Clinical trial NCT02325739
Conditions: Hepatocellular Carcinoma (HCC) Solid Malignancies
Keywords: FGF401 PDR001 PD-1 FGFR4 FGF19 HCC solid malignancies characterized by positive FGFR4 and KLB expression
Sponsor: Novartis Pharmaceuticals
Start date: 2014-12-29; Completion date: 2019-05-30
Enrollment: 172 participants; Allocation: NON_RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Estimate the maximum tolerated dose and/or recommended phase II dose and efficacy of FGF401 as single agent and in combination with PDR001 in patients with hepatocellular carcinoma and as single agent in patients with other solid malignancies based on RECIST 1.1.

Detailed description:
The primary objectives of this study were in 2 parts: Phase l \& Phase II.

The study included different periods starting by molecular pre-screening (applicable for all subjects enrolled under protocol versions 00 to 03, or applicable only for Phase I and Group 3 in Phase II of FGF401 single agent, for subjects enrolled under protocol version 04), Screening, Treatment, End of Treatment, Disease progression follow-up (if applicable), Safety follow-up and then ended by survival follow-up period

In the Phase I part, subjects with HCC or other advanced solid tumors characterized by positive FGFR4 and KLB expression were enrolled and treated with FGF401 as a single agent or in combination with PDR001. Subjects in this phase were dosed under fasted or fed conditions.

In the Phase 2 part, subjects with advanced HCC or other solid tumors bearing positive FGFR4 and KLB expression were enrolled into three groups (Group 1: HCC subjects from Asian countries; Group 2: HCC subjects from non-Asian countries; Group 3: Subjects with other solid malignancies regardless of geography) to assess the preliminary anti-tumor activity of FGF401 in Phase ll. This Phase II part investigated the anti-tumor activity of FGF401 single agent and in combination with PDR001.

Each group within the Phase II dose expansion part targeted a different number of subjects. Group 1 and Group 2 planned to enroll around 40 subjects each and Group 3 planned to enroll approximately 20 subjects. Subjects in this phase were dosed under fasted conditions.

Oral FGF401 was administered on a continuous once daily (QD) dosing regimen for both FGF401 single agent and in combination with PDR001 parts. Intravenous PDR001 was administered in a fixed dosing regimen of 300 mg iv every three weeks as per protocol until subject experienced unacceptable toxicity, progressive disease and/or treatment was discontinued at the discretion of the Investigator or withdrawal of consent.

Because the enrollment of new subjects in this study was halted for business reason on 03-Jul-2018 early enrollment termination was declared following the initial halt of enrollment once the global last subject last visit was achieved as per protocol, and consequently the phase II part of the FGF401+PDR001 combination did not start, none of the planned analyses related to the phase II part of the FGF401+PDR001 combination arm were performed.

Duration of treatment: Subjects could continue study treatment until they experienced any of the following: Disease progression (radiologically documented according to RECIST v1.1) as assessed by the Investigator, unacceptable toxicity, \& treatment was discontinued at the discretion of the Investigator or the subject.

Subjects who permanently discontinued the study treatment for any reason other than disease progression or withdrawal of consent had to continue efficacy assessments as scheduled in the protocol until the time of disease progression.

Arms: arm 1: Participants received single agent FGF401 50 mg while fasted arm 2: Participants received single agent FGF401 80 mg while fasted arm 3: Participants received single agent FGF401 80 mg while fed arm 4: Participants received single agent FGF401 120 mg while fasted arm 5: Participants received single agent FGF401 120 mg while fed arm 6: Participants received single agent FGF401 150 mg while fasted arm 7: Participants received FGF401 80 mg in combination with PDR001 300 mg while fasted arm 8: Participants received FGF401 120 mg in combination with PDR001 300 mg while fasted arm 9: Group 1 was comprised of HCC participants from Asian countries who received single agent FGF401 120 mg QD while fasted arm 10: Group 2 was comprised of HCC participants from non-Asian countries who took single agent FGF401 120 mg QD while fasted arm 11: Group 3 was comprised of participants with other solid malignancies regardless of geography who took single agent FGF401 120 mg QD while fasted
Interventions: intervention 1: FGF401 intervention 2: PDR001
Intervention descriptions: intervention 1: FGF401 is a FGFR4 inhibitor. intervention 2: PDR001 is a humanized anti-PD1 IgG4 antibody that blocks the binding of PD-L1 and PD-L2

Protocol documents:
Prot_000.pdf: 
Clinical Development
FGF401
Protocol CFGF401X2101 / NCT02325739
A phase I/II, multicenter, open-label study of oral FGF401 in 
adult patients with hepatocellular carcinoma or solid 
malignancies characterized by positive FGFR4 and KLB 
expression
Document type
Amended Protocol Version
EUDRACT number
2014-002929-35
Version number
05 (Clean)
Development phase
I
Document status
Final
Release date
27-Sep-2018
Property of Novartis
Confidential
May not be used, divulged, published, or otherwise disclosed
without the consent of Novartis


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Table of contents
Table of contents .................................................................................................................2
List of figures ......................................................................................................................8
List of tables ........................................................................................................................8
List of abbreviations..........................................................................................................11
Glossary of terms...............................................................................................................14
Protocol summary:.............................................................................................................15
Amendment 5 (27-Sep-2018)............................................................................................18
Amendment 4 (06-Dec-2016)............................................................................................21
Amendment 03 ..................................................................................................................24
Amendment 02 ..................................................................................................................24
Amendment 01 ..................................................................................................................25
1
Background........................................................................................................................26
1.1
Overview of disease pathogenesis, epidemiology and current treatment..............26
1.2
Introduction to investigational treatments .............................................................26
1.2.1
Overview of FGF401 ............................................................................26
1.2.2
Overview of PDR001............................................................................30
1.2.3
Overview of FGF401 and PDR001.......................................................31
2
Rationale............................................................................................................................32
2.1
Study rationale and purpose...................................................................................32
2.2
Rationale for the study design ...............................................................................33
2.2.1
FGF401 single agent .............................................................................33
2.2.2
FGF401 in combination with PDR001 .................................................35
2.3
Rationale for dose and regimen selection..............................................................35
3
Objectives and endpoints...................................................................................................36
4
Study design ......................................................................................................................39
4.1
Description of study design ...................................................................................39
4.1.1
FGF401 single agent .............................................................................40
4.1.2
FGF401 in combination with PDR001 .................................................41
4.2
Timing of interim analyses and design adaptations...............................................42
4.3
Definition of end of the study................................................................................43
4.4
Early study termination..........................................................................................43
5
Population..........................................................................................................................44
5.1
Patient population..................................................................................................44
5.2
Inclusion criteria ....................................................................................................44
5.3
Exclusion criteria...................................................................................................46


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Treatment...........................................................................................................................50
6.1
Study treatment......................................................................................................50
6.1.1
Dosing regimen.....................................................................................50
6.1.2
Ancillary treatments..............................................................................51
6.1.3
Treatment duration................................................................................52
6.2
Dose escalation guidelines.....................................................................................52
6.2.1
Starting dose rationale...........................................................................52
6.2.2
Provisional dose levels..........................................................................53
6.2.3
Guidelines for dose escalation and determination of MTD ..................54
6.2.4
Definitions of dose limiting toxicities (DLTs)......................................57
6.3
Dose modifications ................................................................................................58
6.3.1
Dose modification and dose delay ........................................................58
6.3.2
Follow-up for toxicities.........................................................................64
6.3.3
Anticipated risks and safety concerns of the study drug.......................65
6.4
Concomitant medications ......................................................................................65
6.4.1
Permitted concomitant therapy .............................................................65
6.4.2
Permitted concomitant therapy requiring caution and/or action...........66
6.4.3
Prohibited concomitant therapy ............................................................66
6.5
Patient numbering, treatment assignment or randomization .................................67
6.5.1
Patient numbering .................................................................................67
6.5.2
Treatment assignment ...........................................................................67
6.6
Study drug preparation and dispensation...............................................................67
6.6.1
Study drug packaging and labeling.......................................................67
6.6.2
Drug supply and storage........................................................................68
6.6.3
Study drug compliance and accountability ...........................................68
6.6.4
Disposal and destruction .......................................................................68
7
Visit schedule and assessments .........................................................................................69
7.1
Study flow and visit schedule................................................................................69
7.1.1
Molecular pre-screening........................................................................77
7.1.2
Screening...............................................................................................77
7.1.3
Treatment period...................................................................................78
7.1.4
Discontinuation of Study Treatment.....................................................79
7.1.5
Withdrawal of consent ..........................................................................80
7.1.6
Follow up period ...................................................................................81
7.1.7
Lost to follow-up...................................................................................81
7.2
Assessment types...................................................................................................82


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7.2.1
Efficacy assessments.............................................................................82
7.2.2
Safety and tolerability assessments.......................................................83
7.2.3
Pharmacokinetics and immunogenicity assessments............................89
94
8
Safety monitoring and reporting........................................................................................98
8.1
Adverse events.......................................................................................................98
8.1.1
Definitions and reporting ......................................................................98
8.1.2
Laboratory test abnormalities..............................................................100
8.2
Serious adverse events.........................................................................................100
8.2.1
Definitions...........................................................................................100
8.2.2
Reporting.............................................................................................101
8.3
Pregnancies..........................................................................................................102
8.4
Warnings and precautions....................................................................................102
8.5
Data Monitoring Committee................................................................................102
8.6
Steering Committee .............................................................................................103
9
Data collection and management.....................................................................................104
9.1
Data confidentiality .............................................................................................104
9.2
Site monitoring ....................................................................................................104
9.3
Data collection.....................................................................................................105
9.4
Database management and quality control..........................................................105
10 Statistical methods and data analysis ..............................................................................106
10.1
Analysis sets ........................................................................................................106
10.1.1
Full Analysis Set .................................................................................106
10.1.2
Safety Set ............................................................................................107
10.1.3
Per-Protocol Set ..................................................................................107
10.1.4
Dose-determining analysis set.............................................................107
10.1.5
Pharmacokinetic analysis set...............................................................107
10.2
Patient demographics/other baseline characteristics ...........................................108
10.3
Treatments (study treatment, concomitant therapies, compliance) .....................108
10.3.1
Study treatment ...................................................................................108
10.3.2
Concomitant therapies.........................................................................108
10.3.3
Compliance .........................................................................................108
10.4
Primary objective.................................................................................................108
10.4.1
Variable...............................................................................................109
10.4.2
Statistical hypothesis, model, and method of analysis........................109
10.4.3
Handling of missing values/censoring/discontinuations.....................113


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10.4.4
Supportive analyses.............................................................................113
10.5
Secondary objectives ...........................................................................................114
10.5.1
Efficacy objectives..............................................................................114
10.5.2
Safety objectives .................................................................................114
10.5.3
Pharmacokinetics ................................................................................116
118
118
10.7
Interim analysis....................................................................................................118
10.7.1
FGF401 single agent ...........................................................................118
10.7.2
FGF401 in combination with PDR001 ...............................................119
10.8
Sample size calculation........................................................................................119
10.8.1
FGF401 single agent ...........................................................................119
10.8.2
FGF401 in combination with PDR001 ...............................................121
10.9
Power for analysis of key secondary variables....................................................125
11 Ethical considerations and administrative procedures ....................................................125
11.1
Regulatory and ethical compliance......................................................................125
11.2
Responsibilities of the investigator and IRB/IEC/REB.......................................125
11.3
Informed consent procedures...............................................................................125
11.4
Discontinuation of the study................................................................................126
11.5
Publication of study protocol and results.............................................................126
11.6
Study documentation, record keeping and retention of documents.....................126
11.7
Confidentiality of study documents and patient records .....................................127
11.8
Audits and inspections.........................................................................................127
11.9
Financial disclosures............................................................................................127
12 Protocol adherence ..........................................................................................................128
12.1
Amendments to the protocol................................................................................128
13 References (available upon request)................................................................................129
14 Appendices ......................................................................................................................132
14.1
Appendix 1 – Guidelines for response, duration of overall response, TTF, 
TTP, progression-free survival and overall survival (based on RECIST 1.1).....132
14.1.1
Introduction.........................................................................................134
14.1.2
Efficacy assessments...........................................................................134
14.1.3
Definitions...........................................................................................134
14.1.4
Disease measurability..........................................................................134
14.1.5
Eligibility based on measurable disease..............................................135
14.1.6
Methods of tumor measurement - general guidelines.........................135


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14.1.7
Baseline documentation of target and non-target lesions ...................137
14.1.8
Follow-up evaluation of target and non-target lesions........................137
14.1.9
Follow-up and recording of lesions.....................................................138
14.1.10
Non-nodal lesions................................................................................138
14.1.11
Nodal lesions.......................................................................................138
14.1.12
Determination of target lesion response..............................................139
14.1.13
Determination of non-target lesion response ......................................140
14.1.14
New lesions .........................................................................................141
14.1.15
Evaluation of overall lesion response .................................................142
14.1.16
Efficacy definitions .............................................................................142
14.1.17
Best overall response...........................................................................142
14.1.18
Time to event variables .......................................................................145
14.1.19
Progression-free survival ....................................................................145
14.1.20
Overall survival...................................................................................145
14.1.21
Time to progression.............................................................................145
14.1.22
Time to treatment failure.....................................................................145
14.1.23
Duration of response ...........................................................................146
14.1.24
Time to response .................................................................................147
14.1.25
Definition of start and end dates for time to event variables ..............147
14.1.26
Handling of patients with non-measurable disease only at baseline...148
14.1.27
Sensitivity analyses .............................................................................149
14.1.28
Data handling and programming rules................................................151
14.1.29
Study/project specific decisions..........................................................151
14.1.30
End of treatment phase completion.....................................................151
14.1.31
End of post-treatment follow-up (study phase completion)................152
14.1.32
Medical validation of programmed overall lesion response ...............152
14.1.33
Programming rules..............................................................................153
14.1.34
Calculation of ‘time to event’ variables..............................................153
14.1.35
Incomplete assessment dates...............................................................153
14.1.36
Incomplete dates for last known date patient alive or death ...............153
14.1.37
Non-target lesion response..................................................................153
14.1.38
Study/project specific programming...................................................153
14.1.39
Censoring reason.................................................................................154
14.1.40
References (available upon request) ...................................................155
14.2
Appendix 2 – Child-Pugh classification of severity of liver disease...................156
14.3
Appendix 3 – Hepatocellular carcinoma staging systems ...................................157


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14.4
Appendix 4 – Prohibited concomitant medications and permitted concomitant 
medications requiring caution..............................................................................158
14.5
Appendix 5 – Guidelines for management of diarrhea........................................158
14.6
Appendix 6 - Guidelines for management of hyperphosphatemia......................160
162
14.8
Appendix 8 – Test meal guidelines .....................................................................163
14.9
Appendix 9- Guidelines for immune-related Response Criteria (irRC) using 
one-dimensional measurements (simulating RECIST 1.1) .................................164
14.9.1
Introduction.........................................................................................164
14.9.2
New lesions and non-target lesions.....................................................164
14.9.3
Follow-up evaluation of target and non-target lesions........................165
14.9.4
Definitions of response categories and evaluation of overall lesion 
response...............................................................................................165
14.9.5
References (available upon request) ...................................................166
 
166
166
166
176
181
14.11 Appendix 11- Recommended management algorithms for suspected toxicities.182
14.11.1
GI adverse event management algorithm............................................183
14.11.2
Renal adverse event management algorithm.......................................184
14.11.3
Pulmonary adverse event management algorithm ..............................185
14.11.4
Endocrinopathy management algorithm .............................................186
14.11.5
Skin adverse event management algorithm.........................................187
14.11.6
Hepatic adverse event management algorithm ...................................188
14.11.7
References (available upon request) ...................................................189


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List of figures
Figure 4-1
Study design..........................................................................................39
Figure 4-2
Study design- FGF401 in combination with PDR001 ..........................41
Figure 4-3
Study Flow ............................................................................................42
162
List of tables
Table 3-1
Objectives and related endpoints ..........................................................37
Table 6-1
Dose and treatment schedule.................................................................50
Table 6-2
FGF401 Provisional dose levels............................................................53
Table 6-3
Criteria for defining dose-limiting toxicities.........................................57
Table 6-4
Criteria for interruption and re-initiation of FGF401  as single 
agent and in combination with PDR001 ...............................................60
Table 6-5
Criteria for interruption and re-initiation of PDR001 treatment ...........64
Table 7-1
Visit evaluation schedule (applicable for protocol amendment 04 -
following approval of protocol amendment 05 refer to Table 7-1b 
below)....................................................................................................70
Table 7-1b
Visit evaluation schedule – applicable upon approval of protocl 
amendment 05.......................................................................................76
Table 7-2
Imaging collection plan.........................................................................82
Table 7-3
ECOG performance status.....................................................................84
Table 7-4
Local clinical laboratory parameters collection plan (applicable for 
protocol amendment 04 - following approval of protocol 
amendment 05 refer to Table 7-4b below)............................................85
Table 7-4b
Local clinical laboratory parameters collection plan- applicable 
upon approval of protocol amendment 05 ............................................85
Table 7-5
Central clinical laboratory parameters collection plan**......................86
Table 7-6
Central ECG collection plan .................................................................89
Table 7-7
Phase I parts: Pharmacokinetic blood collection log for QD 
FGF401 administration .........................................................................90
Table 7-8
Phase II parts: Pharmacokinetic blood collection log for QD 
FGF401 administration .........................................................................91
Table 7-9
Phase I parts: Pharmacokinetic blood collection log for BID 
FGF401 administration (if BID dosing is implemented)......................91
Table 7-10
Phase II parts: Pharmacokinetic blood collection log for BID 
FGF401 administration (if BID dosing is implemented)......................92
Table 7-11
Schedule of blood (serum) collection for PDR001 PK and IG for 
patients participating in phase I of FGF401 and PDR001 
combination...........................................................................................93


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Table 7-12
Schedule of blood (serum) collection for PDR001 PK and IG for 
patients participating in Phase II of FGF401 and PDR001 
combination...........................................................................................93
94
96
Table 10-1
Noncompartmental pharmacokinetic parameters................................117
Table 10-2
Probability of Success under different number of sample size in 
Group 1 (drop rate = 15%)..................................................................120
Table 10-3
Probability of Success under different number of sample size in 
Group 2 (drop rate = 15%)..................................................................121
Table 10-4
Cumulative probability (upper tail) of responses observed or more 
given true ORR and 20 patients ..........................................................121
Table 10-5
Operating Characteristics (scenario 1: the percentages of FGF19
positive and FGF19 negative patients enrolled in the Stage 1 are 
20% and 80%).....................................................................................123
Table 10-6
Operating Characteristics (scenario 2: the percentages of FGF19
positive and FGF19 negative patients enrolled in the Stage 1 are 
40% and 60%).....................................................................................124
Table 14-1
Response criteria for target lesions .....................................................139
Table 14-2
Response criteria for non-target lesions..............................................140
Table 14-3
Overall lesion response at each assessment ........................................142
Table 14-4
Overall lesion response at each assessment: patients with non-
target disease only...............................................................................149
Table 14-5
Options for event dates used in PFS, TTP, duration of response........150
Table 14-6
Child-Pugh score calculation ..............................................................156
Table 14-7
Child-Pugh score interpretation ..........................................................156
Table 14-8
Barcelona-Clinic Liver Cancer system ...............................................157
Table 14-9
Prohibited concomitant medications...................................................158
Table 14-10
Permitted concomitant medications requiring caution........................158
Table 14-11
Criteria for interruption and re-initiation of FGF401 treatment for 
diarrhea management ..........................................................................159
Table 14-12
Criteria for for interruption and re-initiation of FGF401 treatment 
for hyperphosphatemia management ..................................................160
163
Table 14-14
Test meal examples.............................................................................164
Table 14-15
Overall response at each assessment...................................................166
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List of abbreviations
AASLD
American Association for the Study of Liver Diseases
AE
Adverse Event
AFP
Alpha-fetoprotein
ALT
Alanine aminotransferase/glutamic pyruvic transaminase/GPT
ANC
Absolute neutrophil count
AST
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT
ATC
Anatomic-Therapeutic-Chemical classification
ATP
Adenosine triphosphate
AUC
Area under the concentration-time curve
b.i.d.
bis in diem/twice a day
BAS
Bile acid sequestrant
BCLC
Barcelona Clinic Liver Cancer
BCRP
Breast Cancer Resistance Protein
BCS 
Biopharmaceutics classification system
BHLRM
Bayesian hierarchical logistic regression model
BLRM
Bayesian logistic regression model
BOR
Best overall response
BSA
Body surface area
BSEP
Bile Salt Export Pump
BUN
Blood urea nitrogen
cfDNA
Cell free DNA
CL
Clearance
Cmax
Maximum observed concentration
Cmin
Minimum observed concentration
CMO&PS
Chief Medical Office and Patient Safety
CNS
Central nervous system
COPD
Chronic obstructive pulmonary disease
CR
Complete response
CRO
Contract Research Organization
CSR
Clinical study report
CRS
Cytokine Release Syndrome
CTCAE
Common terminology criteria for adverse events
Ctrough
The concentration that is just prior to the beginning of, or at the end, of a dosing interval
CYP
Cytochrome P450
DCR
Disease control rate
DDI
Drug-Drug interaction
DDS 
Dose-determining analysis set
DLT
Dose Limiting Toxicity
EC
Ethics Committee
ECG
Electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
EOT
End of Treatment
EWOC
Escalation with overdose control
FAS
full analysis set
FGF
Fibroblast growth factor


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FGFR
Fibroblast growth factor receptor
FU
follow-up
G-CSF
Granulocyte colony stimulating factor
GI
Gastro-Intestinal
GLP
Good laboratory practice
GM-CSF
Granulocyte macrophage colony stimulating factor
HBV
Hepatitis B virus
HCC 
Hepatocellular carcinoma
hCG
Human Chorionic Gonadotropin
HCV
Hepatitis C virus
HDL 
High-density lipoprotein
HIV
Human immunodeficiency virus
HLM
Human liver microsomes
i.v.
intravenous
IC50
Inhibitory concentration (at half-maximum inhibition)
ICF
Informed consent form
ICH
International Conference on Harmonization
IEC
Independent Ethics Committee
IFN-γ
Interferon-gamma
IG
Immunogenicity
IL
Interleukin
INR
International normalized ratio
irAE
Immune-related adverse event
IRB
Institutional Review Board
irRC
Immune-related response criteria
IUD
intrauterine device
IUS
intrauterine system
KD
constant of dissociation
KLB
β-Klotho
LC-MS/MS
Liquid chromatography-tandem mass spectrometry 
LDL 
Low-density lipoprotein
LLOQ
Lower limit of quantification
M-CSF
Macrophage colony stimulating factor
MRP
Multidrug resistance-associated protein
MTD
Maximum Tolerated Dose
NADPH
Nicotinamide adenine dinucleotide phosphate
NTCP
Na+-taurocholate cotransporting polypeptide
OATP
Organic anion-transporting polypeptide
ORR
Overall response rate
OS
Overall survival
p.o.
per os/by mouth/orally
P-gp
P-glycoprotein
p/t
Phosphorylated over total
PAS 
Pharmacokinetic analysis set
PBMCs
Peripheral blood mononuclear cells
PBPK
Physiologically-based pharmacokinetics
PD
Pharmacodynamics


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PD-1
Programmed Death-1
PD-L
Programmed Death-Ligand
PFS
Progression-free survival
PK
Pharmacokinetics
PR
Partial response
PPI
Proton pump inhibitors
PPS 
Per-Protocol Set
PT
Prothrombin time
Q3W
Every three weeks
Raf
Rapidly accelerated fibrosarcoma
RAP
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses
REB
Research Ethics Board
RECIST
Response Evaluation Criteria in Solid Tumors
RP2D
Recommended phase two dose
SAE
Serious Adverse Event
SD
Stable Disease
SEB
Staphylococcal Enterotoxin B
SI unit
International System of Units
SJS
Stevens Johnson Syndrome
SOP
Standard Operating Procedure
T1/2
Terminal half-life
TACE
Transarterial chemoembolization
TEN
Lyell syndrome/toxic epidermal necrolysis
Tmax
Time to reach observed maximum concentration
TNFα
Tumor necrosis factor-α
TSH
Thyroid-stimulating hormone
TTP
Time to progression
UGT
Uridine diphosphate glucuronyltransferase
ULN
Upper limit of normal
Vss
Volume of distribution (at steady state)


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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.: q21 days)
Dose level
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment
Point/time of patient entry into the study; the point at which informed consent must 
be obtained (i.e. prior to starting any of the procedures described in the protocol)
Investigational drug
The study treatment whose properties are being tested in the study; this definition 
is consistent with US CFR 21 Section 312.3 and is synonymous with 
“investigational new drug.”
Investigational treatment
Drug whose properties are being tested in the study as well as their associated 
placebo and active treatment controls (when applicable). This also includes 
approved drugs used outside of their indication/approved dosage, or that are 
tested in a fixed combination. Investigational treatment generally does not include 
other study treatments administered as concomitant background therapy required 
or allowed by the protocol when used in within approved indication/dosage
Medication number
A unique identifier on the label of each study treatment package which is linked to 
one of the treatment groups of a study
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.
Stratum
A group of patients enrolled and treated in same specific condition (e.g. food 
intake condition)
Subject Number (Subject 
No.)
A unique identifying number assigned to each patient/subject who enrolls in the 
study
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; 
may or may not also be the point/time of premature patient withdrawal
Variable
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified timepoints
Withdrawal of consent
Withdrawal of consent from the study occurs only when a subject does not want 
to participate in the study any longer, and does not allow any further collection of 
personal data.


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Protocol No. CFGF401X2101
Protocol summary: 
Protocol number
CFGF401X2101
Title
A phase I/II, multicenter, open-label study of oral FGF401 in adult patients with 
hepatocellular carcinoma or other solid tumors characterized by positive FGFR4 
and KLB expression
Brief title
FGF401 in HCC and solid tumors characterized by positive FGFR4 and KLB 
expression
Sponsor and Clinical 
Phase
Novartis
Phase I/II
Investigation type
Drug
Study type
Interventional
Purpose and rationale
The purpose of this study is to determine the maximum tolerated dose (MTD) or 
recommended phase II dose (RP2D) of FGF401 as single agent and in 
combination with PDR001 in patients with hepatocellular carcinoma and as 
single agent in other solid tumors characterized by positive FGFR4 and KLB 
expression; and to estimate the preliminary anti-tumor activity of FGF401 single 
agent and in combination with PDR001 in these populations.
Based on preclinical studies, FGF401 is a highly potent, selective FGFR4 
inhibitor, thereby making it a good candidate for use in the clinic. Positive 
prediction for sensitivity to FGF401 was identified to be associated with positive 
expression of FGFR4, KLB and FGF19. Based on the emerging clinical efficacy
results, the combination of FGF401 with PDR001 will be evaluated in parallel to
the FGF401 single agent, in unselected HCC population for both parts of the 
study.
Primary Objective(s) and 
Key Secondary Objective
Phase I: To estimate the MTD or RP2D of FGF401 single agent and in 
combination with PDR001
Phase II: To investigate the anti-tumor activity of FGF401 single agent and in 
combination with PDR001
Secondary Objectives
● To characterize the safety and tolerability of FGF401 single agent and in 
combination with PDR001
● To further investigate the anti-tumor activity of FGF401 single agent and in 
combination with PDR001
● To characterize the PK properties of FGF401 single agent and in combination 
with PDR001
● To evaluate food effect on FGF401 exposure and safety profile
Study design
This study has been designed as a phase I/II, multi-center, open-label study 
starting with a phase I dose escalation part followed by a phase II dose 
expansion part. Oral FGF401 and intravenous PDR001 (for the FGF401 and 
PDR001 combination part) will be administered as per protocol until patient 
experiences unacceptable toxicity, progressive disease and/or treatment is 
discontinued at the discretion of the investigator or withdrawal of consent. A 
cycle is defined as 21 days.
The phase II part of the FGF401 and PDR001 combination has a 2-stage study 
design with an interim efficacy analysis in unselected HCC patients and a sub-
group futility analysis, based on FGF19 pathway activation if the efficacy criteria 
are not satisfied. Enrollment with a molecularly selected population will continue 
at Stage 2 if the futility criteria are not satisfied.
Population
Phase I-FGF401 single agent: adult patients with hepatocellular carcinoma or 
other solid malignancies characterized by positive FGFR4 and KLB expression.
Phase II-FGF401 single agent: 
Group 1: adult HCC patients from Asian countries
Group 2: adult HCC patients from non-Asian regions
Group 3: adult other solid tumor patients, characterized by positive FGFR4 and 
KLB expression regardless of geography
FGF401 and PDR001 combination: adult patients with advanced HCC


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Key Inclusion criteria
1. Patients (male or female) ≥ 18 years of age
2. ECOG Performance Status ≤ 1
3. Presence of at least one measurable lesion according to RECIST v1.1. 
4. FGF401 single agent-Phase I and Phase II-Group 3: Patients with confirmed 
positive expression of FGFR4 and KLB at pre-screening.
5. For HCC patients: the diagnosis must be made based on AASLD Guidelines 
with confirmed stage C advanced HCC (BCLC staging classification). Current 
cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy and/or 
ascites.
6. FGF401 single agent-Phase I and Phase II, Group 3: Patients with HCC or 
advanced solid tumors, who have progressed despite standard therapy or are 
intolerant of standard therapy, or for whom no standard therapy exists.
7. FGF401 single agent-Phase II, Groups 1 and 2: HCC patients previously 
treated with sorafenib for advanced HCC with documented disease progression 
during or after discontinuation of sorafenib treatment, or intolerance to sorafenib 
treatment.
8. FGF401 in combination with PDR001-Phase I and Phase II: Advanced HCC 
patients who have received up to 2 previous lines of systemic treatment and one 
treatment must have included sorafenib with documented disease progression 
during or after discontinuation of sorafenib treatment, or intolerance to sorafenib 
treatment
9. FGF401 in combination with PDR001-Phase II-Stage 2: Documented FGF19 
expression level and/or FGF19 pathway activation
Key Exclusion criteria
1. Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or 
pan-FGFR inhibitor.
2. For HCC patients in FGF401 single agent-Phase II part: any previous systemic 
anti-cancer therapies other than sorafenib or any anti-cancer therapy (including 
locoregional therapy) after disease progression during or after sorafenib 
treatment.
3. Ongoing active diarrhea requiring medications (e.g. BAS, loperamide)
4. Irritable bowel syndrome with signs/symptoms and requires medications
5. Symptomatic CNS metastases which are neurologically unstable or requiring 
increasing doses of steroids to control their CNS disease.
6. Patient having out of range laboratory values defined as:
● Hematology
Hemoglobin ≤ 9 g/dL (SI Units: 90 g/L)
Platelet count < 75000/mm3
Absolute neutrophil count (ANC) < 1500/mm3
● Chemistry
Total bilirubin > 1.5 x ULN
AST and/or ALT > 3 x ULN
Serum creatinine > 1.5 x ULN and/or creatinine clearance < 40 mL/min
● Coagulation: PT > 4 seconds more than the ULN or INR > 1.7
7. Unable to stop any prohibited medications, including CYP1A2, CYP2C9 and 
CYP3A4/5 substrates with a narrow therapeutic index and known BSEP efflux 
transporter inhibitors.
Additional exclusion criteria for FGF401 and PDR001 combination:
8. Impaired cardiac function
9. History of liver or other organ transplantation
10. Patients who discontinued prior anti-PD-1/PD-L1 therapy due to an anti PD-
1/PD-L1-related toxicity
Investigational and 
reference therapy
The investigational therapy is FGF401 single agent and FGF401 in combination 
with PDR001. There is no reference therapy.
Efficacy assessments
Tumor assessment per RECIST v1.1 for FGF401 single agent; RECIST v1.1 and 
irRC for FGF401+PDR001 combination
Safety assessments
Incidence and severity of AEs and SAEs, including changes in laboratory values, 
vital signs and ECGs


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Other assessments
PK parameters
Immunogenicity analysis for PDR001
 
 
Data analysis
Phase I: in order to estimate the MTD and/or RP2D of the FGF401 single agent
and in combination with PDR001, the corresponding primary analysis methods
are based on Bayesian  adaptive models for the dose escalation with overdose 
control (EWOC) principle.
Phase II: For the FGF401 single agent, anti-tumor activity will be primarily 
assessed in terms of overall response rate (ORR) for solid tumor patients and 
time to progression (TTP) for HCC patients. For FGF401 in combination with 
PDR001, anti-tumor activity will be primarily assessed in terms of ORR for HCC 
patients.
The study data will be analyzed and reported based on all patients’ data of the 
Phase I and Phase II parts up to the time when all patients have potentially 
completed at least six cycles of treatment or discontinued the study.
Key words
Phase I/II, FGF401, PDR001, PD-1, FGFR4 selective inhibitor, positive 
expression of FGFR4, KLB, FGF19 pathway


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Amendment 5 (27-Sep-2018) 
Amendment rationale 
The main purposes of this amendment are: 

To incorporate health authority-requested language requiring study treatment 
discontinuation in the event of Stevens-Johnson syndrome (SJS)/ toxic epidermal 
necrolysis (TEN) (already implemented as part of an urgent safety measure released on 15 
June 2018) and,

To reduce study visits and assessments to ease the burden on patients who have been on 
study for more than 7 cycles, while maintaining access to study treatment and monitoring 
safety. 
After the occurrence of a case of Stevens-Johnson syndrome in a study with PDR001 in 
combination with another investigational agent, the dose modification guidelines for protocols 
using PDR001 were updated to mandate permanent discontinuation of study treatment for 
patients who experience SJS or Lyell syndrome/toxic epidermal necrolysis (TEN). This change 
has already been implemented as part of an urgent safety measure released on 15 June 2018. 
This protocol amendment is now finalizing these changes in the dose modification section and 
corresponding tables describing the criteria for interruption and re-initiation of study treatment.
The primary objectives in the Phase I parts (FGF401 single agent and in combination with 
PDR001) of the study have been reached. Enrollment in the Phase II part of the FGF401 single 
agent has been completed. As of 03 July 2018, patient enrollment in this study has been halted 
and the phase II part of the FGF401 in combination with PDR001 will not be initiated. This 
enrollment halt was due to business reason and was not a consequence of any safety concerns.
As of 01 September 2018, 9 patients remain on treatment, 6 patients on the FGF401 single agent 
and 3 patients on FGF401 in combination with PDR001. This amendment will reduce the study 
assessments in order to ease the visit and sampling burden for these patients.
All of these patients have been on study for more than 7 cycles and are tolerating study treatment 
well. Their safety profiles are consistent with the overall cumulative safety data for FGF401 
and PDR001. The most commonly reported AEs suspected to be related to study treatment 
include diarrhea, AST and ALT elevations which are thought to be on target effects of FGFR4 
inhibition (refer to the current version of FGF401 IB) and will continue to be monitored for 
these patients. 
The required study visits for patients who receive FGF401 as single agent are reduced from 
every 3 to every 6 weeks and the efficacy assessments are reduced from every 6 to every 12 
weeks. The study visits for patients who receive FGF401 in combination with PDR001 remain 
the same in alignment with the PDR001 regimen of every 3 weeks and the efficacy assessments 
are reduced from every 6 to every 12 weeks. For all patients the basic panel of clinical laboratory 
parameters will be performed at each study visit. Other assessments and visits will continue to 
be performed at the investigator’s discretion following standard of care at the site. 
The central review of ECGs is no longer required and cardiac assessments may be performed 
at the investigator’s discretion following local standard of care, since the available data and 
analysis of centrally reviewed ECGs collected during the study, do not indicate cardiac risk. In 


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addition, the pharmacokinetic, immunogenicity 
collections will be stopped since 
sufficient samples have been collected for analysis to support the study objectives. 
Additional changes introduced with this amendment are described below:

The blood sample collection for the assessment of cytokines in the event of a cytokine 
release syndrome (CRS) was removed.  In this protocol, the assessment of cytokines in the 
event of CRS is retrospective and is not utilized to support clinical treatment decision by 
study investigators. In addition, clinically assessed events of cytokine release syndrome 
were not reported in this study. 

To align with the EMA standard term list, the PDR001 pharmaceutical form has been 
updated to “Powder for solution for infusion”.

The withdrawal of consent language was revised to differentiate sample use after a patient 
withdraws consent based on different regulations/laws around the world.

Other minor corrections were made for consistency and/or clarifications.
Study status
A total of 160 patients have been treated with FGF401 as single agent, 74 in the dose escalation 
and 86 in the Phase II part. A total of 12 patients have been treated with FGF401 in combination 
with PDR001; all patients were enrolled in the dose escalation part. Due to the enrollment halt, 
the Phase II part of the combination did not start.
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 has been updated to add the “Personal data” term and revise the 
“Withdrawal of consent” term. 

Tables 6-4 and 6-5 are modified to mandate permanent discontinuation of study treatment 
for patients who experience SJS or Lyell syndrome/toxic epidermal necrolysis (TEN) – as 
per the USM letter dated 15 June 2018.

Section 6.3.2 and Table 6-5 are updated to remove the collection of blood samples for 
cytokines measurement.

Section 6.6 and 6.6.6: The pharmaceutical form for PDR001 was changed to “powder for 
solution for infusion”.

Section 7 has been updated in all relevant sub-sections as follows: 

New tables for reduced assessments (Table 7-1b) and for the local clinical laboratory 
parameters collection plan (Table 7-4b) are added.

Sections 7.1.4, 7.1.6 and 7.2.1 have been updated to include reduced frequency of 
efficacy assessments and clarify that the central collection of imaging data is not 
required.

Section 7.2.2 has been updated to remove the following assessments: height, weight, 
performance status, coagulation, urinalysis, 
, thyroid functions, 
cytokines and cardiac evaluations. In addition, vital signs will be performed only for 
patients treated with FGF401 in combination with PDR001. 


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
Sections 7.2.3 and 7.2.4 have been updated to remove further sample collections for 
pharmacokinetic 
 assessments.

Section 7.1.5 Withdrawal of consent language was updated.

Section 8.2.2 and Section 8.3: The name of the Novartis Drug Safety and Epidemiology 
department was updated to Chief Medical Office and Patient Safety. In addition, 
clarification was added in the pregnancy section to specify that the follow-up of the newborn 
will be for 12 months.

Section 14-4: Appendix 4 was updated to remove from Table 14-10 (Permitted concomitant 
medications requiring caution) duplicate records of drugs which were also listed in Table 
14-9 (Prohibited concomitant medications).
IRBs/IECs
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities.
The changes in this amendment identified above as being related to the USM have already been 
implemented by a USM letter issued on 15 June 2018. These changes are required for patient 
safety (i.e. necessary to eliminate immediate hazards to the trial subjects ICH GCP 3.3.8). 
Therefore they were required to have been implemented prior to IRB/IEC approval of this 
amendment. 
All other changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment.


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Amendment 4 (06-Dec-2016)
Amendment rationale 
As of 15 November 2016, the Phase I part of the study has been completed with a total of 67
patients enrolled and received different dose levels (ranging from 50mg QD to 150mg QD) of 
FGF401 as a single agent administered under fasted or fed conditions. The RP2D for FGF401 
single agent was declared in 29 July 2016 as 120mg QD administered under fasted conditions. 
This decision was based on the analysis of available patients' safety, pharmacokinetic, 
pharmacodynamic and efficacy data. In parallel, cohorts of FGF401 administered under fed 
conditions are being explored at the dose level of 80mg QD and 120mg QD with no dose 
limiting toxicities (DLTs) observed so far. The Phase II part of the study is ongoing with 17 
patients enrolled in all 3 Groups and treated with FGF401 single agent at the RP2D dose level. 
The primary purpose of this amendment is to add a combination treatment of FGF401 and 
PDR001, a humanized anti-programmed death-1 (PD-1) IgG4 antibody, in patients with 
advanced hepatocellular carcinoma. 
This amendment is introducing a dose escalation part, in order to identify a MTD/RP2D for the 
FGF401 and PDR001 combination and will be followed by a two stage Phase II part in order to 
further characterize the safety and evaluate the clinical activity of the combination in parallel to 
the FGF401 single agent. The introduction of the FGF401 and PDR001 combination treatment 
is based on the rationale that both FGFR4 and PD-1 inhibition have demonstrated promising 
anti-tumor activity in patients with HCC and that the combination will provide additional 
clinical benefit to patients. Emerging results from biomarker associative studies from the Phase 
I -FGF401 single agent available data support the removal of the FGFR4/KLB/FGF19 
molecular screening selection requirement for HCC patients in the Phase II part of the FGF401 
single agent. Molecular screening for these biomarkers will not be performed either for the dose 
escalation or the first stage of the Phase II in the FGF401 and PDR001 combination; however, 
based on the planned interim analysis results it may be introduced in the Stage 2-Phase II part 
of the combination treatment.
This amendment also introduces the collection of tumor tissue upon the development of 
acquired resistance to treatment. The emergence of acquired resistance to therapy is a major 
problem for patients with cancer. The purpose of collecting this tumor sample along with a
sample of normal tissue to aid in the identification of somatic variants in the tumor is to identify 
genetic changes in the tumor that may underlie treatment resistance.
Furthermore, additional updates in patients’ eligibility criteria and other operational aspects of 
the protocol are being implemented in this amendment as described below:
The laboratory values in the exclusion criteria section and other eligibility criteria for 
enrollment in the FGF401 single agent part have been amended to align with the eligibility 
requirements for the FGF401 and PDR001 combination. In addition, the laboratory values for 
bilirubin have been amended in order to be consistent with CTCAE version 4.03 grading and 
clarification was added for the coagulation parameters.
Language has been updated in the protocol to differentiate among the discontinuation of study 
treatment or study visits, the withdrawal of consent and the lost to follow-up patients.


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The methods of highly effective contraception, SAE reporting and publication language of 
study protocol and results have been updated to reflect the most recent Novartis definitions, 
procedures and policies.
The list of concomitant medications that are prohibited and to be used with caution has been 
updated based on the latest internal drug-drug interaction guideline. The restrictions of 
concomitant use of acid-reducing agents, including the prohibition of proton pump inhibitors 
(PPI), are also removed, considering the accompanying gastric symptoms which are often seen 
in HCC patients. This removal is supported by the preliminary GastroPlus PBPK modeling 
results using the available human PK data from the FGF401 single agent-Phase I part of the 
study. These results suggest minimally negative impact on FGF401 exposures with PPI co-
administration.
Other minor changes and corrections were made throughout the protocol for consistency and/or 
clarifications.
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.

All relevant Sections, Tables and Figures throughout the protocol were updated to include 
the addition of FGF401 in combination with PDR001 and to distinguish between FGF401 
administered as single agent or in combination with PDR001. 

The following new sections, tables and appendices have been added for PDR001: Section 
1.2.2 and Section 1.2.3-Overview of PDR001 and of the FGF401 and PDR001 
combination; Section 6.1.2- Ancillary treatments; Table 6-5- criteria for interruption and 
re-initiation of PDR001; Section 14.9- Guidelines for immune-related Response Criteria 
(irRC); Section 14.11-Recommended management algorithms for PDR001-suspected 
toxicities. 

Section 1.2.1.2 has been updated with FGF401 clinical experience.

Section 2-Rationale, Section 4-Study design, Section 5-Population, Section 7.1.1-
Molecular pre-screening,
, Section 10-Statistical Methods and 
data analysis and Tables 7-1 and 7-14 , have been updated to remove molecular pre-
screening requirements from HCC patients (Group 1 and Group 2) in FGF401 single agent 
Part II.

