Clinical trial NCT03773302
Conditions: Advanced Cholangiocarcinoma FGFR2 Gene Mutation
Keywords: cholangiocarcinoma unresectable cholangiocarcinoma metastatic cholangiocarcinoma fibroblast growth factor receptor inhibitor FGFR2 FGFR2 gene fusions/translocations BGJ398
Sponsor: QED Therapeutics, Inc., a Bridgebio company
Start date: 2019-12-27; Completion date: 2023-03-02
Enrollment: 48 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
Infigratinib is an oral drug which selectively binds to fibroblast growth factor receptor (FGFR) 2 and is being developed to treat participants with FGFR2 mutated cholangiocarcinoma. The purpose of the study is to evaluate the efficacy and safety of the investigational agent oral infigratinib vs standard of care chemotherapy (gemcitabine plus cisplatin) in first-line treatment of participants with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 fusion/rearrangement. Subjects will be randomized 2:1 to receive infigratinib or gemcitabine plus cisplatin.

Detailed description:

Arms: arm 1: Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off. arm 2: Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib if certain criteria are met.
Interventions: intervention 1: BGJ398 intervention 2: Gemcitabine intervention 3: Cisplatin
Intervention descriptions: intervention 1: Infigratinib (BGJ398) 125 mg orally daily, 3 weeks on, 1 week off. intervention 2: Gemcitabine 1000 mg/m2 IV D1 and D8 for a 21-day cycle. Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib. intervention 3: Cisplatin 25 mg/m2 IV D1 and D8 for a 21-day cycle. Participants who experience disease progression while receiving gemcitabine + cisplatin will be allowed to cross over and receive infigratinib.

Protocol documents:
Prot_000.pdf: 
Infigratinib
QED Therapeutics
Protocol QBGJ398-301 Amendment 4.0 (Version 4.0)
Confidential
27 July 2021
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Clinical Development
Protocol QBGJ398-301
A Phase 3 Multicenter, Open-Label, Randomized, Controlled 
Study of Oral Infigratinib Versus Gemcitabine With Cisplatin in 
Subjects With Advanced/Metastatic or Inoperable 
Cholangiocarcinoma With FGFR2 Gene Fusions/Translocations: 
the PROOF Trial
Investigational Product:
Infigratinib (BGJ398)
Phase of Development
3
US IND Number:
104,187
EUDRACT number:
2018-004004-19
Protocol:
Version 4.0 (27 July 2021)
Supersedes:
Version 3.0 (15 April 2021)
Sponsor:
QED Therapeutics, Inc. 
8000 Marina Blvd, Suite 400  
Brisbane, CA 94005
Medical Monitor:
 MD
Vice President, Clinical Development
QED Therapeutics, Inc. 
Property of QED Therapeutics
Confidential
May not be used, divulged, published, or otherwise disclosed without the consent of QED Therapeutics
PPD
PPD
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INVESTIGATOR’S AGREEMENT 
 
I have read Protocol QBGJ398-301 and agree to conduct the study as outlined. I agree to 
maintain the confidentiality of all information received or developed in connection with 
this protocol.  
 
 
 
Printed Name of Investigator 
 
 
 
Signature of Investigator 
 
 
 
Date 
 
 
 
Study Center Number 
 
 
 
Study Center Name 
 
Signature on this page assures the sponsor that, to the best of the investigator’s 
knowledge, the affiliated Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all 
governing regulatory obligations and the International Council for Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) and country and regional (local) 
requirements while conducting this clinical investigation. Additionally, the investigator 
agrees to give access to all relevant data and records to the sponsor’s monitors, auditors, 
sponsor Clinical Quality Assurance representatives, designated agents of the sponsor, 
IRBs/IECs/REBs, and regulatory authorities as required. 
 


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TRIAL CONTACTS 
Table 1: 
Trial Contact Information 
Role in Study 
Name 
Contact Information 
Vice President, 
Clinical 
Development 
 MD 
email: 
 
Telephone: 
 
Pharmacovigilance/ 
Safety 
Management 
Covance Safety 
email: SAEintake@covance.com 
FAX: refer to the Study Manual for 
country-specific FAX numbers 
Abbreviations: FAX, facsimile.  
 
