 - 30 
mg/dL 
< 2.2 - 1.7 
mmol/L 
< 30 
mg/dL 
< 1.7 
mmol/L 
Potassium (2)
(Hyperkalemia) 
mm
ol/L 
K 
3.5 - 5.0 mmol/L
(0.2558 x mg/dL = mEq/L 
= mmol/L)

ULN 
> ULN - 5.5 
mmol/L 
> 5.5 - 6.0 
mmol/L 
> 6.0 - 7.0 
mmol/L 
> 7.0 
mmol/L 
Potassium (2) 
(Hypokalemia) 
mm
ol/L 
K 

LLN 
< LLN - 3.0 
mmol/L 
-
< 3.0 - 2.5 
mmol/L 
< 2.5 
mmol/L 
Sodium (2)
(Hypernatremia) 
mm
ol/L 
SODIUM 
136 - 145 mmol/L
(0.435 x mg/dL = mEq/L = 
mmol/L)

ULN 
> ULN - 150 
mmol/L 
> 150 - 155 
mmol/L 
> 155 - 160 
mmol/L 
> 160 
mmol/L 
Sodium (2)
(Hyponatremia) 
mm
ol/L 
SODIUM 
  

LLN 
< LLN - 130 
mmol/L 
-
< 130 - 120 
mmol/L 
< 120 
mmol/L 
Triglyceride (2) ↑
mm
ol/L 
TRIG 
< 2.82 mmol/L or < 250 
mg/dL  
(0.01129  x mg/dL = 
umol/L)
< 
150  
< 
1.71  
 150 - 300 
mg/dL 
 1.71 – 3.42 
mmol/L
> 300 - 500 
mg/dL 
> 3.42 – 5.7 
mmol/L 
> 500 -
1000 mg/dL 
> 5.7 – 11.4 
mmol/L 
> 1000 
mg/dL 
> 11.4 
mmol/L 
Coagulation
INR (2)↑
1 
INR 
0.8 – 1.2  

ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 2.5 x ULN 
> 2.5 x ULN 
-
Activated partial 
thromboplastin 
time(2)↑
sec 
APTT 
25 - 35 sec 

ULN 
> ULN - 1.5 x 
ULN  
> 1.5 - 2.5 x ULN 
> 2.5 x ULN 
  
-  
Fibrinogen (4)↓
g/L 
FIBRIN
O 
1.5 – 3.5 g/L or 150 – 350 
mg/dL   
(0.01 x mg/dL = g/L)
 LLN < LLN - 0.75 
x LLN  
< 0.75 - 0.5 x LLN  < 0.5 - 0.25 
x LLN  
< 0.25 x 
LLN  
ULN = Upper Limit of Normal range; LLN = Lower Limit of Normal range   
(1) =  LAB CTC grades 1, 2, 3, 4 overrule the study specific (central or local) normal range criteria, e.g. if ULN of Sodium is 
151 mmol/L and the value is 151 mmol/L, CTC grade 2 is assigned although the value is  ULN. 
(2) =  Life-threatening consequences and/or hospitalization are not considered for determination of LAB CTC grades 3 and 4. 
Concomitant usage of anticoagulation therapy (for INR and Fibrinogen) is not considered either.  
(3) =  Values and LNRs for blood differentials can be given as %, absolute values should then be calculated using WBC. Generally,  1.5 x 
109 /L (lymphocytes) and  2 x 109 /L (neutrophils) are considered as LAB CTC grade 0
(4) =  For Creatinine and Fibrinogen, the comparison with baseline is not considered for derivation of LAB CTC grades 


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6
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Kalbfleisch, J. D., and Prentice, R. L. (1980). The Statistical Analysis of Failure Time Data. 
New York: John Wiley & Sons.
Klein and Moeschberger (1997) Survival Analysis Techniques for Censored and truncated data, 
Springer
Neuenschwander B, Michael Branson M, Gsponer T (2008) Critical aspects of the Bayesian 
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