Specific requirements for Japan have been added in Section 5.2-Inclusion criteria and 
Section 7.1- Study Flow and visit schedule

Clarification for the possibility to introduce a BID dosing regimen for FGF401 has been 
added in Section 4.1-Study design and Section 6.1.1-Dosing regimen. 

Section 4.1-Description of study, Tables 7-1, 7-3 and 7-4 and Section 9.3-Data collection: 
references to the optional companion protocol have been removed since the requirements 
to study the mechanisms of resistance to study treatment are now included in this 
amendment.

Section 5.3- Exclusion criteria: The methods of highly effective contraception have been 
updated and clarification of the post-menopausal clinical profile was added. In addition, 
the prohibition of treatment with proton pump inhibitors (PPI) has been deleted.


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
Section 6.4.2 and Section 6.4.3: The restrictions of concomitant use of acid-reducing 
agents, including the prohibition of PPI, have been removed. 

Section 7.1.4 has been updated to clarify patient’s discontinuation from study treatment; 
new sections (Section 7.1.5 and Section 7.1.7) have been added to describe the withdrawal 
of consent and lost to follow-up.

Section 8.2.2 has been updated to include clarifications on SAE reporting.

Section 8.6-Steering Committee, has been updated to include the planned interim analysis 
for the Phase II part of the FGF401 and PDR001 combination. 

Section 11.5 has been updated to reflect latest procedures on the publication of study 
protocol and results.

Section 14.4- list of concomitant medications that are prohibited and to be used with 
caution has been updated based on the latest internal DDI guideline.

Section 14.10 has been added to include the Bayesian model used for the combination 
treatment.
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 03
Amendment rationale
The purpose of this amendment is to add the amylase and lipase measurements to the local 
chemistry laboratory parameters collection plan in order to align with the criteria for dose-
limiting toxicities specified in the protocol.
Changes to the protocol
Table 7-4, Local clinical laboratory parameters collection plan, has been updated to add amylase 
and lipase under Chemistry test category.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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.
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.
Amendment 02
Amendment rationale
The rationale for the amendment is to comply with the health authority suggestion to include 
the following:

clarification of the starting dose planned for exploratory food effect cohort

clarification of the prophylactic treatment with anti-emetics in cycle 1
[For Japan only]

specification of the informed consent procedure when patient is under the age of 20 years

specification of the additional ECG collection on Cycle 1 Day 1 for Japanese patients only
Changes to the protocol
Section 4.1, Description of study design, specifically for exploratory food effect cohort has been 
updated to indicate the starting dose of the fed cohort under different circumstance.
Section 6.3.3, Anticipated risks and safety concerns of the study drug, has been updated to 
specify the prophylactic treatment with anti-emetics is prohibited in cycle 1.
Table 7-6, Central ECG collection plan, has been updated to add additional triplicate 12-lead 
ECG collection at 2 hour post-dose on Cycle 1 Day 1.


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Section 11.3, Informed consent procedures, has been updated to indicate the Japan specific 
requirement of legal representative when patient is under the age of 20 years.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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. 
Amendment 01
Amendment rationale
The rationale for the amendment is to comply with health authority request to update the 
definition of Grade 3 diarrhea and Grade 3 hypercalcemia based on the NCI CTCAE.
Additionally, typo corrections have been made.
Changes to the protocol
Table 6-2, Criteria for defining dose-limiting toxicities have been modified based on the 
CTCAE and therefore footnotes b and c have been deleted.
Table 7-9 and Table 7-10, Pharmacokinetic blood collection log for BID administration, have 
been updated to correct typos of dose reference ID.
Table 18-1, Criteria for interruption and re-initiation of FGF401 treatment for diarrhea 
management has been modified based on the CTCAE and therefore footnote b has been deleted.
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions.
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, if the changes herein affect the Informed Consent, sites are 
required to update and submit for approval a revised Informed Consent that takes into account 
the changes described in this protocol amendment.


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1
Background
1.1
Overview of disease pathogenesis, epidemiology and current 
treatment
Hepatocellular carcinoma (HCC) is the fifth most common form of cancer worldwide and the 
third most common cause of cancer-related deaths. HCC often occurs in the background of a 
cirrhotic liver. Most cases of HCC (approximately 80%) are associated with chronic hepatitis 
B virus (HBV) or hepatitis C virus (HCV) infections (Raza A et al 2014, El-Serag HB 2012). 
Potentially curative therapies, such as surgical resection, liver transplant or other local 
treatments, result in survival rates of between 50-70% at 5 years for patients with early stage 
HCC (Llovet and Bruix 2008). However, despite advances in diagnostic techniques and 
increased surveillance, the majority of HCC cases present with advanced, inoperable tumors.
Untreated patients with intermediate stage HCC (multinodular asymptomatic tumors without 
an invasive pattern) have a median survival of 16 months. Treatment with transarterial 
chemoembolization (TACE), where the chemotherapy agent is directly introduced into the 
vessels feeding the tumor, followed by embolization, extends the median survival of this group 
of patients to approximately 19-20 months (Llovet and Bruix 2008).
HCC is considered to be a chemo-resistant tumor. Despite reports of partial responses to 
doxorubicin in a small number of patients, no clear survival advantage has been shown with 
this agent, and its use is limited due to its toxicity in patients with liver function impairment 
(Lopez et al 2006). TACE was the only treatment that had been associated with prolonged 
survival in intermediate HCC until the approval of the multikinase inhibitor sorafenib, which 
targets intracellular Raf serine/threonine kinase isoforms including Raf-1 (or C-Raf), wild-type 
B-Raf and mutant B-Raf and other cell surface kinases.
Two phase III studies have been published that compare sorafenib to placebo in advanced HCC 
patients in the first-line setting (i.e. patients with no prior systemic therapy): The “SHARP” 
study was conducted primarily in non-Asian countries and reported a median time to tumor 
progression (TTP) and overall survival (OS) of 5.5 months and 10.7 months, respectively, in 
the group of patients treated with sorafenib (Llovet et al 2008). The second study was conducted 
in Asia-Pacific region, reported median TTP and OS of 2.8 and 6.2 months, respectively (Cheng 
et al 2009).
The patterns of treatment for HCC are different in various parts of the world and may have 
accounted for the difference in OS and TTP results observed in the SHARP study and the Asia-
Pacific sorafenib study. 
1.2
Introduction to investigational treatments
1.2.1
Overview of FGF401
FGF401 is a Biopharmaceutics classification system (BCS) class II compound with low 
solubility at pH 6.8, high permeability and low to moderate food effect risk.  FGF401 is a highly 
selective and potent FGFR4 inhibitor through binding the ATP site of FGFR4. FGF401 inhibits 
HCC and gastric cancer cell lines expressing FGFR4, KLB and FGF19 (triple positive) with 


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excellent selectivity over non-sensitive cell lines. In xenograft models, FGF401 induces 
regression/stasis in triple positive HCC tumors. In addition to expression by triple positive 
tumors, FGF19 is also induced in the ileum in response to bile acids, circulates in the human 
body and might stimulate the growth of the tumors expressing FGFR4 and KLB (double 
positive). Considering the supportive preclinical data, FGF401 provides a unique opportunity 
to target solid tumors and specifically HCC characterized by double or triple biomarkers 
positivity.


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1.2.1.2
FGF401 clinical experience
This first in human study started enrollment on 29-Dec-2014. As of 30-May-2016, a total of 
42 patients have been treated with FGF401 as single agent at different dose levels from 50 mg
to 150 mg QD under fasted or fed (light meal) conditions.
Four DLTs were observed in three out of 33 patients that were included in the dose determining 
analysis set. The DLTs were: ALT increase in one patient at 50 mg QD fasted; AST increase in 
one patient at 150mg QD fasted; AST and ALT elevation, which was considered two-DLTs in 
one patient at 150mg QD fasted. The maximum tolerated dose (MTD) for FGF401 as single 
agent was not reached. The recommended phase II dose (RP2D) for FGF401 as single agent 
was determined to be 120 mg QD under fasted condition.
Overall, the most common AEs (≥ 15%) considered possibly related to FGF401 were diarrhea 
(66.7%), AST increase (40.5%) and ALT increase (38.1%) including Grade 3 or Grade 4 events 
experienced by one (2.4%), seven (16.7%) and six (14.3%) patients respectively.
Preliminary results from the dose escalation part of the study demonstrated objective responses 
in 3 out of 39 patients (7.69%) with HCC (2 confirmed and 1 non-confirmed partial response 
[PR]). None of the patients with objective responses had detectable FGF19 expression by RT-
PCR. In addition, exploratory studies performed to date have not identified an association 
between tumor metrics and either FGF19, FGFR4, or KLB expression. These observations 
suggest that HCC patients have the potential to benefit from the FGF401 treatment irrespective 
of their FGF19, FGFR4 or KLB expression level, as measured by RT-PCR.
1.2.1.3
Clinical pharmacokinetics and metabolism
As of the PK cut-off date 04-Feb-2016, a total of 31 patients were administered FGF401 orally 
as a capsule at doses ranging from 50 to 150 mg QD either fed (light meal) or fasted. FGF401 
was well absorbed, with Tmax ranging from 1.0 to 2.9 hours. Absorption was independent of 
dose and unchanged after multiple oral doses. FGF401 has a short to moderate T1/2, which 
ranged from 3.9 to 7.5 hours, and also appeared to be independent of dose and time. Plasma 
drug exposure of FGF401 increased with increasing doses with a trend toward under 
proportionality. Drug accumulation of FGF401 following multiple dosing was minimal. No 
substantial exposure difference was observed in clinic between fed (light meal) and fasted 
cohorts at 80 mg. 
The plasma concentrations of FGF401 within a steady-state dosing interval almost all exceeded 
the preclinical in vivo pFGFR4 IC90 value, as well as the in vitro cellular pFGFR4 IC90 at the 
starting dose of 50 mg. 


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Human metabolism, excretion and clinical drug-drug interaction studies have not yet been
performed. 
 
 
 
 
1.2.2
Overview of PDR001
PDR001 is a high-affinity, ligand-blocking, humanized anti-PD-1 IgG4 antibody that blocks 
the binding of Programmed Death- Ligand 1 (PD-L1) and Programmed Death Ligand-2 (PD-
L2) to Programmed Death-1 (PD-1). PDR001 recognizes PD-1 in cynomolgus monkeys and 
shows functional activity in vitro/ex vivo. 
1.2.2.2
PDR001 Clinical experience
The first in human phase I/II study [CPDR001X2101] started enrollment on 27 April 2015 and 
is ongoing in patients with advanced malignancies. The dose escalation part of the study was 
completed with a total of 58 patients treated at the dose levels of 1, 3 and 10 mg/kg every two 
weeks and 3 and 5 mg/kg every four weeks. No patient experienced a DLT. The PK analysis of 
the dose escalation data using a population approach and the expected wide therapeutic index 
of PD-1 inhibitors support the use of flat dosing for PDR001 of 400 mg every four weeks or 
300 mg every three weeks (Q3W). The expected PDR001 Ctrough concentrations using either 
dosing regimen exceed the EC50 for PD-1 blockade by approximately 75-fold in an ex vivo 
assay in peripheral blood mononuclear cells (PBMCs). Based on the available PK and safety 
data, the RP2D of PDR001 has been declared as 400 mg i.v. every four weeks or 300 mg i.v. 
Q3W for combination treatment regimens for which this may be more convenient. 


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PDR001 is currently being studied alone or in combination with other agents in ongoing phase 
I/Ib/II clinical trials. The preliminary toxicity profile appears to be similar to that of marketed 
inhibitors of PD-1 including the type, severity and frequency of occurrence of immune-
mediated adverse events. As observed with other PD-1 inhibitors, immune-mediated toxicities 
observed with PDR001 are reversible in many cases. In some cases, they may require treatment 
with corticosteroids. Certain toxicities are expected to be lifelong and may require replacement 
therapy with hormones, for example in the case of hypothyroidism. The most frequent suspected 
AEs (data cut-off: 17-Dec-2015) included diarrhea (8 patients, 13.8%), fatigue (8 patients, 
13.8%), nausea (6 patients, 10.3%), hypothyroidism (5 patients, 8.6%), pruritus (5 patients, 
8.6%), vomiting (4 patients, 6.9%), anemia (3 patients, 5.2%), constipation (3 patients, 5.2%), 
decreased appetite (3 patients, 5.2%), dry mouth (3 patients, 5.2%) and maculopapular rash (3 
patients, 5.2%).
Based on the preliminary data, PDR001 was well tolerated with a safety profile similar to those 
of other marketed anti-PD-1 antibodies. 
1.2.3
Overview of FGF401 and PDR001
1.2.3.1
Non clinical and clinical experience with the FGF401 and PDR001 
combination
There is no experience with this combination in the non-clinical and clinical setting.
1.2.3.2
Potential of drug interactions
Specific studies to investigate DDI have not been conducted with FGF401 and PDR001. As an 
antibody, PDR001 is eliminated through protein catabolism and target-mediated disposition.
Cytokines produced by activated lymphocytes may impact the levels of Pgp and the activity of 
P450 enzymes. The clinical relevance of cytokines impacting levels of Pgp and P450 with 
administration of PDR001 is unknown but considered unlikely. FGF401 is a small molecule 
eliminated mainly by hepatic metabolism with both phase I and II enzymes involved.
Pharmacokinetic DDI between FGF401 and PDR001 is therefore not expected.
1.2.3.3
Potential overlapping toxicities
From the preclinical safety profile of FGF401 and PDR001 no overlapping target organ toxicity 
is expected. However, preliminary clinical data from the ongoing single agent CFGF401X2101
study suggests that FGF401 associated toxicities may overlap with those of PD-1 inhibitors 
including PDR001 observed in the clinic. 
Potential overlapping toxicities include diarrhea and increased AST/ALT, which have been 
reported for PD-1 inhibitors including PDR001. Lipase increase is another potential 
overlapping toxicity, which although not reported for PDR001, has been reported for other PD-
1 inhibitors.


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2
Rationale
2.1
Study rationale and purpose
FGF19 has unique specificity for FGFR4. In addition, cellular co-expression of KLB is required 
for FGF19 binding to FGFR4 and for the subsequent intracellular signaling. Therefore, the 
distribution and the relative levels of FGFR4 and KLB dictate the organ/tumor of FGF19 action
(Lin et al 2007, Lin et al 2012).
FGF19-FGFR4 pathway plays an important homeostatic physiological role in the regulation of 
bile acid homeostasis. The expression of FGF19 is induced in the ileum in response to bile acids 
that are released into the intestinal lumen after feeding. FGF19 then circulates to the liver where 
FGFR4 and KLB are highly co-expressed to suppress CYP7A1, the rate-limiting enzyme for 
bile acid synthesis. FGF19 also limits bile acid release into the intestine by triggering 
gallbladder filling. In this manner, FGF19 serves as a key regulator in the postprandial negative 
feedback loop modulating bile acid synthesis and release (Lin et al 2012, Mellor 2014).
Recent data suggests that the FGF19-FGFR4 signaling network may be a key driver in certain 
forms of HCC, making the pathway an interesting, emerging molecular target for potential 
therapeutic intervention (Ho et al 2009, Miura et al 2012, Poh et al 2012). 
In vivo, the ectopic expression of FGF19 in the skeletal muscle in mice promotes hepatocyte 
proliferation and induces HCC formation in a paracrine fashion (Nicholes et al 2002) and an 
anti-FGF19 monoclonal antibody prevents tumor formation (Desnoyers et al 2008). Further, 
when FGF19 transgenic mice were bred with FGFR4 knockout mice, they failed to develop 
liver tumors highlighting the relevance of FGFR4 in FGF19-driven HCC (French et al 2012).
Several publications
 that FGF19 aberrant expression, occurring as a 
consequence of focal gene amplification (11q13) or by some other yet unknown mechanism, 
occurs in subsets of HCCs, where FGFR4 and KLB are also co-expressed. In this setting, FGF19 
leads to constitutive FGFR4 activation by acting in an autocrine fashion (Sawey at el 2011;
Guagnano et al 2012).
Other publications indicated that a subset of HCC patients characterized by elevated FGFR4 
and/or FGF19 expression in the tumors have a poorer prognosis and might be amenable to anti-
FGFR4 therapy (Ho et al 2009, Miura et al 2012, Poh et al 2012).
FGF401 is a highly selective and potent FGFR4 inhibitor, which will be developed in patients 
with HCC or other solid malignancies characterized by positive expression of FGFR4 and KLB. 
The initial clinical strategy for the FGF401 development was driven by the following 
assumptions:
1. Clinical activity of FGF401 will be restricted to patients with double (FGFR4+ and KLB+) 
or triple (FGFR4+ and KLB+ and FGF19+) positive solid tumors, and it is assumed that 
HCC will account for >95% of the patients enrolled in the phase I. The incidence of 
double positivity in other solid tumors is very low (1-2%).Within the HCC patient 
population however, approximately 30-40% of tumors are double positive and around 10-
15% are triple positive. 
2. FGF19 secreted from non-tumor cells, e.g. ileum, stromal cell, might stimulate the growth 
of the double positive tumors and it might act as a growth factor in triple positive tumors.


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Preliminary results from the dose escalation part of this study demonstrated objective responses 
in 3 out of 39 patients (7.69%) with HCC (2 confirmed and 1 non-confirmed PR). 
 
 
 
hese observations suggest that HCC 
patients have the potential to benefit from the FGF401 treatment irrespective of their FGF19, 
FGFR4 or KLB expression level, as measured by RT-PCR. 
Additionally, preliminary results showing objective clinical activity in 2 out of 8 patients (1 
unconfirmed PR and 1 stable disease [SD]) were recently reported in a clinical study with 
another FGFR4 inhibitor in advanced HCC patients. These patients were FGF19 positive by 
IHC (Kim ENA 2016). Collectively these data further implicate the FGFR4 pathway as a driver 
in HCC and suggest that the FGFR4 inhibition may have a role in the treatment of HCC.
Recent clinical studies have highlighted the potential of targeting the PD-L1/PD-1 pathway in 
HCC. A phase I/II study of Nivolumab, a monoclonal antibody that results in PD-1 checkpoint 
inhibition, showed durable responses in advanced HCC; the objective response rate was 16% 
and the 9-month overall survival rate was 71% (Bruno ASCO 2016). This study also suggested 
that Nivolumab has a manageable safety profile in HCC, including in those patients with HBV 
and HCV infections. 
Together, these clinical results suggest that the combined inhibition of the FGFR4 signal with 
FGF401 and the inhibition of PD-1 with the checkpoint inhibitor PDR001 may lead to 
additional clinical benefit for patients with advanced HCC.
In this study the safety and clinical activity of the FGF401 and PDR001 combination will be 
evaluated in parallel to FGF401 single agent, in an unselected HCC population. Associative 
studies of immunomodulatory and FGF pathway expression changes in tumor and blood 
samples with clinical outcome will be retrospectively explored.
2.2
Rationale for the study design
2.2.1
FGF401 single agent
Phase I part
The design of the phase I, open label, dose finding part was chosen in order to establish the 
MTD and/or RP2D of FGF401 in patients with HCC or solid tumors characterized by positive 
expression of FGFR4 and KLB. The dose escalation will be guided by a Bayesian hierarchical 
logistic regression model (BHLRM). This model estimates the relationship between dose and 
the probability of a patient experiencing a DLT in fasted condition (stratum 1) and in fed 
condition (stratum 2). The BHLRM will allow for both full exchangeability between the strata 
parameters and non-exchangeability between strata parameters. In this way the model has the 
flexibility to allow for both the case in which the dose-toxicity relationship is similar for the 
two strata, and the case in which the relationship is different for each. In the event that the 
relationship is similar, then the model structure will allow borrowing of information between 
the two strata, which will in turn lead to improved estimation of the dose-toxicity relationship.


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This model is a hierarchical adaptation of the Bayesian logistic regression model (BLRM), a 
well-established method to estimate the MTD and/or RP2D in cancer patients. The BHLRM 
will be guided by the escalation with overdose control (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 EMEA (“Guideline on clinical trials in small populations”, 
February 1, 2007) and endorsed by numerous publications (Babb et al 1998, Neuenschwander 
et al 2008, Bailey et al 2009), and its development and appropriate use is one aspect of the 
FDA’s Critical Path Initiative.
The decisions on new dose levels are made by the Investigators and Novartis study personnel 
and will be based upon the recommendations made by the BHLRM, patient tolerability and 
safety, PK, 
 and efficacy information available at the time of the decision (Section 6.2.3).
Phase II part
Once the MTD and/or RP2D has been defined, a phase II part will open at the MTD or RP2D 
to further characterize safety, anti-tumor activity and PK profile of FGF401 at this dose. The 
phase II part will include 3 Groups as summarized in Figure 4-1, each having specific 
enrollment criteria.
Group 1 will enroll HCC patients from Asian countries
Group 2 will enroll HCC patients from non-Asian regions
Group 3 will enroll patients with other solid malignancies regardless of the geography
Epidemiology and preclinical data supports the feasibility and activity of FGF401 in HCC 
patients, respectively. Considering that the treatment guidance for HCC (specifically the 
locoregional treatments such as percutaneous hepatic arterial embolization, radiofrequency 
ablation, and percutaneous interventional therapy) are different in various parts of the world 
reflected in the difference in OS and TTP results observed in the SHARP study and the Asia-
Pacific sorafenib studies, subgrouping based on the geography and corresponding patterns of 
treatment will be implemented in this study. The HCC patients recruited in Asian countries will 
be enrolled in Group 1 and the HCC patients from non-Asian regions will be enrolled in Group 
2.
For Japan, the epidemiology pattern of hepatitis viral infection (HCV infections) is more similar 
to the non-Asian regions instead of other Asian countries (HBV infections) (Bosch et al 2004). 
However, the patterns of treatment for locally or advanced HCC may account for the difference 
in efficacy results. In some clinical studies, Japan has been stratified into the Asian group due 
to the similarity in term of locoregional treatment (number of TACE) (Lencioni et al 2012, 
Johnson et al 2013). In this study, considering the relevance of the locoregional treatment, Japan 
will be sub grouped into Group 1 (Asian patients).
Group 1 and Group 2 will focus on characterizing the activity and tolerability of FGF401 in 
HCC patients irrespective of their FGFR4, KLB and FGF19 expression. 
Group 3 will focus on characterizing the activity and tolerability of FGF401 in any other solid 
tumor patients with double positive expression. Preclinical data supports the activity of FGF401 
in one of the gastric cancer cell lines and may potentially work on other tumor types based on 
the mechanism described in Section 2.1.


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Exploratory food effect cohort
. Within the phase I part, the
exploratory food effect cohort(s) will be included to assess the effect of food uptake on FGF401 
PK properties and safety profiles in the patients.
According to the human physiology, when a meal is ingested, gallbladder emptying occurs and 
delivers bile acids to the small intestinal lumen. This physiological release of bile acids might 
be increased by FGF401 administered under fed condition. Therefore, the food effect 
exploration coupled with laboratory analysis described in Table 7-1 will also help to understand 
the food effect on 
 AEs under different feeding 
conditions. 
2.2.2
FGF401 in combination with PDR001
Phase I part
The design of the phase I, open label, dose finding part was chosen in order to characterize the 
safety and tolerability of FGF401 in combination with PDR001 in patients with advanced HCC 
and determine a RP2D or MTD. The dose escalation will be guided by a Bayesian Logistic 
Regression Model (BLRM). The use of Bayesian response adaptive models is a well-established 
method to estimate the MTD and/or RP2D in cancer patients as described above and in Section 
6.2.3. 
Phase II PartThe Phase II part of the FGF401 in combination with PDR001 will start once a 
MTD and/or RP2D is identified. This part has a staged study design. Initially the study will 
enroll HCC patients without molecular selection. If the clinical activity in this unselected 
population is below the pre-defined target range, the clinical activity will be further evaluated 
in sub-groups of patients, based upon FGF19 expression and/or FGF19 pathway activation to 
inform next decisions for clinical development (see Section 4.2). This design provides the 
opportunity to evaluate the combination in a molecular pre-selected HCC population, should 
the combination have limited activity in an unselected population. Considering the difference 
in OS and TTP results observed in the SHARP study and the Asia-Pacific sorafenib studies, 
sensitivity analyses by geographic region will be explored.
2.3
Rationale for dose and regimen selection
The starting dose and regimen of FGF401 single agent is 50 mg once daily based on the 
preclinical safety and tolerability data. 
 
 
 
 
 
 
 
 
 


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For the dose escalation part of the FGF401 and PDR001 combination, the starting dose is 80mg 
QD for FGF401 and 300mg Q3W for PDR001.
The RP2D for single agent FGF401 is 120mg QD administered under fasted condition. The 
dose of 80mg QD for FGF401 was selected for the combination as it is one dose level below 
the RP2D.
The dose of 300mg Q3W for PDR001, as a flat fixed dose, was selected as this is the RP2D for 
single agent PRD001 declared in the [CPDR001X2101] study.
The selected starting dose of FGF401 on a continuous daily schedule in combination with the 
fixed dose of PDR001 administered every 3 weeks is supported by the risk assessment. This 
includes that the starting dose meets the EWOC with the new combination BLRM that leverages 
single agent FGF401 and PDR001 dose-DLT data. Although pharmacokinetic DDI between 
FGF401 and PDR001 is not expected (Section 1.2.3.2), the exposure of FGF401 and PDR001 
will be monitored in the study to assess any potential DDI. 
3
Objectives and endpoints
Objectives and related endpoints are described in Table 3-1 below.


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Table 3-1
Objectives and related endpoints
Objective
Endpoint
Analysis
Primary
Refer to Section 10.4
Phase I part
To estimate the MTD and/or RP2D of FGF401
single agent and in combination with PDR001
Incidence rate and characteristics of DLT during the first cycle of dosing for FGF401 
single agent and during the first two cycles of dosing for FGF401 in combination with 
PDR001
Phase II part
To investigate the anti-tumor activity ofFGF401
single agent and in combination with PDR001
FGF401 single agent: Group 1 and Group 2: Time to progression (TTP); Group 3:
Overall response rate (ORR), based on local assessment per RECIST v1.1
FGF401 in combination with PDR001: ORR based on local assessment per RECIST 
v1.1. 
Secondary (Phase I and II part)
Refer to Section 10.5
To characterize the safety and tolerability of 
FGF401 single agent and in combination with 
PDR001
Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
values, vital signs and ECGs
Tolerability: Dose interruptions and reductions
Refer to Section 10.5.2
To further investigate the anti-tumor activity of 
FGF401 single agent and in combination with 
PDR001
Phase I part
BOR, ORR, DCR, TTP and OS, based on local assessment per RECIST v1.1 for 
FGF401 single agent or RECISTv1.1. and irRC for the FGF401 and PDR001 
combination
Phase II part- FGF401 single agent
Group 1 and Group 2: BOR, ORR, OS and DCR, based on local assessment per 
RECIST v1.1
Group 3: BOR, DCR, OS and PFS, based on local assessment per RECIST v1.1
Phase II part- FGF401 and PDR001 combination
TTP, PFS, OS, BOR, DOR and DCR, based on local assessment per RECIST v1.1. 
and irRC
Refer to Section 10.5.1
To characterize the PK properties of:
-FGF401 single agent and in combination with 
PDR001 
-PDR001 in combination with FGF401 
Plasma concentration of FGF401, PDR001 and PK parameters including but not 
limited to Cmax, Cmin, AUCinf, AUClast, AUCtau and T1/2
Refer to Section 10.5.3
To assess immunogenicity of PDR001
Presence and/or concentration of anti-PDR001 antibodies
Refer to Section 10.5.3


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Objective
Endpoint
Analysis
Phase I part- FGF401 single agent
To evaluate food effect on FGF401 exposure 
and safety profile
● Plasma concentration of FGF401 and PK parameters when dosing under fed 
condition
● Safety: Incidence and severity of AEs and SAEs, including changes in laboratory 
values, vital signs and ECGs when dosing under fed condition
Refer to Section 10.5.3.2.3


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4
Study design
4.1
Description of study design
This study has been designed as a phase I/II, multi-center, open-label study starting with a phase 
I dose escalation part followed by a phase II dose expansion part. The study treatment will be 
taken until patient experiences unacceptable toxicity, progressive disease and/or treatment is 
discontinued at the discretion of the investigator or patient’s withdrawal of consent. Figure 4-1
summarizes the study design overall while Figure 4-2 provides additional details for the study 
design for the FGF401 and PDR001 combination.
FGF401 will be administered on a continuous once daily (QD) dosing regimen for both FGF401 
single agent and in combination with PDR001 parts. However, based upon emerging FGF401 
clinical safety, efficacy and related exposure-response analysis data, the FGF401 dose regimen 
may change from QD to BID at any time during the study for all newly enrolled patients.
Figure 4-1
Study design
*refer to Figure 4-2 for additional details
Molecular pre-screen/FGF 
single agent (newly
obtained tumor samples) 
Phase I & Phase II-Group3 
only
Phase I
Phase II
FGF401 single agent
HCC/Solid tumor
FGFR4+ + KLB+
Dosing in fasted stage
FGF401 single agent
HCC/Solid tumor
FGFR4+ + KLB+
Dosing in fed stage
FGF401 
single agent
MTD/RP2D
FGF401 single agent-Group 2:
HCC, non-Asian regions (N~40)
with retrospective analysis for
FGFR4/KLB/FGF19
FGF401 single agent-Group 1:
HCC, Asian countries (N~40)
with retrospective analysis for
FGFR4/KLB/FGF19
FGF401 single agent-Group 3:
Solid malignancies, regardless of the
geography (N~20)
FGFR4+ + KLB+
FGF401+ PDR001 combination*
HCC  (N ~35 to 55)
Stage 1 unselected HCC → Stage 2 molecularly 
selected HCC (based on analyses results after 
Stage 1)
combination
MTD/RP2D
FGF401 in combination
with PDR001
unselected HCC patients


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4.1.1
FGF401 single agent
Phase I part
In the phase I part, patients with HCC or other advanced solid tumors characterized by positive 
FGFR4 and KLB expression will be enrolled. Patients will be tested for the expression of 
FGFR4 and KLB in the molecular pre-screening of this study to confirm the eligibility, refer to 
Section 7.1.1 for details. A BHLRM with EWOC will guide the dose escalation to determine 
the MTD and/or RP2D. At least 21 evaluable patients should be treated in the phase I part, for 
the model to have reasonable operating characteristics relating to its MTD and/or RP2D 
recommendation. If significant activity is seen early in the phase I dose escalation, then a 
recommended dose may be identified and the phase II Groups may be initiated without 
determination of the MTD; therefore fewer than 21 patients may be required.
Phase II part
Once the MTD and/or RP2D is declared, additional patients with advanced HCC or other solid 
tumors bearing positive FGFR4 and KLB expression will be enrolled into 3 Groups to assess 
the preliminary anti-tumor activity of FGF401 in Phase II dose expansion part. HCC patients 
will be enrolled irrespective of the FGFR4 and KLB expression which will be analyzed 
retrospectively. For patients with other solid tumors, positive FGFR4 and KLB expression is 
required for enrollment. HCC patients recruited in Asian countries will be enrolled in Group 1;
HCC patients from non-Asian regions will be enrolled in Group 2; patients with other solid 
malignancies regardless of the geography will be enrolled in Group 3. 
Each group within the phase II dose expansion part will target a different number of patients. 
Details of the sample size calculations leading to the patient numbers are provided in Section 
10.8. Group 1 and Group 2 will enroll around 40 patients each and Group 3 will enroll 
approximately 20 patients.
Exploratory food effect cohort
Within the phase I part, the exploratory food effect cohort(s) will be included to assess FGF401 
PK properties, safety and tolerability in patients under fed conditions. This food effect cohort 
will start when 
 clinical activity is 
observed and will be conducted in parallel with the phase I fasted dose escalation. If at this time, 
the MTD under the fasted condition has not been declared yet, the starting dose of the fed cohort 
will be equal or lower than the highest dose shown to be tolerated during the first cycle in the 
cohort of fasted patients. If at this time, the MTD under fasted conditions has been declared, the 
starting dose of the fed cohort will be lower than the MTD under the fasted condition. For both 
scenarios, the starting dose of the fed cohort will satisfy the escalation with overdose control 
(EWOC) criterion. The fed dose escalation will be guided by a BHLRM. The decision to 
continue with fed and/or fasted condition in the phase I and phase II part(s) will be made by the 
Investigators and Novartis study personnel based on the tolerability, safety profile, PK, PD and 
efficacy information available at the time of the decision. The dosing regimen and 
administration requirements are outlined in Section 6.1.1.
PK samples will be collected following the same PK collection schedule selected for the phase 
I part of the study (refer to Table 7-7 and Table 7-9).


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4.1.2
FGF401 in combination with PDR001
Figure 4-2 summarizes the study design for FGF401 in combination with PDR001.
Figure 4-2
Study design- FGF401 in combination with PDR001
Phase I part
In the Phase I part cohorts of patients will be treated with FGF401 in combination with a fixed 
dose of PDR001 until the MTD is reached or a recommended Phase II dose is established. The
FGF401 dose will be increased and the PDR001 dose will remain constant. For each untested 
dose level the administration of the first dose of the study treatment will be staggered by 24 
hours for the first three patients. The dose escalation will be guided by a BLRM following the 
EWOC principle. A minimum of 12 patients are required in the phase I part for the model to 
have reasonable operating characteristics to determine the MTD of FGF401 in combination 
with PDR001. If significant activity is seen early in the phase I dose escalation, then a 
recommended dose may be identified and the phase II part may be initiated without 
determination of the MTD; therefore fewer than 12 patients may be required.
Phase II part
The Phase II part of this study has a 2-stage design. In Stage 1, approximately 35 HCC patients 
will be enrolled without molecular selection (e.g. irrespective of their FGFR4, KLB or FGF19 
expression). Upon completion of the Stage 1 enrollment, an interim analysis will be performed 
to assess the clinical activity in this population. The phase II part will be stopped at Stage 1, if 
the criteria for substantial efficacy as described in Section 4.2 and Section 10.7.2 are met.
Additional HCC patients
enrolled based on 
positive/negative
FGF19 expression and/or 
FGF19 pathway activation 
FGF19 positive
N ~25
If FGF19 positive 
patients from 
Stage 1 < 25
FGF19 negative
N ~25
If FGF19 negative 
patients from Stage 
1 < 25
unselected HCC 
FGF401 + 
PDR001
Unselected HCC 
with retrospective analysis for FGF19 pathway activation
N~35
MTD/
RP2D
Phase II
Phase I
Stage 2
Stage 1
Interim analysis in unselected 
HCC population
Efficacy evaluation 
criteria NOT satisfied 
FGF19 pathway activation
sub-group analysis
and/or
Futility criteria NOT satisfied 
Efficacy 
evaluation 
criteria 
satisfied 
Futility criteria 
satisfied 
Enrollment 
completed
Enrollment 
completed


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Should these criteria not be met, sub-group analysis, based upon FGF19 expression and/or 
FGF19 pathway activation will be performed.
Based on the futility criterion specified in Section 4.2 and Section 10.7.2, if the efficacy in a
sub-group is insufficient, no further patients will be enrolled to that subgroup. Otherwise, 
enrollment will continue until a total of approximately 25 patients are identified for the specific 
sub-group(s) in order to further assess the efficacy. At this time, molecular pre-screening will 
be employed in order to identify the appropriate molecular sub-group(s).
The sub-group analysis will be based upon FGF19 pathway expression and/ or activation.  The 
molecular sub-group will be defined based upon emerging molecular data and associative 
analyses of the FGF401 single agent parts of the study and the definition for each sub-group 
will be available at the time of the interim analysis. If based on these associative studies, a 
molecular sub-group is not identified, patient enrollment will not continue beyond Stage 1.
Study visit flow
The study includes different periods starting by Molecular pre-screening (applicable only for 
Phase I and Group 3 in Phase II of FGF401 single agent and at Stage 2 of FGF401 and PDR001 
combination should it proceed), Screening, Treatment, End of Treatment, Disease progression 
follow-up (if applicable), Safety follow-up (refer to Section 7.1.6) and then ended by Survival 
follow-up period (Figure 4-3).
Figure 4-3
Study Flow
*Refer to Section 7.1.6 for additional details.
4.2
Timing of interim analyses and design adaptations
No formal interim analysis will take place in the FGF401 single agent part. 
In the phase I parts of this study for both FGF401 single agent and FGR401 in combination 
with PDR001, the MTD and/or RP2D will be determined based on available safety, tolerability, 
PK, 
 and efficacy data, guided by the recommendations from the Bayesian model using 
EWOC criterion and participating investigators. The phase II part will then begin as specified 
in Section 4.1. Details about the timing of data monitoring can be found in Section 8.5 and 
Section 10.7.
In the Phase II part of the FGF401 in combination with PDR001, a 2-stage design with interim 
efficacy evaluation of this combination treatment in HCC patients will be used. Stage 1 will 
initially enroll approximately 35 HCC patients irrespective of their FGFR4, KLB or FGF19 
expression status. An interim analysis of efficacy will be performed after the first 35 patients 
have been enrolled and have had at least one-post treatment tumor evaluation or discontinued 
earlier (Stage 1). Interim decision making will be primarily based on the estimation of ORR 
Molecular pre-
screening 
as applicable
Screening
Treatment
End of treatment 
due to disease 
progression
End of treatment 
for reason other 
than disease 
progression i.e. AE
Safety FU* 
and disease 
progression FU
Survival FU
Safety FU* 


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based on local assessment per RECIST v1.1. Based on the interim efficacy evaluation, the phase 
II part will not be continued after Stage 1 if the posterior probability of ORR in the unselected 
population included in the no/limited anti-tumor activity interval [0, 0.15) is less than 0.10 and 
the posterior median ORR is 0.30 or more. Considering the exploratory nature of the study, 
when the aforementioned criteria are not met but the evaluation of overall efficacy and safety 
suggests that the treatment is promising for further development, decision to stop at Stage 1 for 
success can also be made by Novartis. 
Should the efficacy criteria not be met, go/no go decision to Stage 2 will be made by evaluating 
the anti-tumor activity in subgroups defined by the FGF19 expression and/or FGF19 pathway 
activation based on the predictive probability of ORR. If a subgroup(s) satisfies the criterion 
that the predictive probability to not meet the efficacy criteria (i.e. posterior probability of ORR 
included in the no/limited anti-tumor activity interval is less than 0.10 and the posterior median 
ORR is 0.30 or more) at the final analysis is not greater than 0.90, and the number of patients 
in that subgroup is less than 25, the study will move to Stage 2 and further enrollment to that 
subgroup will be permitted until a total number of approximately 25 patients is reached to 
further characterize efficacy within that subgroup. If 25 or more patients are already enrolled to 
the subgroup, interim analysis will be performed but no further enrollment will be allowed in 
that subgroup.
4.3
Definition of end of the study
The study will end when the treatment period, safety follow-up, disease progression follow-up 
and survival follow-up have been completed for all patients as described in Section 7.1.6, or 
when the study is terminated early.
Completion of the survival follow-up period will occur once a minimum of 80% of patients in 
the phase II part of both FGF401 single agent and FGF401 in combination with PDR001 have 
died, have been lost to follow-up, or have been followed for survival for minimum 18 months 
after receiving the first dose of study treatment, whichever is sooner see Section 7.1.6.
See Section 10 Statistical Methods and Data Analysis for details of timing of the primary 
analysis and final reporting of data.
The disease and survival follow-up evaluations might not be completed in case Novartis decides 
to stop enrollment prematurely. In such cases, end of study will be when the treatment period 
and the safety follow-up have been completed for all patients.
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 an End of Treatment (EOT) visit, and the 
assessments for EOT as described in Section 7.1.4 should be performed for a prematurely 
withdrawn patient. The investigator may be informed of additional procedures to be followed 
in order to ensure that adequate consideration is given to the protection of the patient’s interests. 
The investigator will be responsible for informing IRBs and/or ECs of the early termination of 
the trial.


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5
Population
5.1
Patient population
The phase I part of this trial with oral FGF401 as single agent will be conducted in adult patients 
with hepatocellular carcinoma or other solid malignancies characterized by positive FGFR4 and 
KLB expression. The phase II part will include 3 Groups as summarized in Figure 4-1.
FGF401 in combination with PDR001 will be administered in adult patients with advanced 
HCC.
The expression of FGFR4, KLB and FGF19 will be tested by a Novartis designated laboratory, 
see Section 7.1.1 and Section 7.2.4.
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study.
5.2
Inclusion criteria
Patients eligible for inclusion in this study have to meet all of the following criteria:
1. Written informed consent must be obtained prior to any  procedures that are not 
considered standard of care. [For Japan only: written consent is necessary both from the 
patient and his/her legal representative if he/she is under the age of 20 years.]
2. Patients (male or female) ≥ 18 years of age
3. ECOG Performance Status ≤ 1
4. Presence of at least one measurable lesion according to RECIST v1.1 (see Section 14.1). 
For HCC patients, lesions previously treated with loco-regional therapy, such as radiation 
therapy, hepatic arterial embolization, radiofrequency ablation, and percutaneous 
interventional therapy should not be considered measurable unless progression is noted at 
baseline.
5. Patients must have a site of disease amenable to biopsy and be suitable and willing to 
undergo the study’s required biopsies according to treating institution’s guidelines and 
requirements for such procedures.
6. Inclusion criteria specific for FGF401 single agent Patients with confirmed positive 
expression of FGFR4 and KLB at molecular pre-screening for Phase I and Phase II-
Group 3. The biomarker positivity will be defined by a Novartis designated laboratory. 
Patients with FGFR4 mutations can be enrolled in the study following discussion and 
agreement with Novartis.
7. Phase I part:
a. Patients with HCC or advanced solid tumors, who have progressed despite standard 
therapies, are intolerant of standard therapy, or for whom no standard therapy exists.
b. For HCC patients:
a. Diagnosis of advanced HCC according to the AASLD Guidelines
b. HCC stage C according to the BCLC staging classification


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c. Current cirrhotic status of Child-Pugh class A (5-6 points), with no 
encephalopathy and/or ascites. Child-Pugh status must be calculated based on 
clinical findings and laboratory results during the Screening period.
8. Phase II part:
a. Group 1: HCC patients from Asian countries
b. Group 2: HCC patients from non-Asian regions
For Group 1 and 2:
a) Diagnosis of advanced HCC according to the AASLD Guidelines
b) HCC stage C according to the BCLC staging classification
c) Prior systemic treatment with sorafenib for advanced HCC with documented 
disease progression during or after discontinuation of sorafenib treatment, or 
intolerance to sorafenib treatment. Specifically, this can be defined as:

Documented radiological confirmation (radiology scans or report) of disease 
progression during or after sorafenib treatment. [For France only: patients must 
have received at least 8 weeks of prior sorafenib treatment.]

Intolerance to sorafenib (at any dose and/or duration) is defined as documented 
sorafenib-related Grade 3 or 4 adverse events that led to sorafenib 
discontinuation.
d) Current cirrhotic status of Child-Pugh class A (5-6 points), with no 
encephalopathy and/or ascites. Child-Pugh status must be calculated based on 
clinical findings and laboratory results during the Screening period.
c. Group 3: Patients with other advanced solid tumor
a) Patients have progressed despite standard therapies, are intolerant of standard 
therapy, or for whom no standard therapy exists.
Inclusion criteria specific for FGF401 in combination with PDR001
9. Patients with HCC as defined below:
a. Diagnosis of advanced HCC according to the AASLD Guidelines
b. HCC stage C according to the BCLC staging classification
c. Current cirrhotic status of Child-Pugh class A (5-6 points), with no encephalopathy 
and/or ascites. Child-Pugh status must be calculated based on clinical findings and 
laboratory results during the Screening period
10. Patients who have received up to 2 previous lines of systemic treatment for advanced 
HCC and one treatment must have included sorafenib with documented disease 
progression during or after discontinuation of sorafenib treatment, or intolerance to 
sorafenib treatment. Specifically, this can be defined as:

Documented radiological confirmation (radiology scans or report) of disease 
progression during or after sorafenib treatment. [For France only: patients must have 
received at least 8 weeks of prior sorafenib treatment.]