PROTOCOL VERSION HISTORY 
Protocol Version 
Amendment Number 
Date 
0.0 
Not applicable 
04 October 2018 
1.0 
1.0 
11 March 2019 
2.0 
2.0 
08 October 2019 
2.1 
2.1 
10 October 2019 
2.2 
2.2 
02 April 2020 
2.3 
2.3 
27 July 2020 
3.0 
3.0 
15 April 2021 
4.0 
4.0 
27 July 2021 
 
 
 
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TABLE OF CONTENTS, LISTS OF FIGURES AND TABLES 
TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ................................................................................2 
TRIAL CONTACTS ..........................................................................................................3 
PROTOCOL VERSION HISTORY ................................................................................3 
TABLE OF CONTENTS, LISTS OF FIGURES AND TABLES .................................4 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...................................8 
1 
SYNOPSIS .................................................................................................................12 
2 
SCHEDULE OF ASSESSMENTS ..........................................................................21 
3 
BACKGROUND .......................................................................................................32 
3.1 
Overview of Disease Pathogenesis, Epidemiology and Current 
Treatment .............................................................................................................32 
3.2 
Overview of Infigratinib ......................................................................................33 
3.3 
Nonclinical Experience with Infigratinib...........................................................33 
3.4 
Clinical Experience with Infigratinib.................................................................34 
3.4.1 
Clinical Pharmacokinetics and Phase 1 Data ..............................................34 
3.4.2 
Clinical Safety .................................................................................................35 
3.4.3 
Clinical Efficacy .............................................................................................36 
3.5 
Rationale ...............................................................................................................37 
3.5.1 
Study Rationale and Purpose ........................................................................37 
3.5.2 
Rationale for the Study Design .....................................................................38 
3.5.3 
Rationale for Dose and Regimen Selection ..................................................38 
3.6 
Benefit/Risk Assessment ......................................................................................39 
4 
OBJECTIVES AND ENDPOINTS .........................................................................40 
4.1 
Objectives..............................................................................................................40 
4.2 
Endpoints ..............................................................................................................41 
5 
INVESTIGATIONAL PLAN ..................................................................................42 
5.1 
Overall Study Design ...........................................................................................42 
5.2 
Number of Subjects and Time on Study ............................................................45 
6 
STUDY POPULATION ...........................................................................................45 
6.1 
Inclusion Criteria .................................................................................................45 
6.2 
Exclusion Criteria ................................................................................................47 
7 
TREATMENTS ........................................................................................................50 
7.1 
Treatments Administered ...................................................................................50 
7.2 
Information on Infigratinib ................................................................................51 
7.2.1 
Subject Instructions for Infigratinib Dosing ...............................................51 
7.2.2 
Description and Dispensing of Infigratinib .................................................52 
7.2.3 
Packaging and Labeling ................................................................................52 
7.2.4 
Study Drug Accountability, Handling, and Disposal ..................................52 
7.2.5 
Dose Modifications for Infigratinib ..............................................................53 
7.2.6 
Anticipated Risks and Safety Concerns for Infigratinib ............................62 
7.3 
Information on Gemcitabine with Cisplatin......................................................62 
7.4 
Randomization .....................................................................................................64 
7.5 
Compliance ...........................................................................................................64 