Intolerance to sorafenib (at any dose and/or duration) is defined as documented 
sorafenib-related Grade 3 or 4 adverse events that led to sorafenib discontinuation.
11. For Phase II-Stage 2: Documented FGF19 expression level and/or FGF19 pathway 
activation by a Novartis designated laboratory.


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5.3
Exclusion criteria
Patients eligible for this study must not meet any of the following criteria:
1. Previous treatment with a selective FGF19-FGFR4 targeted therapy and/or pan-FGFR 
inhibitor.
2. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the
absorption of oral FGF401 (e.g., ulcerative diseases, uncontrolled nausea, vomiting, small 
bowel resection).
3. Patient have received prior therapies within the following time frames prior to the first 
dose of study treatment:
a. For HCC patients in Phase II (FGF401 single agent) : 

previous systemic anti-cancer therapy other than sorafenib

last dose of sorafenib therapy ≤2 weeks from study treatment start

any other anti-cancer therapy (including locoregional therapy e.g. hepatic arterial 
embolization, radio-frequency ablation, radiation therapy) after disease 
progression during or after sorafenib treatment with the exception of palliative 
radiotherapy to a limited field, such as for the treatment of bone pain.
b. For HCC patients in FGF401 combination with PDR001:

last dose of systemic anti-cancer therapy with sorafenib: ≤2 weeks or

unconjugated monoclonal antibody therapies ≤6 weeks or 5 half-lives, 
whichever is shorter

last dose of conventional cytotoxic chemotherapy: ≤2 weeks (≤6 weeks for 
nitrosoureas and mitomycin-C)

any other anti-cancer therapy (including locoregional therapy e.g. hepatic arterial 
embolization, radio-frequency ablation, radiation therapy) after disease 
progression during or after last systemic treatment with the exception of 
palliative radiotherapy to a limited field, such as for the treatment of bone pain.
c.
For other solid tumor patients: 

The last dose of conventional cytotoxic chemotherapy: ≤2 weeks (≤6 weeks for 
nitrosoureas and mitomycin-C)

Biological therapy (e.g., antibodies): ≤6 weeks

Non-cytotoxic small molecule therapeutics (e.g., sorafenib): ≤5 half-lives or ≤2 
weeks (whichever is longer)

Previous wide field radiotherapy (including therapeutic radioisotopes such as 
strontium 89) ≤ 4 weeks and limited field radiation for palliation ≤ 2 weeks

Participation in a prior investigational study within 7 days or within 5 half-lives 
of the investigational product, whichever is longer
Note: exceptions to the above prior therapy timeframes are possible, on a case by case basis, 
following discussion and mutual agreement between Investigator and Novartis.
4. 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 


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within 3 years prior to study entry; completely resected basal cell and squamous cell skin 
cancers and completely resected carcinoma in situ of any type.
5. Symptomatic CNS metastases which are neurologically unstable, or CNS metastases 
requiring local CNS directed therapy (such as radiotherapy or surgery), or  increasing 
doses of corticosteroids within 2 weeks of first dose of study treatment.
Note: Patients with controlled CNS metastases may participate in this trial. Patients must 
be neurologically stable, having no new neurologic deficits on clinical examination, and 
no new findings on CNS imaging for 4 weeks and before receiving the first dose of study 
treatment and not requiring steroid therapy for at least two weeks before receiving the 
first dose of study treatment. 
6. Any medical condition that would, in the investigator’s judgment, prevent the patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures. Any severe, acute, or chronic medical or psychiatric condition or laboratory 
abnormality that may increase the risk associated with study participation or study 
treatment administration or that may interfere with the interpretation of study results and, 
in the judgment of the investigator, would make the patient inappropriate for the study.
7. Ongoing active diarrhea requiring medications (e.g. bile acid sequestrant (BAS), 
loperamide)
8. Irritable bowel syndrome with signs/symptoms or requires medications
9. Current evidence of calcium-phosphate homeostasis impairment, defined as:
a. Inorganic phosphorus > 5.5 mg/dL
b. Total calcium > 11.5 mg/dL
c. Ionized serum calcium > 1.5 mmol/L
d. Patients with current evidence of endocrine alteration of calcium/phosphate 
homeostasis, e.g. parathyroid disorders, tumor lysis, tumoral calcinosis etc.
10. Patient having out of range laboratory values defined as:
Hematology
a) Hemoglobin < 9 g/dL (SI Units: 90 g/L)
b) Platelet count < 75000/mm3
c) Absolute neutrophil count (ANC) < 1500/mm3
Chemistry
a) 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
b) AST or ALT > 3 x ULN
c) Serum creatinine > 1.5 x ULN or creatinine clearance (calculated using the 
Cockcroft-Gault formula or measured) < 40 mL/min
Coagulation: PT > 4 seconds more than the ULN or INR > 1.7
11. Patients receiving treatment with CYP1A2, CYP2C9 and CYP3A4/5 substrates with a 
narrow therapeutic index (NTI) that cannot be discontinued for the duration of the study 
(refer to Appendix 4).
12.


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13. Patients receiving known BSEP efflux transporter inhibitors that cannot be discontinued 3 
days prior to the start of study treatment and during the course of the study (refer to 
Appendix 4).
14. 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.
15. 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 with study treatment and for the following duration after discontinuation of 
study treatment:

For patients enrolled in FGF401 single agent: 3 days after the last dose of FGF401

For patients enrolled in FGF401 in combination with PDR001: 150 days after the last 
dose of PDR001, and 3 days after the last dose of FGF401 in cases where PDR001 
was discontinued more than 150 days before the last dose of FGF401
Highly effective contraception methods include:

Total abstinence (when this is in line with the preferred and usual lifestyle of the 
subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation 
methods) and withdrawal are not acceptable methods of contraception

Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy), total hysterectomy or 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 subjects on the 
study the vasectomized male partner should be the sole partner for that subject.

Use of oral, injected or implanted hormonal methods of contraception or placement of 
an intrauterine device (IUD) or intrauterine system (IUS), or other forms of hormonal 
contraception that have comparable efficacy (failure rate <1%), for example hormone 
vaginal ring or transdermal hormone contraception. 
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 
(e.g. age appropriate [generally age from 40 to 59 years], history of vasomotor symptoms
[e.g. hot flush]) in the absence of other medical justification, or have had surgical bilateral 
oophorectomy (with or without hysterectomy), 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.
16. Sexually active males unless they use a condom during intercourse while receiving study 
treatment and for the following period after the last dose of study treatment, and should 
not father a child in this period. 

For patients enrolled in FGF401 single agent: 3 days after the last dose of FGF401


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
For patients enrolled in FGF401 in combination with PDR001: 150 days after the last 
dose of PDR001, and 3 days after the last dose of FGF401 in cases where PDR001 
was discontinued more than 150 days before the last dose of FGF401
A condom is required to be used also by vasectomized men in order to prevent delivery of 
the drug via seminal fluid.
17. Major surgery within 2 weeks of receiving 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).
In addition patients eligible for the FGF401 in combination with PDR001 part must not 
meet any of the below criteria:
18. Clinically significant pleural effusion that either required tapping or is associated with 
shortness of breath.
19. Known human immunodeficiency virus (HIV) infection or known acquired 
immunodeficiency syndrome.
20. Active HBV or HCV infection. Patients whose disease is controlled under antiviral 
therapy can be included.
21. Active known or suspected autoimmune disease. Patients with vitiligo, residual 
hypothyroidism only requiring hormone replacement, psoriasis not requiring systemic 
treatment or conditions not expected to recur in the absence of an external trigger can be 
included. Patients previously exposed to anti-PD-1/PD-L1 treatment who are adequately 
treated for skin rash or with replacement therapy for endocrinopathies can be included.
22. History of severe hypersensitivity reactions to any ingredient of study treatment and other 
mAbs and/or their excipients
23. Impaired cardiac function or clinically significant cardiac disease, including any of the 
following: 

Clinically significant or uncontrolled heart disease such as congestive heart failure 
requiring treatment (New York Heart Association Grade ≥ 2), uncontrolled 
hypertension (defined by Systolic Blood Pressure > 160 mmHg/ Diastolic Blood 
Pressure > 100mmHg (average of three consecutive readings) at rest despite medical 
treatment, clinically significant arrhythmia

QTcF > 470 msec on screening ECG (as mean of triplicate ECGs) or congenital long 
QT syndrome

Acute myocardial infarction or unstable angina pectoris < 3 months prior to screening
24. Use of systemic chronic steroid therapy (≥ 10mg/day prednisone or equivalent) or any 
immunosuppressive therapy two weeks prior to start of study treatment. Topical, inhaled, 
nasal and ophthalmic steroids are allowed.
25. Use of any live vaccines against infectious diseases within 4 weeks of initiation of study 
treatment (except inactivated seasonal influenza vaccines).
26. Use of hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF), 
thrombopoietin mimetics or erythroid stimulating agents ≤ 2 weeks prior to start of study 
treatment. If erythroid stimulating agents were initiated more than 2 weeks prior to the 
first dose of study treatment and the patient is on a stable dose, they can be maintained.
27. History of liver or other organ transplantation.


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28. History of immunotherapy-induced pneumonitis or current pneumonitis grade > 2.
29. Patients who discontinued prior anti-PD-1/PD-L1 therapy due to an anti PD-1/PD-L1-
related toxicity.
6
Treatment
6.1
Study treatment
The study treatments are FGF401 as single agent or FGF401 in combination with PDR001.
There is no reference therapy.
6.1.1
Dosing regimen
Table 6-1
Dose and treatment schedule
Study drugs
Pharmaceutical form and 
route of administration
Dose
Frequency and/or 
Regimen
FGF401
capsule for oral use
as assigned 
once daily (QD) on a 
continuous schedule
PDR001
intravenous infusion
300mg
every three weeks 
(3QW)
Patients will be assigned to receive FGF401 on a continuous once daily dosing regimen or the 
combination of FGF401 on a continuous once daily dosing regimen and PDR001 administered 
every three weeks.
The FGF401 dose regimen may change from QD to BID at any time during the study (Section 
4.1).
FGF401
FGF401 will be administered orally on a flat scale of mg/day and not by weight or BSA. 
FGF401 should be taken as follows:

Patients should be instructed to take their dose at approximately the same time every day.

On days when blood for PK samples need to be collected prior to taking study drug, 
patients should be instructed to bring their drug supply to the site, and take the dose in the 
clinic, under supervision of the site personnel.

Each dose should be taken with a glass of water and consumed over as short a time as 
possible unless otherwise instructed.

Patients should be instructed to swallow pill(s) whole and to not chew or open them.

FGF401 should be administered in the fasted state, at least 1 hour before or 2 hours after a 
meal (unless otherwise instructed). Water and other medications are permitted during this 
period.

On days of PK/
 sampling, every effort must be made to capture the time of any 
vomiting within 4 hours of drug administration in both source documents and 
corresponding eCRF. The occurrence and frequency of any vomiting and/or diarrhea (or 


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increase stool frequency) during a treatment cycle must be noted in the Adverse Events 
eCRF.

If vomiting occurs during the course of the treatment, no re-dosing of the patient is 
allowed before the next scheduled dose.

If the patient forgets to take his/her daily dose, then he/she should take FGF401 within 6 
hours after the missed dose. If more than 6 hours have passed, then that dose should be 
omitted and the patient should continue treatment with the next scheduled dose.

Patients should inform the investigational site staff of any missed or delayed doses.
Exploratory food effect cohort- FGF401 single agent

Patients will be treated under fed conditions only when he/she is allocated to the food 
effect cohort in the phase I part.

Patients enrolled in the food effect cohorts will receive each dose of FGF401 with a light 
meal. FGF401 needs to be administered within 30 minutes following the assigned meal, 
see Appendix 8 for test meal guidance.

On days of PK profiles collection (Section 7.2.3.1), the light breakfast will be adapted to 
the local preference and prepared by a registered dietician.
PDR001
PDR001 will be administered via intravenous infusion once every 3 weeks (Section 6.6). 
Sequence of FGF401 and PDR001 administration
FGF401 will be administered prior to PDR001 along with PDR001 pre-medication (if pre-
medication is necessary). The sequence will allow consistent time of daily dosing for FGF401. 
A minimum of 1 hour must pass from the time of FGF401 dose administration to the 
administration of PDR001.
6.1.2
Ancillary treatments
6.1.2.1
Infusion reactions with PDR001
Patients should not receive pre-medication to prevent an infusion reaction before the first 
infusion of study treatment, in order to determine if pre-medication is necessary. If a 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 discontinue study treatment. The patient may resume study treatment 
following documented discussion with the Novartis medical monitor. Guidelines on 
management of infusion reactions are provided in Table 6-5.
The CTCAE category of “Infusion related reaction” should be used to describe study treatment 
related infusion reactions, unless the investigator considers another category, such as “Allergic 


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reaction,” “Anaphylaxis,” or “Cytokine release syndrome” more appropriate in a specific 
situation.
6.1.3
Treatment duration
Patients may continue study treatment until they experience any of the following:

Disease progression (radiologically documented according to RECIST v1.1) as assessed 
by the Investigator if they are treated with FGF401 single agent

Disease progression per irRC if they are treated with FGF401 in combination with 
PDR001. These patients should not be withdrawn from study treatment due solely to 
progressive disease per RECIST v1.1. Refer to Section 7.1.3 and Section 7.1.4 for further 
details.

Unacceptable toxicity 

Treatment is discontinued at the discretion of the Investigator or the patient
Patients who permanently discontinue the study treatment for any reason other than disease 
progression or withdrawal of consent shall continue efficacy assessments as scheduled in the 
protocol Section 7.1.5 until the time of disease progression.
6.2
Dose escalation guidelines
6.2.1
Starting dose rationale
The recommended starting dose of FGF401 single agent for patients enrolled in this trial is 50 
mg p.o. administered continuously once daily (see Appendix 7). This dose is expected to be 
safe and might be pharmacologically active based on human efficacious dose prediction. Safety 
of the starting dose is supported by results of 4-week Good Laboratory Practice (GLP)
toxicology studies conducted in mice and dogs
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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The starting dose of FGF401 in combination with PDR001 is 80mg QD (fasted) which is one 
dose level below the declared RP2D for FGF401 as single agent. The RP2D for FGF401 as 
single agent is 120mg QD administered under fasted conditions.
PDR001 will be administered at a fixed dose of 300mg i.v. every three weeks which is the 
RP2D declared for PDR001 as single agent.
The starting dose of the FGF401 in combination with PDR001 selected satisfies the EWOC 
criteria (Section 2.3) for the combination BLRM.
6.2.2
Provisional dose levels
Table 6-2 describes the starting dose and the dose levels that may be evaluated during this trial
for FGF401 single agent and in combination with PDR001. Dose escalation will continue until 
MTD is reached and/or RP2D is determined. At all decision time points, the BLRM permits 
alterations in the dose increments based on the observed DLTs.
If at any time during the phase I of the FGF401 single agent part of the study, the pre-clinical 
and/or clinical data suggest change of dosing schedule, such as BID dosing or intermittent 
dosing, then the starting total daily dose will be a dose that has previously been confirmed to 
be well tolerated on a continuous once daily dosing schedule within this study and is supported 
by an adjusted BLRM (see Section 6.2.3.1 and Section 10.4 for details). 
With the exception of starting dose level 1, actual dose levels will be determined following a 
discussion with the participating Investigators during the dose escalation teleconferences.
The dose for PDR001 will be fixed for all dose escalation cohorts in the FGF401 and PDR001 
combination part of the study (Section 6.2.1).
Table 6-2
FGF401 Provisional dose levels
Dose level
Proposed total daily dose*
Increment from previous dose
FGF401 as single agent
-2**
20 mg
-33.3%
-1**
30 mg
-40%
1 
50 mg
(starting dose)
2
100 mg
100%
3
200 mg
100%
4
250 mg
25%
5
300 mg
20%
6
400 mg
33%
7
500 mg
25%


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Dose level
Proposed total daily dose*
Increment from previous dose
FGF401 in combination with PDR001
-1
50mg
-37.5%
1
80 mg
starting dose
2
120mg
50%
*It is possible for additional and/or intermediate dose levels to be added during the course of the study. 
Dose levels may also be skipped if the safety data and BLRM analyses support a higher increase limited to 
at most 100% increase in dose level (e.g. a dose increase from 100 mg to 200 mg with the same 
frequency). Cohorts may be added at any dose level below the MTD/RP2D in order to better understand 
safety, PK 
**Dose level -1 and -2 represent treatment doses for patients requiring a dose reduction from the starting 
dose level. No dose reduction below dose level -2 is permitted for this study.
6.2.3
Guidelines for dose escalation and determination of MTD
6.2.3.1
MTD definition
The MTD is defined as the highest drug dosage not expected to cause DLT in 33% or more of 
the treated patients in the evaluation period of FGF401 single agent and FGF401 in combination 
with PDR001 during the phase I respective parts of the study. The evaluation period of DLTs 
for the dose escalation decisions is defined as 1 cycle (21 days) from treatment start for FGF401 
single agent and as 2 cycles (42 days) starting from the first dose of PDR001 administered in 
combination with FGF401. Adverse events and laboratory abnormalities considered to be DLTs 
are defined in Table 6-3.
6.2.3.2
Dose cohort modification
For the purposes of dose escalation decisions, each cohort will consist of 1 to 6 newly enrolled 
evaluable patients for the FGF401 single agent and, 3 to 6 newly enrolled evaluable patients for 
the FGF401 in combination with PDR001, who will be treated at the specified dose level. The 
first cohort will be treated with the starting dose as described in Section 6.2.1. For the FGF401 
and PDR001 combination, for each untested dose level the administration of the first dose of 
the study treatment will be staggered by 24 hours for the first three patients. When two patients
enrolled in an escalation arm (FGF401 single agent or in combination with PDR001; who may 
be in different cohorts) have experienced a toxicity of CTCAE grade 2 for which relationship 
to study drug cannot be ruled out; or when any single patient experiences a DLT or AE of 
CTCAE grade 3 or greater during Cycle 1, the cohort size will be changed to between 3 and 6 
evaluable patients for the current and subsequent cohorts.
Patients must complete a minimum of 1 cycle of treatment with FGF401 single agent and a 
minimum of 2 cycles of treatment with FGF401 in combination with PDR001, with the 
minimum safety evaluation and drug exposure or have had a DLT within the evaluation period 
to be considered evaluable for dose escalation decisions (Section 10.1.4). Dose escalation 
decisions will occur when the cohort of patients has met these criteria. 
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 the DLT evaluation period, PK 
 data from evaluable patients. The 
recommended dose for the next cohort of patients will be guided by the Bayesian models with 


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EWOC principle (Section 2.2). The adaptive Bayesian methodology provides an estimate of all 
dose levels of FGF401 single agent and FGF401 in combination with PDR001 that do not 
exceed the MTD for each treatment 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 and/or changes of dosing schedule 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 
recommended by the Bayesian model using the EWOC principle. If needed to better define the 
dose-toxicity relationship additional patients may be enrolled to the current dose level, to a 
preceding dose level, or to an intermediate dose level before proceeding with further dose 
escalation.
If 2 patients in a previously untested dose level experience a DLT, enrollment to that cohort 
will stop, the Bayesian model will be updated and the next cohort will be opened at the next 
lower dose level or an intermediate dose level 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 Bayesian model will be updated with this new information and re-evaluation of 
the available safety, PK, 
 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 dose 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 as agreed by Investigators and Novartis personnel and if the 
Bayesian model predicts that the risk for this lower dose 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 
highest among potential doses, or
b. a minimum of 21 patients for the FGF401 single agent and a minimum of 12 patients 
for the FGF401 in combination with PDR001 have already been treated on the trial, or
c. significant activity is seen early in the phase I part, in which case a recommended 
dose for expansion may be made 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.
To better understand the safety, tolerability and PK of FGF401 as single agent and in 
combination with 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.


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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 Bayesian model 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.
In the event of a change in dosing schedule for either FGF401 single agent or FGF401 in 
combination with PDR001, then a new Bayesian model will be set up.  This new Bayesian 
model will have the same functional form as that described in Section 10.4.2.1 (for FGF401 
single agent) and in Section 10.4.2.2 (for FGF401 in combination with PDR001) and will
incorporate existing dose escalation data in the prior distributions and a starting dose will be 
identified at that time. Subsequent dosing decisions for the new schedule will follow the same 
rules defined within the above paragraphs of this section.
6.2.3.3
Implementation of dose escalation decisions
To implement dose escalation decisions, the available toxicity information (including adverse 
events and laboratory abnormalities that are not DLTs), the recommendations from the
Bayesian model, and the available PK 
 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 fourth cycle is completed, individual patients may be considered for treatment at a 
dose of FGF401 higher than the dose to which they were initially assigned. In order for a patient 
to be treated at a higher dose of FGF401, he or she must have tolerated the lower dose for at 
least four cycles of therapy without experiencing any treatment -related toxicity defined as 
CTCAE grade ≥ 2 or worse than baseline 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 not exceeded the maximum tolerated dose (MTD). 
There is no limit to the number of times a patient may have his or her dose of FGF401 increased. 
For any further increase after the initial intra-patient dose escalation, the same rules as for the 
initial intra-patient dose escalation will apply. 
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 DLT evaluation period at the new dose level will 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.


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6.2.4
Definitions of dose limiting toxicities (DLTs)
A dose-limiting toxicity (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 evaluation period of DLTs and meets any of the criteria 
included in Table 6-3. For the purpose of dose-escalation decisions, DLTs will be considered 
and included in the Bayesian model. However, events occurring after the DLT evaluation period 
may contribute to the determination of the RP2D. DLTs will not be collected during the phase 
II dose expansion parts of the study. 
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.
Table 6-3
Criteria for defining dose-limiting toxicities
Toxicity
Any of the following criteria occurring in the evaluation period during the phase I 
part of the study for which relationship to study treatment cannot be ruled out a
Hematology
Any Grade 3 hematologic toxicity, lasting for >7 consecutive days
Any ≥Grade 4 hematologic toxicity of any duration
≥Grade 3 Febrile neutropenia 
Renal
≥Grade 3 serum Creatinine increased
Pancreas
Grade 3 Lipase or Serum Amylase increased (asymptomatic), which is not resolved to ≤ 
Grade 2 within 7 days
Grade 4 Lipase or Serum Amylase increased (asymptomatic) of any duration
≥Grade 3 Pancreatitis
Cardiac
≥Grade 3 cardiac disorders
≥Grade 3 ECG QTc corrected interval prolonged
Any cardiac event that is symptomatic or requiring medical intervention
General 
disorders
Grade 3 Fatigue, lasting for >7 consecutive days
Gastrointestinal 
disorders
Grade 2 Diarrhea, which is not resolved to ≤ Grade 1 within 7 days after starting an 
adequate treatment
Grade 3 Diarrhea 
lasting for more than 24 hours after starting an adequate treatment
OR
improved to Grade 2 within 24 hours but not resolved to ≤ Grade 1 within 7 days after 
starting an adequate treatment
≥Grade 4 Diarrhea
Grade 3 Nausea, lasting for >48 hours, despite the use of adequate treatment
≥Grade 3 Vomiting, lasting for >24 hours, despite the use of anti-emetic therapy
Hepatic
For patient’s baseline bilirubin within normal range: Blood bilirubin increased to > 2.0 x ULN
For patient’s baseline bilirubin out of normal range: Blood bilirubin increased to > 1.5 times 
above baseline
For patient’s baseline AST or ALT within normal range: AST or ALT increased to > 5.0 x 
ULN
For patient’s baseline ASTor ALT out of normal range: AST or ALT increased to > 3 times 
above baseline AND > 5.0 x ULN
Metabolic
Serum Pi > 7.0 mg/dL which is not resolved to ≤ 7.0 mg/dL within 7 days after the maximum 
dosing of phosphorus lowering therapy


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Serum Pi > 9.0 mg/dL
≥ Grade 3 hypercalcemia
Other toxicity
Any other CTCAE Grade ≥3 toxicity (except those that can be resolved within 7 days and 
are considered by the investigator to be not clinically important)
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 the evaluation period, may be 
considered to be DLTs by the Investigators and Novartis, even if not CTCAE grade 3 or 
higher.
In addition, the below criteria are considered as DLTs only for the FGF401 and PDR001 combination 
Eye disorders
Grade 2 eye pain or changes in vision that does not respond to topical therapy and does 
not improve to Grade 1 within 2 weeks of the initiation of topical therapy or requires 
systemic treatment
Infection
Grade 3 infection or fever in the absence of neutropenia lasting for > 5 consecutive days
Grade 4 infection
Pneumonitis
Grade 2 pneumonitis not resolving within 7 days after starting treatment with corticosteroids
≥Grade 3 pneumonitis
Immune-
mediated
toxicities
Grade 3 immune mediated toxicities which are not resolved to ≤Grade 1 within 7 days 
despite treatment with corticosteroids.
Grade 4 immune mediated toxicities
a CTCAE version 4.03 will be used for all grading.
6.3
Dose modifications
6.3.1
Dose modification and dose delay
For patients who do not tolerate the protocol-specified dosing schedule due to treatment related 
toxicities, dose adjustments are permitted in order to allow the patient to continue the study 
treatment. 
Patients in the FGF401 and PDR001 combination, who discontinue treatment due to PDR001
or FGF401 related toxicities may continue treatment with FGF401 or PDR001 single agent
respectively, after documented discussion with the Novartis medical monitor.
All changes in the administration of FGF401 or PDR001 must be recorded on the respective 
Dosage Administration Record eCRF pages.
The following guidelines for FGF401 either administered as single agent or in combination with 
PDR001 need to be applied:

For the phase I dose escalation part of the study, dose reductions for FGF401 during the 
evaluation period of DLTs are only allowed if a DLT is observed and recorded. 

All dose modifications should be based on the worst preceding toxicity and guidelines are 
provided in Table 6-4.

If a patient requires a dose interruption of >21 days from the intended day of the next 
scheduled dose, then the patient must be discontinued from the study treatment.

In exceptional situations, study treatment may continue even if the patient experienced one 
of the treatment stopping rules.  The decision to allow for continuation of treatment will be 
made on a case-by-case basis following documented discussion between the Novartis
medical monitor and the Investigator.


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
If a patient remains on study treatment despite dose interruption of > 21 days, i.e. patient 
with evidence of clinical benefit and in the opinion of the investigator it is in the best interest 
of the patient to remain on study, then the rationale for remaining on the study and the
decision and documentation of the discussion with the Novartis medical monitor must be 
available in the source documentation and described as an investigator comment in the 
eCRF.
The following guidelines for PDR001 need to be applied:

Dose reductions are not permitted for PDR001.

PDR001 may be delayed due to toxicities. The PDR001 dosing may resume once the
adverse event has resolved to ≤Grade 1 or to the patient’s screening value and the start of 
the cycle will be shifted accordingly. Disease assessments will continue to occur at the 
frequency that was originally specified within protocol.

Overall, for adverse events of potential immune-related etiology (irAE) that do not recover 
to ≤ Grade 1 or patient’s screening value at a dose of immunosuppression of ≤ 10 mg/day 
prednisone or equivalent within 12 weeks after initiation of immunosuppressive therapy, 
PDR001 must be permanently discontinued.

If a patient experiences an AE meeting the criteria for DLT as outlined in Section 6.2.4
(including events occurring after cycle 2), treatment with PDR001 should be withheld. 
The same applies for any Grade 3 irAE that would require the use of systemic steroids. A 
decision to resume treatment with PDR001 following the occurrence of a DLT or any 
Grade 3 irAE is at the discretion of the Investigator. 

If the Investigator considers it to be in the patient’s best interest to resume therapy before 
the toxicity has resolved to Grade 1, or to resume without dose reduction of FGF401 if 
applicable, this may be permitted on a case by case basis, following documented 
discussion with the Novartis medical monitor.

If more than 12 consecutive weeks are required before recovery from PDR001-related 
toxicities, then the patient must permanently discontinue PDR001 treatment.

Table 6-4 and Table 6-5 outline the recommended dose modifications for selected 
toxicities. Additional recommended dose modifications are provided in the Appendix 11, 
which outlines management algorithms for the following groups of AEs: Pulmonary, 
Gastrointestinal, Renal, Endocrinopathy, Hepatic and Skin.


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Table 6-4
Criteria for interruption and re-initiation of FGF401 as single agent and in combination with PDR001
Recommended Dose Modifications for FGF401
For the FGF401 in combination with PDR001 treatment: Dose level maintenance, dose omission and treatment discontinuation refer to both FGF401 and PDR001. 
Reduction of one dose level refers to FGF401 only while PDR001 dose level should be maintained, unless otherwise specified.
Worst toxicity
CTCAE v4.03 Grade
Recommended dose modifications any time during a cycle of therapy (including intended day of dosing)
No toxicity
Maintain dose level
Investigations (Hematologic)
Neutropenia (Neutrophil count decreased)
Grade 3 (ANC < 1000 - 500/mm3)
Maintain dose level, if not resolved to ≤ Grade 1 or baseline* within 7 days, then omit dose until resolved to ≤ 
Grade 1 or baseline, and then ↓1 dose level
Grade 4 (ANC < 500/mm3)
Omit dose until resolved to ≤ Grade 1 or baseline, then ↓1 dose level
Thrombocytopenia (Platelet count decreased)
Grade 3 (PLT < 50,000 – 25,000/mm3)
Maintain dose level, if not resolved to ≤ Grade 1 or baseline within 7 days, then omit dose until resolved to ≤ 
Grade 1 or baseline, and then ↓1 dose level
Grade 4 (PLT < 25,000/mm3)
Omit dose until resolved to ≤ Grade 1 or baseline, then ↓1 dose level
Grade 3 Febrile neutropenia
Omit dose until resolved, then:
If resolved in ≤ 7 days, then maintain dose level
If resolved in > 7 days, then ↓1 dose level
Investigations (Renal)
Serum creatinine increased 
Grade 1 (> 1 - 1.5 x baseline; > ULN - 1.5 x ULN)
Maintain dose level
Grade 2 (> 1.5 – 3.0 x baseline; > 1.5 - 3.0 x ULN)
Maintain dose level
Grade 3 (> 3.0 x baseline; > 3.0 - 6.0 x ULN)
Omit dose until resolved to ≤ Grade 1 or baseline, then↓1 dose level
Grade 4 (> 6.0 x ULN)
Omit dose and discontinue patient from study drug treatment
Investigations (Pancreatic)
Asymptomatic Amylase and/or Lipase increased
Grade 3 (> 2.0 - 5.0 x ULN)
Maintain dose level, if not resolved to ≤ Grade 1 or baseline within 7 days, then omit dose until resolved to ≤ 
Grade 1 or baseline, and then ↓1 dose level
Grade 4 (> 5.0 x ULN)
Omit dose and discontinue patient from study drug treatment


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Recommended Dose Modifications for FGF401
For the FGF401 in combination with PDR001 treatment: Dose level maintenance, dose omission and treatment discontinuation refer to both FGF401 and PDR001. 
Reduction of one dose level refers to FGF401 only while PDR001 dose level should be maintained, unless otherwise specified.
Worst toxicity
CTCAE v4.03 Grade
Recommended dose modifications any time during a cycle of therapy (including intended day of dosing)
≥Grade 3 Pancreatitis
Omit dose and discontinue patient from study drug treatment
Investigations (Hepatic)
Blood bilirubin increased
For patient’s baseline total bilirubin is ≤ ULN
> ULN – 2.0 x ULN
Maintain dose level
> 2.0 - 3.0 x ULN
Omit dose and consider excluding immune mediated etiology** until resolved to ≤ 2.0 x ULN, then:
If resolved in ≤ 7 days, then ↓1 dose level (any subsequent > 2.0 x ULN requiring discussion  with Novartis)
If resolved in > 7 days, then discontinue patient from study drug treatment
> 3.0 x ULN
Omit dose and discontinue patient from study drug treatment
Blood bilirubin increased
For patient’s baseline total bilirubin is > ULN
> ULN – 1.5 times above baseline
Maintain dose level
> 1.5 – 3.0 times above baseline
Omit dose and consider excluding immune mediated etiology** until resolved to ≤ 1.5 times above baseline, 
then:
If resolved in ≤ 7 days, then ↓1 dose level (any subsequent > 1.5 times above baseline requiring discussion  
with Novartis)
If resolved in > 7 days, then discontinue patient from study drug treatment
> 3.0 times above baseline
Omit dose and discontinue patient from study drug treatment
AST and/or ALT increased
For patient’s baseline AST/ALT are ≤ ULN
Grade 1 (> ULN – 3.0 x ULN)
Maintain dose level
Grade 2 (> 3.0 - 5.0 x ULN)
Maintain dose level
Grade 3 (> 5.0 – 20.0 x ULN)
Omit dose and consider excluding immune mediated etiology** until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then ↓1 dose level (any subsequent > 5.0 x ULN requiring discussion  with Novartis)
If resolved in > 7 days, then discontinue patient from study drug treatment
Grade 4 (> 20.0 x ULN)
Omit dose and discontinue patient from study drug treatment
AST and/or ALT increased
For patient’s baseline AST/ALT are > ULN


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Recommended Dose Modifications for FGF401
For the FGF401 in combination with PDR001 treatment: Dose level maintenance, dose omission and treatment discontinuation refer to both FGF401 and PDR001. 
Reduction of one dose level refers to FGF401 only while PDR001 dose level should be maintained, unless otherwise specified.
Worst toxicity
CTCAE v4.03 Grade
Recommended dose modifications any time during a cycle of therapy (including intended day of dosing)
> ULN – 3.0 times above baseline
Maintain dose level
> 3.0 – 5.0 times above baseline but < 5.0 x ULN
Maintain dose level
> 3.0 – 5.0 times above baseline AND > 5.0 x ULN
Omit dose and consider excluding immune mediated etiology** until resolved to ≤ Grade 1, then:
If resolved in ≤ 7 days, then ↓1 dose level (any subsequent > 5.0 x ULN requiring discussion  with Novartis)
If resolved in > 7 days, then discontinue patient from study drug treatment
> 5.0 times above baseline
Omit dose and discontinue patient from study drug treatment
Metabolic
Hyperphosphatemia
Please refer to the guidelines for study drug-induced hyperphosphatemia provided in Appendix 6.
Hypercalcemia
Grade 1
Maintain dose level
Grade 2
Maintain dose level and start adequate therapy immediately
≥Grade 3
Start adequate therapy immediately and omit dose until resolved to ≤ G1, then:
If resolved in ≤ 7 days, then 1 dose level
If resolved in > 7 days, then discontinue patient from study drug treatment
Gastrointestinal disorders
Diarrhea
Grade 1-4
Please refer to the guidelines for FGF401-induced diarrhea provided in Appendix 5. If diarrhea is not improved 
with cholestyramine, consider immune mediated toxicity and refer to guidelines provided in Appendix 11
Grade 3 Nausea
Maintain dose level, if not resolved to ≤ Grade 2 within 48 hours despite the use of adequate treatment, then 
omit dose until resolved to ≤ Grade 2, and then ↓1 dose level
≥ Grade 3 Vomiting
Maintain dose level, if not resolved to ≤ Grade 2 within 24 hours after the optimal anti-emetic therapy start, then 
omit dose until resolved to ≤ Grade 2, and then ↓1 dose level
General disorders
Grade 3 Fatigue
Maintain dose level, if not resolved to ≤ Grade 2 within 7 days, then omit dose until resolved to ≤ Grade 2, and 
then ↓1 dose level
Stevens-Johnson syndrome (SJS), or Lyell 
syndrome/toxic epidermal necrolysis (TEN)
Permanently discontinue study treatment.
Other adverse events


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Recommended Dose Modifications for FGF401
For the FGF401 in combination with PDR001 treatment: Dose level maintenance, dose omission and treatment discontinuation refer to both FGF401 and PDR001. 
Reduction of one dose level refers to FGF401 only while PDR001 dose level should be maintained, unless otherwise specified.
Worst toxicity
CTCAE v4.03 Grade
Recommended dose modifications any time during a cycle of therapy (including intended day of dosing)
Grade 1 or 2
Maintain dose level
Grade 3
Omit dose until resolved to ≤ grade 1, then ↓1 dose level. 
Note: Dose level can be maintained in case they are resolved within 7 days and are considered not clinically 
important.
Grade 4
Omit dose and discontinue patient from study
All dose modifications should be based on the worst preceding toxicity.
CTCAE version 4.03 will be used for all grading.
*baseline refers to respective laboratory values before start of the study treatment
** in case immune mediated etiology cannot be excluded; consider following the guidelines in Appendix 11


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Table 6-5
Criteria for interruption and re-initiation of PDR001 treatment
Recommended dose modifications for PDR001
Worst toxicity CTCAE v4.03 grade
Anytime during a cycle of therapy and after the DLT evaluation period*
Infusion Reaction
Grade 1
Infusion interruption not indicated; decrease infusion rate until recovery of 
symptoms
Grade 2
Stop infusion of PDR001. 
Before resuming infusion pre-medicate according to local institutional 
guidelines.
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 discontinue patient from PDR001
Grade 3 or 4
Discontinue infusion immediately, and discontinue patient from PDR001
Stevens-Johnson syndrome (SJS), or 
Lyell syndrome/toxic epidermal 
necrolysis (TEN)
Permanently discontinue study treatment
Pulmonary: Pneumonitis
Management Algorithms (Appendix 11)
Renal: Serum Creatinine
Management Algorithms (Appendix 11)
Gastro-intestinal: Diarrhea/Colitis
Management Algorithms (Appendix 11)
Skin: Rash
Management Algorithms (Appendix 11)
Endocrinopathy: TSH
Management Algorithms (Appendix 11)
Other clinically significant toxicities thought to be immune-mediated and not covered in Appendix 11
Grade 1
Monitor closely until resolution and treat symptoms as appropriate
Grade 2
Delay PDR001 treatment until resolved to ≤ Grade 1
Grade 3 or 4
Permanently discontinue PDR001 treatment
Cytokine Release Syndrome (CRS)
Grade 2, 3 or 4
If CRS is suspected (very high fever and precipitous drops in blood 
pressure) treat with corticosteroids. 
Take blood for cytokine measurements immediately after the occurrence
and during treatment (Section 7.2.2.5.10). Following approval of protocol 
amendment 05, no further sample collection will be performed for the 
cytokine measurements.
If very high levels of IL-6 can be confirmed, a more specific treatment 
may be used.
*for infusion reaction and cytokine release syndrome the dose modifications are applicable anytime during a cycle 
of therapy (including intended day of dosing)
6.3.2
Follow-up for toxicities
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 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) until resolution or 
stabilization of the event, whichever comes first. For patients with ≥Grade 2 hepatic toxicities 
which relationship to study treatment cannot be ruled out, the hepatic laboratory parameters 
should be followed up within 72 hours. 
The emergence of irAE may be anticipated based on general experience in clinical studies with 
similar class of compounds that block the negative immune regulators.


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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 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.
Management Algorithms (Appendix 11) have been developed to assist Investigators in 
assessing and managing specific groups of AEs.
All 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-weeks intervals, until resolution or stabilization of the event, 
whichever comes first. Appropriate clinical experts should be consulted as deemed necessary. 
In case of toxicity suspected to be a cytokine release syndrome, the assessments outlined in 
Section 7.2.2.5.10 must be performed. Following approval of protocol amendment 05, no 
further sample collection will be performed for the cytokine analysis.
All patients must be followed-up for irAEs, AEs and SAEs as described in Section 7.1.6.
6.3.3
Anticipated risks and safety concerns of the study drug
Appropriate eligibility criteria and specific DLT definitions, as well as specific dose 
modification and stopping rules are included in this protocol. Prophylactic or supportive 
treatment for expected toxicities, including management of study-treatment induced adverse 
events will be as per institutional guidelines. Recommended guidelines for the management of 
FGF401-induced diarrhea and hyperphosphatemia are provided in Appendix 5 and Appendix 6
respectively. Moreover, patients will not initially receive prophylactic treatment with anti-
emetics in cycle 1, but should receive treatment for nausea/vomiting as per institutional 
guidelines. 
In addition, recommended guidelines for prophylactic or supportive treatment for expected 
toxicities with the FGF401 and PDR001 combination, including management of immune 
related toxicities, are provided in Section 6.3 and Appendix 11.
Refer to Section 1.2
 
6.4
Concomitant medications
6.4.1
Permitted concomitant therapy
In general, concomitant medications and therapies deemed necessary for the supportive care
(e.g. phosphate lowering therapy and anti-diarrhea therapies) and safety of the patient are 
allowed, except for those prohibited as stated in Section 6.4.3.
Prophylactic phosphate lowering and/or anti-diarrhea therapies should be considered as per the 
management guidelines provided in Appendix 5 and Appendix 6. Prophylactic phosphate 
lowering and/or anti-diarrhea therapies are also recommended once the MTD and/or RP2D have


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been established during the FGF401 single agent phase I and dose-related hyperphosphatemia 
and diarrhea have been well-characterized.
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of the study drug. All medications (other than study treatment) and 
significant non-drug therapies (including physical therapy, herbal/natural medications and 
blood transfusions) administered during the study must be listed on the Prior and Concomitant 
Medications eCRF or the Surgical and Medical Procedures eCRF.
6.4.2
Permitted concomitant therapy requiring caution and/or action
Medications that are inducers or inhibitors of CYP3A4/5 are not prohibited but should be 
administered with caution. Concomitant medications that may potentially inhibit BSEP ( the 
known BSEP inhibitors  are prohibited), MRP2/3/4, NTCP and OATP1B1/3, which are 
involved in bile acid transport, should be administered with caution, as increase in bile acid 
synthesis is expected at efficacious doses. Refer to Appendix 4 for a list of the medications that 
require caution when concomitantly used with FGF401 as single agent or in combination with 
PDR001.
Anti-hypertensives are allowed as concomitant medications; however, because transient 
hypotension has occurred during infusions of monoclonal antibodies, consideration should be 
given to withholding anti-hypertensive medications for 12 hours prior to infusion with PDR001
for patients receiving the FGF401 and PDR001 combination treatment.
6.4.3
Prohibited concomitant therapy
FGF401 is a time-dependent inhibitor of CYP1A2, CYP2C9 and CYP3A4/5. CYP1A2, 
CYP2C9 and CYP3A4/5 substrates with a narrow therapeutic index (NTI) are prohibited during 
the course of the study. FGF401 treatment may increase the levels of bile acids as a result of 
mechanism of action. Therefore medications that are reported to be inhibitors of the bile acid 
efflux transporter BSEP shall be prohibited during this study.
Additionally, for patients receiving FGF401 in combination with PDR001:
Treatment with the following agents is not permitted within 2 weeks prior to the first dose of 
study treatment:

hematopoietic colony-stimulating growth factors (e.g. G-CSF, GM-CSF, M-CSF)

thrombopoietin mimetics or 

erythroid stimulating agents; however, if erythroid stimulating agents were initiated more 
than 2 weeks prior to the first dose of study treatment and the patient is on a stable dose, 
they can be maintained. 
The use of systemic steroid therapy and other immunosuppressive drugs is not allowed except 
for the treatment of infusion reaction, irAEs, for prophylaxis against imaging contrast dye 
allergy or replacement-dose steroids in the setting of adrenal insufficiency (providing this is ≤
10 mg/day prednisone or equivalent), or transient exacerbations of other underlying diseases 
such as chronic obstructive pulmonary disease (COPD) requiring treatment for ≤3 weeks. 
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 


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next study drug administration. If more than 10 mg/day prednisone is used, study treatment 
should be suspended. Topical, inhaled, nasal and ophthalmic steroids are allowed.
The use of live vaccines is not allowed through the duration of the study. Inactivated vaccines 
are allowed.
During the course of the study, patients must not receive other additional investigational drugs, 
devices, chemotherapy, or any other therapies that may be active against cancer or modulate 
the immune responses. However, limited-field palliative radiotherapy to non-target lesion(s) 
may be allowed as concomitant therapy after documented discussion with Novartis. Such local 
therapies administered during the study treatment must be entered into the CRF. Additionally, 
no other therapeutic monoclonal antibodies and no immunosuppressive medication may be 
administered while on this study unless given for the management of immune toxicity.
Refer to Appendix 4 for a list of the medications that are prohibited when concomitantly used 
with FGF401 as single agent and in combination with PDR001.
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 molecular pre-screening or screening as applicable 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 subject is 
numbered uniquely across the entire database. Upon signing the informed consent form, the 
patient is assigned to the next sequential Subject No. available to the investigator through the 
Oracle Clinical RDC interface.
6.5.2
Treatment assignment
This is a non-randomized trial and Integrated Response Technology (IRT) will not be used. The 
assignment of a patient to a particular cohort during the phase I parts, and during the  phase II
parts will be coordinated by Novartis.
6.6
Study drug preparation and dispensation
The investigator or responsible site personnel must instruct the patient or caregiver to take 
FGF401 as per protocol. FGF401 will be dispensed to the patient by authorized site personnel 
only. All dosages prescribed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record eCRF.
PDR001 
 will be administered intravenously as a 30 
minute infusion (up to 2 hour, if clinically indicated). Further instructions for the preparation 
and dispensation of PDR001 are described in the Pharmacy Manual.
6.6.1
Study drug packaging and labeling
The FGF401 packaging has a 2-part label. Responsible site personnel will add the patient 
number on the label. Immediately before dispensing the package to the patient, site personnel 


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will detach the outer part of the label from the packaging and affix it to the source document
for that patient’s unique subject number.
 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug and but no information about the 
patient.
6.6.2
Drug supply and storage
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, FGF401 and PDR001 should be stored according to 
the instructions specified on the drug labels 
 
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 
record. 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 according to local institutional drug 
accountability processes. Drug accountability will be noted by the field monitor during site 
visits and at the completion of the study. 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.
Arrange for drug supply to be destroyed at the site only if permitted by local regulations and 
authorized by Novartis in a prior agreement.


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7
Visit schedule and assessments
7.1
Study flow and visit schedule
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. No CRF will be used as a source document. The table indicates which 
assessments produce data to be entered into the clinical database (D) or remain in source 
documents only (S) (“Category” column).
For Japan only, patients are required to be hospitalized in Cycle 1 of the dose escalation parts.
For all visits, there is a ± 3 days window on assessments if not explicitly specified otherwise. 
In particular, full PK sampling should be performed on the specified day of dosing and time-
point. In any case, if the dosing schedule is changed, the visit evaluation schedule will follow 
Table 7-1 without changes. In general, where possible, every effort must be made to follow the 
schedule outlined in Table 7-1.
Screening assessments need to be performed within 14 days from the first dose of study 
treatment with the exception of pregnancy test which must be performed within 72 hours from 
study treatment start. Laboratory assessments performed as part of the screening evaluations 
and within 72 hours of the cycle 1 day 1, are not required to be repeated on the first dosing day. . 
Screening radiological assessment should be performed preferably within 7 days prior to the 
first study treatment dose; however radiological assessments that are performed up to 21 days 
before the first study treatment dose will be acceptable; (except whole body scans, if applicable, 
which can be performed within 6 weeks of study treatment start) On-study radiological 
assessments can be performed within a ± 7 days window from the scheduled date of the 
assessment.
Following approval of protocol amendment 05, the ongoing patients will follow a reduced 
schedule of safety and efficacy assessments as detailed in Table 7-1b. The assessments in Table 
7-1 will no longer be applicable. Table 7-1b indicates which assessments produce data to be 
entered into the clinical database (D) or remain in source documents only (S) (“Category” 
column).
Other assessments may be performed at the Investigator’s discretion following standard of care 
at the site. When abnormal laboratory values or test results constitute an adverse event, they 
must be recorded on the Adverse Events eCRF.


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Table 7-1
Visit evaluation schedule (applicable for protocol amendment 04 - following approval of protocol amendment 05
refer to Table 7-1b below) 
Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15
Obtain molecular pre-
screening Informed 
Consent
D
7.1.1
X as 
appicable
Obtain Informed 
Consent
D
7.1.2
X
Patient History
Demography
D
7.1.2.2
X
X
Inclusion/exclusion 
criteria
D
5
X
X
Relevant medical 
history/current medical 
conditions
D
7.1.2.2
X
Diagnosis and extent of 
cancer
D
7.1.2.2
X
Child-Pugh and BCLC 
classification, 
applicable to HCC 
patients
D
7.1.2.2
X
Prior antineoplastic 
therapies
D
7.1.2.2
X


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Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15
Prior/concomitant 
medications
D
7.1.2.2
X
Continuous (for 150-day safety FU: until the 30-day safety FU or the start of new 
antineoplastic therapy, whatever occurs first)
Physical examination
S
7.2.2.1
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
ECOG Performance 
status
D
7.2.2.4
X
X
X
X
X
Laboratory assessments
Hematology
D
7.2.2.5.1
X
X
X
X
X
X
X
X
X
C3/C4 
only
X
Chemistry
D
7.2.2.5.2
X
X
X
X
X
X
X
X
X
C3/C4 
only
X
Coagulation
D
7.2.2.5.3
X
X
X
X
X
X
Urinalysis
D
7.2.2.5.4
X
X
X
Pregnancy test 
D
7.2.2.5.8
X
X
X
X
S
Xb


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Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15
AFP, applicable to HCC 
patients, every 6 weeks
D
7.2.2.5.5
X
X
Hepatitis markers, 
every 6 weeks starting 
from C3
D
7.2.2.5.6
X
X
X
HIV (for 
FGF401+PDR001 only)
D
7.2.2.5.6
X
Thyroid function (for 
FGF401+PDR001 only)
D
7.2.2.5
X
X
X
X
X
Cytokines for safety 
(FGF401+PDR001 
only)
D
7.2.2.5.10
X
any time when a suspected cytokine release syndrome occurs, within 5 hours (or 
as soon as possible) after the occurrence of the AE, and one week after 
occurrence of the AE
Efficacy assessments
Tumor response 
assessment , every 6 
weeks starting by C3D1
D
7.2.1
X
X
X
X
Cardiac assessments
12-lead ECG
D
7.2.2.6.1
X
X
X
X
X
PK sampling
FGF401 PK sampling 
(Phase I parts)- all 
patients
D
7.2.3.1
X
X
X
X
X
X
X
X
C3/C4 
only


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Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15
FGF401 PK sampling 
(Phase II parts)- all 
patients
D
7.2.3.1
X
X
X
X
X
X
X
C3-
C6 
only
PDR001 PK sampling 
(Phase I part)- for 
FGF401+PDR001 only
D
7.2.3.1
X
X
X
X
X up 
to C6
X for 
C3 
only
X
Xc
PDR001 PK sampling 
(Phase II part)-for 
FGF401+PDR001 only
D
7.2.3.1
X
X
X up 
to C6
X
Xc
PDR001
immunogenicity (IG) 
sampling- for 
FGF401+PDR001 only
D
7.2.3.1
X
X
X up 
to C6
X
Xc


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Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15


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Category
Protocol 
Section 
Molecular 
pre-screening
Screening
Cycle 1
Cycle 2
Subsequent 
Cycle
End of study 
treatment 
30 or 150-day 
Safety-FUa
Disease 
progression
Survival FU
Visit Name
Day -14 to 
Day 1
Day 1
Day 2
Day 8
Day 9
Day 15
Day 1
Day 2
Day 8
Day 15
Day 1
Day 15
FGF401administration
D
6
Continuous
PDR001 infusion (for 
FGF401+PDR001 only)
D
6
i.v. every 3 weeks (in case of sequential schedule start from C3D1)
Antineoplastic therapies 
since discontinuation of 
study treatment
D
7.1.5
X
X
X
Adverse events
D
8
SAE
Only
Continuous (for 150-day safety FU: after initiation of new antineoplastic therapy only AEs/SAEs 
suspected to be related to study treatment will be collected)
Survival contact
D
7.1.5
X
a for FGF401 single agent safety evaluations for 30 days after the last dose of FGF401. For FGF401 and PDR001 combination safety evaluations for 150 days after the 
last dose of PDR001 with contacts at 30-, 90- and 150-day (see Section 7.1.6).
b only for FGF401 and PDR001 combination with tests every month until the end of 150-day safety FU. Pregnancy tests can be performed at home or at a local 
doctor’s office if the patient is not coming to the clinic.
c only for patients coming to the site for the 150-day safety follow-up visit
e collect at screening or anytime thereafter


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Table 7-1b
Visit evaluation schedule – applicable upon approval of protocol amendment 05
Category
Treatment Phase- all cycles until end of study treatment
End of 
study 
treatment 
30 or 
150-
day  
Safety
-FUa
Disease 
progression 
FU
Survival FU
FGF401 single agent:
Visit every 2 cycles (i.e. every 6 
weeks)
FGF401+PDR001 combination:
Visit every cycle (i.e. every 3 
weeks)
Visit Name
Day 1 
Physical examination
S
X
X
X
Vital signs 
D
X
Hematology
D
X
X
X
Chemistry
D
X
X
X
Pregnancy test 
D
Xc
X
X
S
Xb
Hepatitis markers
D
X 
X every 6 weeks
X
Tumor response assessment
D
X every 12 weeks
X
X
FGF401 administration
D
Continuous
PDR001 infusion 
D
X i.v. every 3 weeks
Adverse events
D
Continuous a
Concomitant medications
D
Continuous a
Antineoplastic therapies since 
discontinuation of study treatment
D
X
X
X
Survival contact
D
X
a for FGF401 single agent safety evaluations for 30 days after the last dose of FGF401. For FGF401 and PDR001 combination safety evaluations for 150 days after the 
last dose of PDR001 with contacts at 30-, 90- and 150-day (see Section 7.1.6). 
For the 150-day safety FU: After initiation of new antineoplastic therapy only AEs/SAEs suspected to be related to study treatment will be collected. Collection of 
concomitant medications will be until the 30-day safety FU or the start of new antineoplastic therapy, whatever occurs first.
b only for FGF401 and PDR001 combination with tests every month until the end of 150-day safety FU. Pregnancy tests can be performed at home or at a local 
doctor’s office if the patient is not coming to the clinic. 
c Serum pregnancy test at Day 1 of each cycle (note that on the release date of protocol amendment 05, there were no female participants that are of child-bearing
potential on study).


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7.1.1
Molecular pre-screening
During the phase I part of FGF401 single agent, FGFR4 and KLB expression will be assessed 
using RT-PCR and/or IHC assays. Biomarker positivity will be defined by a Novartis 
designated laboratory that is certified to perform clinical assays. FGF19 mRNA expression will 
be also assessed by RT-PCR, but it will not be used as inclusion criterion. During the phase II 
part of the FGF401 single agent, evidence of positive expression of FGFR4 and KLB is required 
in order to begin screening activities only for patients in Group 3. FGF19 expression will be 
also assessed, but it will not be used as inclusion criterion. In exceptional cases, patients with a 
tumor harboring a documented FGFR4 mutation can be enrolled in the study following 
discussion and agreement with Novartis.
Molecular pre-screening will not be performed for the FGF401 and PDR001 combination part.
However, should, the Stage 2 of the FGF401 and PDR001 combination part proceed, based on 
the interim analyses results (Section 4.2), the FGF pathway expression level and/or FGF19 
pathway activation as deemed necessary, will be required for enrollment and molecular pre-
screening will be initiated at that stage.
The molecular status must be obtained through the submission of newly obtained tumor samples 
which are collected after the latest anti-neoplastic treatment failure to a Novartis designated 
laboratory for testing. The potential patients will be asked to sign a “molecular pre-screening 
informed consent” to allow for the collection and analysis of the newly obtained tumor samples. 
The newly obtained tumor samples can be submitted for analysis as formalin fixed tumor 
sample or FFPE block prepared from multiple (3-6) passes of a core needle tumor biopsy. For 
details of sample quality requirements refer to the applicable study Laboratory Manual . If the 
patient is enrolled in the main study, the newly obtained tumor sample submitted for molecular 
pre-screening can be used for other 
 study assessments. For other details, refer to
Section 7.2.4.
7.1.2
Screening
The allocation of patients to treatment cohorts and Groups will be handled by Novartis study 
team.
A written informed consent form (ICF) will be obtained from each patient before any study 
related procedures are initiated. Laboratory and radiological evaluations which are part of the 
patient’s standard of care may be performed before obtaining the ICF, if within the acceptable 
screening window (Section 7.1).
Patients will be evaluated against study inclusion and exclusion criteria and safety assessments.
A complete list of screening evaluations is provided in the visit of assessments table (Table 7-
1).
7.1.2.1
Information to be collected on screening failures
Patients who signed a molecular pre-screening ICF but are considered ineligible after molecular 
pre-screening, as well as patients who are found not eligible after signing the main study consent 
will be considered screening failures, and data will be handled in the same manner. The reason 


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for molecular pre-screening failure or screening failure will be entered on the Screening Phase 
Disposition Page.
The demographic information, informed consent, and Inclusion/Exclusion pages must also be 
completed for Screen Failure patients. No other data will be entered into the clinical database 
for patients who are screen failures, unless the subject experienced a Serious Adverse Event 
during the Screening Phase (see Section 8 for SAE reporting details). For molecular pre-
screening failures, only SAEs possibly related to a study procedure will be reported.
7.1.2.2
Patient demographics and other baseline characteristics
Data will be collected on patient characteristics including demographic information (age, 
gender, race) and other background or relevant medical history, including history of disease and 
current disease status, diagnosis and extent of cancer (for HCC patients, BCLC staging and 
Child-Pugh classification systems are applied), prior anticancer therapies, prior medication/ 
significant non-drug therapies and any other assessments that are done for the purpose of 
determining eligibility for inclusion in the study.
7.1.3
Treatment period
A treatment cycle is defined as 21 days (3 calendar weeks) for the purposes of scheduling 
procedures and evaluations. Please refer to Table 7-1 or Table 7-1b following approval of 
protocol amendment 05 for details of the timing of required assessments and Section 7.1 for 
visit windows.
Patients may continue treatment with FGF401 single agent or in combination with PDR001
until the patient experiences unacceptable toxicity that precludes any further treatment, disease 
progression, and/or treatment is discontinued at the discretion of the investigator or by patient 
request. 
In general, patients who have disease progression and have evidence of clinical benefit, such as
disease shrinkage at other sites or symptomatic improvement, may continue receiving study 
treatment. In addition, study treatment may be temporarily interrupted to permit local therapy 
for symptomatic metastases after disease progression has been documented. Patients who 
continue on treatment after disease progression should discontinue study treatment once they 
are no longer deriving benefit as assessed by the investigator. All patients will continue to 
follow the assessments as outlined in the visit evaluation table, Table 7-1 or Table 7-1b
following approval of protocol amendment 05.
For patients treated with immunotherapy, including PD-1 inhibitor, clinical experience 
indicates that objective responses to immunotherapy follows delayed kinetics of weeks or 
months, and can be preceded by initial apparent radiological progression or appearance of new 
lesions or some enlarging lesions while other target lesions are regressing (“mixed response”) 
(Wolchok 2009). It is therefore reasonable to allow for these possibilities and continue to treat 
the patient until progression is confirmed and found to be advancing at the next imaging 
assessment as per irRC. An outline of the irRC is provided in Appendix 9.
Patients treated with FGF401 in combination with PDR001 will continue study treatment in 
additional cycles if they meet the following criteria:

Unconfirmed irPD, SD/irSD, PR/irPR and unconfirmed CR/irCR.


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Patients treated with FGF401 in combination with PDR001 will not continue study treatment 
in additional cycles if they meet any of the following criteria:

Experience unacceptable toxicity.

Confirmed irPD. These patients will then enter the Safety follow-up period. 

Patients with an unconfirmed irPD who show signs of clinical deterioration or toxicity will 
enter the Safety follow-up period, and will continue to be followed-up until confirmed 
irPD or initiation of a new treatment.
Patients with confirmed irPD might continue receiving study treatment, if the Investigator 
considers it to be in the patient’s best interest to remain on the study, and after documented 
discussion with the Novartis medical monitor.
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.
7.1.4
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 should make a 
reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for this 
decision and record this information in the patient’s chart and on the appropriate CRF pages. 
They may be considered withdrawn if they state an intention to withdraw, fail to return for visits, 
or become lost to follow-up for any other reason.
Study treatment must be discontinued under the following circumstances:

Adverse events, that results in a significant risk to the patient’s safety.

The following deviation from the prescribed dose regimen for study treatment: dose 
interruption of > 21 days from the intended day of the next scheduled dose for FGF401 or 
in case > 12 consecutive weeks are required before recovery from PDR001-related 
toxicities, unless otherwise specified in Section 6.3.1

Pregnancy

Any other protocol deviation that results in a significant risk to the patient’s safety
Patients who discontinue study treatment should NOT be considered withdrawn from the study. 
They should return for the assessments indicated in Table 7-1 or Table 7-1b following approval 
of protocol amendment 05 (end of study treatment visit) and then enter the follow-up epoch. If 
they fail to return for these assessments for unknown reasons, every effort (e.g. telephone, email, 
letter) should be made to contact them as specified in Section 7.1.6. An EOT visit should be 
conducted within 14 days of the last dose of study treatment or within 14 days of the decision 
to permanently discontinue study treatment. If the patient discontinues from the study treatment
at a scheduled visit, the EOT assessment can be performed on that day. An End of Treatment 
Phase Disposition eCRF page should be completed to include the date and reason for 
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For patients who discontinue study treatment for reasons other than documented disease 
progression, death, lost to follow-up, or withdrawal of consent, tumor assessments must 
continue to be performed every 6 weeks or every 12 weeks following approval of protocol 
amendment 05 until documented disease progression, death, lost to follow-up, or withdrawal of 
consent.
7.1.4.1
Replacement policy
Phase I Part
Patients will not be replaced on study. However, if a patient is considered as non-evaluable for 
the 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 (1 or 3 for FGF401 single agent or 3 for FGF401 in 
combination with PDR001) or at most the maximum number (6) of evaluable patients is 
achieved within the cohort.
Phase II Part
During the phase II part, no replacement will be needed.
7.1.5
Withdrawal of consent
Subjects may voluntarily withdraw consent to participate in the study for any reason at any time. 
Withdrawal of consent occurs only when a subject does not want to participate in the study 
anymore, and does not allow further collection of personal data.
In this situation, the Investigator should make a reasonable effort (e.g. telephone, e-mail, letter) 
to understand the primary reason for the subject’s decision to withdraw his/her consent and 
record this information.
Study treatment must be discontinued and no further assessments conducted, and the data that 
would have been collected at subsequent visits will be considered missing.
Further attempts to contact the subject are not allowed unless safety findings require 
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 subject’s study withdrawal should be made as detailed in the 
assessment table.
Novartis will continue to keep and use collected study information (including any data resulting 
from the analysis of a subject’s samples until their time of withdrawal) according to applicable 
law.
For US and Japan: All biological samples not yet analyzed at the time of withdrawal may still 
be used for further testing/analysis in accordance with the terms of this protocol and of the 
informed consent form.
For EU and RoW: All biological samples not yet analyzed at the time of withdrawal will no 
longer be used, unless permitted by applicable law. They will be stored according to applicable 
legal requirements.


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7.1.6
Follow up period
Safety follow-up
All patients treated with FGF401 single agent must have safety evaluations for 30 days after the 
last dose of FGF401. 
All patients treated with FGF401 and PDR001 combination must have safety evaluations for 
150 days after the last dose of PDR001. During the 150-day safety follow-up for PDR001, the 
patient should be contacted, by telephone call or visit, at least on day 30, 90, and 150. 
Concomitant medications will be collected until the 30-day safety follow-up has been 
completed, or the start of a new antineoplastic therapy, whichever occurs first. A PK and 
immunogenicity sample should be collected at 150 days as described in Section 7.2.3. If the 
150-day safety evaluation is conducted by phone, samples do not need to be collected.
In case patients discontinue PDR001 more than 141 days before the last dose of FGF401, then 
they must have safety evaluations for 30 days after the last dose of FGF401. 
Disease progression follow-up
Any patient who has not progressed at the time of discontinuation of study treatment will 
continue to have tumor assessments performed every 6 weeks or every 12 weeks following 
approval of protocol amendment 05 until disease progression, initiation of subsequent 
anticancer therapies, or death, whichever occurs first.
Survival follow-up
Upon completion of the 30 or 150 day safety follow-up as applicable or disease progression 
follow-up, all patients, except those who died, withdrew consent or were lost to follow-up, will 
be followed for survival (can be done by telephone call) every 4 weeks (±1 week) until death.
Completion of the survival follow-up period will occur once a minimum of 80% of patients in 
the phase II part for both FGF401 single agent and FGF401 in combination with PDR001 have 
died, have been lost to follow-up, or have been followed for survival for minimum 18 months 
after receiving the first dose of study treatment, whichever occurs first.
7.1.7
Lost to follow-up
For patients whose status is unclear because they fail to appear for study visits without stating 
an intention to withdraw consent, the Investigator should show "due diligence" by contacting 
the patient, family or family physician as agreed in the informed consent and by documenting 
in the source documents steps taken to contact the patient (e.g. dates of telephone calls, e-mail, 
letters). A patient should not be considered lost to follow-up until due diligence has been 
completed. Patients lost to follow-up should be recorded as such on the appropriate Disposition 
eCRF page.


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7.2
Assessment types
7.2.1
Efficacy assessments
Following approval of protocol amendment 05, efficacy assessments will be performed every 
12 weeks until progression of disease. 
Table 7-2
Imaging collection plan
Procedure
Screening/Baseline
During Treatment/Follow-up
Chest, abdomen and pelvis CT 
or MRI with contrast 
enhancement
(for HCC patients, the scan must 
include dual-phase imaging of 
the entire liver)
Mandated
Mandated, every 6 weeks (±7 
days )
Whole body bone scan
If clinical evidence of bone metastasis
If clinically indicated
Brain CT or MRI
If clinical evidence of brain metastasis
If brain lesions at screening
every 6 weeks (±7 days)
Bone X-ray, CT or MRI
(bone lesions only)
If lesions on bone scan that are not 
visible on the chest, abdomen or 
pelvis CT/MRI
If bone lesions at screening, then 
every 6 weeks (±7 days)
Skin color photography (skin 
lesions only)
If clinical evidence of skin lesions
If skin lesions at screening, then 
every 6 weeks (±7 days)
If no skin lesion noted at 
screening, then if clinical 
indicated
Tumor response will be determined locally according to Response Evaluation Criteria in Solid 
Tumors (RECIST) v1.1 (Appendix 1) for patients treated with FGF401 single agent. In addition
for patients treated with FGF401 and PDR001 combination the tumor response will be 
determined according to RECIST v1.1 (Appendix 1) and irRC (Appendix 9). The local 
investigator’s assessment will be used for the primary endpoint analysis and for treatment 
decision making.
Additionally, imaging data from the FGF401 single agent and the FGF401 and PDR001 
combination phase II parts of the study will be centrally collected and checked for quality by 
an imaging CRO designated by Novartis and may undergo independent review according to the 
Novartis guideline, based on RECIST v1.1 and irRC (as applicable) if deemed necessary.
Novartis may also decide to have a central review of the radiological assessments from the dose 
escalation phase I parts of the study. In such case, the Investigators will be instructed on how 
to send data from these radiological assessments to a Novartis designated CRO for central 
review, when needed.
Following approval of protocol amendment 05, the imaging data (CT/MRI scans) will not be 
centrally collected.
CT/MRI scans will be performed at baseline within 21 days before start of treatment and 
subsequently every 6 weeks starting on cycle 3 day 1 until progression of disease (Section 7.1.3). 
There is a ±7 days evaluation window for all tumor assessments, see Table 7-2 for details. 
CT/MRI scan will be performed at EOT if not conducted within 30 days prior to EOT. Disease 
progression follow-up should be performed as described in Section 7.1.6.


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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 baseline and 
during follow up.
If at baseline a patient has a medical contraindication to CT i.v. contrast or develops a 
contraindication during the trial, a non-contrast CT of chest plus contrast-enhanced MRI of 
abdomen is acceptable.
Patients with clinical evidence of bone metastases must have a whole body bone scan at baseline 
per local institutional practice. Lesions identified on the whole body bone scan at baseline, 
which are not visible on the chest, abdomen or pelvis CT (or MRI) scan should be imaged at 
baseline and followed at subsequent scheduled visits using localized CT, MRI or X-ray. After 
baseline, whole body bone scans need not be repeated, unless clinically indicated.
Skin lesions present at baseline 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 
should be continued at subsequent tumor assessments for any lesions that were photographed 
at screening.
Baseline brain CT or MRI will be mandated for patients with clinical sign or symptoms of brain 
metastases. Subsequent brain scans should only be conducted if brain lesions are documented 
at baseline for eligible patients or in patients that develop symptoms indicative of brain 
metastases.
All CRs and PRs must be confirmed by a second assessment not earlier than 4 weeks after the 
criteria for response are first met.
Any potentially measurable lesion that has been previously treated with radiotherapy and/or 
loco-regional therapy should be considered as a non-measurable lesion. However, if a lesion 
previously treated with radiotherapy and/or loco-regional therapy has clearly progressed since 
these therapies, it can be considered as a measurable lesion.
PET/CT may be used only if the CT is of similar diagnostic quality as a CT performed without 
PET, including the utilization of oral and intravenous contrast media.
7.2.2
Safety and tolerability assessments
Safety will be monitored by assessment as well as collection of all serious and non-serious 
adverse events. For details on AE collection and reporting, refer to Section 8.
Following approval of protocol amendment 05, assessments for height, weight, and 
performance status are not required by the protocol.
7.2.2.1
Physical examination
A complete physical examination must be performed as indicated in Table 7-1 or Table 7-1b
following approval of protocol amendment 05.
Physical examination will be performed on the scheduled day, even if study treatment is being 
withheld. More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated.


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Physical examination will be performed according to the standards at each institution. Usually, 
the 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 should be considered.
Information about the physical examination must be present in source documents at the study 
site. Significant findings that are present prior to signing of informed consent form for the study 
must be included in the Medical History eCRF. Significant new findings that begin or worsen 
after informed consent for the study must be recorded on the Adverse Events eCRF.
7.2.2.2
Vital signs
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1 or Table 7-1b following approval of protocol amendment 05 according 
to the standards at each institution.
Vital signs will be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated.
Following approval of protocol amendment 05, vital signs will be performed only for patients 
treated with FGF401 and PDR001 combination as indicated in Table 7-1b.
7.2.2.3
Height and weight
Height (screening only) in centimeters and body weight in kilograms (in indoor clothing, 
without shoes) will be measured as indicated in Table 7-1.
7.2.2.4
Performance status
ECOG performance status will be assessed as defined in Table 7-1 and Table 7-3.
Table 7-3
ECOG performance status
Grade
ECOG Status
0
Fully active, able to carry on all pre-disease performance without restriction
1
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or 
sedentary nature (e.g., light house work, office work)
2
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and about more 
than 50% of waking hours
3
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours
4
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair
7.2.2.5
Laboratory assessments
The laboratory parameters assessed for safety purposes will be evaluated locally at the site, 
except for 
 cytokines for safety (applicable for the FGF401 in combination 
with PDR001 only), which will be analyzed centrally at the Novartis designed central laboratory. 
Refer to Table 7-4 and Table 7-5 or Table 7-4b following approval of protocol amendment 05 


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for a summary of the parameters to be evaluated according to Table 7-1, or Table 7-1b following 
approval of protocol amendment 05. 
Unscheduled assessment can be performed if clinically indicated.
Table 7-4
Local clinical laboratory parameters collection plan (applicable for 
protocol amendment 04 - following approval of protocol amendment 
05 refer to Table 7-4b below) 
Test Category
Test Name
Hematology
Hematocrit, Hemoglobin, Platelets, Red blood cells, White blood cells, WBC Morphology 
with Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils and 
others)
Chemistry (Fasting)
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Bicarbonate, Calcium, 
ionized Calcium, Chloride, Creatinine, Creatine kinase, Direct Bilirubin, Glucose, 
Gamma-glutamyl transpeptidase, Inorganic phosphorus, Magnesium, Potassium, 
Sodium, Indirect Bilirubin, Total Bilirubin, Total Cholesterol, LDL, HDL, Total Protein, 
Triglycerides, Blood Urea Nitrogen (BUN) or Urea, Uric Acid, Amylase, Lipase
Coagulation
Prothrombin time (PT) or International normalized ratio (INR)
Urinalysis
Macroscopic Panel (Dipstick): Bilirubin, Blood, Glucose, Ketones, Leukocytes, pH, 
Protein, Specific gravity
Any clinically significant findings on dipstick will be followed up with a microscopic 
evaluation.
Hepatitis markers
HBsAg, HBcAb, HBsAb, HBV-DNA, HCV RNA-PCR
Pregnancy 
Serum hCG/urine pregnancy test
HCC patients specific laboratory parameter
Other
Alpha-fetoprotein
Thyroid function*
Free T4 and TSH (Thyroid Stimulating Hormone)
Virology*
HIV
*applicable only for FGF401 in combination with PDR001
Table 7-4b
Local clinical laboratory parameters collection plan- applicable upon 
approval of protocol amendment 05
Test Category 
Test Name 
Hematology
Hematocrit, Hemoglobin, Platelets, White blood cells
Chemistry (Fasting)
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium, Creatinine, 
Inorganic phosphorus, Total Bilirubin, Total Cholesterol, Triglycerides
Hepatitis markers
HBsAg, HBcAb, HBsAb, HBV-DNA, HCV RNA-PCR
Pregnancy
Serum hCG/urine pregnancy test


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Table 7-5
Central clinical laboratory parameters collection plan**
Test Category
Test Name
Cytokines for safety*
IFN-γ, IL-6
* applicable only for FGF401 in combination with PDR001
** following approval of protocol amendment 05,
 cytokines for safety are not required
7.2.2.5.1 Hematology
Hematology panel outlined in Table 7-4 or Table 7-4b following approval of protocol 
amendment 05 will be performed as per the assessment schedule provided in Table 7-1 or Table 
7-1b following approval of protocol amendment 05.
7.2.2.5.2 Clinical chemistry
Clinical chemistry panel outlined in Table 7-4 or Table 7-4b following approval of protocol 
amendment 05 will be performed as per the assessment schedule provided in Table 7-1 or Table 
7-1b following approval of protocol amendment 05. The patient should be instructed to fast for 
at least 12 hours before specimen collection. 
7.2.2.5.3 Coagulation
Coagulation panel outlined in Table 7-4 will be performed as per the assessment schedule 
provided in Table 7-1.
Following approval of protocol amendment 05, coagulation panel is not required.
7.2.2.5.4 Urinalysis
Urinalysis panel outlined in Table 7-4 will be performed as per the assessment schedule 
provided in Table 7-1.
Following approval of protocol amendment 05, urinalysis panel is not required.
7.2.2.5.5 Alpha-fetoprotein
Alpha-fetoprotein will be analyzed for HCC patients on Day 1 of every other cycle from Cycle 
1 as per the assessment schedule provided in Table 7-1.
Following approval of protocol amendment 05, alpha-fetoprotein analysis will not be performed.
7.2.2.5.6 Hepatitis markers-Virology
During the screening period, patients must be screened for HBV and HCV (current or past 
history of infection). Careful medical history must be taken for all patients to look for risk 
factors (family history of HBV and HCV, intravenous drug abuse, unprotected sex, dialysis, 
blood transfusions, etc.), and any past or present HBV symptoms (e.g., jaundice, dark urine, 
light colored stools, right upper quadrant pain).
Hepatitis B:
At screening, all patients will be tested for:


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
HBV-DNA level

Hepatitis B surface antigen (HBsAg)

Hepatitis B core antibody (HBcAb)

Hepatitis B surface antibody (HBsAb)
Monitoring for HBV –DNA level on Day 1 of every other cycle from Cycle 3 and EOT is 
required for:

Patients known to have a history of HBV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)

Patients positive for viral load on HBV-DNA test at screening

Patients positive for any of the serology at screening
Hepatitis C:
All patients will be tested for quantitative HCV RNA-PCR at the screening visit.
Monitoring for HCV RNA-PCR level on Day 1 of every other cycle from Cycle 3 and EOT is 
required for:

Patients known to have a history of HCV infection, despite a negative viral load test at 
screening (including those that were treated and are considered ‘cured’)

Patients positive for viral load on HCV RNA-PCR test at screening
HIV
In addition to the above assessments, for the FGF401 and PDR001 combination HIV testing 
will be performed at screening for all patients.
 
 
 
 
7.2.2.5.8 Pregnancy and assessments of fertility
All females of childbearing potential will have a serum pregnancy test within ≤72 hours before 
first dose of study treatment and during the study at day 1 of each cycle starting from Cycle 2, 
and at EOT. 
In addition, for the FGF401 in combination with PDR001 a urine pregnancy test should be 
performed every month during and at the end of the safety follow-up period. If the patient is 
not coming to the clinic during the safety follow-up, it can be performed at home or at a local 
doctor’s office, and the results will be communicated to the site staff. These follow-up 
pregnancy tests will be recorded only in the source documentation, not in the eCRF.


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If a pregnancy test (urine or serum) is positive, but the patient is thought not to be pregnant, 
study treatment should be stopped until it is determined that the test was falsely positive, and 
pregnancy is excluded. In case pregnancy is confirmed, study treatment must be permanently 
discontinued and reporting requirements must be followed as described in Section 8.3.
7.2.2.5.9 Thyroid function – for FGF401 in combination with PDR001 only
Thyroid function assessments outlined in Table 7-4 will be performed as per the schedule 
provided in Table 7-1.
Following approval of protocol amendment 05, thyroid function assessments will not be 
performed.
7.2.2.5.10
Cytokines – for FGF401 in combination with PDR001 only
Samples analyzed for the cytokines as outlined in Table 7-5 will be collected at the following 
time points (Table 7-1):

Screening

On an ad-hoc basis in case a patient has an adverse event suspected to be a cytokine 
release syndrome. In such case, this assessment should be performed at the following time 
points:
a. within 5 hours (or as soon as possible) after the occurrence of the adverse event,
b. one week after the occurrence of the adverse event. 
The analysis of the samples will be done only for patients who experienced an adverse event 
suspected to be a cytokine release syndrome and had follow-up samples collected.
Following approval of protocol amendment 05, no further sample collection will be performed 
for the cytokine analysis. 
7.2.2.6
Cardiac assessments
Following approval of protocol amendment 05, cardiac assessments are not required. These 
assessments may be performed at the investigator’s discretion following local standard of care.
When abnormal results constitute an adverse event, they must be recorded on the Adverse 
Events eCRF.
7.2.2.6.1 Electrocardiogram (ECG)
Standard 12-lead ECG will be performed as per the assessment schedule provided in Table 7-1
and Table 7-6. For all patients, 3 sequential 12-lead ECGs must be performed during screening
(or Cycle 1 Day 1 if screening assessment was performed >72 hours prior to first dose) and 
Cycle 2 Day1. One single ECG will be performed for the other time-points during the trial.


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Table 7-6
Central ECG collection plan
Cycle
Day
Time
ECG Measurement
Screening
-
-
Triplicate 12-lead
1
1
Pre-dose
Triplicate 12-lead
C1D1 assessment is required only if screening 
assessment was performed >72 hours prior to first 
dose.
1a
1a
2 hr post-dose (±30 minutes)a
Triplicate 12-leada
2
1
Pre-dose
Triplicate 12-lead
2
1
2 hr post-dose (±30 minutes)b
Triplicate 12-lead
subsequent
1
Pre-dose
Single 12-lead
EOT
-
Anytime
Single 12-lead
Unscheduled
-
Anytime
Single 12-lead
a [For Japan only, ECG is performed additionally at 2 hr post dose (estimated Tmax) on Cycle 1 Day 1]
b ECG is performed at 2 hr post-FGF401 administration (estimated Tmax) prior to 2 hr post- FGF401 
administration PK sampling completion
Interpretation of the tracing will be made by a central ECG laboratory. Each ECG tracing should 
be labeled with the study number, patient initials (where regulations permit), patient number, 
date, and kept as source documents at the study site. Clinically significant abnormalities present 
when the patient signed informed consent should be reported on the Medical History eCRF. 
Such clinically significant findings must be discussed with Novartis prior to enrolling the 
patient in the study. New or worsened clinically significant observations occurring after 
informed consent must be recorded on the Adverse Events eCRF.
7.2.3
Pharmacokinetics and immunogenicity assessments
Serial blood samples will be collected from all patients at all dose levels for the determination
of FGF401 plasma concentration. Serum PDR001 concentrations as well as immunogenicity 
(IG) analysis will be performed for all patients receiving PDR001. The pharmacokinetic (PK) 
analysis will be performed according to Section 10.5.3.
 
 
Following approval of protocol amendment 05, no further blood sample collection will be 
performed for pharmacokinetics and immunogenicity assessments.
7.2.3.1
Pharmacokinetic blood sample collection and handling
Blood samples will be collected in both the phase I and phase II parts for FGF401 and for 
PDR001 (as applicable).
The PK blood sampling schedule for all patients receiving FGF401 is outlined in Table 7-7, 
Table 7-8, Table 7-9 and Table 7-10 and the sampling time points are relative to the time of 
FGF401 administration.
Blood samples for PDR001 and IG analysis will be collected as outlined in Table 7-11 and 
Table 7-12. If the dosing of Cycle 3 Day 1 is delayed, the PK sampling for the full PK profile 


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should be delayed accordingly to match the scheduled time points for Cycle 3 as outlined in 
Table 7-11 and Table 7-12. PK and IG samples will be collected also in the event of a clinically 
significant AE (such as infusion reaction/anaphylaxis) or if immunogenicity by PDR is 
suspected.
Table 7-7
Phase I parts: Pharmacokinetic blood collection log for QD FGF401 
administration
Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
1
1
Pre-C1D1 dose/0 hr a
1
1
1
1
0.5 hr (±10 minutes)
1
2
1
1
1 hr (±10 minutes)
1
3
1
1
2 hr (±10 minutes)
1
4
1
1
3 hr (±15 minutes)
1
5
1
1
4 hr (±15 minutes)
1
6
1
1
6 hr (±30 minutes)
1
7
1
1
8 hr (±1 hr)
1
8
1
1
12 hr (±2 hr) b
1
9
1
2
24 hr/pre-C1D2 dose
1/101 
10
1
8
Pre-C1D8 dose/0 hr a
2/102 c
11
1
8
0.5 hr (±10 minutes)
2
12
1
8
1 hr (±10 minutes)
2
13
1
8
2 hr (±10 minutes)
2
14
1
8
3 hr (±15 minutes)
2
15
1
8
4 hr (±15 minutes)
2
16
1
8
6 hr (±30 minutes)
2
17
1
8
8 hr (±1 hr)
2
18
1
8
12 hr (± 2 hr) b
2
19
1
9
24 hr/pre-C1D9 dose
2/103
20
1
15
Pre-C1D15 dose/0 hr a
3/104 c
21
2
1
Pre-C2D1 dose/0 hr a
4/105 c
22
2
1
0.5 hr (±10 minutes)
4
23
2
1
1 hr (±10 minutes)
4
24
2
1
2 hr (±10 minutes) f
4
25
2
1
3 hr (±15 minutes)
4
26
2
1
4 hr (±15 minutes)
4
27
2
1
6 hr (±30 minutes)
4
28
2
1
8 hr (±1 hr)
4
29
2
1
12 hr (± 2 hr) b
4
30
2
2
24 hr/pre-C2D2 dose 
4/106
31
3
1
Pre-C3D1 dose/0 hr a
5/107 c
32
4
1
Pre-C4D1 dose/0 hr a
6/108 c
33
-
-
Biopsy-matched time point d
-
1001+ e
-
-
Unscheduled
-
2001+ e


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Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
a Take samples immediately prior to the administration of FGF401
b Optional and only for the Japanese patients hospitalized according to the local guidance
c The first dose reference ID is for current dose, while the second dose reference ID is for last dose the subject 
received prior to the collection of the PK sample
d Time of the blood sample taken close to biopsy sample; this blood sampling needs to be collected within 60
minutes before or after biopsy procedure 
e Blood samples will be uniquely, sequentially numbered as 1001, 1002, etc and 2001, 2002, etc
f Samples will be taken after ECG collection
Table 7-8
Phase II parts: Pharmacokinetic blood collection log for QD FGF401
administration
Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
1
1
Pre-C1D1 dose/0 hr a
11
101
1
1
1 hr (±10 minutes)
11
102
1
1
2 hr (±10 minutes)
11
103
1
1
6 hr (±15 minutes)
11
104
1
2
24 hr/pre-C1D2 dose 
11/201
105
1
8
Pre-C1D8 dose/0 hr a
12/202 b
106
1
15
Pre-C1D15 dose/0 hr a
13/203 b
107
2
1
Pre-C2D1 dose/0 hr a
14/204 b
108
2
1
1 hr (±10 minutes)
14
109
2
1
2 hr (±10 minutes) e
14
110
2
1
6 hr (±15 minutes)
14
111
2
2
24 hr/pre-C2D2 dose
14/205
112
3
1
Pre-C3D1 dose/0 hr a
15/206 b
113
4
1
Pre-C4D1 dose/0 hr a
16/207 b
114
5
1
Pre-C5D1 dose/0 hr a
17
115
6
1
Pre-C6D1 dose/0 hr a
18
116
-
-
Biopsy-matched time point c
-
3001+ d
-
-
Unscheduled
-
4001+ d
a Take samples immediately prior to the administration of FGF401
b The first dose reference ID is for current dose, while the second dose reference ID is for last dose the subject 
received prior to the collection of the PK sample
c Time of the blood sample taken close to biopsy sample; this blood sampling needs to be collected within 60
minutes before or after biopsy procedure
d Blood samples will be uniquely, sequentially numbered as 3001, 3002, etc and 4001, 4002, etc
e Samples will be taken after ECG collection
Table 7-9
Phase I parts: Pharmacokinetic blood collection log for BID FGF401
administration (if BID dosing is implemented)
Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
1
1
Pre-C1D1 dose/0 hr a
21
201
1
1
1 hr (±10 minutes)
21
202
1
1
2 hr (±10 minutes)
21
203
1
1
6 hr (±30 minutes)
21
204
1
8
Pre-C1D8 dose/0 hr a
22/301 c
205
1
8
0.5 hr (±10 minutes)
22
206
1
8
1 hr (±10 minutes)
22
207
1
8
2 hr (±10 minutes)
22
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Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
1
8
3 hr (±15 minutes)
22
209
1
8
4 hr (±15 minutes)
22
210
1
8
6 hr (±30 minutes)
22
211
1
8
8 hr (±1 hr)
22
212
1
15
Pre-C1D15 dose/0 hr a
24/302 c
213
2
1
Pre-C2D1 dose/0 hr a
25/303 c
214
2
1
1 hr (±10 minutes)
25
215
2
1
2 hr (±10 minutes) b
25
216
2
1
6 hr (±30 minutes)
25
217
3
1
Pre-C3D1 dose/0 hr a
27/304 c
218
4
1
Pre-C4D1 dose/0 hr a
28/305 c
219
-
-
Biopsy-matchedtime point d
-
5001+ e
-
-
Unscheduled
-
6001+ e
a Take samples immediately prior to the administration of FGF401
b Samples will be taken after ECG collection
c The first dose reference ID is for current dose, while the second dose reference ID is for last dose the subject 
received prior to the collection of the PK sample
d Time of the blood sample taken close to biopsy sample; this blood sampling needs to be collected within 60
minutes before or after biopsy procedure 
e Blood samples will be uniquely, sequentially numbered as 5001, 5002, etc and 6001, 6002, etc
Table 7-10
Phase II parts: Pharmacokinetic blood collection log for BID FGF401
administration (if BID dosing is implemented)
Cycle
Day
Scheduled Time Point
Dose Reference ID
Sample number
1
1
Pre-C1D1 dose/0 hr a
31
301
1
1
1 hr (±10 minutes)
31
302
1
1
2 hr (±10 minutes)
31
303
1
1
6 hr (±15 minutes)
31
304
1
8
Pre-C1D8 dose/0 hr a
32/401 b
305
1
15
Pre-C1D15 dose/0 hr a
33/402 b
306
2
1
Pre-C2D1 dose/0 hr a
34/403 b
307
2
1
1 hr (±10 minutes)
34
308
2
1
2 hr (±10 minutes) e
34
309
2
1
6 hr (±15 minutes)
34
310
2
2
Pre-C2D2 dose/0 hr a
35/405 b
311
3
1
Pre-C3D1 dose/0 hr a
36/404 b
312
4
1
Pre-C4D1 dose/0 hr a
37/406 b
313
5
1
Pre-C5D1 dose/0 hr a
38
314
6
1
Pre-C6D1 dose/0 hr a
39
315
-
-
Biopsy-matched time point c
-
7001+ d
-
-
Unscheduled
-
8001+ d
a Take samples immediately prior to the administration of FGF401
b The first dose reference ID is for current dose, while the second dose reference ID is for last dose the subject 
received prior to the collection of the PK sample
c Time of the blood sample taken close to biopsy sample; this blood sampling needs to be collected within 60
minutes before or after biopsy procedure
d Blood samples will be uniquely, sequentially numbered as 7001, 7002, etc and 8001, 8002, etc
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Table 7-11
Schedule of blood (serum) collection for PDR001 PK and IG for 
patients participating in phase I of FGF401 and PDR001 combination 
Cycle*
Day
Scheduled Time Point (h)
Analytes
1
1
0 hr/pre-C1D1 dosea
PDR001 and IG
1
1
1 hr (±5 min)b
PDR001
1
8
168 hr (±8hr)
PDR001
1
15
336 hr (±24hr)
PDR001
2
1
504 hr (±24hr)/ pre-C2D1 dosea
PDR001 and IG
3
1
0hr/pre-C3D1 dosea
PDR001 and IG
3
1
1 hr (±5 min)b
PDR001
3
15
336 hr (±24hr)
PDR001
4
1
504 hr (±24hr)/ pre-C4D1 dosea
PDR001 and IG
5
1
0hr/pre-C5D1 dosea
PDR001 and IG
6
1
0hr/pre-C6D1 dosea
PDR001 and IG
EOT
PDR001 and IG
150-day safety follow-up**
PDR001 and IG
Unscheduled
PDR001 and IG
*refers to PDR001 administration cycle
**only for patients who come to the site for the 150-day safety follow-up visit
a take samples immediately prior to PDR001 infusion
b take samples after completion of PDR001 infusion
Table 7-12
Schedule of blood (serum) collection for PDR001 PK and IG for 
patients participating in Phase II of FGF401 and PDR001 combination
Cycle*
Day
Scheduled Time Point (h)
Analytes
1
1
0 hr/pre-C1D1 dosea
PDR001 and IG
1
1
1 hr (±5 min)b
PDR001
2
1
0 hr/pre-C2D1 dosea
PDR001 and IG
3
1
0 hr/pre-C3D1 dosea
PDR001 and IG
3
1
1 hr (±5 min)b
PDR001
4
1
0 hr/pre-C4D1 dosea
PDR001 and IG
5
1
0hr/pre-C5D1 dosea
PDR001 and IG
6
1
0hr/pre-C6D1 dosea
PDR001 and IG
EOT
PDR001 and IG
150-day safety follow-up**
PDR001 and IG
Unscheduled
PDR001 and IG
*refers to PDR001 administration cycle
**only for patients who come to the site for the 150-day safety follow-up visit
a take samples immediately prior to PDR001 infusion
b take samples after completion of PDR001 infusion
The exact date and clock times of drug administration and the actual collection date and time 
of each sample will be recorded on the appropriate eCRF pages. The timing of meals related to 
the dose, on days when PK profiles are drawn, should be recorded in the source documents and 
eCRF. If vomiting occurs within 4 hours following FGF401 administration on the day of PK 
blood sampling, the clock time of vomiting should be recorded on the corresponding eCRF. 