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7.6 
Supportive Care Guidelines ................................................................................65 
7.6.1 
Infigratinib Group .........................................................................................65 
7.6.2 
Gemcitabine with Cisplatin Group ..............................................................67 
7.7 
Prior and Concomitant Medications ..................................................................68 
7.7.1 
Infigratinib Group .........................................................................................68 
7.7.2 
Gemcitabine with Cisplatin Group ..............................................................70 
7.7.3 
COVID-19 Vaccinations ................................................................................70 
7.8 
Non-drug Therapies .............................................................................................71 
8 
SUBJECT DISCONTINUATION AND STUDY TERMINATION ....................71 
8.1 
Subject Discontinuation.......................................................................................71 
8.1.1 
Discontinuation of Study Drug .....................................................................71 
8.1.2 
Discontinuation from Study ..........................................................................73 
8.2 
Study Termination ...............................................................................................73 
9 
STUDY VISITS AND PROCEDURES ..................................................................74 
9.1 
Molecular Prescreening .......................................................................................74 
9.2 
Main Informed Consent ......................................................................................75 
9.3 
Screening (Day −28 to −1) ...................................................................................75 
9.4 
Treatment Period: Cycle 1 Day 1 .......................................................................76 
9.5 
Rest of Treatment Period ....................................................................................77 
9.6 
EOT Visit ..............................................................................................................78 
9.7 
30-day Safety Follow-up Visit .............................................................................79 
9.8 
Follow-up of Disease Progression and Survival Status ....................................80 
9.9 
Crossover to Infigratinib .....................................................................................80 
9.10 
End of Study .........................................................................................................81 
10 STUDY ASSESSMENTS .........................................................................................81 
10.1 
Efficacy Assessments ...........................................................................................81 
10.2 
Pharmacokinetic Assessments ............................................................................84 
10.3 
Assessment of Biomarkers ..................................................................................85 
10.3.1 
Sample Collection Procedures and Requirements ......................................85 
10.3.2 
Potential Use for Future Research ...............................................................87 
10.4 
Quality of Life ......................................................................................................88 
10.5 
Safety Assessments ...............................................................................................89 
10.5.1 
Adverse Events ...............................................................................................89 
10.5.2 
Pregnancies .....................................................................................................93 
10.5.3 
Laboratory Parameters .................................................................................93 
10.5.4 
Vital Signs .......................................................................................................94 
10.5.5 
Physical Examinations ...................................................................................94 
10.5.6 
Electrocardiograms........................................................................................95 
10.5.7 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status ...............................................................................................................95 
10.5.8 
Ophthalmic Assessments ...............................................................................95 
10.5.9 
Early Stopping Guidelines and Data Monitoring Committee ...................96 
11 STATISTICAL METHODOLOGY .......................................................................97 
11.1 
General Considerations .......................................................................................97 
11.2 
Sample Size Determination .................................................................................97 
11.3 
Statistical Hypothesis, Model, and Method of Analysis ...................................98 


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11.3.1 
Disposition of Subjects ...................................................................................98 
11.3.2 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications .............................................................................99 
11.3.3 
Efficacy Analyses ...........................................................................................99 
11.3.4 
Pharmacokinetic Analyses ..........................................................................100 
11.3.5 
Biomarker Analyses .....................................................................................101 
11.3.6 
Companion Diagnostic Assay Analyses .....................................................101 
11.3.7 
Analyses of Quality of Life Assessments ....................................................101 
11.3.8 
Safety Analyses .............................................................................................102 
12 DATA COLLECTION AND MANAGEMENT ..................................................103 
12.1 
Data Confidentiality...........................................................................................103 
12.2 
Study Center Monitoring ..................................................................................104 
12.3 
Data Collection ...................................................................................................104 
12.4 
Database Management and Quality Control ...................................................105 
12.5 
Study Documentation, Record Keeping and Retention of Documents .........105 
12.6 
Audits and Inspections ......................................................................................106 
13 REGULATORY AND ETHICAL CONSIDERATIONS ...................................106 
13.1 
Regulatory and Ethical Compliance ................................................................106 
13.2 
Responsibilities of the Investigator and IRB/IEC/REB .................................106 
13.3 
Informed Consent Procedures ..........................................................................107 
13.4 
Confidentiality of Study Documents and Subject Records ............................107 
14 FINANCIAL CONSIDERATIONS AND INSURANCE ....................................108 
15 PUBLICATION POLICY ......................................................................................108 
16 REFERENCE LIST................................................................................................109 
17 APPENDICES .........................................................................................................114 
17.1 
Appendix 1: List of Concomitant Medications (Infigratinib 
Treatment) ..........................................................................................................114 
17.2 
Appendix 2: List of Prohibited Medications and Substances 
(Infigratinib Treatment) ....................................................................................116 
17.3 
Appendix 3: List of Highly Effective Methods of Contraception ..................117 
17.4 
Appendix 4: QOL Instruments .........................................................................118 
17.5 
Appendix 5: Acceptable Prestudy Gemcitabine-based Chemotherapy ........120 
 