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Blood samples will be taken by either direct venipuncture or an indwelling cannula inserted in 
a forearm vein. Blood samples should be collected from the arm opposite the one from PDR001 
infusion, or from another site, or alternatively the infusion site will need to be flushed with 
10mL saline. At specified time points, a total of 3 mL blood will be collected for FGF401
analysis and 2 mL blood for PDR001 as applicable. For time points when PDR001 (mAb) PK 
and IG are to be measured, a single blood sample of 5 mL in total will be collected. . Refer to 
the applicable study Laboratory Manual  for detailed instructions for the collection, handling 
and shipment of samples.
7.2.3.2
Analytical method
FGF401 and PDR001 concentrations in human plasma and serum will be determined using  
validated LC-MS/MS assays, respectively. Any results below the lower limit of quantification 
(LLOQ) and any missing samples will be labeled accordingly.


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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 patients who sign the molecular pre-screening ICF, AEs which occur after signature of this 
consent will only be captured if they meet the definition of serious as outlined in Section 8.2
and are reported to be causally related with study procedures (e.g. an invasive procedure such 
as biopsy). Once the main study ICF is signed, all AEs per the descriptions below will be 
captured in the Adverse Event eCRF.
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).


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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 150 days following the last dose of PDR001 (for patients who have 
been treated with PDR001), or at least 30 days following the last dose of FGF401 (Section 
7.1.6). 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.
After initiation of new post-treatment antineoplastic therapy, only AEs suspected to be related 
to study treatment will be collected in the Adverse Events eCRF.
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.03.
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
eCRF.
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:
1. The severity grade (CTCAE Grade 1-4)
2. Its duration (Start and end dates)
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes)
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable)
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy)
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown)
7. Whether it is serious, where a serious adverse event (SAE) is defined as in Section 8.2.1
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF.
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome.


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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RECIST or irRC criteria for solid tumors), should not be reported 
as a serious adverse event.
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug.
8.1.2
Laboratory test abnormalities
8.1.2.1
Definitions and reporting
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events eCRF. Whenever 
possible, a diagnosis, rather than a symptom should be provided (e.g. anemia instead of low 
hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should be 
followed until they have returned to normal or an adequate explanation of the abnormality is 
found. When an abnormal laboratory or test result corresponds to a sign/symptom of an already 
reported adverse event, it is not necessary to separately record the lab/test result as an additional 
event.
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 
the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such.
8.2
Serious adverse events
8.2.1
Definitions
Serious adverse event (SAE) is defined as one of the following:

Is fatal or life-threatening

Results in persistent or significant disability/incapacity

Constitutes a congenital anomaly/birth defect

Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above

Requires inpatient hospitalization or prolongation of existing hospitalization, 

Note that hospitalizations for the following reasons should not be reported as serious 
adverse events:

Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition

Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
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
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
8.2.2
Reporting
For patients who sign the molecular pre-screening ICF (applicable only for Phase 1 and Group 
3 in Phase II of FGF401 single agent and for Stage 2 of the FGF401 and PDR001 combination 
should it proceed), SAE collection will start upon signing the molecular pre-screening ICF. 
SAEs will only be reported if the event is suspected to be causally related to a study procedure 
as assessed by the investigator (e.g. an invasive procedure such as biopsy). SAEs will be 
followed until resolution or until clinically relevant improvement or stabilization. If the main 
ICF is not signed (molecular pre-screen failure), SAE collection ends 30 days after the last study 
related procedure.
For all other patients who sign the main study ICF, SAE collection starts at time of main study 
informed consent whether the patient is a screen failure or not.
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided main informed consent and until at least 150 days following the last dose 
of PDR001 (for patients who have been treated with FGF401 and PDR001 combination), or at 
least 30 days after discontinuation of FGF401 (for patient who have been treated with FGF401
single agent), 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 SAEs experienced after the above defined period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Any additional information 
for the SAE including recurrent episodes, complications, or progression of the initial SAE must 
be reported as follow-up to the original episode within 24 hours of the investigator receiving 
the follow-up information. An SAE occurring at a different time interval or otherwise 
considered completely unrelated to a previously reported one should be reported separately as 
a new event.
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and submit the completed form within 24 hours to Novartis. Detailed 
instructions regarding the SAE submission process and requirements for signatures are to be 
found in the investigator folder provided to each site.
Follow-up information is submitted in the same way as the original SAE Report. Each re-
occurrence, complication, or progression of the original event should be reported as a follow-
up to that event regardless of when it occurs. The follow-up information should describe 
whether the event has resolved or continues, if and how it was treated, whether the blind was 
broken or not, and whether the patient continued or withdrew from study participation.


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If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the Novartis study treatment, a Novartis Chief 
Medical Office and Patient Safety department associate may urgently require further 
information from the investigator for Health Authority reporting. Novartis may need to issue 
an Investigator Notification (IN), to inform all investigators involved in any study with the same 
drug that this SAE has been reported. Suspected Unexpected Serious Adverse Reactions 
(SUSARs) will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC or as per national regulatory requirements 
in participating countries.
8.3
Pregnancies
Study treatment must be stopped if a patient becomes pregnant.
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. After the mother has provided consent, the newborn will be 
followed-up for 12 months.
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to Novartis Chief Medical Office and Patient Safety (CMOPS&). Pregnancy 
follow-up should be recorded on the same form and should include an assessment of the 
possible relationship to the study treatment and 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’s. 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
Phase I Parts:
A data monitoring board will not be used for this study. This is an open-label, Phase I/II study 
and 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, 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 


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first cycle of treatment, and all available 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 Bayesian model’s (with EWOC) recommendation, 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 and/or RP2D, escalate the dose any further, or whether 
to de-escalate and/or recruit an additional cohort of patients at the current dose level, see Section 
10.4.2.1.
Phase II Parts:
An independent data monitoring committee will not be formed for this exploratory phase II 
parts of the study. Individual patient data will be reviewed on an ongoing basis and aggregate 
safety data and the primary endpoint will be monitored frequently by the study team across the 
duration of the trial. The data review and analysis will be based on the available data in the 
clinical database at the respective time.
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 (PPOS)) will be communicated to the 
Steering Committee for decision making purposes.
In the Phase II part of the FGF401 in combination with PDR001, an interim analysis for efficacy 
and futility will be performed after the first 35 patients have been enrolled and have had at least 
one-post treatment tumor evaluation or discontinued earlier (Stage 1). Interim decision making 
will be based on the Bayesian posterior probability of ORR and posterior median ORR. The 
interim analysis of ORR will be based on unconfirmed response. The phase II part in the 
combination arm will be stopped due to efficacy if the posterior probability of ORR in the 
unselected population included in the no/limited anti-tumor activity interval [0, 0.15) is less 
than 0.10 and the posterior median ORR is 0.30 or more. Considering the exploratory nature of 
the study, when the aforementioned success criteria are not met but the evaluation of overall 
efficacy and safety suggests the treatment is promising for development, decision of stop at 
Stage 1 for success can also be made by Novartis. 
Should the study not stop at Stage 1 for success in the unselected HCC population, go/no go 
decision to Stage 2 will be made by evaluating the anti-tumor activity in subgroups defined by 
FGF19 expression and/or FGF19 pathway activation based on the predictive probability of 
ORR. For an individual subgroup, if that predictive probability to not meet the efficacy criteria 
(i.e. posterior probability of ORR included in the no/limited anti-tumor activity interval is less 
than 0.10 and the posterior median ORR is 0.30 or more) at the final analysis is not greater than 
0.90, and the number of patients in the subgroup is less than 25, the study will move to Stage 2 
and more patients will be enrolled to the subgroup until a sample size of approximately 25 is 
reached. If 25 or more patients are already enrolled to the subgroup at the time of interim 


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analysis, interim analysis will be performed but no further enrollment will be allowed in that 
subgroup.
9
Data collection and management
9.1
Data confidentiality
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following:

What protected health information (PHI) will be collected from subjects in this study

Who will have access to that information and why

Who will use or disclose that information

The rights of a research subject to revoke their authorization for use of their PHI.
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g. has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period.
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training.
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
the site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subject Initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results.
9.2
Site monitoring
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits.
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 


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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.
Blood and tumor samples for PK 
 will be collected by sites and sent to a Central 
laboratory for processing. The Laboratory results will be sent electronically to Novartis. 
Radiological and photography data will be acquired by the sites and interpreted locally. Details 
regarding all CRO procedures including collection and shipment of data will be described in 
the manual provided by the respective CRO. ECG data collected during the study will be 
reviewed and processed centrally by a specialist CRO.
9.4
Database management and quality control
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the
investigational site via the EDC system. Designated investigator site staff is required to respond 
promptly to queries and to make any necessary changes to the data.
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Medical history/current medical conditions and adverse events will be coded using the 
Medical dictionary for regulatory activities (MedDRA) terminology.
PK 
 samples will be processed centrally and the results will be sent electronically 
to Novartis (or a designated CRO). At some sites, part(s) of the hospital data may also be 
processed centrally.
After the data has been verified to be complete and accurate, the database will be declared 
locked and made available for data analysis. Authorization is required prior to making any 
database changes to locked data, by joint written agreement between the Global Head of 
Biostatistics and Data Management and the Global Head of Oncology Translational Medicine.


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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
Study data will be summarized with respect to demographic and baseline characteristics, 
efficacy observations and measurements, safety observations and measurements, and all 
relevant pharmacokinetics (PK)
measurements. Categorical data 
will be presented as contingency tables (frequencies and percentages). For continuous data,
summary statistics of mean, standard deviation, median, minimum, and maximum will be 
presented. In addition, individual listings of all raw data captured in the clinical database will 
be presented by treatment group and patient.
All data from participating centers in this protocol will be combined, so that an adequate number 
of patients will be available for analysis. The following rules will be followed for reporting 
results unless otherwise stated:

Phase I part: Patients with the same dose level, feeding regimen and schedule of FGF401
single agent or FGF401 in combination with PDR001 will be pooled into a single 
treatment group. All summaries, listings, figures and analyses will be performed by 
treatment group, unless otherwise stated.

Phase II part: Patients will be analyzed according to the Group to which they were 
assigned for FGF401 single agent. For FGF401 in combination with PDR001, if 
subgroups based on FGF19 expression and/or pathway activation are identified, patients 
will be analyzed according to the subgroup. All summaries, listings, figures and analyses 
will be performed by Group (FGF401 single agent) or subgroup (FGF401 in combination 
with PDR001), unless otherwise stated.
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 according to Section 
7.1.2.1 will not be included in any analysis, but will be reported in the CSR as separate listings.
The study data will be analyzed and reported based on all patients’ data of the phase I and the 
phase II parts up to the time when all patients have potentially completed at least six cycles of 
treatment or discontinued the study. Any additional data for patients continuing to receive study 
treatment past the data cutoff date for the primary CSR, as allowed by the protocol, will be 
reported following the end of study (refer to Section 4.3 for definition).
Details of the statistical analysis and data reporting will be provided in the Novartis Report and 
Analysis Plan (RAP) document finalized prior to database lock.
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 
medication. Patients enrolled in the phase I part will be analyzed according to the treatment 
they have been assigned to. Patients enrolled in the phase II part will be analyzed by Group.
Unless otherwise specified, the FAS will be the default analysis set used for all analyses.


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10.1.2
Safety Set
The Safety Set includes all patients who received at least one dose of study medication. Patients
enrolled in the phase I part will be analyzed according to the study treatment (regimen) they 
actually received. Patients enrolled in the phase II part will be analyzed by Group.
A precise definition of “actually received” will be added in the RAP.
10.1.3
Per-Protocol Set
The Per-Protocol Set (PPS) will consist of a subset of patients from the FAS who have an 
adequate tumor assessment at baseline and at least one post treatment tumor assessment with a 
result other than UNK, and no major protocol deviations.
All major protocol deviations leading to exclusion from the PPS will be detailed in the RAP.
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 (see Section 10.4). If the PPS and the FAS are 
identical, then analyses described by the PPS below will not be performed.
10.1.4
Dose-determining analysis set
The dose-determining analysis set (DDS) consists of all patients from the safety set from the 
Phase I parts who either meet the following minimum exposure criterion and have sufficient 
safety evaluations, or have experienced a DLT during the applicable evaluation period of DLTs. 
FGF401 single agent
A patient is considered to have met the minimum exposure criterion if he/she received at least 
66% of the planned doses of FGF401 in the first cycle of dosing i.e. at least 14 out of the 21 full 
planned daily dose of FGF401.
Patients who do not experience DLT during the first cycle of treatment are considered to have 
sufficient safety evaluations if they have been observed for ≥ 21 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.
FGF401 in combination with PDR001
A patient is considered to have met the minimum exposure criterion if he/she received at least 
66%, (i.e. at least 28 days) of the planned doses of FGF401, and all planned doses of PDR001 
in cycle 1 and cycle 2 of dosing.
Patients who do not experience DLT during the first 2 cycles of treatment are considered to 
have sufficient safety evaluations if they have been observed for ≥42 days following the first 
dose, and are considered by both Novartis and Investigators to have enough safety data to 
conclude that a DLT did not occur.
10.1.5
Pharmacokinetic analysis set
The pharmacokinetic analysis set (PAS) includes all subjects who provide at least one evaluable 
drug concentration. For those requiring non-compartment analyses, the PAS includes all 


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subjects who provide an evaluable PK profile. Patients will be removed from the determination 
of individual PK parameters on a case by case basis (to be described in detail in the Clinical 
Study Report).
The PAS will be used for summaries of drug concentration data, non-compartment PK analysis 
and/or population PK analysis. The analysis of the food effect on the FGF401 PK exposures 
will also use the PAS.
10.2
Patient demographics/other baseline characteristics
Demographic and other baseline data including disease characteristics will be summarized 
descriptively using the FAS.
10.3
Treatments (study treatment, concomitant therapies, 
compliance)
The safety set will be used for the analyses of treatments.
10.3.1
Study treatment
Duration of exposure to FGF401 and PDR001and as well as the actual total dose, the dose 
intensity (calculated as the ratio of actual dose received to actual duration) and the relative dose 
intensity (calculated as the ratio of dose intensity to planned dose received/planned duration) of 
the study treatment will be summarized descriptively.
Categories for relative dose intensity of FGF401 and 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 falling 
in each category will be presented.
10.3.2
Concomitant therapies
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study treatment will be summarized by Anatomic-Therapeutic-Chemical classification (ATC) 
term.
10.3.3
Compliance
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by treatment group for the FAS.
10.4
Primary objective
Phase I parts
The primary objective is to determine the maximum tolerated dose (MTD) and/or the 
recommended Phase II dose (RP2D) of single agent FGF401 and FGF401 in combination with 
PDR001.


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Phase II parts
For FGF401 single agent, the primary objective is to assess preliminary anti-tumor activity  in 
the following three groups of patients:

Group 1: HCC patients from Asian countries 

Group 2: HCC patients from non-Asian regions 

Group 3: patients who have other solid tumors regardless of geography and positive 
FGFR4/KLB expression
For FGF401 in combination with PDR001, the primary objective is to assess the preliminary 
anti-tumor activity of this combination in adult patients with HCC.
10.4.1
Variable
Phase I parts
The primary endpoint is the incidence of dose limiting toxicities (DLTs). For FGF401 single 
agent and in combination with PDR001, respectively, estimation of the MTD of the treatment 
will be based upon the estimation of the probability of DLT during the evaluation period for 
patients in the DDS. This probability is estimated by the corresponding model described in 
Section 10.4.2.
Phase II parts
Group 1 and 2-FGF401 single agent: The primary endpoint is time to progression (TTP), as 
per local assessment, defined as the time from the date of baseline evaluation to the date of the 
first documented event that the radiological confirmation of disease progression or death due to 
underlying cancer (RECIST v1.1). 
Group 3-FGF401 single agent: The primary endpoint is overall response rate, defined as the 
proportion of patients having a best overall response of either complete response (CR) or PR at 
any time on study as per local assessment according to RECIST v1.1.
FGF401 and PDR001 combination: The primary endpoint is overall response rate, defined as 
the proportion of patients having a best overall response of either CR or PR at any time on study 
as per local assessment according to RECIST v1.1.
10.4.2
Statistical hypothesis, model, and method of analysis
10.4.2.1 FGF401 single agent
Phase I part
A Bayesian hierarchical logistical regression model (BHLRM) will be applied to estimate the 
relationship between dose and the probability of a patient experiencing a dose limiting toxicity 
(DLT) for patients in fasted condition (stratum 1) and in fed condition (stratum 2). The standard 
Bayesian hierarchical model assumes full exchangeability of strata parameters; for the 
methodology and an application to binary data see Thall et al. 2003 and Chugh et al. 2009. Here, 
we extend the standard Bayesian hierarchical model to dose-toxicity data, and exchangeable as 
well as non-exchangeable strata parameters. 


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For the two patient strata, the probability of experiencing a DLT is modeled as follows:
logit	


 = log	
 + 	
 log( ∗
⁄
)
logit
  = log +  log( ∗
⁄
)
where  denotes dose; ∗is a fixed reference dose; 	


and 

are the probability of a 
patient experiencing a DLT at dose  in respectively fasted and fed conditions; and the two 
parameter
vectors 
	
 = (	
), (	
)
and 
 =
(), () describe the relationship between dose and toxicity for the two strata.
We further let the parameter vectors 	
 and  be either exchangeable or non-
exchangeable, with probability  and (1 −), respectively.
1. Under exchangeability, the parameter vectors 	
 and  are assumed to follow a 
bivariate normal distribution:
	
 ,
 ~  !"(μ$%&, '$%&),
where ($%& = ()*, )+) and '$%& = ,
-*
+
.-*-+
.-*-+
-+
+
/ are the mean vector and 
covariance matrix.
Prior distributions for μ$%& and '$%& of the exchangeability distribution complete the model 
specifications for the exchangeability component of the model 
The prior distributions for the component of μ$%& will be normal and the prior distributions for 
the standard deviations and the correlation in '$%& will be log-normal and uniform, 
respectively.
2. Under non-exchangeability, the parameter vectors 	
 and  are assumed to have a 
weakly informative bivariate normal prior distribution.
	
 ,  ~  !"(01, S1),
where 31 = (01*, 01+) and 41 = ,
-1*
+
5-1*-1+
5-1*-1+
-1+
+
/ are the mean vector and 
covariance matrix.
The specification of prior distributions is described in Appendix 10.
Change in dosing schedule
In the event of a change in dosing schedule, a new BLRM will be set up. This new BLRM will 
have the same functional form as that described above and will incorporate existing dose 
escalation data in the prior distributions. For comparability, doses for the new and old model 
will be normalized to dose in mg per day.
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels for fasted and fed conditions are obtained. The results of this analysis are 


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summarized in terms of the probabilities that the true rate of DLT for fasted and fed conditions 
at each dose-level will lie within each of the following intervals:

[0, 0.16) under-dosing

[0.16, 0.33) targeted toxicity

[0.33, 1.00] excessive toxicity
The overdose control criterion mandates that under each of the patient conditions, any dose of 
FGF401 for which the DLT rate has more than a 25% risk of being excessively toxic, i.e. P(DLT) 
is 0.33 or higher, will not be considered for the next dose cohort. The final estimate of the 
MTD/RP2D will also satisfy this condition.
Details of the criteria for dose escalation and the estimation of the MTD are provided in Section 
6.2.3.
Summary of DLTs
DLTs will be listed and their incidence summarized by primary system organ class and
preferred term. The dose-determining analysis set will be used for these summaries.
Phase II part
The FAS will be used for the primary analysis.
Group 1 and 2: The distribution of TTP will be estimated using the Kaplan-Meier method. A 
positive trend regarding the activity of FGF401 will be concluded if the observed lower limit 
of one-sided 90% confidence interval (CI) of TTP ≥ 1.5 months (Group 1) and 2.2 months 
(Group 2), which are the expected median TTPs without FGF401 treatment in group 1 and 2, 
respectively. The median TTP and quantiles (along with one-sided 90% CI) will be presented. 
The Kaplan-Meier curve will be presented graphically. TTP rate estimates (along with one-
sided 90% CI) at 1.5, 3 and 6 months will be presented, as given by the Kaplan-Meier analysis.
Group 3: BOR, defined in Appendix 1, will be summarized by tumor type. The number (%) of 
patients having BOR as CR, PR, SD, PD and unknown per RECIST 1.1 will be provided. The 
overall response rate (ORR), the proportion of patients having BOR of either CR or PR, of an 
individual tumor type will be summarized if the number of observations is reasonable large.
10.4.2.2 FGF401 in combination with PDR001
Phase I part
A 5-parameter adaptive Bayesian logistic regression model (BLRM), guided by the EWOC 
principle will be used to make dose recommendations and estimate the MTD/RDE of the 
combination.
The respective single agent dose-DLT relationships are defined as follows:
FGF401:
logitπ*(d*) = log(α*) + β* log(* *
∗
⁄
)
PDR001:
logitπ+(d+) = log(α+) + β+ log(+ +
∗
⁄
)


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Where, π1(d1) and π2(d2) are respectively the probability that a patient has a DLT during the 
first 2 cycles of combination treatment with FGF401 and PDR001 given at the Q3W dose d1
and d2 respectively, and *
∗=120 mg and +
∗=300 mg are respectively the FGF401 and PDR001 
reference doses. αi, βi > 0 are the parameters of the model.
Then, the dose-DLT relationship of the combination FGF401 + PDR001 is defined as follows:
?@*+(*, +) =
*+(*, +)
1 −*+(*, +) = exp(η *
*
∗
+
+
∗) E*(*) + +(+) −*(*)+(+)
(1 −*(*))(1 −+(+))
F
Where η is the log-odds ratio between the interaction and no-interaction model at the reference 
doses. Here η = 0 corresponds to no-interaction, η > 0 represents synergistic toxicity, and η < 0 
represents antagonistic toxicity. The specification of prior distributions is described in 
Appendix 10.
Change in dosing schedule
In the event of a change in dosing schedule, a new BLRM will be set up. This new BLRM will 
have the same functional form as that described above and will incorporate existing dose 
escalation data in the prior distributions. 
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels for FGF401 in combination with PDR001 are obtained. The results of this 
analysis are summarized in terms of the probabilities that the true rate of DLT for FGF401 in 
combination with PDR001 at each dose-level will lie within each of the following intervals:

[0, 0.16) under-dosing

[0.16, 0.33) targeted toxicity

[0.33, 1.00] excessive toxicity
The overdose control criterion mandates that under each of the patient conditions, any dose of 
FGF401 for which the DLT rate has more than a 25% risk of being excessively toxic, i.e. P(DLT) 
is 0.33 or higher, will not be considered for the next dose cohort. The final estimate of the 
MTD/RP2D will also satisfy this condition.
Details of the criteria for dose escalation and the estimation of the MTD are provided in Section 
6.2.3.
Summary of DLTs
DLTs will be listed and their incidence summarized by primary system organ class and 
preferred term. The dose-determining analysis set will be used for these summaries.
Phase II part
The FAS will be used for the primary analysis.
The number (%) of patients having BOR as CR, PR, SD, PD and unknown per RECIST 1.1 will 
be provided. The overall response rate (ORR), the proportion of patients having BOR of either 
CR or PR, will be summarized.


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If at interim analysis the efficacy is declared (for more details, refer to Section 10.7.2), the 
primary analysis will be overall. In addition, summary by subgroup(s) defined by FGF19 
expression and/or FGF19 pathway activation will be conducted as an exploratory analysis. If at 
interim analysis the efficacy is not declared, the primary analysis will be done by subgroup(s)
defined by the FGF19 expression and/or FGF19 pathway activation.
A Bayesian method will be used in order to estimate the distribution of the ORR and to provide 
inferential summaries (mean, median, interval probabilities). A minimally informative Beta 
prior distribution (Neuenschwander 2008) with b = 1 and a = 3/7 is specified for the ORR 
assuming the true mean ORR is 30%. 
Anti-tumor activity is classified based on ORR intervals as following: 

[0, 0.15) no/limited anti-tumor activity

[0.15, 0.30) moderate anti-tumor activity

[0.30, 1.00] clinically significant anti-tumor activity
10.4.3
Handling of missing values/censoring/discontinuations
Phase I parts
Patients in the phase I parts who are ineligible for the DDS will be excluded from the primary 
analysis, although their additional data (e.g., safety, PK, 
 efficacy etc.) will be used in the 
review of patient data at the dose-escalation meeting. Missing data will simply be treated as 
missing on appropriate tables/listings.
Phase II parts
FGF401 single agent Group 1 and 2: If a patient has not had the event at the date of analysis 
cut-off or when he/she received any further anti-neoplastic therapy, TTP will be censored at the 
time of the last adequate assessment before the cut-off date, or start date of other anti-neoplastic 
therapy.
FGF401 single agent Group 3 and FGF401 and PDR001 combination treatment group:
BOR will be considered missing if the patient does not have both baseline and at least one post-
baseline RECIST assessment by the investigator, allowing the assignment of a BOR under 
RECIST 1.1 (see Appendix 1). For ORR calculation, patients who have missing BOR will be 
considered as non-responder (non-CR/PR).
10.4.4
Supportive analyses
For the phase II parts, the analyses of the primary endpoint will be repeated using the PPS, if 
PPS is different from FAS. 
For the FGF401 in combination with PDR001, the same analyses will be performed using the 
tumor response evaluation as per irRC (Appendix 9).
For the FGF401 in combination with PDR001, supportive analysis by geographical region 
(Asian vs. non-Asian) will be performed for key efficacy endpoints.


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Additional supportive or exploratory analyses will be conducted to support the primary 
objective if appropriate and details of the analysis will be defined in the Reporting and Analysis 
Plan (RAP).
10.5
Secondary objectives
Please refer to Section 3 for the secondary objectives.
10.5.1
Efficacy objectives
For all efficacy analyses, the FAS will be used unless otherwise specified.
Phase I parts
BOR, ORR and DCR will be summarized by treatment group.
The Kaplan-Meier plot for TTP at the MTD/RP2D will be presented. The estimated TTP rate 
at the MTD/RP2D along with 95% CI at 1.5, 3 and 6 months will be presented. If appropriate, 
the Kaplan-Meier plots for OS at the MTD/RP2D will also be presented. These analyses will 
only be provided if there are at least 10 enrolled patients at MTD/RP2D. Otherwise, data will 
only be listed.
Phase II parts
FGF401 single agent- Group 1 and 2: BOR, ORR and DCR will be summarized by treatment 
group. 
The Kaplan-Meier plot for OS will be presented by group, and by FGF19 status within 
individual HCC groups. The estimated OS rate along with 95% CI at 3, 5, 7 and 9 months will 
be presented by group.
FGF401 single agent- Group 3: BOR and DCR will be summarized by tumor type. 
The Kaplan-Meier analysis for PFS and OS will be provided by tumor type. This analysis will 
only be provided for tumor type with which there are at least 10 enrolled patients. Otherwise,
data will only be listed.
FGF401 and PDR001 combination: The Kaplan-Meier analysis for TTP, PFS, OS and DOR 
will be provided. BOR and DCR will be summarized. The same analyses will be performed 
using the tumor response evaluation as per irRC (Appendix 9).
10.5.2
Safety objectives
10.5.2.1 Analysis set and grouping for the analyses
For all safety analyses, the safety set will be used unless otherwise specified. Listings and 
summary tables will be presented by treatment group.
The overall observation period will be divided into three mutually exclusive segments:
1. pre-treatment period: from day of patient’s pre-screening informed consent to the day 
before first dose of study medication


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2. on-treatment period: from day of first dose of study medication to 30 days after the last 
dose of study medication
3. -For patients receiving FGF401 single agent: post-treatment period: starting at day 31 after 
last dose of study medication. 
-For patients receiving FGF401 in combination with PDR001: extended safety follow-up 
period: starting at day 31 after last dose of study medication, ending at least 150 days 
after last dose of PDR001.
10.5.2.2 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) 
and relation to study treatment.
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event.
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.
For patients receiving FGF401 in combination with PDR001, additional summaries of related 
AEs, related SAEs, and related AESIs will be produced covering all events with onset or 
worsening at any time during the extended safety follow-up period.
10.5.2.3 Laboratory abnormalities
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, laboratory data will be graded accordingly. For laboratory tests covered 
by CTCAE, a Grade 0 will be assigned for all non-missing values not graded as 1 or higher. 
Grade 5 will not be used.
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges.
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests:

frequency table for newly occurring on-treatment grades 3 or 4

shift tables using CTCAE grades to compare baseline to the worst on-treatment value

for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.


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
listing of all laboratory data with values flagged to show the corresponding CTCAE 
grades and the classifications relative to the laboratory normal ranges.
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots might 
be specified in the RAP.
10.5.2.4 Other safety data
ECG

shift table baseline to worst on-treatment result for overall assessments

listing of ECG evaluations for all patients with at least one abnormality.
Vital signs

shift table baseline to worst on-treatment result

table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points.
10.5.2.5 Tolerability
Tolerability of study drug will be assessed by summarizing the number of dose interruptions 
and dose reductions. Reasons for dose interruption and dose reductions will be listed by patient 
and summarized.
10.5.3
Pharmacokinetics
The PAS will be used in the pharmacokinetic data analysis and PK summary statistics.
Concentration data will be listed by time point, patient and treatment group. Descriptive 
statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, geometric mean, 
geometric CV%, minimum and maximum) for PDR001 and FGF401 concentrations will be 
presented at each scheduled timepoint by treatment. 
All concentration data for PDR001 and FGF401 will be displayed graphically. Individual 
concentration-time profile as well as mean concentration-time profile will be plotted.
PK parameters will be determined for all PK-evaluable patients with noncompartmental 
method(s) using Phoenix WinNonlin version 6.2 or above (Pharsight, Mountain View, CA). 
Exploratory population PK analyses will be conducted to derive PK parameters using 
compartmental modeling method when necessary. For FGF401, the PK parameters include but 
may be not limited to those listed in Table 10-1. For PDR001, PK parameters would be limited 
to Cmax, Tmax, AUClast and Ctrough. The descriptive statistics (n, mean, CV%, standard 
deviation (SD), median, geometric mean, geometric CV%, minimum and maximum) will be 
presented by treatment for all PK parameters defined in Table 10-1 except Tmax, where only n, 
median, minimum and maximum will be presented. Missing data will not be imputed.


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Table 10-1
Noncompartmental pharmacokinetic parameters
AUClast
The AUC from time zero to the last measurable concentration sampling time (tlast) (mass x time x 
volume-1)
AUCinf
The AUC from time zero to infinity (mass x time x volume-1)
AUCtau
The AUC calculated to the end of a dosing interval (tau) at steady-state (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma drug concentration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration (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
CL/F
The apparent total body clearance of drug from the plasma after oral administration (vol x time-1)
Racc
Accumulation ratio calculated using AUCtau at steady state divided by AUCtau at day 1
10.5.3.1 Data handling principles
Only PK blood samples with date and time and for which the last prior dose dates and times are 
adequately recorded will be included in the PK analyses. For FGF401, samples taken from 
patients who vomited within 4 hours of dosing may be excluded from the analysis.
All concentrations below their respective LLOQs (lower limits of quantification) or missing 
data will be labeled as such in the concentration data listings. Concentrations below the LLOQ 
will be treated as zero in summary statistics and for the calculation of pharmacokinetic 
parameters.
10.5.3.2 Data analysis principles
10.5.3.2.1
Summary tables and figures
The individual plasma concentration time profiles and mean concentration time profile of
analytes will be summarized descriptively and graphically by treatment group in phase I part 
and group in phase II part.
Descriptive statistics of PK parameters shown in Table 10-1 will be provided if appropriate.
Further graphical exploratory analyses will be carried out if deemed appropriate. 
10.5.3.2.2
Dose proportionality
The assessment of dose proportionality will be conducted for AUC and Cmax of FGF401 using 
a power model on log-transformed scale. The log-transformed PK parameters will each be 
regressed onto a fixed factor for log (dose). The 90% CI of the slope for each parameter will be 
computed from the model and presented in the summary table. The dose proportionality
assessment is exploratory analysis due to insufficient power to demonstrate dose proportionality.
10.5.3.2.3
Food effect
As exploratory analysis to assess the food effect on FGF401 pharmacokinetics, exposure 
measures (Cmax, Tmax and AUC) will be compared among patients taking study drug under 
different feeding regimens (fasted or fed) as appropriate. 


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10.5.3.2.5
Immunogenicity 
Immunogenicity of PDR001 will be characterized descriptively by tabulating antidrug 
antibodies (ADA) prevalence at baseline and ADA incidence on-treatment. The impact of ADA 
on the occurrence of safety endpoints, efficacy endpoints, and PDR001 PK will be assessed 
using appropriate methods. Further details will be provided in the SAP or in a stand-alone 
analysis plan document.
10.7
Interim analysis
10.7.1
FGF401 single agent
Phase I part
No formal interim analysis is planned. However, 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. Details of this procedure and the process for communication with investigators are 
provided in Section 6.2.3.
Phase II part
No formal interim analysis is conducted. However, individual patient data will be reviewed on 
an ongoing basis by the study team across the duration of the trial (Section 8.5 and Section 8.6).


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10.7.2
FGF401 in combination with PDR001
Phase I part
No formal interim analysis is planned. However, 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. Details of this procedure and the process for communication with investigators are 
provided in Section 6.2.3.
Phase II part
An interim analysis for efficacy and futility will be performed after the first 35 patients have 
been enrolled and have had at least one-post treatment tumor evaluation or discontinued earlier
(Stage 1). Interim decision making will be based on the Bayesian posterior probability of ORR 
and posterior median ORR. The interim analysis of ORR will be based on unconfirmed response.
The phase II part in the combination arm will be stopped due to efficacy if the posterior 
probability of ORR in the unselected population included in the no/limited anti-tumor activity 
interval [0, 0.15) is less than 0.10 and the posterior median ORR is 0.30 or more. Considering 
the exploratory nature of the study, when the aforementioned success criteria are not met but 
the evaluation of overall efficacy and safety suggests the treatment is promising for 
development, decision to stop at Stage 1 for success can also be made by Novartis. 
Should the study not stop at Stage 1 for success in the unselected HCC population, go/no go 
decision to Stage 2 will be made by evaluating the anti-tumor activity in subgroups defined by 
FGF19 expression and/or FGF19 pathway activation based on the predictive probability of 
ORR. For an individual subgroup, if that predictive probability to not meet the efficacy criteria 
(i.e. posterior probability of ORR included in the no/limited anti-tumor activity interval is less 
than 0.10 and the posterior median ORR is 0.30 or more) at the final analysis is not greater than 
0.90, and the number of patients in the subgroup is less than 25, the study will move to Stage 2 
and more patients will be enrolled to the subgroup until a sample size of approximately 25 is 
reached. If 25 or more patients are already enrolled to the subgroup at interim analysis, interim 
analysis will be performed but no further enrollment will be allowed in that subgroup.
10.8
Sample size calculation
10.8.1
FGF401 single agent
10.8.1.1 Phase I part
Initially, cohorts of 1 to 6 evaluable patients will be enrolled in the phase I part. Upon 
observation of specific toxicities (see Section 6.2.3 for details), cohorts of 3 to 6 evaluable 
patients will be enrolled including at least six evaluable patients at the MTD/RP2D level, as 
described in Section 6.2.3. Multiple cohorts may be sequentially enrolled to the same dose level. 
Additional cohorts of 1 to 6 evaluable patients may be enrolled at any dose level below the 
estimated MTD/RP2D for further elaboration of safety and pharmacokinetic parameters as 
required. At least 21 evaluable patients are expected to be treated in the phase I part, for the 
model to have reasonable operating characteristics relating to its MTD and/or RP2D 
recommendation.


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10.8.1.2 Phase II part 
Group 1
Group 1 is designed to assess the preliminary anti-tumor activity of FGF401 in HCC patients 
with positive expression of FGFR4 and KLB from Asian countries. If the lower limit of one-
sided 90% CI of TTP is equal to or greater than 1.5 months, which is the expected median TTP 
without FGF401 treatment, it will be considered as preliminary evidence of clinically relevant 
efficacy of FGF401 in Group 1. 
It is assumed that TTP has an exponential distribution and the true median TTP with FGF401 
treatment is 3.0 months, which is considered a clinically relevant improvement with treatment 
in this patient population, and the enrollment rate is 3.5 patients per month. Analysis will be 
provided when all patients have potentially completed at least six cycles of treatment or 
discontinued the study. Table 10-2 shows the probability of success (PoS), i.e., the probability 
of the lower limit of observed one-sided 90% CI of TTP equal to or greater than 1.5 months, 
calculated by simulation given these assumptions and different sample sizes. 
Approximately 40 patients will be enrolled, however, more patients with double positive tumors 
may be enrolled if the emerging clinical data supports, see Section 4.1. Considering a drop-out 
rate of 15%, the PoS is 90.6%.
Table 10-2
Probability of Success under different number of sample size in 
Group 1 (drop rate = 15%)
Sample size
Expected number of events
P (lower limit of one-sided 90% CI ≥1.5)
30
20.4
0.833
35
24.2
0.888
40
28.9
0.906
Group 2
Group 2 is designed to assess the preliminary anti-tumor activity of FGF401 in HCC patients 
with positive expression of FGFR4 and KLB from non-Asian regions. If the lower limit of one-
sided 90% CI of TTP is equal to or greater than 2.2 months, which is the expected median TTP 
without FGF401 treatment, it will be considered as preliminary evidence of clinically relevant 
efficacy of FGF401 in Group 2.
It is assumed that TTP has an exponential distribution and the true median TTP with FGF401 
treatment is 4.2 months, which is considered a clinically relevant improvement with treatment 
in this patient population, and the enrollment rate is 3.5 patients per month. Analysis will be 
provided when all patients have potentially completed at least six cycles of treatment or 
discontinued the study. Table 10-3 shows the PoS, i.e., the probability of the lower limit of 
observed one-sided 90% CI of TTP equal to or greater than 2.2 months, calculated by simulation 
given these assumptions and different sample sizes. 
Approximately 40 patients will be enrolled, however, more patients with double positive tumors 
may be enrolled if the emerging clinical data supports, see Section 4.1. Considering a drop-out 
rate of 15%, the PoS is 87.7 %.


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Table 10-3
Probability of Success under different number of sample size in 
Group 2 (drop rate = 15%)
Sample size
Expected number of events
P (lower limit of one-sided 90% CI ≥ 2.2)
30
17.8
0.800
35
21.2
0.857
40
25.6
0.877
Group 3
Group 3 is designed to assess the preliminary anti-tumor activity of FGF401 in other solid 
tumors with positive expression of FGFR4 and KLB. Overall approximately 20 patients are 
planned to be enrolled. Table 10-4 shows the probabilities of observing at least a certain number 
of responders given different values of true ORR.
If the true ORR of a tumor type is 0.05, 0.10 and 0.25, the probabilities of observing 1 or more 
responders with 20 patients are 0.642, 0.878 and 0.997, respectively.
Table 10-4
Cumulative probability (upper tail) of responses observed or more 
given true ORR and 20 patients
True ORR (p)
Responses observed (n)
P (responses≥ n | N=20, p)
0.05
1
0.642
2
0.264
3
0.075
4
0.016
0.10
1
0.878
2
0.608
3
0.323
4
0.133
5
0.043
6
0.011
0.25
1
0.997
2
0.976
3
0.909
4
0.775
5
0.585
6
0.383
10.8.2
FGF401 in combination with PDR001
10.8.2.1 Phase I part
Cohorts of 3 to 6 evaluable patients will be enrolled including at least six evaluable patients at 
the MTD/RP2D level, as described in Section 6.2.3. Multiple cohorts may be sequentially 
enrolled to the same dose level. Additional cohorts of 1 to 6 evaluable patients may be enrolled 
at any dose level below the estimated MTD/RP2D for further elaboration of safety and 
pharmacokinetic parameters as required. At least 12 evaluable patients are expected to be 
treated in the phase I part, for the model to have reasonable operating characteristics relating to 
its MTD and/or RP2D recommendation.


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10.8.2.2 Phase II part
The phase II part is designed to assess the preliminary anti-tumor activity of FGF401 in 
combination with PDR001 in HCC patients. If the posterior probability of ORR in the 
unselected population included in the no/limited anti-tumor activity interval [0, 0.15) is less 
than 0.10 and the posterior median ORR is 0.30 or more, it will be considered as preliminary 
evidence of clinically relevant efficacy of FGF401 in combination with PDR001. 
At interim analysis, if the predictive probability of ORR (based on unconfirmed response) to 
not be considered as preliminary evidence of clinically relevant efficacy defined above at the 
final analysis is more than 0.90, that subgroup will not be open for further enrolment. If 25 or 
more patients are already enrolled to the subgroup, interim analysis will be performed but no 
further enrollment will be allowed in that subgroup.
In order to show how the design performs, simulation studies are conducted assuming 35 
patients are enrolled in the Stage 1, and the biopsy failure rate is 15%. In addition, due to the 
uncertainty of the proportions of FGF19 positive and FGF19 negative patients (per FGF19 
expression and/or FGF19 pathway activation status), the following 2 scenarios are investigated:
(1) the percentages of FGF19 positive and FGF19 negative patients enrolled in the Stage 1 are 
20% and 80% respectively, and (2) the percentages of FGF19 positive and FGF19 negative 
patients enrolled in the Stage 1 are 40% and 60%. For each scenario, 50,000 trials were 
simulated.
The operating characteristics under several scenarios of true ORRs of FGF19 positive and 
negative patients are shown in Table 10-5 and Table 10-6.
Under the scenario 1 (the percentages of FGF19 positive and FGF19 negative patients enrolled 
in the Stage 1 are 20% and 80%),

If the true ORR in both FGF19 positive and negative patients is 40%, the probability to 
stop at Stage 1 for efficacy in unselected population is 0.889. 

If the true ORR in FGF19 positive and negative patients is 10%, probabilities to stop 
enrollment early for futility are 0.600 (FGF19 positive group) and 0.564 (FGF19 negative 
group), and the probability to show efficacy in either unselected or at least one subgroup is 
0.004.

If the true ORRs in FGF19 positive and negative patients are 10% and 40% respectively, 
the probability to stop enrollment early for efficacy is 0.685, and the probability to stop 
enrollment early for futility in FGF19 positive group is 0.232.

If the true ORRs in FGF19 positive and negative patients are 40% and 10% respectively, 
the probability to stop enrollment early for efficacy is 0.017, and probability to show 
efficacy in either unselected of at least one subgroup is 0.796.


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Table 10-5
Operating Characteristics (scenario 1: the percentages of FGF19
positive and FGF19 negative patients enrolled in the Stage 1 are 20% 
and 80%)
True ORR
Probability to 
stop study for 
success* at 
Stage 1
Probability to stop 
subgroup 
enrollment for 
futility** at Stage 1
Probability to 
show clinically 
relevant efficacy* 
at final analysis***
Overall probability to 
show clinically relevant 
efficacy* in either 
unselected, or at least 
one subgroup
FGF19+
FGF19-
FGF19+
FGF19-
FGF19+
FGF19-
5%
5%
0.000
0.889
1.000
0.000
0.176
0.000
5%
10%
0.000
0.888
0.994
0.000
0.316
0.002
5%
20%
0.026
0.869
0.850
0.000
0.640
0.105
5%
30%
0.241
0.693
0.450
0.000
0.801
0.488
5%
40%
0.643
0.336
0.125
0.001
0.886
0.849
10%
5%
0.000
0.765
1.000
0.007
0.250
0.002
10%
10%
0.000
0.761
0.994
0.009
0.317
0.004
10%
20%
0.039
0.743
0.847
0.007
0.635
0.113
10%
30%
0.289
0.579
0.443
0.007
0.787
0.500
10%
40%
0.685
0.274
0.120
0.003
0.876
0.856
20%
5%
0.000
0.501
1.000
0.181
0.111
0.090
20%
10%
0.002
0.502
0.993
0.178
0.271
0.091
20%
20%
0.074
0.489
0.835
0.169
0.598
0.200
20%
30%
0.387
0.368
0.421
0.154
0.757
0.566
20%
40%
0.768
0.162
0.108
0.142
0.853
0.881
30%
5%
0.000
0.294
1.000
0.581
0.154
0.410
30%
10%
0.006
0.292
0.990
0.580
0.298
0.415
30%
20%
0.128
0.283
0.808
0.567
0.572
0.491
30%
30%
0.490
0.206
0.387
0.536
0.730
0.727
30%
40%
0.835
0.085
0.093
0.511
0.836
0.928
30%
5%
0.000
0.294
1.000
0.581
0.154
0.410
40%
5%
0.002
0.151
0.998
0.886
0.000
0.752
40%
10%
0.017
0.150
0.980
0.883
0.264
0.753
40%
20%
0.201
0.144
0.758
0.873
0.564
0.785
40%
30%
0.590
0.101
0.337
0.857
0.715
0.886
40%
40%
0.889
0.039
0.073
0.844
0.815
0.971
* show the posterior probability of ORR included in [0, 0.15) is less than 0.10 and the posterior median ORR is 
0.30 or more
** show the posterior probability of ORR in a FGF19-based subgroup being included in [0, 0.15) is more than 
0.80
*** conditional probability to show clinically relevant efficacy and move to Stage 2 without stop study for success 
or futility at Stage 1
Under the scenario 2 (the percentages of FGF19 positive and FGF19 negative patients enrolled 
in the Stage 1 are 40% and 60%),

If the true ORR in both FGF19 positive and negative patients is 40%, the probability to 
stop at Stage 1 for efficacy in unselected population is 0.889. 

If the true ORR in FGF19 positive and negative patients is 10%, probabilities to stop 
enrollment early for futility are 0.817 (FGF19 positive group) and 0.940 (FGF19 negative 


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group), and probability to show efficacy in either unselected or at least one subgroup is 
0.004.

If the true ORRs in FGF19 positive and negative patients are 10% and 40% respectively, 
the probability to stop enrollment early for efficacy is 0.386, and the probability to stop 
enrollment early for futility in FGF19 positive group is 0.553.

If the true ORRs in FGF19 positive and negative patients are 40% and 10% respectively, 
the probability to stop enrollment early for efficacy is 0.126, and probability to show 
efficacy in either unselected or at least one subgroup is 0.829.
Table 10-6
Operating Characteristics (scenario 2: the percentages of FGF19
positive and FGF19 negative patients enrolled in the Stage 1 are 40% 
and 60%)
True ORR
Probability to 
stop study for 
success* at 
Stage 1
Probability to stop 
subgroup 
enrollment for 
futility** at Stage 1
Probability to 
show clinically 
relevant efficacy* 
at final analysis***
Overall probability to 
show clinically 
relevant efficacy* in 
either unselected, or 
at least one subgroup
FGF19+
FGF19-
FGF19+
FGF19-
FGF19+
FGF19-
5%
5%
0.000
0.980
0.997
0.000
0.004
0.000
5%
10%
0.000
0.980
0.968
0.001
0.060
0.002
5%
20%
0.006
0.976
0.724
0.001
0.350
0.101
5%
30%
0.076
0.910
0.346
0.001
0.670
0.463
5%
40%
0.287
0.707
0.105
0.000
0.879
0.822
10%
5%
0.000
0.909
0.997
0.019
0.008
0.002
10%
10%
0.000
0.909
0.967
0.021
0.051
0.004
10%
20%
0.018
0.901
0.719
0.019
0.333
0.107
10%
30%
0.128
0.817
0.346
0.015
0.648
0.470
10%
40%
0.385
0.592
0.104
0.010
0.860
0.825
20%
5%
0.001
0.629
0.996
0.250
0.000
0.094
20%
10%
0.006
0.628
0.965
0.245
0.051
0.097
20%
20%
0.075
0.613
0.710
0.224
0.297
0.206
20%
30%
0.286
0.527
0.337
0.200
0.602
0.545
20%
40%
0.591
0.337
0.097
0.181
0.825
0.857
30%
5%
0.011
0.315
0.988
0.635
0.000
0.439
30%
10%
0.039
0.320
0.939
0.625
0.052
0.441
30%
20%
0.201
0.306
0.658
0.587
0.263
0.521
30%
30%
0.489
0.248
0.290
0.553
0.544
0.737
30%
40%
0.767
0.145
0.078
0.500
0.782
0.920
40%
5%
0.055
0.119
0.944
0.894
0.000
0.793
40%
10%
0.130
0.118
0.857
0.890
0.031
0.800
40%
20%
0.388
0.115
0.538
0.861
0.238
0.827
40%
30%
0.686
0.086
0.216
0.830
0.507
0.908
40%
40%
0.886
0.047
0.054
0.810
0.748
0.972
* show the posterior probability of ORR included in [0, 0.15) is less than 0.10 and the posterior median ORR is 
0.30 or more
** show the posterior probability of ORR in a FGF19-based subgroup being included in [0, 0.15) is more than 0.80
*** conditional probability to show clinically relevant efficacy and move to Stage 2 without stop study for success or 
futility at Stage 1


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10.9
Power for analysis of key secondary variables
Not applicable.
11
Ethical considerations and administrative procedures
11.1
Regulatory and ethical compliance
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki.
11.2
Responsibilities of the investigator and IRB/IEC/REB
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 
Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required.
11.3
Informed consent procedures
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent if applicable:  or, if 
incapable of doing so, after such consent has been provided by a legally acceptable 
representative of the patient. In cases where the patient’s representative gives consent, the 
patient should be informed about the study to the extent possible given his/her understanding. 
If the patient is capable of doing so, he/she should indicate assent by personally signing and 
dating the written informed consent document or a separate assent form.
[For Japan only: written consent is necessary both from the patient and his/her legal 
representative if he/she is under the age of 20 years.]
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs.
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval.
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 


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in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study.
11.4
Discontinuation of the study
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in Section 4.4.
11.5
Publication of study protocol and results
Novartis is committed to following high ethical standards for reporting study results for its 
innovative medicine, including the timely communication and publication of clinical trial 
results, whatever their outcome. Novartis assures that the key design elements of this protocol 
will be posted on the publicly accessible database, e.g.  www.clinicaltrials.gov, before study 
start. In addition, results of interventional clinical trials in adult patients are posted on 
www.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 (www.icmje.org) and other specific 
guidelines of the journal or congress to which the publication will be submitted.
Authors will not receive remuneration for their writing of a publication, either directly from 
Novartis or through the professional medical writing agency. Author(s) may be requested to 
present poster or oral presentation at scientific congress; however, there will be no honorarium 
provided for such presentations.
As part of its commitment to full transparency in publications, Novartis supports the full 
disclosure of all funding sources for the study and publications, as well as any actual and 
potential conflicts of interest of financial and non-financial nature by all authors, including 
medical writing/editorial support, if applicable.
For the Novartis Guidelines for the Publication of Results from Novartis-sponsored Research, 
please refer to www.novartis.com. 
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 


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checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial.
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. Any change or correction to a paper CRF should 
be dated, initialed, and explained (if necessary) and should not obscure the original entry. For 
electronic CRFs an audit trail will be maintained by the system. The investigator should retain 
records of the changes and corrections to paper CRFs.
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents.
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines.
11.7
Confidentiality of study documents and patient records
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site.
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.


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


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Ho HK, Pok S, Streit S, et al (2009) Fibroblast growth factor receptor 4 regulates 
proliferation, anti-apoptosis and alpha-fetoprotein secretion during hepatocellular carcinoma 
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Poh W, Wong W, Ong H, et al (2012) Klotho-beta overexpression as a novel target for 
suppressing proliferation and fibroblast growth factor receptor-4 signaling in hepatocellular 
carcinoma. Mol.Cancer.; 11:14. doi: 10.1186/1476-4598-11-14.:14-11. 
 
Raza A, Sood GK (2014) Hepatocellular carcinoma review: current treatment, and evidence-
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Rogatko A, Schoeneck D, Jonas W, et al (2007) Translation of innovative designs into phase I 
trials. J.Clin.Oncol.; 25 (31):4982-4986. 
Sawey ET, Chanrion M, Cai C, et al (2011) Identification of a therapeutic strategy targeting 
amplified FGF19 in liver cancer by Oncogenomic screening. Cancer Cell.; 19 (3):347-358. 
Thall PF, Wathen JK, Bekele BN, et al (2003) Hierarchical Bayesian approaches to phase II 
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15:7412-20.


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14
Appendices
14.1
Appendix 1 – Guidelines for response, duration of overall 
response, TTF, TTP, progression-free survival and overall 
survival (based on RECIST 1.1)
Harmonization of Efficacy Analysis of Solid Tumor Studies
Document type:
TA Specific Guideline
Document status:
Version 3.1: 29-Nov-2011
Version 3:0: 19-Oct-2009
Version 2:0: 18-Jan-2007
Version 1:0: 13-Dec-2002
Release date:
29-Nov-2011
Authors (Version 3.1):
 
Authors (Version 3):
 
Authors (Version 2):
Authors (Version 1):


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Glossary
CR
Complete response
CRF
Case Report Form
CSR
Clinical Study Report
CT
Computed tomography
DFS
Disease-free survival
eCRF
Electronic Case Report Form
FPFV
First patient first visit
GBM
Glioblastoma multiforme
MRI
Magnetic resonance imaging
LPLV
Last patient last visit
OS
Overall survival
PD
Progressive disease
PFS
Progression-free survival
PR
Partial response
RAP
Reporting and Analysis Plan
RECIST
Response Evaluation Criteria in Solid Tumors
SD
Stable disease
SOD
Sum of Diameter
TTF
Time to treatment failure
TTP
Time to progression
UNK
Unknown


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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 14.1.17 are based on the RECIST 1.1 criteria but also give more detailed instructions 
and rules for determination of best response. Section 14.1.18 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 14.1.28 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.
14.1.3
Definitions
14.1.4
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 14.1.26.
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.


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
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.
14.1.5
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 
14.1.26.
14.1.6
Methods of tumor measurement - general guidelines
In this document, the term “contrast” refers to intravenous (i.v) contrast.
The following considerations are to be made when evaluating the tumor:

All measurements should be taken and recorded in metric notation (mm), using a ruler or 
calipers. All baseline evaluations should be performed as closely as possible to the 
beginning of treatment and never more than 4 weeks before the beginning of the 
treatment.

Imaging-based evaluation is preferred to evaluation by clinical examination when both 
methods have been used to assess the antitumor effect of a treatment.

For optimal evaluation of patients, the same methods of assessment and technique should 
be used to characterize each identified and reported lesion at baseline and during follow-
up. Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed 
using a 5 mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan 
slice thickness should not exceed 8 mm cuts using a contiguous reconstruction algorithm. 
If, at baseline, a patient is known to have a medical contraindication to CT contrast or 
develops a contraindication during the trial, the following change in imaging modality will 
be accepted for follow up: a non-contrast CT of chest (MRI not recommended due to 
respiratory artifacts) plus contrast-enhanced MRI of abdomen and pelvis.


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


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and residual malignant lesions in tumor types such as germ cell tumors). Cytologic 
confirmation of neoplastic nature of any effusion that appears or worsens during treatment 
is required when the measurable tumor has met the criteria for response or stable disease. 
Under such circumstances, the cytologic examination of the fluid collected will permit 
differentiation between response and stable disease (an effusion may be a side effect of the 
treatment) or progressive disease (if the neoplastic origin of the fluid is confirmed).

Clinical examination: Clinical lesions will only be considered measurable when they are 
superficial (i.e., skin nodules and palpable lymph nodes). For the case of skin lesions, 
documentation by color photography, including a ruler to estimate the size of the lesion, is 
recommended.
14.1.7
Baseline documentation of target and non-target lesions
For the evaluation of lesions at baseline and throughout the study, the lesions are classified at 
baseline as either target or non-target lesions:

Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of five 
lesions in total (and a maximum of two lesions per organ), representative of all involved 
organs should be identified as target lesions and recorded and measured at baseline. Target 
lesions should be selected on the basis of their size (lesions with the longest diameter) and 
their suitability for accurate repeated measurements (either by imaging techniques or 
clinically). Each target lesion must be uniquely and sequentially numbered on the CRF 
(even if it resides in the same organ).
Minimum target lesion size at baseline

Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 10 
mm in longest diameter. See Section 14.1.4.

Nodal target: See Section 14.1.4.
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.
14.1.8
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 


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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.
14.1.9
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.
14.1.10
Non-nodal lesions
Following treatment, lesions may have longest diameter measurements smaller than the image 
reconstruction interval. Lesions smaller than twice the reconstruction interval are subject to 
substantial “partial volume” effects (i.e., size may be underestimated because of the distance of 
the cut from the longest diameter; such lesions may appear to have responded or progressed on 
subsequent examinations, when, in fact, they remain the same size).
If the lesion has completely disappeared, the lesion size should be reported as 0 mm.
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter are 
likely to be non-reproducible. Therefore, it is recommended to report a default value of 5 mm,
instead of the actual measurement. This default value is derived from the 5 mm CT slice 
thickness (but should not be changed with varying CT slice thickness). Actual measurement 
should be given for all lesions larger than 5 mm in longest diameter irrespective of slice 
thickness/reconstruction interval.
In other cases where the lesion cannot be reliably measured for reasons other than its size (e.g., 
borders of the lesion are confounded by neighboring anatomical structures), no measurement 
should be entered and the lesion cannot be evaluated.
14.1.11
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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14.1.12
Determination of target lesion response
Table 14-1
Response criteria for target lesions
Response Criteria
Evaluation of target lesions
Complete Response (CR):
Disappearance of all non-nodal target lesions. In addition, any pathological lymph 
nodes assigned as target lesions must have a reduction in short axis to < 10 mm 1
Partial Response (PR):
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters.
Progressive Disease (PD):
At least a 20% increase in the sum of diameter of all measured target lesions, taking 
as reference the smallest sum of diameter of all target lesions recorded at or after 
baseline. In addition to the relative increase of 20%, the sum must also demonstrate 
an absolute increase of at least 5 mm2.
Stable Disease (SD):
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions which 
would qualify for PD.
Unknown (UNK)
Progression has not been documented and one or more target lesions have not been 
assessed or have been assessed using a different method than baseline.3
1. SOD for CR may not be zero when nodal lesions are part of target lesions
2. Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and all nodal 
lesions are <10 mm in size. In this case, the target lesion response is CR
3. Methodology change See Section 14.1.6.
Notes on target lesion response
Reappearance of lesions: If the lesion appears at the same anatomical location where a target 
lesion had previously disappeared, it is advised that the time point of lesion disappearance (i.e., 
the “0 mm” recording) be re-evaluated to make sure that the lesion was not actually present 
and/or not visualized for technical reasons in this previous assessment. If it is not possible to 
change the 0 value, then the investigator/radiologist has to decide between the following three 
possibilities:
The lesion is a new lesion, in which case the overall tumor assessment will be considered 
as progressive disease
The lesion is clearly a reappearance of a previously disappeared lesion, in which case the 
size of the lesion has to be entered in the CRF and the tumor assessment will remain based 
on the sum of tumor measurements as presented in Table 14-1 above (i.e., a PD will be 
determined if there is at least 20% increase in the sum of diameters of all measured target 
lesions, taking as reference the smallest sum of diameters of all target lesions recorded at or 
after baseline with at least 5 mm increase in the absolute sum of the diameters). Proper 
documentation should be available to support this decision. This applies to patients who 
have not achieved target response of CR. For patients who have achieved CR, please refer 
to last bullet in this section.
For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD.
Missing measurements: In cases where measurements are missing for one or more target 
lesions it is sometimes still possible to assign PD based on the measurements of the 
remaining lesions. For example, if the sum of diameters for 5 target lesions at baseline is 
100 mm at baseline and the sum of diameters for 3 of those lesions at a post-baseline visit 
is 140 mm (with data for 2 other lesions missing) then a PD should be assigned. However, 


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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.
14.1.13
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.


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Response Criteria
Evaluation of non-target lesions
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 14.1.12 for assigning PD following a CR for the 
non-target lesion response in the presence of non-target lesions nodal lesions should be 
applied.
14.1.14
New lesions
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded as a new lesion in the New Lesion CRF page.

If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion.

If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment 
(see Section 14.1.15).

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 14.1.6.


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14.1.15
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 14.1.8.
If there are no baseline scans available at all, then the overall lesion response at each assessment 
should be considered Unknown (UNK).
If the evaluation of any of the target or non-target lesions identified at baseline could not be 
made during follow-up, the overall status must be ‘unknown’ unless progression was seen.
In some circumstances it may be difficult to distinguish residual disease from normal tissue. 
When the evaluation of complete response depends on this determination, it is recommended 
that the residual lesion be investigated (fine needle aspirate/biopsy) to confirm the CR.
14.1.16
Efficacy definitions
The following definitions primarily relate to patients who have measurable disease at baseline. 
Section 14.1.26 outlines the special considerations that need to be given to patients with no 
measurable disease at baseline in order to apply the same concepts.
14.1.17
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 


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cancer therapy is taken while on study any subsequent assessments would ordinarily be 
excluded from the best overall response determination. If response assessments taken after 
withdrawal from study treatment and/or alternative therapy are to be included in the main 
endpoint determination, then this should be described and justified in the protocol.
Where a study requires confirmation of response (PR or CR), changes in tumor measurements 
must be confirmed by repeat assessments that should be performed not less than 4 weeks after 
the criteria for response are first met.
Longer intervals may also be appropriate. However, this must be clearly stated in the protocol. 
The main goal of confirmation of objective response is to avoid overestimating the response 
rate observed. In cases where confirmation of response is not feasible, it should be made clear 
when reporting the outcome of such studies that the responses are not confirmed.

-For non-randomized trials where response is the primary endpoint, confirmation is 
needed.

-For trials intended to support accelerated approval, confirmation is needed

For all other trials, confirmation of response may be considered optional.
The best overall response for each patient is determined from the sequence of overall (lesion) 
responses according to the following rules:

CR = at least two determinations of CR at least 4 weeks apart before progression where 
confirmation required or one determination of CR prior to progression where confirmation 
not required

PR = at least two determinations of PR or better at least 4 weeks apart before progression 
(and not qualifying for a CR) where confirmation required or one determination of PR 
prior to progression where confirmation not required

SD = at least one SD assessment (or better) > 6 weeks after randomization/start of 
treatment (and not qualifying for CR or PR).

PD = progression 12 weeks after randomization/ start of treatment (and not qualifying 
for CR, PR or SD).

UNK = all other cases (i.e. not qualifying for confirmed CR or PR and without SD after 
more than 6 weeks or early progression within the first 12 weeks)
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 


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response is not required after a single PR the overall lesion response should still be considered 
PR (or UNK) until progression is documented or the lesion totally disappears in which case a 
CR assignment is applicable.
Example: In a case where confirmation of response is required the sum of lesion diameters is 
200 mm at baseline and then 140 mm - 150 mm - 140 mm - 160 mm - 160 mm at the subsequent 
visits. Assuming that non-target lesions did not progress, the overall lesion response would be 
PR - SD - PR - PR - PR. The second assessment with 140 mm confirms the PR for this patient. 
All subsequent assessments are considered PR even if tumor measurements decrease only by 
20% compared to baseline (200 mm to 160 mm) at the following assessments.
If the patient progressed but continues study treatment, further assessments are not considered 
for the determination of best overall response.
Note: these cases may be described as a separate finding in the CSR but not included in the 
overall response or disease control rates.
The best overall response for a patient is always calculated, based on the sequence of overall 
lesion responses. However, the overall lesion response at a given assessment may be provided 
from different sources:

Investigator overall lesion response

Central Blinded Review overall lesion response

Novartis calculated overall lesion response (based on measurements from either 
Investigator or Central Review)
The primary analysis of the best overall response will be based on the sequence of 
investigator/central blinded review/calculated (investigator)/calculated (central) overall lesion 
responses.
Based on the patients’ best overall response during the study, the following rates are then 
calculated:
Overall response rate (ORR) is the proportion of patients with a best overall response of CR 
or PR. This is also referred to as ‘Objective response rate’ in some protocols or publications.
Disease control rate (DCR) is the proportion of patients with a best overall response of CR or 
PR or SD.
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, 


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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).
14.1.18
Time to event variables
The protocol should state which of the following variables is used in that study.
14.1.19
Progression-free survival
Usually in all Oncology studies, patients are followed for tumor progression after 
discontinuation of study medication for reasons other than progression or death. If this is not 
used, e.g. in Phase I or II studies, this should be clearly stated in the protocol. Note that 
randomized trials (preferably blinded) are recommended where PFS is to be the primary 
endpoint.
Progression-free survival (PFS) is the time from date of randomization/start of treatment to 
the date of event defined as the first documented progression or death due to any cause. If a 
patient has not had an event, progression-free survival is censored at the date of last adequate 
tumor assessment.
14.1.20
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.
14.1.21
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.
14.1.22
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.


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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.
14.1.23
Duration of response
The analysis of the following variables should be performed with much caution when restricted 
to responders since treatment bias could have been introduced. There have been reports where 
a treatment with a significantly higher response rate had a significantly shorter duration of 
response but where this probably primarily reflected selection bias which is explained as 
follows: It is postulated that there are two groups of patients: a good risk group and a poor risk 
group. Good risk patients tend to get into response readily (and relatively quickly) and tend to 
remain in response after they have a response. Poor risk patients tend to be difficult to achieve
a response, may have a longer time to respond, and tend to relapse quickly when they do respond. 
Potent agents induce a response in both good risk and poor risk patients. Less potent agents 
induce a response mainly in good risk patients only. This is described in more detail by Morgan 
(1988)
It is recommended that an analysis of all patients (both responders and non-responders) be 
performed whether or not a “responders only” descriptive analysis is presented. An analysis of 
responders should only be performed to provide descriptive statistics and even then interpreted 
with caution by evaluating the results in the context of the observed response rates. If an 
inferential comparison between treatments is required this should only be performed on all 
patients (i.e. not restricting to “responders” only) using appropriate statistical methods such as 
the techniques described in Ellis et al (2008). It should also be stated in the protocol if duration 
of response is to be calculated in addition for unconfirmed response.
For summary statistics on “responders” only the following definitions are appropriate. (Specific 
definitions for an all-patient analysis of these endpoints are not appropriate since the status of 
patients throughout the study is usually taken into account in the analysis).
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.


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14.1.24
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 14.1.23. It is recommended that an 
analysis of all patients (both responders and non-responders) be performed whether or not a 
“responders only” descriptive analysis is presented. Where an inferential statistical comparison 
is required, then all patients should definitely be included in the analysis to ensure the statistical 
test is valid. For analysis including all patients, patients who did not achieve a response (which 
may have to be a confirmed response) will be censored using one of the following options.

at maximum follow-up (i.e. FPFV to LPLV used for the analysis) for patients who had a 
PFS event (i.e. progressed or died due to any cause). In this case the PFS event is the 
worst possible outcome as it means the patient cannot subsequently respond. Since the 
statistical analysis usually makes use of the ranking of times to response it is sufficient to 
assign the worst possible censoring time which could be observed in the study which is 
equal to the maximum follow-up time (i.e. time from FPFV to LPLV)

at last adequate tumor assessment date otherwise. In this case patients have not yet 
progressed so they theoretically still have a chance of responding
Time to overall complete response (CR) is the time between dates of randomization/start of 
treatment until first documented CR. Similar analysis considerations including (if appropriate) 
censoring rules apply for this endpoint described for the time to overall response endpoint.
14.1.25
Definition of start and end dates for time to event variables
Assessment date
For each assessment (i.e. evaluation number), the assessment date is calculated as the latest of 
all measurement dates (e.g. X-ray, CT-scan) if the overall lesion response at that assessment is 
CR/PR/SD/UNK. Otherwise - if overall lesion response is progression - the assessment date is 
calculated as the earliest date of all measurement dates at that evaluation number.
Start dates
For all “time to event” variables, other than duration of response, the randomization/ date of 
treatment start will be used as the start date.
For the calculation of duration of response the following start date should be used:

Date of first documented response is the assessment date of the first overall lesion 
response of CR (for duration of overall complete response) or CR / PR (for duration of 
overall response) respectively, when this status is later confirmed.


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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 14.1.26).
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.
14.1.26
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.


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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 14.1.8.
In general, the non-CR/non-PD response for these patients is considered equivalent to an SD 
response in endpoint determination. In summary tables for best overall response patients with 
only non-measurable disease may be highlighted in an appropriate fashion e.g. in particular by 
displaying the specific numbers with the non-CR/non-PD category.
In considering how to incorporate data from these patients into the analysis the importance to 
each endpoint of being able to identify a PR and/or to determine the occurrence and timing of 
progression needs to be taken into account.
For ORR it is recommended that the main (ITT) analysis includes data from patients with only 
non-measurable disease at baseline, handling patients with a best response of CR as “responders” 
with respect to ORR and all other patients as “non-responders”.
For PFS, it is again recommended that the main ITT analyses on these endpoints include all 
patients with only non-measurable disease at baseline, with possible sensitivity analyses which 
exclude these particular patients. Endpoints such as PFS which are reliant on the determination 
and/or timing of progression can incorporate data from patients with only non-measurable 
disease.
14.1.27
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 14.1.25, 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:


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Table 14-5
Options for event dates used in PFS, TTP, duration of response
Situation
Options for end-date (progression or 
censoring)1
(1) = default unless specified differently in 
the protocol or RAP
Outcome
A
No baseline assessment
(1) Date of randomization/start of treatment3
Censored
B
Progression at or before next scheduled 
assessment
(1) Date of progression
(2) Date of next scheduled assessment2
Progressed
Progressed
C1
Progression or death after exactly one
missing assessment
(1) Date of progression (or death)
(2) Date of next scheduled assessment2
Progressed
Progressed
C2
Progression or death after two or more
missing assessments
(1) Date of last adequate assessment2
(2) Date of next scheduled assessment2
(3) Date of progression (or death)
Censored
Progressed
Progressed
D
No progression
(1) Date of last adequate assessment
Censored
E
Treatment discontinuation due to ‘Disease 
progression’ without documented 
progression, i.e. clinical progression based 
on investigator claim
(1) N/A
(2) Date of discontinuation (visit date at which 
clinical progression was determined)
Ignored
Progressed
F
New anticancer therapy given
(1) Date of last adequate assessment
(2) Date of secondary anti-cancer therapy
(3) Date of secondary anti-cancer therapy
(4) N/A
Censored
Censored
Event
Ignored
G
Deaths due to reason other than 
deterioration of ‘Study indication’
(1) Date of last adequate assessment
Censored 
(only TTP and 
duration of 
response)
1.=Definitions can be found in Section 14.1.25
2.=After the last adequate tumor assessment. “Date of next scheduled assessment” is defined in Section 14.1.25.
3.=The rare exception to this is if the patient dies no later than the time of the second scheduled assessment as 
defined in the protocol in which case this is a PFS event at the date of death.
The primary analysis and the sensitivity analyses must be specified in the protocol. Clearly 
define if and why options (1) are not used for situations C, E and (if applicable) F.
Situations C (C1 and C2): Progression or death after one or more missing assessments: The 
primary analysis is usually using options (1) for situations C1 and C2, i.e.

(C1) taking the actual progression or death date, in the case of only one missing 
assessment.

(C2) censoring at the date of the last adequate assessment, in the case of two or more 
consecutive missing assessments.
In the case of two or missing assessments (situation C2), option (3) may be considered jointly 
with option (1) in situation C1 as sensitivity analysis. A variant of this sensitivity analysis 
consists of backdating the date of event to the next scheduled assessment as proposed with 
option (2) in situations C1 and C2.
Situation E: Treatment discontinuation due to ‘Disease progression’ without documented 
progression: By default, option (1) is used for situation E as patients without documented PD 
should be followed for progression after discontinuation of treatment. However, option (2) may 
be used as sensitivity analysis. If progression is claimed based on clinical deterioration instead 
of tumor assessment by e.g. CT-scan, option (2) may be used for indications with high early 
progression rate or difficulties to assess the tumor due to clinical deterioration.


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Situation F: New cancer therapy given: the handling of this situation must be specified in 
detail in the protocol. However, option (1), i.e. censoring at last adequate assessment may be 
used as a default in this case.
Additional suggestions for sensitivity analyses
Other suggestions for additional sensitivity analyses may include analyses to check for potential 
bias in follow-up schedules for tumor assessments, e.g. by assigning the dates for censoring and 
events only at scheduled visit dates. The latter could be handled by replacing in Table 14-5 the
“Date of last adequate assessment” by the “Date of previous scheduled assessment (from 
baseline)”, with the following definition:

Date of previous scheduled assessment (from baseline) is the date when a tumor 
assessment would have taken place, if the protocol assessment scheme was strictly 
followed from baseline, immediately before or on the date of the last adequate tumor 
assessment.
In addition, analyses could be repeated using the Investigators’ assessments of response rather 
than the calculated response. The need for these types of sensitivity analyses will depend on the 
individual requirements for the specific study and disease area and have to be specified in the 
protocol or RAP documentation.
14.1.28
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).
14.1.29
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).
14.1.30
End of treatment phase completion
Patients may voluntarily withdraw from the study treatment or may be taken off the study 
treatment at the discretion of the investigator at any time. For patients who are lost to follow-
up, the investigator or designee should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, etc.
The end of treatment visit and its associated assessments should occur within 7 days of the last 
study treatment.
Patients may discontinue study treatment for any of the following reasons:

Adverse event(s)

Lost to follow-up

Physician decision


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
Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

Progressive disease

Study terminated by the sponsor

Non-compliant with study treatment

No longer requires treatment

Treatment duration completed as per protocol (optional, to be used if only a fixed number 
of cycles is given)
14.1.31
End of post-treatment follow-up (study phase completion)
End of post-treatment follow-up visit will be completed after discontinuation of study treatment
and post-treatment evaluations but prior to collecting survival follow-up.
Patients may provide study phase completion information for one of the following reasons:

Adverse event

Lost to follow-up

Physician decision

Pregnancy

Protocol deviation

Technical problems

Subject/guardian decision

Death

New therapy for study indication

Progressive disease

Study terminated by the sponsor
14.1.32
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 


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at that specific assessment is to be kept in a dataset. This must be clearly documented in the 
RAP documentation and agreed before database lock. This dataset should be created and stored 
as part of the ‘raw’ data.
Any discontinuation due to ‘Disease progression’ without documentation of progression by 
RECIST criteria should be carefully reviewed. Only patients with documented deterioration of 
symptoms indicative of progression of disease should have this reason for discontinuation of 
treatment or study evaluation.
14.1.33
Programming rules
The following should be used for programming of efficacy results:
14.1.34
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.
14.1.35
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 14.1.25). 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.
14.1.36
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.
14.1.37
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)’.
14.1.38
Study/project specific programming
The standard analysis programs need to be adapted for each study/project.


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14.1.39
Censoring reason
In order to summarize the various reasons for censoring, the following categories will be 
calculated for each time to event variable based on the treatment completion page, the study 
evaluation completion page and the survival page.
For survival the following censoring reasons are possible:

Alive

Lost to follow-up
For PFS and TTP (and therefore duration of responses) the following censoring reasons are 
possible:

Ongoing without event

Lost to follow-up

Withdrew consent

Adequate assessment no longer available*

Event documented after two or more missing tumor assessments (optional, see Table 14-5)

Death due to reason other than underlying cancer (only used for TTP and duration of 
response)

Initiation of new anti-cancer therapy
*Adequate assessment is defined in Section 14.1.25. This reason is applicable when adequate 
evaluations are missing for a specified period prior to data cut-off (or prior to any other 
censoring reason) corresponding to the unavailability of two or more planned tumor 
assessments prior to the cut-off date. The following clarifications concerning this reason should 
also be noted:

This may be when there has been a definite decision to stop evaluation (e.g. 
reason=“Sponsor decision” on study evaluation completion page), when patients are not 
followed for progression after treatment completion or when only UNK assessments are 
available just prior to data cut-off).

The reason "Adequate assessment no longer available" also prevails in situations when 
another censoring reason (e.g. withdrawal of consent, loss to follow-up or alternative anti-
cancer therapy) has occurred more than the specified period following the last adequate 
assessment.

This reason will also be used to censor in case of no baseline assessment.


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14.1.40
References (available upon request)
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465
FDA Guidelines: 2005 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005
FDA Guidelines: 2007 Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16


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14.2
Appendix 2 – Child-Pugh classification of severity of liver
disease
Child-Pugh classification system
The CPC is used to assess the severity of impaired hepatic function in patients with liver 
cirrhosis (Child 1964, FDA guidance 2003). In general, it is used to determine the risk to a 
patient with regard to the treatment(s) (e.g. surgery, transplant, medication), and, to suggest the 
perceived survival of the patient over a period of time.
Hepatocellular carcinoma patients who have Child-Pugh grade A score (5 - 6 points) at the 
baseline screening are eligible for participating in Study CFGF401X2101, provided that the 
patients meet all other eligibility criteria, see Section 5.
Calculation and interpretation for Child-Pugh scores
The severity of liver disease is based on the CPC criteria, which will be calculated based on 
clinical findings and laboratory results during the screening period. Five variables are 
considered (severity of ascites, hepatic encephalopathy, abnormality in serum bilirubin, serum 
albumin and clotting times). A score (between 1 and 3) is accordingly assigned to each of these 
factors (Table 14-6). The sum of the scores provides the Child-Pugh score, which corresponds 
to a Child-Pugh grade (or Child’s grade) of A, B or C (Table 14-7).
Table 14-6
Child-Pugh score calculation
Variables
Points assigned
Units
1
2
3
Total Bilirubin
< 2 (< 34)
2-3 (34-50)
> 3 (> 50)
mg/dL (µmol/L)
Serum Albumin
> 35 (> 3.5)
28-35 (2.8-3.5)
< 28 (< 2.8)
g/L (g/dL)
PT (or INR)
< 4 (< 1.7)
4-6 (1.7-2.30)
> 6 (> 2.30)
sec (no unit)
Ascites
Absent
Slight
Moderate
no unit
Hepatic Encephalopathy*
None
Grade 1-2
Grade 3-4
no unit
*Grade 0: normal consciousness, personality, neurological examination, electroencephalogram
*Grade 1: restless, sleep disturbed, irritable/agitated, tremor, impaired handwriting, 5 cps waves
*Grade 2: lethargic, time-disoriented, inappropriate, asterixis, ataxia, slow triphasic waves
*Grade 3: somnolent, stuporous, place-disoriented, hyperactive reflexes, rigidity, slower waves
*Grade 4: unrousable coma, no personality/behavior, decerebrate, slow 2-3 cps delta activity
Table 14-7
Child-Pugh score interpretation
Severity (grade)
Child-Pugh Score
A
5 - 6
B
7 - 9
C
10 - 15
References (available upon request)
Child CG, Turcotte JG (1964). Surgery and portal hypertension. In: The liver and portal 
hypertension. Edited by CG Child. Philadelphia: Saunders:50-64
FDA Guidance for industry (2003). pharmacokinetics in patients with impaired hepatic 
function: study design, data analysis, and impact on dosing and labeling


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14.3
Appendix 3 – Hepatocellular carcinoma staging systems
Staging systems
Clinical staging is crucial for risk stratification during cancer management. For HCC, a number 
of clinical staging systems have been developed mainly from HCC patients of different 
etiologies and extent of disease. The BCLC system is most widely studied and will be assessed 
at screening for all patients participating in this study:
For more information on patient eligibility, please refer to the core text of the study protocol.
Barcelona-Clinic Liver Cancer system
The BCLC staging system (Table 14-8) was developed based on the combination of data from 
several independent studies representing different disease stages and/or treatment modalities. It 
includes variables related to tumor stage, liver functional status, physical status and cancer 
related symptoms (Llovet et al 2008).
Table 14-8
Barcelona-Clinic Liver Cancer system
BCLC stage
PS
Tumor Features
Liver Function
Stage A* (early HCC)
A1
0
Single < 5 cm
No portal HTN** and normal bilirubin
A2
0
Single < 5 cm
Portal HTN, normal bilirubin
A3
0
Single < 5 cm
Portal HTN, abnormal bilirubin
A4
0
Up to 3 tumors < 3 cm
Child-Pugh class A - B
Stage B (intermediate HCC)
0
Large multinodular
Child-Pugh class A - B
Stage C (advanced HCC)
1 - 2
Vascular invasion or 
extrahepatic spread
Child-Pugh class A - B
Stage D (end-stage HCC)
3 - 4
Any of the above
Child-Pugh class C
* Stages A1, A2, A3 and A4 will be considered “Stage A” for data collection.
** HTN = Hypertension
Only BCLC Stage C HCC patients are eligible for participating in this study, provided that the 
patients meet all other eligibility criteria, see Section 5.
References (available upon request)
Llovet, J. M., et al. "Sorafenib in advanced hepatocellular carcinoma." N.Engl.J.Med. 359.4 
(2008): 378-90.