LIST OF TABLES 
Table 1: 
Trial Contact Information ........................................................................3 
Table 2: 
Schedule of Assessments: Subjects in the Infigratinib Group .............22 
Table 3: 
Schedule of Assessments: PK Sampling in a Substudy of 40 Subjects 
in the Infigratinib Group.........................................................................26 
Table 4: 
Schedule of Assessments: Subjects in the Gemcitabine plus Cisplatin 
Group ........................................................................................................27 
Table 5: 
Schedule of Assessments: Subjects in the Gemcitabine plus Cisplatin 
Group who Cross Over to Infigratinib ..................................................30 
Table 6: 
Dose Reduction Scheme for Infigratinib ................................................54 


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Table 7: 
Criteria for Interruption and Re-initiation of Infigratinib for Adverse 
Events Considered to be Possibly Related to Infigratinib ....................55 
Table 8: 
Dose Reduction/Interruption Guidelines for Gemcitabine and 
Cisplatin ....................................................................................................63 
Table 9: 
Recommendations for Management of Alopecia, Palmar-Plantar 
Erythrodysesthesia Syndrome, Paronychia, and Stomatitis ................67 
Table 10: 
Response Criteria for Target Lesions ....................................................83 
Table 11: 
Response Criteria for Non-target Lesions .............................................83 
Table 12: 
Overall Lesion Response at each Assessment ........................................84 
Table 13: 
Pharmacokinetic Parameters for Infigratinib .......................................85 
Table 14: 
Safety Laboratory Parameters ...............................................................94 
Table 15: 
Drugs to be used with Caution While on Study ..................................114 
Table 16: 
List of Prohibited Medications and Substancesa While on Study .....116 
 
LIST OF FIGURES 
Figure 1: 
Study Design .............................................................................................44 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term/Definition 
ADL 
activities of daily living 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic-pyruvic transaminase 
ANC 
absolute neutrophil count  
ASCO 
American Society of Clinical Oncology 
AST/SGOT 
aspartate aminotransferase/serum glutamic-oxaloacetic 
transaminase 
AUC 
area under the curve 
BCRP 
breast cancer resistance protein  
BGJ398 
infigratinib 
BICC1 
bicaudal c homolog 1 
BICR 
blinded independent central review 
BOR 
best overall response 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration after drug administration 
Cmin 
measured concentration at the end of a dosing interval   
CR 
complete response 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome p 
DEB-TACE 
drug eluting bead-TACE 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
end of study 


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Abbreviation 
Term/Definition 
EOT 
end of treatment 
EPO 
erythropoietin 
EQ-5D 
EuroQOL five dimensions questionnaire 
ESMO 
European Society of Medical Oncology 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
FGFR1 
fibroblast growth factor receptor 1 
FGFR2 
fibroblast growth factor receptor 2 
FGFR3 
fibroblast growth factor receptor 3 
FGFR4 
fibroblast growth factor receptor 4 
FMI 
final market image 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GI 
gastrointestinal 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IMP 
investigational medicinal product 
IPCW 
inverse probability of censoring weighting 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 
IVD 
in vitro diagnostic medical devices 
K-M 
Kaplan-Meier 
LLN 
lower limit of normal 
LLOQ  
lower limit of quantification 
LVEF 
left ventricular ejection fraction  
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen activated protein kinase  