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14.4
Appendix 4 – Prohibited concomitant medications and permitted 
concomitant medications requiring caution
Table 14-9
Prohibited concomitant medications
Mechanism of Interaction
Drug Name
Known BSEP inhibitors
Atorvastatin, cerivastatin, cyclosporine , glyburide, reserpine, rifampicin, 
troglitazone, valinomycin
CYP1A2 substrate with NTI
Theophylline, tizanidine
CYP2C9 substrate with NTI
Phenytoin, warfarin
CYP3A4/5 substrate with NTI
Quinidine, [terfenadine], astemizole, cyclosporine, sirolimus, tacrolimus, 
pimozide, alfentanil, fentanyl, diergotamine, ergotamine, cisapride, 
thioridazine, dihydroergotamine
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interactions (DDI) and Co-medication 
considerations  (release date: Apr 2015) 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
Dawson S et al, Drug Met Dispos, 2012, 40 :130-138
Morgan et al, Tox Sci, 2013, 136: 216-241
NTI: narrow therapeutic index
Table 14-10
Permitted concomitant medications requiring caution
Mechanism of Interaction
Drug Name
Strong CYP3A4/5 inhibitor
Clarithromycin, troleandomycin, indinavir,  itraconazole, posaconazole, 
voriconazole, boceprevir, telaprevir, cobicistat, conivaptan,  mibefradil,
grapefruit juice, ketoconazole,  lopinavir/ritonavir, nefazodone, nelfinavir,
ritonavir,  saquinavir, sequinavir/ritonavir,  telithromycin,
indinavir/ritonavir, tipranoavir/ritonavir, danoprevir/ritonavir, 
eltegravir/ritonavir
Strong CYP3A4/5 inducer
Avasimibe, carbamazepine, mitotane, phenobarbital, rifabutin, St. John's 
wort, rifampin, enzalutamide
Potential BSEP inhibitors
Benzbromarone, everolimus, fenofibrate, fusidic acid, indinavir, lopinavir, 
nelfinavir, olmesartan, sitaxsentan, tolcapone
MRP2/3/4 and/or NTCP and/or 
OATP1B1/3 inhibitors
Atazanavir, bendroflumethiazide, clarithromycin, clofazimine, 
clotrimazole, doxazosin, entacapone, epalrestat, ezetimibe, febuxostat, 
gemfibrozil, indomethacin, lopinavir, losartan, lovastatin, nelfinavir, 
nifedipine, olmesartan, repaglinide, rifaximin, rilpivirine, sildenafil, 
simvastatin, telmisartan, tranilast, valsartan
Source: Adapted from Oncology Clinical Pharmacology Drug-Drug Interactions (DDI) and Co-medication 
considerations (release date: Apr2015) 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
Dawson S et al, Drug Met Dispos, 2012, 40 :130-138
Dong Z et al, Mol Pharmaceutics, 2013, 10 :1008-1019
Kalliokoski A and Niemi M, Br J Pharmacol, 2009, 158 :693-705
Morgan et al, Tox Sci, 2013, 136: 216-241
14.5
Appendix 5 – Guidelines for management of diarrhea
Patients should receive clear instructions regarding the possibility of experiencing diarrhea and 
the necessity to contact the treating physician. As bile acid-induced diarrhea is a predictable 


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effect of the trial drug, patients experiencing diarrhea ≥ grade 1 should be treated with 
cholestyramine (also named as colestyramine), 4 g daily initially, following local prescribing 
guidance.
It is recommended that patients initially take cholestyramine at bed time and if needed for 
further control of diarrhea take an extra dose of cholestyramine in the afternoon (e.g. 3-4 pm) 
and/or late morning (e.g. 11 am). Other drugs need to be administered at least 1 hour before or 
4 hours after cholestyramine administration.
The maximum recommended daily dose is six packets or scoopfuls of cholestyramine (4 g/dose) 
for oral suspension (24 g anhydrous cholestyramine resin), and according to the local 
prescribing document. Although the recommended dosing schedule is maximal 1 to 4 doses
daily, cholestyramine for oral suspension may be administered in 1 to 6 doses per day. 
Cholestyramine should not be taken in its dry form and should be mixed with water or other 
juices before ingesting.
Patients need to be alerted to the possibility of symptoms of bloating, and should consider 
reducing the dose to 2 g if these symptoms are more severe than the diarrhea.
It is recommended that increases in dose be gradual, such as 2 – 4 g every 3 days.  Other 
treatment of diarrhea and complications (e.g. repletion of electrolytes) should follow local 
guidance.
Because cholestyramine binds bile acids, long-term treatment with cholestyramine may 
interfere with normal fat digestion and absorption and thus may prevent absorption of fat-
soluble vitamins such as A, D, E and K. Monitor of vitamins, including vitamin K, should be 
done according to the local clinical guidelines. When cholestyramine is given for long periods 
of time, concomitant supplementation with water-miscible (or parenteral) forms of fat-soluble 
vitamins should be considered. If cholestyramine is poorly tolerated loperamide should be 
considered, initially 4–8 mg daily and a maximum of 16 mg daily.
Table 14-11
Criteria for interruption and re-initiation of FGF401 treatment for 
diarrhea management
Worst toxicitya
Recommended dose modifications any time during a cycle of therapy (including 
intended day of dosing)c, d
Grade 1
Maintain dose level, then:
If resolved to normal within 24 hours, then no need to prescribe colestyramine
If Grade 1 is persistent after 24 hours, then colestyramine should be considered based on 
investigator’s decision
Grade 2
Maintain dose level and start colestyramine immediately, then:
1. If resolved to ≤ Grade 1 within 24 hours after colestyramine administered, then 
colestyramine should be kept based on investigator’s decision
2. If Grade 2 is persistent after 24 hours of colestyramine administered, then continuously 
administer colestyramine for another 6 days and by then:
a. If resolved to ≤ Grade 1, maintain dose level and keep using colestyramine
b. If Grade 2 is persistent, then ↓1 dose level and keep using colestyramine


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Worst toxicitya
Recommended dose modifications any time during a cycle of therapy (including 
intended day of dosing)c, d
Grade 3b
Maintain dose level and start colestyramine immediately, then:
1. If resolved to ≤ Grade 1 within 24 hours after colestyramine administered, then keep 
using colestyramine
2. If resolved to Grade 2 by 24 hours of colestyramine administered, then continuously 
administer colestyramine for another 6 days and by then:
a. If resolved to ≤ Grade 1, maintain dose level and keep using colestyramine
b. If Grade 2 is persistent, then ↓1 dose level and keep using colestyramine
If Grade 3 is persistent after 24 hours of colestyramine administered, then omit dose and 
continuously administer colestyramine for another 6 days, by then:
a. If resolved to ≤ Grade 1, then ↓1 dose level and keep using colestyramine
b. If ≥ Grade 2 is persistent, then discontinue patient from study drug treatment
Grade 4b
Omit dose and start colestyramine immediately, then:
1. If resolved to ≤ Grade 1 within 7 days after colestyramine administered, then ↓1 dose 
level and keep using colestyramine
2. If not resolved to ≤ Grade 1 within 7 days after colestyramine administered, then 
discontinue patient from study drug treatment
a CTCAE version 4.03 will be used for all grading.
b For Grade 3 and 4 diarrhea, the supportive measurement should be implemented based on local clinical 
guidance
c For any ≥ Grade 2 diarrhea with multiple occurrences, investigator should discuss with Novartis for any 
opportunity to change dosing schedule or further dose reductions.
d In any circumstance if patient needs to be discontinued from study drug treatment due to diarrhea, 
investigator should discuss with Novartis for any opportunity to change dosing schedule or further dose 
reductions.
14.6
Appendix 6 - Guidelines for management of hyperphosphatemia
Hyperphosphatemia is a disorder characterized by laboratory test results that indicate an 
elevation in the concentration of inorganic phosphorus in blood. Clinical judgment and 
institutional standards in the management of hyperphosphatemia and the timing of stopping 
and/or re-initiating FGF401 treatment as a function of phosphate levels will be left to the 
discretion of the treating physician. Differences in phosphate management will not be 
considered as protocol deviations. Please refer to the Sevelamer Package Insert for additional 
information.
Table 14-12
Criteria for for interruption and re-initiation of FGF401 treatment for 
hyperphosphatemia management
Serum inorganic phosphorus (Pi) value
Recommended Dose Modifications any time during a 
cycle of therapy
Serum Pi > 5.5 – 7.0 mg/dL
Maintain dose level and start phosphorus lowering 
therapy:
Sevelamer dose should be adjusted based on the serum 
phosphorus level with the goal of maintaining ≤ 7.0 
mg/dL. Refer to Package Insert of Sevelamer for dosing 
guidelines.


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Serum inorganic phosphorus (Pi) value
Recommended Dose Modifications any time during a 
cycle of therapy
Serum Pi > 7.0 mg/dL lasting more than 7 days 
despite maximal dosing of Sevelamer 
or
Confirmed single serum phosphorus > 9.0 mg/dL 
regardless of Sevelamer dose
Omit dose until resolved to serum Pi ≤ 7.0 mg/dL, then:
● Continue Sevelamer and adjust the Sevelamer dose 
with the goal of maintaining serum phosphorus ≤ 7.0 
mg/dL.  Hold Sevelamer once serum phosphorus is ≤ 5.5 
mg/dL
● If serum phosphorus is resolved to ≤ 7.0 mg/dL within 
14 days of suspending FGF401, then resume FGF401 at 
the same dose level
● If serum phosphorus is not ≤ 7.0 mg/dL within 14 days 
of suspending FGF401 despite maximal dosing of 
Sevelamer, discontinue patient from the study drug 
treatment
● All patients will continue to be followed-up until 
resolution to serum phosphorus ≤ 7.0 mg/dL
If hyperphosphatemia recurs and requires another 
FGF401 dose interruption: FGF401 dose should be 
restarted based on above criteria at ↓1 dose level. 
Further dose reductions of FGF401 may be taken as 
needed, but should first be discussed with Novartis.
Serum phosphorus > 10.0 mg/dL
Discontinue patient from the study


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14.8
Appendix 8 – Test meal guidelines
During the food effect portion of the study, food intake should be supervised on days of PK 
profiles collection. Patients on food effect cohort will consume a low-fat, light breakfast and 
then will receive the treatment with FGF401. The meal should be consumed within 30 minutes. 
FGF401 will be administered with one glass of water. No food will be allowed for at least 4 
hours post-dose.  Subjects should receive standardized meals scheduled at the same time in each 
period of the study.
Note: For the fed conditions, the meal should be consumed within 30 minutes. If > 30 minutes 
is required to complete the meal, then FGF401 should be administered relative to the end of the 
meal.
Recommendations for sample test meals are outlined in Table 14-14. Alternative meals with 
equivalent nutritional content may be used.


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Table 14-14
Test meal examples
Low-fat Breakfast
(approximately 500 calories and 20 grams of fat)
6 ounces of orange juice (except Seville)
8 ounces of 2% milk
1 banana
¾ cups of cereal
1 slice of toast
2 teaspoons of butter
Coffee, tea, or grapefruit juice is not permitted as part of either test meal. Water is allowed during the test meal.
A registered dietician at the research site should determine the appropriate meal to be consumed, 
based on the fat and calorie requirements assigned to the patient for that treatment day. The 
start/stop time of meal consumption, and estimated % of test meal consumed (based on fat and 
caloric content), must be listed in the Meal Record eCRF for patients allocated in exploratory 
food effect cohort.
14.9
Appendix 9- Guidelines for immune-related Response Criteria 
(irRC) using one-dimensional measurements (simulating RECIST 
1.1)
14.9.1
Introduction
The currently used immune-related response criteria (irRC) uses unidimensional measurements 
to assess tumor response and it is an adaptation of the original irRC published by Wolchok 
(Wolchok 2009, Nishino 2013).
The purpose of this document is to summarize the irRC guidelines in details focusing on 
differences in tumor response assessments between irRC and RECIST v1.1. 
The primary difference between irRC and RECIST 1.1 is the definition of progressive disease. 
The definitions of baseline target/non target lesions, number of lesions selected at baseline,  the 
criteria for lesion measurement method of evaluation of response and definition of response are 
the same for irRC and RECIST 1.1 and are available in the RECIST 1.1 guidelines (Appendix 
1).
14.9.2
New lesions and non-target lesions
In irRC a new lesion does not automatically indicate progressive disease. 
New measurable lesions are added to the sum of diameters of the previously existing target 
lesions, and the sum of diameters is followed at each subsequent tumor assessment.
New measureable lesions are defined using the same criteria as for baseline target lesions in 
RECIST v1.1. New measurable lesions shall be prioritized according to size, and the largest 
lesions shall be selected as new measured lesions up to 10 lesions in total.
Non-target lesions (baseline and new non-measurable lesions) are used primarily for 
determination of Complete Response (CR). The RECIST v1.1 definitions for the assessment of 
non-target lesions apply. A CR requires that all non-target lesions disappear (both those present 


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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 14-15).
14.9.3
Follow-up evaluation of target and non-target lesions
To assess tumor response, the sum of diameters for all target lesions is calculated (at baseline 
and throughout the study). The diameters of any new measurable lesions are included in the 
sum of diameters at each assessment to provide the total tumor burden. At each assessment, 
percent change in the sum of diameters is calculated and compared to baseline or to nadir in 
order to evaluate the target lesion response (including new measurable lesions) (Section 14.9.4). 
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 14-15). The 
thresholds for irPR and irPD assessment are the same as for RECIST v1.1.
14.9.4
Definitions of response categories and evaluation of overall lesion 
response
In irRC, the overall response is primarily based on target lesions (baseline and new measurable 
lesions). The non-target lesions only contribute to define irCR, and irPD in the case of 
unequivocal progression, as shown below in Table 14-15. 
Like in RECIST 1.1, irCR and irPR must be confirmed at a new assessment after at least 4 
weeks. Unlike RECIST 1.1, irPD also requires confirmation at a new assessment after at least 
4 weeks.
The response categories are defined as follows:

Immune related Complete Response (irCR): Disappearance of all non-nodal target lesions 
and non-target lesions in two consecutive observations not less than 4 weeks apart. In 
addition, any pathological lymph nodes assigned as target lesions must have a reduction in 
short axis to < 10 mm. (Sum of diameters may be greater than zero at the time of CR, if 
nodal lesions are included as target lesions).

Immune related Partial Response (irPR): At least a 30% decrease in the sum of diameters 
of all target lesions including new measurable lesions in two consecutive observations not 
less than 4 weeks apart, taking as reference the baseline sum of diameters. 

Immune related Progressive Disease (irPD): At least a 20% increase in the sum of 
diameters of all measured target lesions including new measurable lesions. The irPD must 
be confirmed in a second evaluation not less than 4 weeks later, taking as reference the 
smallest sum of diameter of all target lesions recorded at or after baseline (nadir). In 
addition to the relative increase of 20%, the sum must also demonstrate an absolute 
increase of at least 5 mm. Worsening of non-target lesions (existing or new) only indicate 
PD when there is unequivocal evidence of progression, confirmed in a second evaluation 
not less than 4 weeks later. 

Immune related Stable Disease (irSD): Neither a sufficient shrinkage to qualify for irPR or 
irCR, nor an increase in lesions which would qualify for irPD. 


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
Unknown (UNK):  Progression has not been documented and one or more target lesions 
have not been assessed or have been assessed using a method significantly different from 
baseline that prevents reasonable comparison to the prior assessments.
Table 14-15
Overall response at each assessment
Target and new measurable 
lesions (Tumor burden), * (%)
Non-target lesions 
(both baseline and new non-
measurable)
Overall
lesion response
-100
Absent
irCRa
-100
Stable/not evaluated
irPRa
≤-30
Absent/Stable/not evaluated
irPRa
> -30 and <+20
Absent/Stable/not evaluated
irSD
≥ +20 
Any
irPDa
Any
Unequivocal progression
irPDa
* the diameter of new measurable lesions is included in the calculation of the sum of diameters
a to be confirmed after at least 4 weeks
14.9.5
References (available upon request)
Wolchok JD, Hoos A, O'Day S et al (2009). Guidelines for the Evaluation of Immune Therapy 
Activity in Solid Tumors: Immune-Related Response Criteria. Clin Cancer Res; 15:7412-20.
Nishino M, Giobbie-Hurder A, Gargano M, et al (2013). Developing a Common Language for 
Tumor 
Response 
to 
Immunotherapy: 
Immune-Related 
Response 
Criteria 
Using 
Unidimensional Measurements. Clin Cancer Res; 19:3936-3943.


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14.11
Appendix 11- Recommended management algorithms for 
suspected toxicities
These guidelines for management of toxicities (Postow 2015) constitute guidance to the 
Investigator and are not intended to substitute institutional standard of care practice.
A general principle is that differential diagnoses should be diligently evaluated according to 
standard medical practice. Non-inflammatory etiologies should be considered and appropriately 
treated.


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14.11.1
GI adverse event management algorithm


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14.11.2
Renal adverse event management algorithm


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14.11.3
Pulmonary adverse event management algorithm


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14.11.4
Endocrinopathy management algorithm


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14.11.5
Skin adverse event management algorithm


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14.11.6
Hepatic adverse event management algorithm


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14.11.7
References (available upon request)
Postow MA, Chesney J, Pavlick AC, et al (2015). Nivolumab and ipilimumab versus 
ipilimumab in untreated melanoma. N Engl J Med.;372(21):2006-17 (supplementary appendix).

SAP_001.pdf: 
Clinical Development
FGF401
CFGF401X2101 / NCT02325739
A phase I/II, multicenter, open-label study of oral FGF401 in 
adult patients with hepatocellular carcinoma or solid 
malignancies characterized by positive FGFR4 and KLB 
expression
Statistical Analysis Plan (SAP) for final CSR
Author:
, 
Document type:
SAP Documentation
Document status:
Amendment 1
Release date:
26-Jun-2019
Number of pages:
46
Property of Novartis
For business use only
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous final version of SAP
Date
Time 
point
Reason for 
update
Outcome for update
Section and title 
impacted (Current)
27-
Nov-
2018
Prior 
to 
DB 
lock
Amendment 
1
Used the new template: SAP instead of 
RAP M3
Added analysis plan for FGF401 in 
combination with PDR001
Removed all analysis plan related to the 
phase II part of the FGF+PDR001 
combination because the phase II part 
of the FGF401+PDR001 combination 
will not start
All sections
Section 2.8.1: removed the definition of 
time to progression and added the 
definition of time to progression
Section 2.8.1.1.1: added the description 
“pooled data of subjects who received 
the MTD/RP2D under fasted and fed 
conditions will be used” 
Section 2.8.2.2.3: removed analyses for 
liver function parameters of interest
section 2.8.1
section 2.8.1.1.1
section 2.8.2.2.3
26-
Jun-
2019
Prior 
to 
DB 
lock 
for 
final 
CSR
Amendment 
1 for final 
CSR
Described rationale to not show Cmin
Added OS analysis at MTD/RP2D for 
the purpose of disclosure office
Added description that no specific 
summary tables or listing for AESIs will 
be provided
Section 2.8.4
Section 2.8.1.1.1
Section 2.8.2.1.2


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Table of contents
Table of contents .................................................................................................................3
List of abbreviations............................................................................................................5
1
Introduction .........................................................................................................................6
1.1
Study design.............................................................................................................6
1.2
Study objectives and endpoints ...............................................................................7
2
Statistical methods...............................................................................................................8
2.1
Data analysis general information ...........................................................................8
2.1.1
General definitions..................................................................................9
2.2
Analysis Set/ Subject Classification/ Withdrawal of ICF/ Subgroups ..................12
2.2.1
Analysis sets..........................................................................................12
2.2.2
Subject Classification............................................................................13
2.2.3
Withdrawal of Informed Consent..........................................................14
2.3
Subject Disposition / Demographics /Other Baseline Characteristics...................14
2.3.1
Subject disposition ................................................................................15
2.3.2
Demographic.........................................................................................15
2.3.3
Medical History.....................................................................................15
2.3.4
Prior antineoplastic therapy...................................................................15
2.3.5
Diagnosis and extent of cancer .............................................................15
2.4
Protocol deviations ................................................................................................15
2.5
Treatments (study treatment, concomitant therapies, compliance) .......................16
2.5.1
Study treatment .....................................................................................16
2.5.2
Prior, concomitant and post therapies...................................................18
2.5.3
Compliance ...........................................................................................18
2.6
Analysis of the primary objective..........................................................................18
2.6.1
FGF401 single agent .............................................................................18
2.6.2
FGF401 in combination with PDR001 .................................................21
2.7
Analysis of the key secondary objective ...............................................................26
2.8
Analysis of secondary objective(s)........................................................................26
2.8.1
Efficacy analysis ...................................................................................26
2.8.2
Safety analyses......................................................................................28
2.8.3
Other safety data ...................................................................................32
2.8.4
Pharmacokinetic analysis......................................................................33
36
36
2.10
Interim analysis......................................................................................................37


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2.10.1
FGF401 single agent .............................................................................37
2.10.2
FGF401 in combination with PDR001 .................................................37
3
Sample size calculation .....................................................................................................37
3.1.1
FGF401 single agent .............................................................................37
3.1.2
FGF401 in combination with PDR001 .................................................39
4
Change to protocol specified analyses – CSR Section 9.8.3.............................................40
5
Appendix ...........................................................................................................................40
5.1
Imputation rules.....................................................................................................40
5.1.1
Study drug.............................................................................................40
5.1.2
AE date imputation ...............................................................................41
5.1.3
Concomitant medication date imputation .............................................41
5.2
Definition and derivation rules for irRC................................................................42
5.2.1
Total measurable disease burden ..........................................................42
5.2.2
Assessment of disease progression .......................................................43
5.2.3
Best overall response.............................................................................44
5.2.4
Time to event analyses:.........................................................................44
5.3
Details of pharmacokinetic data analysis ..............................................................46
6
References .........................................................................................................................46


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List of abbreviations
AE
Adverse event
ATC
Anatomical Therapeutic Classification
AUC
Area Under the Curve
bid
bis in diem/twice a day
CSR
Clinical Study Report
CTC
Common Toxicity Criteria
CTCAE
Common Terminology Criteria for Adverse Events
DMC
Data Monitoring Committee 
FAS
Full Analysis Set
eCRF
Electronic Case Report Form
IVR
Interactive Voice Response
IWR
Interactive Web Response
MedDRA
Medical Dictionary for Drug Regulatory Affairs
NCI
National Cancer Institute
o.d.
Once Daily
OS
Overall Survival
PFS
Progression-Free Survival
PK
Pharmacokinetics
PPS
Per-Protocol Set
PRO
Subject-reported Outcomes
qd
Qua’que di’e / once a day
QoL
Quality of Life
RAP
Report and Analysis Process
RECIST
Response Evaluation Criteria in Solid Tumors 
SAP
Statistical Analysis Plan
SOC
System Organ Class
TFLs
Tables, Figures, Listings
WHO
World Health Organization


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1
Introduction
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis 
of data from study CFGF401X2101 that will be presented in the Clinical Study Report (CSR). 
The output shells (in-text and post-text) accompanying this document can be found in the Tables, 
Figures and Listings (TFL) shells document. The specifications for derived variable and 
datasets can be found in the Programming Datasets Specifications (PDS) document. This 
version of the SAP is based on the Protocol Amendment 5.
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 represents the study design for the single-agent part while figure 1-2 represents the 
same for the combination part. On Figure 1-2, the phase II has not been opened.
Figure 1-1
Study design


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Figure 1-2
Study design – FGF401 in combination with PDR001
1.2
Study objectives and endpoints
Table 1-1
Objectives and related endpoints
Objective
Endpoint
Primary
Phase I part
To estimate the MTD and/or RP2D of 
FGF401 single agent and in 
combination with PDR001
Incidence rate and characteristics of DLT during the first cycle of 
dosing for FGF401 single agent and during the first two cycles of 
dosing for FGF401 in combination with PDR001
Phase II part
To investigate the anti-tumor activity 
of FGF401 single agent and in 
combination with PDR001
FGF401 single agent: Group 1 and Group 2: Time to progression 
(TTP); Group 3: Overall response rate (ORR), based on local 
assessment per RECIST v1.1
Secondary (Phase I and II part)
To characterize the safety and 
tolerability of FGF401 single agent 
and in combination with PDR001
Safety: Incidence and severity of AEs and SAEs, including changes in 
laboratory values, vital signs and ECGs
Tolerability: Dose interruptions and reductions
To further investigate the anti-tumor 
activity of FGF401 single agent and in 
combination with PDR001
Phase I part
BOR, ORR, DCR, TTP and OS, based on local assessment per 
RECIST v1.1 for FGF401 single agent or RECISTv1.1. and irRC for 
the FGF401 and PDR001 combination
Phase II part- FGF401 single agent
Group 1 and Group 2: BOR, ORR, OS and DCR, based on local 
assessment per RECIST v1.1
Group 3: BOR, DCR, OS and PFS, based on local assessment per 
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Objective
Endpoint
To characterize the PK properties of:
-FGF401 single agent and in 
combination with PDR001 
-PDR001 in combination with FGF401 
Plasma concentration of FGF401, PDR001 and PK parameters 
including but not limited to Cmax, Cmin, AUCinf, AUClast, AUCtau
and T1/2
To assess immunogenicity of 
PDR001
Presence and/or concentration of anti-PDR001 antibodies
Phase I part- FGF401 single agent
To evaluate food effect on FGF401 
exposure and safety profile
● Plasma concentration of FGF401 and PK parameters when dosing 
under fed condition
● Safety: Incidence and severity of AEs and SAEs, including changes 
in laboratory values, vital signs and ECGs when dosing under fed 
condition
2
Statistical methods
2.1
Data analysis general information
Study data will be analyzed by Novartis personnel and/or designated CRO(s) using the most 
updated SAS® version in the GPS environment. For analyses using R (version 3.0.2 and 3.2.3)
and/or WinBUGS (version 14) /JAGS (version 4.1.0 and 4.2.0) (e.g. Bayesian analysis) in the 
MODESIM environment will be used. PK parameters will be calculated using non-
compartmental methods available in Phoenix WinNonlin version 6.4 or above.
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred) 
based on all patients’ data up to the time when all patients have potentially completed at least 
six cycles 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 Subjects 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 other 


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relevantmeasurements using descriptive statistics for quantitative data and contingency tables 
(frequencies and percentages) for qualitative data.
A treatment is defined by the dose level, and food condition (fed or fasted, in FGF401 single 
agent phase I part only). During the phase I part of the single agent FGF401, cohorts of patients
with the same treatment will be pooled into one single treatment group. Similarly, during the 
phase I part of the combination FGF401 + PDR001, cohorts of patients with the same 
combination treatment will be pooled into one single treatment group. Unless otherwise 
specified, data from the phase I and phase II parts, of any study arm, will not be pooled. 
Unless otherwise specified, data will be summarized by part and treatment, within each study 
arm.

Study part: phase I, phase II

Study arm: FGF401 single agent, FGF401 in combination with PDR001
In addition, patients in FGF401 single agent phase II part will be analyzed according to the 
following 3 groups to which they were assigned.

Group 1 (HCC patients from Asian countries)

Group 2 (HCC patients from non-Asian countries)

Group 3 (patients who have other solid tumors regardless of geography)
Because the enrollment of this study has been halted for business reason since 03Jul18 and the 
phase II part of the FGF401 in combination with PDR001 will not start, all analysis plan related 
to the phase II part of the FGF401 in combination with PDR001 arm are removed.
2.1.1
General definitions
2.1.1.1
Investigational drug and study treatment
FGF401 single agent:
Investigational drug will refer to FGF401. The terms investigational drug and study treatment
are used interchangeably.
FGF401 in combination with PDR001:
Investigational treatment will refer to FGF401 + PDR001. The term investigational treatment 
may also be referred to as study treatment. For consistency across studies, the term study 
treatment will be used throughout this document. 
2.1.1.2
Monotherapy vs combination studies
FGF401 single agent:
The expression monotherapy will be used to refer to investigational drug FGF401 the only 
component of the study treatment as defined in the study protocol.


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FGF401 in combination with PDR001:
The expression combination therapy will be used to refer to the Investigational treatment 
FGF401 + PDR001, as defined in the protocol.
2.1.1.3
Date of first/last administration of study treatment
FGF401 single agent:
In the single agent arm, the date of first/ last administration of study treatment is derived as the 
first/last date when a non-zero dose of FGF401 was administered and recorded on the Dosage 
Administration Record (DAR) eCRF. 
FGF401 in combination with PDR001:
The date of first administration of each component (FGF401, PDR001) is derived as the first 
date when a non-zero dose of each component was administered and recorded on the DAR 
eCRF. The date of last administration of FGF401 is the last date of administration of a non-zero 
dose of FGF401 was administered and recorded on the DAR eCRF. The date of last 
administration of PDR001 given Q3W is the last date of administration of a non-zero dose of 
PDR001 +20 days.
The date of first (last) administration of study treatment is derived as the first/last date of either
FGF401 or PDR001 whichever earlier/ later respectively..
2.1.1.4
Study day
The study day for safety assessments (e.g. adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption etc.) will be calculated as the difference 
between the date of the event (onset date of an event, assessment date etc.) and the start of study 
treatment plus 1. The first day of study treatment is therefore study day 1. Example: if start of 
study treatment is on 05-Jan-2014 and start date of an adverse event is on 09-Jan-2014 then the 
study day of the adverse event onset is 5. For safety assessments before start of study treatment, 
the study day is negative and derived by (date of event – start date of study treatment). For 
example: if start of study treatment is on 05-Jan-2014 and date of lab measurement is on 02-
Jan-2014 then the study day of the laboratory abnormality is -3. Note, the day of start of study 
treatment is day 1, and the day before the date of first study treatment is day – 1, not day 0.
The study day for other assessments (e.g. efficacy, 
 etc.) will be calculated the same 
way as safey assessments.
2.1.1.5
Baseline
Baseline is the result of an investigation describing the “true” state of the before start of study 
treatment administration.
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as “Baseline” assessment. In case time of assessment and time of treatment 
start is captured (e.g. pre-dose ECG), the last available assessment before the treatment start 
date/time is used for baseline.
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time point, the average of these measurements would be calculated for baseline (if not already 
available in the database).
In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline. If multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the last value should be considered as baseline.
If patients have no value as defined above, the baseline result will be missing.
For efficacy assessments, the last available assessment on or before the date of start of study 
treatment is taken as “baseline” assessment.
2.1.1.6
On-treatment assessment/event and observation periods
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 
administration of study treatment.
on-treatment period: from day of first administration of study treatment to 30 days after date 
of last administration of study treatment (including start and stop date)
post-treatment period: from 31 days after date of last administration of study treatment
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 
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 30 days (for FGF401 single agent) or  
150 days (for FGF401 in combination with PDR001). Following start of new antineoplastic 
therapy only treatment related adverse events will be collected. Select summaries of related 
adverse events and death will be produced for the combined on-treatment and post-treatment 
periods (Section 2.8.2.1).
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided. In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).


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2.2
Analysis Set/ Subject Classification/ Withdrawal of ICF/ 
Subgroups
2.2.1
Analysis sets
2.2.1.1
Full Analysis Set (FAS)
The full analysis set (FAS) comprises all patients who received at least one dose of study 
treatment. Patients enrolled in the phase I part will be analyzed according to the treatment they 
have been assigned to. Patients enrolled in the FGF401 single agent phase II part will be 
analyzed by Group. Unless otherwise specified, the FAS will be the default analysis set used 
for all analyses.
2.2.1.2
Safety Analysis Set (SS)
The Safety Set includes all patients who received at least one dose of study treatment. Patients
enrolled in the phase I part will be analyzed according to the study treatment (regimen) they 
actually received, defined as

The treatment assigned if it will be received at least once, or

The first treatment received when starting therapy with study treatment if the assigned 
treatment will never be received.
Patients enrolled in the FGF401 single agent phase II part will be analyzed by Group.
2.2.1.3
Dose Determing Set (DDS)
The dose-determining analysis set (DDS) consists of all patients from the safety set in phase I 
part who either meet the following minimum exposure criterion and have sufficient safety 
evaluations, or have experienced a DLT during the applicable evaluation period of DLTs. 
FGF401 single agent:
A patient is considered to have met the minimum exposure criterion if he/she received at least 
66% of the planned doses of FGF401 in the first cycle of dosing i.e. at least 14 out of the 21 full 
planned daily dose of FGF401.
Patients who do not experience DLT during the first cycle of treatment are considered to have 
sufficient safety evaluations if they have been observed for ≥ 21 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.
FGF401 in combination with PDR001:
A patient is considered to have met the minimum exposure criterion if he/she received at least 
66%, (i.e. at least 28 days) of the planned doses of FGF401, and all planned doses of PDR001 
in cycle 1 and cycle 2 of dosing.
Patients who do not experience DLT during the first 2 cycles of treatment are considered to 
have sufficient safety evaluations if they have been observed for ≥ 42 days following the first 


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dose, and are considered by both Novartis and Investigators to have enough safety data to 
conclude that a DLT did not occur.
2.2.1.4
Per-Protocol Set (PPS)
The Per-Protocol Set (PPS) will consist of a subset of patients from the FAS who have an 
adequate tumor assessment at baseline and at least one post treatment tumor assessment with a 
result other than UNK, and no major protocol deviations.
All major protocol deviations leading to exclusion from the PPS will be detailed in the SAP.
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 (see section 2.6). If the PPS and the FAS are 
identical, then analyses described by the PPS below will not be performed.
2.2.1.5
PK analysis set
Pharmacokinetic analysis set (PAS)
The pharmacokinetic analysis set (PAS) includes all subjects who provide at least one evaluable 
drug concentration. For those requiring non-compartment analyses, the PAS includes all 
subjects who provide an evaluable PK profile. Patients will be removed from the determination 
of individual PK parameters on a case by case basis (to be described in detail in the Clinical 
Study Report).
The PAS will be used for summaries of drug concentration data, non-compartment PK analysis 
and/or population PK analysis. The analysis of the food effect on the FGF401 PK exposures 
will also use the PAS.
2.2.2
Subject Classification
Subjects may be excluded from the analysis populations defined above based on the protocol 
deviations (PD) entered in the database and/or on specific classification rules defined in Table 
2-1. 
Table 2-1
Classification based on PDs and non-PD criteria
Analysis set
Protocol deviations leading to 
exclusion
Non protocol deviation leading to 
exclusion
Full analysis set 
No written inform consent
Patient did not receive any dose of 
study treatment since day 1 of cycle 1 
evaluation performed
Safety set
No written inform consent
Patient did not receive any dose of 
study treatment since day 1 of cycle 1 
evaluation performed
Dose-determining 
set
No written inform consent
FGF401 single agent:
Patient received less than 66% of the 
planned dose of FGF401 without 
having DLT in the first cycle of 
treatment in phase I part.


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Patient received at least 66% of the 
planned dose of FGF401 without 
having DLT but not received sufficient 
safety evaluation in the first cycle of 
treatment in phase I part
Patient did not receive any dose of 
FGF401 since day 1 of cycle 1 
evaluation performed
FGF401 in combination with PDR001:
Patient received less than 66% of the 
planned dose of FGF401 or not 
planned doses of PDR001 without 
having DLT in cycle 1 and cycle 2 of 
dosing.
Patient received at least 66% of the 
planned dose of FGF401 and all 
planned doses of PDR001 without 
having DLT but not received sufficient 
safety evaluation in the first 2 cycles
of treatment in phase I part
Patient did not receive any dose of 
study treatment since day 1 of cycle 1 
evaluation performed
Per-protocol set
No written inform consent
No measurable lesion is present 
according to RECIST v1.1
Patient did not receive any dose of 
study treatment since day 1 of cycle 1 
evaluation performed
Patient had no appropriate tumor 
assessment post treatment
PK Analysis Set
No written inform consent
Patient did not receive any dose of 
study treatment since day 1 of cycle 1 
evaluation performed
Patient had no blood sample 
providing evaluable PK data
2.2.3
Withdrawal of Informed Consent
Any data collected in the clinical database after a Subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis. The date on which a Subject
withdraws full consent is recorded in the eCRF.
 
 
 
2.3
Subject Disposition / Demographics /Other Baseline 
Characteristics
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS.


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2.3.1
Subject disposition
The following will be tabulated:

Number (%) of Subjects who are still on-treatment at the time of cut-off;

Number (%) of Subjects who discontinued treatment and primary reasons for 
discontinuation;

Number (%) of Subjects who discontinued from study and reasons for discontinuation;

Number of (%) Subjects followed up after discontinuation of study treatment;
2.3.2
Demographic
Demographic data including age, sex, race, ethnicity, height, weight, body mass index, and 
ECOG performance status will be listed and summarized. In addition, following age categories 
will be summarized: 18- <65 years, 65- < 85 years, and ≥ 85 years.
BMI is calculated using the following formulas:

BMI [kg/m2] = weight[kg] / (height[m]**2)
2.3.3
Medical History
A listing of medical history and current medical conditions will be provided, using the latest 
Medical Dictionary for Regulatory Activities (MedDRA) terminology available at the time of 
reporting. 
2.3.4
Prior antineoplastic therapy
All prior anti-neoplastic medication, radiotherapy and surgery will be listed.
The number (%) of Subjects who received any prior anti-neoplastic medication, radiotherapy 
or surgery will be summarized.
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen), setting at last treatment, best 
response at last treatment (defined to be the best response during the last treatment regimens 
recorded) and reason for discontinuation at last medication. Prior antineoplastic medications 
will also be summarized by Anatomical Therapeutic Chemical (ATC) class, and preferred term.
Local HCC therapies will be listed.
2.3.5
Diagnosis and extent of cancer
The diagnosis and extent of cancer (disease history) will be listed. Prognistic factors for HCC 
will be summarized and listed.
2.4
Protocol deviations
The FAS will be used for the protocol deviation summary tables and listing. The number (%) 
of Subjects with any CSR-reportable protocol deviation will be tabulated. The full list of 
protocol deviations is documented in the Study Specification Document (SSD).


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2.5
Treatments (study treatment, concomitant therapies, 
compliance)
2.5.1
Study treatment 
The safety set will be used for all summaries and listings of study treatment. 
Duration of exposure, actual cumulative dose, dose intensity (DI) and relative dose intensity 
(RDI) for each component of study treatment will be summarized. The duration of exposure 
will also be presented for the study treatment. Duration of exposure will be categorized into 
time intervals (≤6 weeks, >6-12 weeks, >12-18 weeks, >18-24 weeks, >24-52 weeks, >52 
weeks); frequency counts and percentages will be presented for the number(%) of patients in 
each interval. The number (%) of patients who have dose reductions or interruptions, and the 
reasons, will be summarized by treatment. See section 5.1.1 for details of the imputation of 
first/last administration date.
Patient level listings of all doses administered on treatment along with dose change reasons will 
be produced.
2.5.1.1
Duration of exposure to study treatment
Duration of exposure to study treatment is considered by taking into account the duration of 
exposure to the investigational drug and any combination partner, if applicable:
Duration of exposure to study treatment (days) = (last date of exposure to study treatment) –
(date of first administration of study treatment) + 1. 
FGF401 single agent:
Duration of exposure to study treatment is calculated by using the date of first/last 
administration of study treatment defined in section 2.1.1.3.
FGF401 in combination with PDR001
Duration of exposure to each component (FGF401, PDR001), as well as duration of exposure 
to study treatment, is calculated by using the date of first/last administration of study treatment 
and each component defined in section 2.1.1.3.
2.5.1.2
Cumulative dose
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components, 
respectively. 
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration. The planned 
cumulative dose is not summarized/listed. It is used for relative dose intensity calculations. The 
actual cumulative dose refers to the total actual dose administered, over the duration for which 
the patient is on the study treatment as documented in the Dose Administration eCRF. 
For patients who did not take any drug, the actual cumulative dose is by definition equal to zero 
for that drug.


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For continuous dosing, the actual cumulative dose is the sum of the non-zero doses recorded 
over the dosing period and the planned cumulative dose is the planned starting dose summed 
over the same dosing period.
For intermittent dosing, the actual cumulative dose should be defined based on the days when 
the patient is assumed to have taken a non-zero dose during dosing periods. 
2.5.1.3
Dose intensity and relative dose intensity
Dose intensity (DI) for s with non-zero duration of exposure is defined as follows: 
DI (dosing unit/unit of time) = Actual Cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
For patients who did not take any drug the DI is by definition equal to zero. 
Planned dose intensity (PDI) is defined as follows:
PDI (dosing unit/unit of time) = Planned Cumulative dose (dosing unit) / Duration of exposure 
(unit of time).
Relative dose intensity (RDI) is defined as follows:
RDI = DI (dosint unit/unit of time) / PDI (dosing unit/unit of time).
DI and RDI will be summarized separately for each of the study treatment components, using 
the duration of exposure of each of the components.
2.5.1.4
Dose reductions, interruptions or permanent discontinuations
The number of who have dose reductions, permanent discontinuations or interruptions, and the 
reasons, will be summarized separately for each of the study treatment components. 
‘Dose interrupted’, and ‘Dose permanently discontinued’ fields from the Dosage 
Administration CRF pages (DAR) will be used to determine the dose interruptions, and 
permanent discontinuations, respectively. Dose reductions will be derived programmatically 
using the dosing information as described below.
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons.
A dose change is either ‘change in prescribed dose level’ or ‘dosing error’ where actual dose 
administered/total daily dose is different from the prescribed dose.
For the purpose of summarizing interruptions and reasons, in case multiple entries for 
interruption that are entered on consecutive days with different reasons will be counted as 
separate interruptions. However, if the reason is the same in this mentioned multiple entries on 
consecutive days, then it will be counted as one interruption. 
Dose reduction: A dose change where the prescribed dose level is lower than the previous 
prescribed dose level or where the actual dose administered/total daily dose is lower than the 
calculated dose amount based on the prescribed dose. Therefore any dose change to correct a 
dosing error will not consider a dose reduction. Only dose change is collected in the CRF, 


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number of reductions will be derived programmatically based on the change and the direction 
of the change.
2.5.2
Prior, concomitant and post therapies
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Concomitant 
Medications/significant non-drug therapies eCRF. These therapies will be coded using the 
WHO Drug Reference Listing (WHO DRL) dictionary that employs the WHO Anatomical 
Therapeutic Chemical (WHO ATC) classification system.
Any concomitant therapies starting prior to or after the start of study treatment will be listed.
Also, antineoplastic therapy since discontinuation 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 2.8.2.1 Adverse events). No imputation will be performed for 
concomitant medication end dates.
2.5.3
Compliance
Compliance to the study treatment will be summarized in terms of the RDI or percentage of 
patients who took a predefined percentage of the number of prescribed. The predefined RDI 
categories are < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and 
proportion of Subjects falling in each category will be presented.
2.6
Analysis of the primary objective
2.6.1
FGF401 single agent
2.6.1.1
Phase I part
Statistical hypothesis, model, and method of analysis
A Bayesian hierarchical logistical regression model (BHLRM) will be applied to estimate the 
relationship between dose and the probability of a patient experiencing a dose limiting toxicity 
(DLT) for patients in fasted condition (stratum 1) and in fed condition (stratum 2). The standard 
Bayesian hierarchical model assumes full exchangeability of strata parameters; for the 
methodology and an application to binary data see Thall et al. 2003 and Chugh et al. 2009. Here, 
we extend the standard Bayesian hierarchical model to dose-toxicity data, and exchangeable as 
well as non-exchangeable strata parameters. 
For the two patient strata, the probability of experiencing a DLT is modeled as follows:
logit	


 = log	
 + 	
 log( ∗
⁄
)
logit

  = log
 + 
 log( ∗
⁄
)
where  denotes dose; ∗is a fixed reference dose; 	


and 


are the probability of a 
patient experiencing a DLT at dose  in respectively fasted and fed conditions; and the two 


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parameter 
vectors 
	
 = (	
), (	
)
and 

 =
(
), (
) describe the relationship between dose and toxicity for the two strata.
We further let the parameter vectors 	
 and 
 be either exchangeable or non-
exchangeable, with probability  and (1 −), respectively.
1. Under exchangeability, the parameter vectors 	
 and 
 are assumed to follow a 
bivariate normal distribution:
	
 , 
 ~  !(μ
#$%, &
#$%),
where '
#$% = ((
), (
*) and &
#$% = +
,
)
*
-,
),
*
-,
),
*
,
*
*
. are the mean vector and 
covariance matrix.
Prior distributions for μ
#$% and &
#$% of the exchangeability distribution complete the model 
specifications for the exchangeability component of the model 
The prior distributions for the component of μ
#$% will be normal and the prior distributions for 
the standard deviations and the correlation in &
#$% will be log-normal and uniform, 
respectively.
2. Under non-exchangeability, the parameter vectors 	
 and 
 are assumed to have a 
weakly informative bivariate normal prior distribution.
	