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Abbreviation 
Term/Definition 
MRI 
magnetic resonance imaging 
MSI 
microsatellite instability 
MSI-H 
microsatellite instability-high 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
NaF 
sodium fluoride 
NCCN 
National Comprehensive Cancer Network 
NK-1 
neurokinin-1 
OCT 
optical coherence tomography 
ORR 
overall response rate 
OS 
overall survival  
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival  
PFS2 
PFS on subsequent therapy 
PHI 
protected health information 
PK 
pharmacokinetics 
PO 
oral 
PR 
partial response 
PT 
preferred term 
QD 
once a day 
QLQ 
quality of life questionnaire 
QOL 
quality of life 
QT 
measure of time between the start of the Q wave and the end of the 
T wave (QT interval) in the heart’s electrical cycle 
QTc 
QT interval corrected for heart rate 
QTcF 
QTc corrected by Fridericia's formula 
Racc 
accumulation ratio calculated as Cmin steady-state/Cmin 
RBC 
red blood cell  
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNA 
ribonucleic acid 


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Abbreviation 
Term/Definition 
RPSFT 
rank-preserving structural failure time 
RPTD 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
TACE 
transarterial chemoembolization  
TC99 
technetium-99 (99Tc) 
TdP 
Torsades de Pointes  
Tmax 
time at which the maximum observed concentration (Cmax) occurs 
ULN 
upper limit of normal 
UNK 
unknown 
WBC 
white blood cell  
WHO 
World Health Organization 
WOCBP 
woman of childbearing potential 
 


I nfi grati ni b 
Q E D T hera pe utics  
Pr ot oc ol Q B GJ 3 9 8 -3 0 1 A me n d me nt 4 . 0 ( Versi o n 4 . 0) 
C o nfi de ntial  
2 7 J ul y  2 0 2 1   
Pa ge 1 2  of 1 2 0  
 
 
1 
S Y N O P SI S  
N a me of S p o ns or/ C o m p a n y:  Q E D T hera pe utics  
N a me of I n vesti g ati o n al Pr o d uct: I nfi grati ni b (f or merl y B GJ 3 9 8 , als o k n o w n as B B P-8 3 1 , 
a n d i nfi grati ni b p h os p hate ) 
N a me of Acti ve I n gre die nt: I nfi grati ni b 
Title of St u d y: A P hase 3 M ultice nter, O pe n -La bel, R a n d o mize d, C o ntr olle d St u d y of O ral 
I nfi grati ni b vers us Ge mcita bi ne wit h Cis plati n i n S u bjects wit h A d va nce d/ Metastatic or 
I n opera ble C h ola n gi ocarci n o ma wit h F G F R 2 Ge ne F usi o ns/ Tra nsl ocati o ns:  T he P R O O F Trial  
St u d y ce nter s: T his is a m ultice nter st u d y i n v ol vi n g a p pr o xi matel y 1 4 5  st u d y ce nters 
w orl d wi de.  
Me dic al M o nit or: 
 M D 
St u d y peri o d ( ye ars):  
F irst s u bject e nr olle d: 2 7 Dec 2 0 1 9  
Esti mate d date last s u bject  c o m plete d: 3 Q 2 0 2 4 
P h ase of de vel o p me nt: 3  
O bjecti ves:  
Pri m ar y: T he pri mar y o bjecti ve is t o deter mi ne if treat me nt wit h i nfi grati ni b i m pr o ves 
pr o gressi o n -free s ur vi val ( P F S) as assesse d b y bli n de d i n de pe n de nt ce ntral re vie w ( BI C R) 
c o m pare d t o treat me nt wit h ge mcita bi ne a n d cis plati n  i n s u bjects wit h u nresecta ble l ocally 
a d va nce d  or metastatic c h ola n gi ocarci n o ma wit h fi br o blast gr o wt h fact or rece pt or 2 ( F G F R 2) 
f usi o n/rearra n ge me nt. 
Sec o n d ar y: T he sec o n dar y o bjecti ves are t o  
•  
Deter mi ne if treat me nt wit h i nfi grati ni b i m pr o ves o verall s ur vi val ( O S) c o m pare d t o 
treat me nt wit h ge mcita bi ne a n d cis plati n i n s u bjects wit h u nresecta ble l ocall y a d va nce d or 
metastatic c h ola n gi ocarci n o ma wit h F G F R 2 f usi o n/ rearra n ge me nt. 
•  
E val uate t he efficac y of i nfi grati ni b treat me nt c o m pare d t o ge mcita bi ne a n d cis plati n i n 
ter ms of i n vesti gat or assesse d P F S.  
•  
F urt her e val uate t he efficac y i n s u bjects treate d wit h i nfi grati ni b vers us ge mcita bi ne a n d 
cis plati n b y o verall res p o nse rate ( O R R ), best o verall res p o nse ( B O R), d urati o n of res p o nse 
a n d disease c o ntr ol rate deter mi ne d b y  BI C R a n d b y t he i n vesti gat or . 
•  
C haracterize t he safet y a n d t olera bilit y of si n gle a ge nt i nfi grati ni b. 
E x pl or at or y: T he e x pl orat or y o bjecti ves are t o  
•  
E val uate t he efficac y of i nfi grati ni b treat me nt c o m pare d t o ge mcita bi ne a n d cis plati n i n 
ter ms of i n vesti gat or assesse d P F S after s u bse q ue nt t hera p y (P F S 2 ). 
•  
C o m pare q ualit y of life ( Q O L ) i n s u bjects treate d wit h i nfi grati ni b or ge mcita bi ne a n d 
cis plati n. 
•  
Assess t he  p har mac o ki netic s ( P K) of  i nfi grati ni b a n d its acti ve meta b olites i ncl u di n g 
B H S 6 9 7  a n d C Q M 1 5 7 . 
•  
E val uate t he o verall ge n o mic la n dsca p e of s u bjects wit h c h ola n gi ocarci n o ma . 
•  
E val uate bi o mar kers relate d t o c h ola n gi ocarci n o ma bi ol o g y a n d t heir p ote ntial c orrelati o n 
t o efficac y, disease pr o gressi o n, a n d resista nce t o st u d y me dicati o ns . 
P P D