 , 
 ~  !(/0, S0),
where 20 = (/0), /0*) and 30 = +
,0)
*
4,0),0*
4,0),0*
,0*
*
. are the mean vector and 
covariance matrix.
The specification of prior distributions is described in protocol Appendix 10.
Change in dosing schedule
In the event of a change in dosing schedule, a new BLRM will be set up. This new BLRM will 
have the same functional form as that described above and will incorporate existing dose 
escalation data in the prior distributions. For comparability, doses for the new and old model 
will be normalized to dose in mg per day.
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels for fasted and fed conditions are obtained. The results of this analysis are 
summarized in terms of the probabilities that the true rate of DLT for fasted and fed conditions 
at each dose-level will lie within each of the following intervals:

[0, 0.16) under-dosing

[0.16, 0.33) targeted toxicity

[0.33, 1.00] excessive toxicity


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The overdose control criterion mandates that under each of the patient conditions, any dose of 
FGF401 for which the DLT rate has more than a 25% risk of being excessively toxic, i.e. P(DLT) 
is 0.33 or higher, will not be considered for the next dose cohort. The final estimate of the 
MTD/RP2D will also satisfy this condition.
Details of the criteria for dose escalation and the estimation of the MTD are provided in protocol 
Section 6.2.3.
Reports of DLT analysis 
Following reports will be produced based on the dose determining set:

A plot of posterior interval probabilities at the time of database lock will be presented in 
the body of the CSR;

Summary of the DLTs with onset during the evaluation period (phase I part only) by 
primary system organ class, preferred term: recommendations at the time of database lock 
will be included in the body of the CSR, for each DEM, summary of recommendations 
will be included in Appendix 16.1.9 of the CSR;

Listing of inferential results from the BHLRM at the time of database lock, will be 
included in Appendix 16.1.9.
2.6.1.2
Phase II part
The FAS will be used for the primary analysis.
Group 1 and 2: 
The distribution of TTP will be estimated using the Kaplan-Meier method. A positive trend 
regarding the activity of FGF401 will be concluded if the observed lower limit of one-sided 90%
confidence interval (CI) of TTP ≥ 1.5 months (Group 1) and 2.2 months (Group 2), which are 
the expected median TTPs without FGF401 treatment in group 1 and 2, respectively. The 
median TTP and quantiles (along with one-sided 90% CI) will be presented. The Kaplan-Meier 
curve will be presented graphically. TTP rate estimates (along with one-sided 90% CI) at 1.5, 
3 and 6 months will be presented, as given by the Kaplan-Meier analysis.
Group 3: 
BOR, defined in Appendix 1 of the study protocol, will be summarized by tumor type. The 
number (%) of patients having BOR as CR, PR, SD, PD and unknown per RECIST 1.1 will be 
provided. The ORR, the proportion of patients having BOR of either confirmed CR or PR, of 
an individual tumor type will be summarized. These analyses will only be provided for tumor 
type with which there are at least 10 enrolled patients. Otherwise, data will only be listed.


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2.6.2
FGF401 in combination with PDR001
2.6.2.1
Phase I part
Statistical hypothesis, model, and method of analysis
A 5-parameter adaptive Bayesian logistic regression model (BLRM), guided by the EWOC 
principle will be used to make dose recommendations and estimate the MTD/RDE of the 
combination.
The respective single agent dose-DLT relationships are defined as follows:
FGF401:
logitπ)(d)) = log(α)) + β) log() )
∗
⁄
)
PDR001:
logitπ*(d*) = log(α*) + β* log(* *
∗
⁄
)
Where, π1(d1) and π2(d2) are respectively the probability that a patient has a DLT during the 
first 2 cycles of combination treatment with FGF401 and PDR001 given at the Q3W dose d1
and d2 respectively, and )
∗=120 mg and *
∗=300 mg are respectively the FGF401 and PDR001 
reference doses. αi, βi > 0 are the parameters of the model.
Then, the dose-DLT relationship of the combination FGF401 + PDR001 is defined as follows:
>?)*(), *) =
)*(), *)
1 −)*(), *) = exp(η )
)
∗
*
*
∗) D)()) + *(*) −)())*(*)
(1 −)()))(1 −*(*))
E
Where η is the log-odds ratio between the interaction and no-interaction model at the reference 
doses. Here η = 0 corresponds to no-interaction, η > 0 represents synergistic toxicity, and η < 0 
represents antagonistic toxicity.
Prior specification
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the FGF401 single agent parameters log(α1), log(β1), the PDR001 single agent 
parameters log(α2), log(β2) and the interaction parameter η. 
The Bayesian approach requires the specification of prior distributions for all model parameters, 
which include the single agent parameters log()) and log()) for FGF401, log(*) and log(*) 
for PDR001, and the interaction parameter η. A meta-analytic-predictive (MAP) approach is 
used to derive a weakly informative prior distribution for the single-agent model parameters 
based upon available DLT data.
Description of the meta-analytic-predictive (MAP) approach
The aim of the MAP approach is to allow variable heterogeneity of the dose-DLT data from 
historical study (i.e., CFGF401X2101) and derive a prior distribution for the logistic parameters 
log(∗), log(∗) for the new trial.
Let F and G be the number of patients with a DLT, and the total number of patients at dose 
 in historical study ? (? = 1, … , I).  The corresponding probability of a DLT is . The model 
specifications for the derivation of the MAP prior are as follows:


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F |  ~ Bin(, G)
logit() = log() +  log(/∗)
(), () L (, M ~ BVN((, M),
s = 1, … , S
(∗), (∗) L (, M ~ BVN((, M)
The parameters ( = ((), (*) and M are the mean and between-trial covariance matrix for the 
logistic parameters, the latter with standard deviations ), *, and correlation .  The parameters 
) and * quantify the degree of between trial heterogeneity. The following priors will be used 
for these parameters:

normal priors for () and (*, 

log-normal priors for ) and *, and 

a uniform prior for .
The MAP prior for FGF401 and PDR001 single agent parameters in the combination part of the 
study, (∗), (∗), is the predictive distribution 
(∗), (∗) L (F, G ∶? = 1, … , I )
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 H 1974).


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Change in dosing schedule
In the event of a change in dosing schedule, a new BLRM will be set up. This new BLRM will 
have the same functional form as that described above and will incorporate existing dose 
escalation data in the prior distributions. 
Dose recommendation
After each cohort of patients, the posterior distributions for the probabilities of DLT rates at 
different dose levels for FGF401 in combination with PDR001 are obtained. The results of this 
analysis are summarized in terms of the probabilities that the true rate of DLT for FGF401 in 
combination with PDR001 at each dose-level will lie within each of the following intervals:

[0, 0.16) under-dosing

[0.16, 0.33) targeted toxicity

[0.33, 1.00] excessive toxicity
The overdose control criterion mandates that under each of the patient conditions, any dose of 
FGF401 for which the DLT rate has more than a 25% risk of being excessively toxic, i.e. P(DLT) 
is 0.33 or higher, will not be considered for the next dose cohort. The final estimate of the 
MTD/RP2D will also satisfy this condition.
Details of the criteria for dose escalation and the estimation of the MTD are provided in protocol 
Section 6.2.3.
Reports of DLT analysis 
Following reports will be produced based on the dose determining set:

A plot of posterior interval probabilities at the time of database lock will be presented in 
the body of the CSR;

Summary of the DLTs with onset during the evaluation period (phase I part only) by 
primary system organ class, preferred term: recommendations at the time of database lock 
will be included in the body of the CSR, for each DEM, summary of recommendations 
will be included in Appendix 16.1.9 of the CSR;

Listing of inferential results from the BLRM at the time of dabase lock, will be included in 
Appendix 16.1.9.


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2.7
Analysis of the key secondary objective
There is no key secondary objective in this study.
2.8
Analysis of secondary objective(s)
All events with start date before or on the cut-off date and end date after the cut-off date will be 
reported as ‘ongoing’. The same rule will be applied to events starting before or on the cut-off 
date and not having documented end date. This approach applies, in particular, to adverse event 
and concomitant medication reports. For these events, the end date will not be imputed and 
therefore will not appear in the listings.
2.8.1
Efficacy analysis
Evaluation of anti-tumor activity will be based on investigator assessment of overall lesion 
response according to RECIST v1.1 (see Protocol Appendix 1) and irRC (only for the FGF401 
in combination with PDR001 part; see Protocol Appendix 9). The endpoints used to evaluate 
anti-tumor activity are BOR, ORR, PFS, TTP, OS, DCR, and DOR using the FAS.
Assessment by irRC (only for the FGF401 in combination with PDR001 part)
For irRC the key difference from RECIST in the assessment of these endpoints is the 
recommendation that irPD be confirmed at least 4 weeks after the criteria for irPD are first met.
A single assessment of irPD followed by a subsequent assessment of irSD or better will be 
considered as a pseudo-progression, these are not considered as progression events for the 
purposes of analysis. Where irPD is confirmed by a second assessment, the date of the first of 
these two assessments is then the date of progression. For Subjects who have ended treatment 
without a valid confirmation assessment, for the purposes of analysis the single assessment of 
irPD will be treated as a confirmed irPD. At time of analysis there may be Subjects whose last 
adequate assessment is an unconfirmed irRC progression but who are continuing treatment. In 
these cases that progression will be treated as a confirmed progression for the primary analysis, 
and sensitivity analysis of time to event endpoints may be conducted in which the Subject is 
censored at the time of last adequate assessment. Additional definitions and derivation rules for 
irRC are provided in protocol Appendix 9.
Best overall response (BOR)
The BOR is the best response recorded from the start of the treatment until disease 
progression/recurrence. For assessment per RECIST v1.1, any assessments taken more than 30 
days after the last dose of study treatment will not be included in the best overall response 
derivation. For irRC this period is extended to 150 days after last dose in recognition that 
response to immunotherapy may be delayed.
Overall response rate (ORR) 
The ORR is the proportion of patients with a best overall response of CR or PR (RECIST v1.1) 
or of irCR or irPR (irRC). Confirmed CR and PR will be used for the calculation of ORR.


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Disease control rate (DCR) 
The DCR is the proportion of patients with a best overall response of CR, PR, or SD (RECIST 
v1.1) or of irCR, irPR, or irSD (irRC). 
Progression free survival (PFS)
For assessment per RECIST v1.1, PFS is the time from date of start of study 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, PFS is censored at the date of last adequate tumor assessment (Protocol 
Appendix 1 section 14.1.19). For irRC, PFS is defined similarly, but with the date of event 
defined as the date of the first documented confirmed progression as defined in Section 5.1.4.1, 
or death due to any cause. For irRC other censoring rules are applied as for RECIST v1.1 (see 
Protocol Appendix 1 section 14.1.25).
Duration of response (DOR)
The DOR applies only to Subjects with a BOR of confirmed CR or PR (RECIST v1.1) or of 
confirmed irCR or irPR (irRC). For assessment per RECIST v1.1, DOR is defined as the time 
from the date of the first documented response (CR or PR) to the date of first documented 
progression, or death due to study indication. For assessment per irRC, DOR is defined as the 
time from the first confirmed response (irCR or irPR), to the date of confirmed progression as
defined in Section 5.1.4.1, or death due to study indication.
Overall survival (OS)
Overall survival (OS) is defined as the time from date of start of study treatment to 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 
know date subject alive. 
Time to progression (TTP)
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.
Use of alternative cancer therapy
For both RECIST v1.1 and irRC, if any alternative cancer therapy is taken any subsequent 
assessments will be excluded from the analysis of endpoints based on tumor response 
assessments.
2.8.1.1
FGF401 single agent
2.8.1.1.1 Phase I part
BOR, ORR and DCR will be summarized by treatment group. For ORR and DCR
accompanying 95% exact binomial CIs will be provided. Waterfall plot will be provided 


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showing best change in sum of diameters (SOD) for RECIST v1.1. Individual lesion 
measurements and overall response assessments will be listed by patient.
The Kaplan-Meier plot for TTP at the MTD/RP2D will be presented. The estimated TTP rate 
at the MTD/RP2D along with 95% CI at 1.5, 3 and 6 months will be presented. If appropriate, 
the Kaplan-Meier plots for OS at the MTD/RP2D will also be presented. The estimated OS rate
at the MTD/RP2D along with 95% CI at 3, 5, 7 and 9 months will be presented. Pooled data of 
subjects who received the MTD/RP2D under fed and fasted conditions will be used. These
analyses will only be provided if there are at least 10 enrolled patients at MTD/RP2D. Otherwise, 
data will only be listed.
2.8.1.1.2 Phase II part
Group 1 and 2:
BOR, ORR and DCR will be summarized by treatment group. 
The Kaplan-Meier plot for OS will be presented by group, and, if data permits,by FGF19 status 
within individual HCC groups. The estimated OS rate along with 95% CI at 3, 5, 7 and 9 months 
will be presented by treatment group.
Group 3: 
BOR and DCR will be summarized by tumor type. 
The Kaplan-Meier analysis for PFS and OS will be provided by tumor type. 
These analyses will only be provided for tumor type with which there are at least 10 enrolled 
patients. Otherwise, data will only be listed.
2.8.1.2
FGF401 in combination with PDR001
2.8.1.2.1 Phase I part
BOR, ORR and DCR will be summarized by treatment group. For ORR and DCR
accompanying 95% exact binomial CIs will be provided. Waterfall plot will be provided 
showing best change in sum of diameters (SOD) for RECIST v1.1, and best change in total 
measurable disease burden (TMTB) for irRC. Individual lesion measurements and overall 
response assessments will be listed by patient.
The Kaplan-Meier plot for TTP at the MTD/RP2D will be presented. The estimated TTP rate 
at the MTD/RP2D along with 95% CI at 1.5, 3 and 6 months will be presented. If appropriate, 
the Kaplan-Meier plots for OS at the MTD/RP2D will also be presented. These analyses will 
only be provided if there are at least 10 enrolled patients at MTD/RP2D. Otherwise, data will 
only be listed.
2.8.2
Safety analyses
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.


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2.8.2.1
Adverse events (AEs)
2.8.2.1.1 Data handling
Adverse events will be coded using the Medical dictionary for regulatory activities (MedDRA)
and assessed according to the Common Terminology Criteria for Adverse Events (CTCAE) 
version 4.03, respectively.
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).
2.8.2.1.2 Data analysis
AE Summaries
AE summaries will include all AEs occurring during on-treatment period. Additionally, for the 
patients receiving PDR001, summaries will be produced using all treatment related AEs starting 
or worsening during the on-treatment or post-treatment periods. All AEs collected in the AE 
(e)CRF page will be listed along with the information collected on those AEs e.g. AE 
relationship to study drug, AE outcome etc. AEs starting during the post-treatment period will 
be flagged in the listings. 
AEs will be summarized by number and percentage of patients having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A patient with multiple occurrences of an AE will be counted only 
once in the respective AE category. A patient with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
In AE summaries the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in the “all patients” column.
The following summaries for AEs occurring during the on-treatment period will be produced 
by treatment:

Overview of adverse events and deaths (number and % of patients who died, with any AE, 
any SAE, any dose reductions/interruptions, AE leading to discontinuation) 

AEs by SOC and PT, summarized by relationship (all AEs and AEs related to study 
treatment);

Seriousness (SAEs and non-SAEs);

Leading to treatment discontinuation;

Leading to dose interruption/adjustment; 

Leading to fatal outcome;
The following listings will be produced:


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
All adverse events (safety set) 

Adverse events among patients who were not treated (all screened patients)
In combo part only, the following summaries will be produced for all AEs starting or worsening 
during the on-treatment or post-treatment periods (within 150 days after the date of last 
administration of study treatment): 

AEs related to study treatment by SOC and PT;

SAEs related to study treatment
Considering the limited number of patients enrolled in the combination arm no specific 
summary tables or listing for AESIs will be provided.
Deaths 
Separate summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by treatment arm, system organ class and preferred term. 
All deaths will be listed for the safety set, post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened patients. 
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries
For the legal requirements of clinicaltrials.gov and EudraCT, two required tables on on-
treatment adverse events which are not serious adverse events with an incidence greater than 5% 
and on on-treatment SAEs and SAEs suspected to be related to study treatment will be provided 
by SOC and PT on the safety set population.
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT:

a single occurrence will be counted if there is ≤ 1 day gap between the end date of the
preceding AE and the start date of the consecutive AE

more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE
For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g. among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE.
The number of deaths resulting from SAEs suspected to be related to study treatment and SAEs 
irrespective of study treatment relationship will be provided by SOC and PT.
2.8.2.2
Laboratory data
2.8.2.2.1 CTC grading for laboratory parameters
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of 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 


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for CTC grading of laboratory parameters. The latest available version of the document based 
on the underlying CTCAE version 4.03 at the time of analysis will be used. 
For laboratory tests where grades are not defined by CTCAE version 4.03, results will be graded 
by the low/normal/high (or other project-specific ranges, if more suitable) classifications based 
on laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
For laboratory tests that are graded for both low and high values, summaries will be done 
separately and labeled by direction, e.g. sodium will be summarized as hyponatremia and 
hypernatremia.
2.8.2.2.2 Imputation rules
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC. 
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100)
Further derivation of laboratory parameters might be required for CTCAE grading. For instance, 
corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4]
In order to apply the above formula, albumin values in g/L will be converted to g/dL by 
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium as defined in the previous section.
2.8.2.2.3 Data analysis
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 30 days after the last study treatment administration date (see Section 2.1.7). 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 

Shift tables using CTC grades to compare baseline to the worst on-treatment value; 

For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value.
The following listings will be produced for the laboratory data: 


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
Listing of all CTC grade 3 or 4 laboratory toxicities 
2.8.3
Other safety data
2.8.3.1.1 ECG and cardiac imaging data
The average of the ECG parameters at that assessment should be used in the analyses.
12-lead ECGs including PR, QRS, QT, QTcF, and HR intervals will be obtained central/local 
for each patient during the study. ECG data will be read and interpreted centrally locally 
The number and percentage of patients with notable ECG values will be presented by treatment 
arm.

QT, or QTcF 

New value of > 450 and ≤ 480 ms 

New value of > 480 and ≤ 500 ms 

New value of > 500 ms 

Increase from baseline of > 30 ms to ≤ 60 ms 

Increase from baseline of > 60 ms 

HR 

Increase from baseline >25% and to a value > 100 bpm 

Decrease from baseline >25% and to a value < 50 bpm 

PR 

Increase from baseline >25% and to a value > 200 ms 

New value of > 200 ms 

QRS 

Increase from baseline >25% and to a value > 120 ms

New value of > 120 ms
A listing of all ECG assessments will be produced by treatment arm and notable values will be 
flagged. In the listing, the assessments collected during the post-treatment period will be flagged.
2.8.3.2
Vital signs
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), pulse
(beats per minute), systolic and diastolic blood pressure (mmHg). 
Values measured during the post-treatment period will be flagged in the listings. The number
and percentage of patients with notable vital sign values (high/low) will be presented by 
treatment arm.
Table 2-8
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 


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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 
--
2.8.4
Pharmacokinetic analysis
The PAS will be used in the pharmacokinetic data analysis and PK summary statistics.
PK parameters will be determined for all PK-evaluable patients with noncompartmental 
method(s) using Phoenix WinNonlin version 6.4 or above (Pharsight, Mountain View, CA).
For FGF401, the PK parameters include but may be not limited to those listed in Table 10-7. 
For PDR001, PK parameters would be limited to Cmax, Tmax, AUClast andT1/2.
All the concentration data are presented in summary table of the concentration data, where the 
minimal concentration (Cmin) is included. Therefore, Cmin was not additionally produced as a 
stand-alone parameter.
Table 2-9
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)
AUCtau
The AUC calculated to the end of a dosing interval (tau), in the current situation it equals 
to AUC0-24h (amount x time x volume-1)
Cmax
The maximum (peak) observed plasma concentration (mass x volume-1)
Tmax
The time to reach maximum (peak) plasma drug concentration (time)
T1/2
The elimination half-life associated with the terminal slope (λz)of a semi logarithmic 
concentration-time curve (time). Use qualifier for other half-lives
CL/F
The apparent total body clearance of drug from the plasma after oral administration 
(volume x time-1)
Racc
Accumulation ratio calculated using AUCtau at steady state divided by AUCtau at Day 1
2.8.4.1
Data handling principles
Only PK blood samples with date and time and for which the last prior dose dates and times are 
adequately and correctly recorded will be included in the PK analyses. For FGF401, samples 
taken from patients who vomited within 4 hours of dosing may be excluded from the analysis, 
based on the judgement of PK analyst.
All concentrations below the lower limit of quantitation (LLOQ) or missing data will be labeled 
as such in the concentration data listings. Concentrations below the LLOQ will be treated as 
zero in summary statistics and for the calculation of pharmacokinetic parameters, unless 
otherwise stated under the Pharmacokinetic Analysis Set. 


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2.8.4.2
Data analysis set
All pharmacokinetic data analyses and PK summary statistics will be based on PAS. 
2.8.4.3
Basic tables, figures, and listing
Concentration data
Concentration data will be listed by time point, patient and treatment group. Descriptive 
statistics (n, m (number of non-zero concentrations), mean, CV%, SD, median, geometric mean, 
geometric CV%, minimum and maximum) for PDR001 and FGF401 concentrations will be 
presented at each scheduled timepoint by treatment.
All concentration data for PDR001 and FGF401 will be displayed graphically. Individual 
concentration-time profile as well as mean concentration-time profile will be plotted.
PK parameters
Descriptive statistics will be presented for all pharmacokinetic parameters. Only for the 
parameter Tmax, the descriptive statistics including median, min and max will be summarized. 
Otherwise noted, mean standard deviation, CV% mean, geometric mean, CV% geo-mean, 
median, minimum, and maximum will be summarized for other PK parameters. In addition, 90% 
CI will be provided for Racc.
Zero concentrations will not be included in the geometric mean calculations. Missing 
concentrations or PK parameter values will not be imputed. A listing of derived PK parameters 
per Subject will be produced by treatment group.
2.8.4.4
Dose proportionality
Analysis of dose-proportionality will be performed if at least three doses of FGF401 are 
investigated.
Cmax and AUCtau will be used for dose proportionality analysis using the power model. The 
power model empirical relationship between a PK parameter and dose is of the form
PK = Exp(α) (?V)W,
where “PK” represents the PK parameter AUCtau or Cmax. For analysis, this equation is log-
transformed (natural log), obtaining the equation
log
(XY) =  +  log
(?V),
The slope beta measures the dose-proportionality between dose and the PK parameter.
The 90% confidence interval of the slope for each parameter will be computed from the model 
and presented in the summary table. The dose proportionality assessment it exploratory analysis 
due to insufficient power to demonstrata dose proportionality.


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Food effect PK analysis
As exploratory analysis, exposure measures (Cmax, Tmax and AUC) of FGF401 will be 
compared among patients taking study drug under different feeding regimens (fasted or fed-
light meal) as appropriate. 
2.8.4.5
Immunogenicity
2.8.4.5.1 Sample ADA status
Each IG sample is assessed in a three tiered anti-drug anti-body (ADA) testing approach. All 
IG samples are analyzed in the initial screening assay (first tier). 

Samples testing negative in the screening assay are defaulted to be negative in the 
confirmatory assay (i.e., no confirmatory testing is done).

Samples testing positive in the screening assay are then subjected to a confirmatory 
assay to demonstrate that ADA are specific for the therapeutic protein product (second 
tier). The titer of confirmatory positive samples will be subsequently determined in the 
titration assay (third tier). 

Samples identified as positive in the confirmatory assay are considered ADA positive 
and are further characterized in the titration assay. 
The following properties of each sample will be provided in the source data: 

Positivity in confirmatory assay according to pre-specified confirmatory cut point: ADA 
positive (yes) or ADA negative (no)

Titer (for positive samples): numerical representation of the magnitude of the ADA response
Sample ADA status will only be listed. It is determined based on the following definitions:

ADA-inconclusive sample: 
o
Sample where ADA confirmatory assay is negative and PDR001 PK 
concentration at the time of IG sample collection is >= 55 μg/mL or missing.

Unevaluable sample: Sample where ADA confirmatory assay is not available.

Determinant sample: Sample that is neither ADA-inconclusive nor unevaluable.

ADA-negative sample: 
o
Determinant sample where ADA confirmatory assay is negative and PDR001 
PK concentration at the time of IG sample collection is < 55 μg/mL.

ADA-positive sample: Determinant sample where ADA confirmatory assay is positive.
The following definitions apply only to post-baseline ADA-positive samples with a 
corresponding determinant baseline sample:
o
treatment-induced ADA-positive sample: ADA-positive sample post-baseline 
with ADA-negative sample at baseline. 


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o
treatment-boosted ADA-positive sample: ADA-positive sample post-baseline 
with titer that is at least twofold greater than the ADA-positive baseline titer.
o
treatment-unaffected ADA-positive sample: ADA-positive sample post-baseline 
with titer that is less than twofold greater than the ADA-positive baseline titer.
2.8.4.5.2 Patient ADA status
Any IG sample collected after 150 days of the last dose of PDR001 and FGF401 will not be 
used for summaries or derivations and will only be included in the listing.
The following overall summaries will be provided using the Safety Analysis Set:

Treatment-boosted ADA-positive: number and percent of subjects with at least one 
treatment-boosted ADA-positive sample. The denominator is the number of subjects 
with an ADA-positive sample at baseline. 

Treatment-induced ADA-positive: number and percent of subjects with at least one 
treatment-induced ADA-positive sample. The denominator is the number of subjects 
with an ADA-negative sample at baseline. 

ADA-negative: number and percent of subjects with no treatment-induced or treatment-
boosted ADA-positive sample.

ADA incidence (i.e. % ADA-positive): number and percent of subjects with at least one 
treatment-induced or treatment-boosted ADA-positive sample. 
The following summaries, both overall and by timepoint (including baseline), will be provided 
using the FAS. For summaries by timepoint, the denominator is the number of subjects at that 
timepoint with determinant samples:

ADA prevalence: number and percent of subjects with at least one ADA-positive sample. 
A listing will be provided by subject with supporting information (i.e. ADA sample status at 
each timepoint (including titer for positive samples) and subject ADA status).


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2.10
Interim analysis
2.10.1
FGF401 single agent
Phase I part
No formal interim analysis is planned. However, 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. Details of this procedure and the process for communication with investigators are 
provided in the Protocol Section 6.2.3.
Phase II part
No formal interim analysis is conducted. However, individual patient data will be reviewed on 
an ongoing basis by the study team across the duration of the trial (Protocol Section 8.5 and 
Section 8.6).
2.10.2
FGF401 in combination with PDR001
Phase I part
No formal interim analysis is planned. However, 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. Details of this procedure and the process for communication with investigators are 
provided in the Protocol Section 6.2.3.
3
Sample size calculation
3.1.1
FGF401 single agent
3.1.1.1
Phase I part
Initially, cohorts of 1 to 6 evaluable patients will be enrolled in the phase I part. Upon 
observation of specific toxicities (see Protocol Section 6.2.3 for details), cohorts of 3 to 6 
evaluable patients will be enrolled including at least six evaluable patients at the MTD/RP2D 
level, as described in the Protocol Section 6.2.3. Multiple cohorts may be sequentially enrolled 
to the same dose level. Additional cohorts of 1 to 6 evaluable patients may be enrolled at any 
dose level below the estimated MTD/RP2D for further elaboration of safety and 
pharmacokinetic parameters as required. At least 21 evaluable patients are expected to be 
treated in the phase I part, for the model to have reasonable operating characteristics relating to 
its MTD and/or RP2D recommendation.


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3.1.1.2
Phase II part 
Group 1
Group 1 is designed to assess the preliminary anti-tumor activity of FGF401 in HCC patients 
with positive expression of FGFR4 and KLB from Asian countries. If the lower limit of one-
sided 90% CI of TTP is equal to or greater than 1.5 months, which is the expected median TTP 
without FGF401 treatment, it will be considered as preliminary evidence of clinically relevant 
efficacy of FGF401 in Group 1. 
It is assumed that TTP has an exponential distribution and the true median TTP with FGF401 
treatment is 3.0 months, which is considered a clinically relevant improvement with treatment 
in this patient population, and the enrollment rate is 3.5 patients per month. Analysis will be 
provided when all patients have potentially completed at least six cycles of treatment or 
discontinued the study. Table 3-1 shows the probability of success (PoS), i.e., the probability 
of the lower limit of observed one-sided 90% CI of TTP equal to or greater than 1.5 months, 
calculated by simulation given these assumptions and different sample sizes. 
Approximately 40 patients will be enrolled, however, more patients with double positive tumors 
may be enrolled if the emerging clinical data supports, see Protocol Section 4.1. Considering a 
drop-out rate of 15%, the PoS is 90.6%.
Table 3-1
Probability of Success under different number of sample size in 
Group 1 (drop rate = 15%)
Sample size
Expected number of events
P (lower limit of one-sided 90% CI ≥1.5)
30
20.4
0.833
35
24.2
0.888
40
28.9
0.906
Group 2
Group 2 is designed to assess the preliminary anti-tumor activity of FGF401 in HCC patients 
with positive expression of FGFR4 and KLB from non-Asian regions. If the lower limit of one-
sided 90% CI of TTP is equal to or greater than 2.2 months, which is the expected median TTP 
without FGF401 treatment, it will be considered as preliminary evidence of clinically relevant 
efficacy of FGF401 in Group 2.
It is assumed that TTP has an exponential distribution and the true median TTP with FGF401 
treatment is 4.2 months, which is considered a clinically relevant improvement with treatment 
in this patient population, and the enrollment rate is 3.5 patients per month. Analysis will be 
provided when all patients have potentially completed at least six cycles of treatment or 
discontinued the study. Table 3-2 shows the PoS, i.e., the probability of the lower limit of 
observed one-sided 90% CI of TTP equal to or greater than 2.2 months, calculated by simulation 
given these assumptions and different sample sizes. 
Approximately 40 patients will be enrolled, however, more patients with double positive tumors 
may be enrolled if the emerging clinical data supports, see Protocol Section 4.1. Considering a 
drop-out rate of 15%, the PoS is 87.7 %.


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Table 3-2
Probability of Success under different number of sample size in 
Group 2 (drop rate = 15%)
Sample size
Expected number of events
P (lower limit of one-sided 90% CI ≥ 2.2)
30
17.8
0.800
35
21.2
0.857
40
25.6
0.877
Group 3
Group 3 is designed to assess the preliminary anti-tumor activity of FGF401 in other solid 
tumors with positive expression of FGFR4 and KLB. Overall approximately 20 patients are 
planned to be enrolled. Table 3-3 shows the probabilities of observing at least a certain number 
of responders given different values of true ORR.
If the true ORR of a tumor type is 0.05, 0.10 and 0.25, the probabilities of observing one or 
more responders with 20 patients are 0.642, 0.878 and 0.997, respectively.
Table 3-3
Cumulative probability (upper tail) of responses observed or more 
given true ORR and 20 patients
True ORR (p)
Responses observed (n)
P (responses≥ n | N=20, p)
0.05
1
0.642
2
0.264
3
0.075
4
0.016
0.10
1
0.878
2
0.608
3
0.323
4
0.133
5
0.043
6
0.011
0.25
1
0.997
2
0.976
3
0.909
4
0.775
5
0.585
6
0.383
3.1.2
FGF401 in combination with PDR001
3.1.2.1
Phase I part
Cohorts of 3 to 6 evaluable patients will be enrolled including at least six evaluable patients at 
the MTD/RP2D level, as described in the Protocol Section 6.2.3. Multiple cohorts may be 
sequentially enrolled to the same dose level. Additional cohorts of 1 to 6 evaluable patients may 
be enrolled at any dose level below the estimated MTD/RP2D for further elaboration of safety 
and pharmacokinetic parameters as required. At least 12 evaluable patients are expected to be 
treated in the phase I part, for the model to have reasonable operating characteristics relating to 
its MTD and/or RP2D recommendation.


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4
Change to protocol specified analyses – CSR Section 9.8.3 
Because the enrollment of this study has been halted for business reason since 03Jul18 and the 
phase II part of the FGF401+PDR001 combination will not start, all analysis plan related to the 
phase II part of the FGF401+PDR001 combination arm are removed.
5
Appendix
5.1
Imputation rules
5.1.1
Study drug
5.1.1.1
Data handling
5.1.1.1.1 Data Imputation for the last administration
The following rule should be used for the imputation of date of last administration for a given 
study treatment component:
Scenario 1: If the date of last administration is completely missing and there is no EOT eCRF 
page, the patient is considered as on-going: 
The patient should be treated as on-going and the cut-off date should be used as the last dosing 
date. 
Scenario 2: If the date of last administration is completely or partially missing and the EOT 
eCRF page is available (prior to any death date or withdrawal of consent date, if available): 
Case 1: The date of last administration is completely missing, and the EOT visit date is complete, 
then this latter date should be used.
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:
      Use Dec31yyyy
Case 3: Only Year(yyyy) of the dose end date is available and yyyy = the year of EOT date: 
      Use EOT date
Case 4: Both Year(yyyy) and Month (mm) are available for the date of last administration, and 
yyyy = the year of EOT date and mm < the month of EOT visit:
      Use last day of the Month (mm).
After imputation, compare the imputed date with the start date of that specific record, if the 
imputed date is < start date of that record
      Use the start date of that record.
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations described in Section 2.5.1.2 and no imputation will be made. If the date of 
first administration is missing, then the date of last administration should not be imputed.


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5.1.1.1.2 Data Imputation of the first administration
Patients with missing start dates are generally considered missing for all study treatment 
component related calculations described in Section 2.5.1.1 and no imputation will be made. If 
the date of first administration is missing, then the date of last administration should not be 
imputed.
However, if the dosing information at C1D1 is entered on the PK DAR page, the date on this 
page will be used to impute the first administration date. Before imputing the date, it will be 
checked that the date is not after the second administration or after the end date of the first 
record.
5.1.2
AE date imputation
A missing AE start date will be imputed using the logic matrix described in Table 5-1.
Table 5-1
Imputation rules for a partially missing AE start date
AEM missing
AEM<TRTM
AEM=TRTM
AEM>TRTM
AEY missing
Not imputation
Not imputation
Not imputation
Not imputation
AEY<TRTY
(D)
(C)
(C)
(C)
AEY=TRTY
(B)
(C)
(B)
(A)
AEY>TRTY
(E)
(A)
(A)
(A)
AEM=Month AE started, AEY=Year AE started
TRTM=Month treatment started, TRTY=Year treatment started
Table 5-2 is the legend to the logic matrix shown in Table 5-1 and details the relationship of 
AE start date to study treatment start date.
Table 5-2
Imputation legend and AE/treatment start date relationship
AE start date relationship
Imputation
(A) After treatment start or uncertain
MAX(01MMMYYYY, TRTSDT+1)
(B) Uncertain
TRTSDT+1
(C) Before treatment start
15MMMYYYY
(D) Before treatment start
01JULYYYY
(E) After treatment start
01JANYYYY
Before treatment start: Partial date indicates AE start date is prior to treatment start date.
After treatment start: Partial date indicates AE start date is after treatment start date.
Uncertain: Partial date insufficient to determine relationship of AE start date to treatment start date.
No imputation will be performed for missing/incomplete AE end dates.
5.1.3
Concomitant medication date imputation
The imputation of a concomitant medication start date will follow the same conventions as for 
an AE start date (see Section 5.1.2). No imputation will be performed for concomitant 
medication end dates.


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5.1.3.1
Prior therapies date imputation
Start date:
The same rule which is applied to the imputation of AE/concomitant medication start date will 
be used with the exception that scenario (B) will be replaced to be ‘start date of study treatment 
- 1’. (see Section 5.1.2)
End Date:
Imputed date = min (start date of study treatment, last day of the month), if day is missing;
Imputed date = min (start date of study treatment, 31DEC), if month and day are missing.
If the end date is not missing and the imputed start date is after the end date, use the end date as 
the imputed start date.
If both the start date and the end date are imputed and if the imputed start date is after the 
imputed end date, use the imputed end date as the imputation for the start date.
5.1.3.2
Post therapies date imputation
Start date:
Imputed date = max (End of Treatment date + 1, first day of the month), if day is missing;
Imputed date = max (End of Treatment date + 1, 01JAN), if day and month are missing.
Imputed date = End of treatment date +1, if the date is completely missing.
End date: 
No imputation.
5.1.3.3
Other imputations
Diagnosis and extent of cancer
When a date is recorded as a partial date, the missing day is imputed to the 15th of the month 
(e.g. DEC2007 imputed to 15DEC2007), and if the day and month are both missing then to 1st
of July of that year (e.g. 2007 imputed to 01JUL2007).
5.2
Definition and derivation rules for irRC
5.2.1
Total measurable disease burden
In irRC target and new measurable lesions are used to evaluate total measurable tumor burden 
(TMTB). TMTB is the sum of diameters (SOD) of all target and new measurable lesions.
Similar to RECIST v1.1 where SOD of the target lesions is used for determination of target 
lesion response, for irRC TMTB is used for determination of target and new measurable lesion 
response.


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5.2.1.1
Best percentage change from baseline in TMTB
Best percentage change from baseline in TMTB is defined as the percentage change from 
baseline to the smallest measured post-baseline TMTB occurring at or before the time of 
confirmed irPD.
5.2.2
Assessment of disease progression
To facilitate analysis, each assessment of progression is categorized as one of three types: 
pseudo progression, confirmed progression and unconfirmed progression.
5.2.2.1
Pseudo-progression 
Subjects with a single irPD, followed by an assessment of irSD or better will be considered to 
have a pseudo-progression (pPD). For the purposes of analysis, pseudo-progressions are not 
treated as progression events. 
5.2.2.2
Confirmed progression 
Confirmed progression 1 (type 1, cPD1) is declared if a Subject has 2 consecutive tumor 
assessments at least 4 weeks (28 days) apart both showing disease progression. Assessments 
with an UNK response or PD assessments < 28 days after initial PD, are discarded.
The first PD is flagged as cPD1 while all subsequent PDs are flagged as xPD1.
The table below shows two hypothetical data scenarios and programming instructions.
Sequence of assessments
Instructions
1  irPD
2  irUNK
3  irPD (Assessment 1 + 30 days)

Assessment 3 is ≥28 days after Assessment 1 

Assessment 3 represents confirmation of irPD at 
assessment 1

Assessment 1 irPD is flagged cPD1

Assessment 3 irPD is flagged xPD1
1  irSD
2  irPD
3  irPD (Assessment 2 + 20 days) 
4  irPD (Assessment 2 + 30 days)

Assessment 3 is < 28 days after Assessment 2

Assessment 4 is ≥ 28 days after Assessment 2 

Assessment 4 represents confirmation of irPD at 
assessment 2

Assessment 2 irPD is flagged cPD1

Assessment 3 and 4 irPDs are flagged xPD1
Confirmed progression 2 (type 2, cPD2) is declared if a Subject discontinues treatment 
following a single PD with no subsequent assessments ≥ 28 days later. Assessments with an 
UNK response or PD assessments < 4 weeks (28 days) after initial PD, are discarded. 
Discontinuation of treatment is obtained from EOT case report form.
The assessment is flagged as cPD2 and subsequent PDs (<28 days after first PD) are flagged as 
xPD2. 
The table below shows two hypothetical data scenarios and programming instructions.


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Sequence of assessments
Instructions
1  irSD
2  irPD
-  EOT

Subject withdraws after initial progression 
(Assessment 2) without confirmation

Assessment 2 irPD is flagged as cPD2
1  irPD
2  irPD (Assessment 1 + 20 days)
-  EOT 

Assessment 2 irPD is <28 days after Assessment 1, so 
does not represent confirmation

However, Subject has completed treatment 

Assessment 1 irPD is flagged cPD2

Assessment 2 irPD is flagged xPD2
5.2.2.3
Unconfirmed progression 
Patients with a single irPD, and no assessment of irSD or better (assessment with an irUNK 
response or irPD assessments < 4 weeks after initial irPD, are discarded) continuing treatment 
at the time of the analysis will be considered as unconfirmed (uPD).
5.2.3
Best overall response
Assessment of BOR will be based on all assessments up to and including the first assessment 
of irPD (cPD1, cPD2, or uPD). Assessments made more than 150 days after EOT will be 
excluded. Assessments made after start of new anti-cancer therapy will be excluded.
BOR will be defined with the following hierarchy:
irCR
Two consecutive determinations of irCR ≥28 days (4 weeks) apart
Non-consecutive assessments of irCR may also result in BOR of irCR if all intervening 
assessments are irUNK
irPR
Two determinations of irPR (or better) ≥28 days (4 weeks) apart
The two determinations of irPR (or better) may be separated by one or more assessments 
of irSD, but may not be separated by an assessment of irPD
irSD
At least one irSD assessment (or better) >[42 days (6 weeks)] after the start of study 
treatment
irPD
Event flagged as cPD1, cPD2 or uPD ≤[84 days (12 weeks)] after the start of study 
treatment
irUNK
All other cases
5.2.4
Time to event analyses: 
5.2.4.1
Progression events
PDs flagged as pPD are not included in time to event analyses. 
Patients are classified as follows:
0
No event (censored)
1
Confirmed PD (cPD1 or cPD2)
2
Unconfirmed PD (uPD)
For the primary analysis of time to event endpoints, both confirmed and unconfirmed 
progression will be included as progression events with date of progression being the date of 


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the assessment flagged as cPD1, cPD2 or uPD according to the algorithm defined in Section 
5.2.2.
A sensitivity analysis of time to event endpoints may be conducted in which Subjects with 
unconfirmed PD are treated as censored, with date of last adequate assessment = visit date for 
assessment flagged uPD.
5.2.4.2
Definition of start and end dates for time to event variables
Assessment date
Assessment date is defined as for RECIST v1.1 (Protocol Appendix 1 section 14.1.25).
Start date 
Start date is as defined for RECIST v1.1 (Protocol Appendix 1 section 14.1.25).
End dates for time to event variables
The end dates which are used to calculate ‘time to event’ variables are defined as follows:

Date of death (recorded on the end of treatment disposition page, the end of post treatment 
phase disposition page, or the survival information page).

Date of death as recorded on death CRF

Date of progression is as defined in Section 5.2.4.1.

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 progression 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 start of study treatment is used.
Note: for sensitivity analyses of time to event endpoints ongoing Subjects with an unconfirmed 
progression may be censored at time of last assessment.
5.2.4.3
Censoring reason
Censoring reason is derived as for RECIST v1.1(Protocol Appendix 1 section 14.1.39).
5.2.4.4
Duration of response
Duration of response is defined as a time interval between the first date of confirmed PR/CR 
and the date of progression as defined in Section 5.2.4.1. Intervening assessments of pPD are 
excluded from the assessment.
Date of confirmed response
Response (irPR or irCR) should be confirmed by a second assessment no less than 4 weeks after 
the first assessment showing response. Date of response is then the date of the first of these two 
assessments. For confirmation of irCR the two assessments must be consecutive (intervening 
assessments of irUNK are permissable). For confirmation of irPR the two assessments do not 
need to be consecutive, but must not be separated by a pseudo-progression event.


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The table below shows a hypothetical data scenarios with programming instructions.
Sequence of assessments
Instructions
1  irPR
2  irPD
3  irPR
4  irPR

The first PR (assessment 1) is followed by a pseudo-progression 
(assessment 2) and is therefore not confirmed

Subsequently the Subject has a irPR (assessment 3) which is 
confirmed at the following assessment (assessment 4)

The BOR for this Subject is irPR, with date of confirmed irPR equal 
to the date of assessment 3
5.3
Details of pharmacokinetic data analysis
For the assessment of dose proportionality, the following SAS code will be used:
PROC MIXED DATA=dataset METHOD=reml;
MODEL log_PK_parameter = log_dose / ddfm=kr solution
                       alpha=0.1 cl;
RUN;
6
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