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Endpoints:  
Primary: 
• 
PFS (from date of randomization until date of progression as determined by BICR or death 
due to any cause, whichever is earlier) 
Secondary:  
• 
OS (from date of randomization until date of death) 
• 
PFS as determined by the investigator 
• 
ORR assessed by BICR according to Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 
• 
ORR assessed by the investigator according to RECIST Version 1.1 
• 
BOR, disease control rate (partial response [PR] + complete response [CR] + stable disease 
[SD]), and duration of response (only for subjects who have a response) assessed by BICR 
and by the investigator according to RECIST 1.1 
• 
Type, frequency, and severity of adverse events (AEs) and serious AEs (SAEs), laboratory 
abnormalities, and other safety findings 
Exploratory:  
• 
PFS2 (from date of randomization until date of progression on the subsequent therapy or 
death due to any cause, whichever is earlier) as determined by the investigator 
• 
QOL as measured by the European Organization for Research and Treatment of Cancer 
(EORTC) quality of life questionnaire (QLQ) C30, EORTC QLQ-BIL21, and EuroQOL 
five dimensions questionnaire (EQ-5D) 
• 
PK parameters (Cmax, Cmin, and Racc) 
• 
The prevalence of genomic alterations and their correlations with available 
clinicopathologic and demographic features in subjects with cholangiocarcinoma 
• 
Genomic and proteomic assessments of tumor biopsies and cell-free DNA (blood) at 
baseline, during treatment, and at disease progression; and determination of the prognostic 
and/or predictive value of biomarkers to the clinical endpoints 
Study Design: This is a multi-center, open label, randomized, controlled Phase 3 study to 
determine if treatment with infigratinib improves PFS assessed by BICR (primary objective) 
and OS (key secondary objective) compared to treatment with gemcitabine and cisplatin in 
subjects with unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 
fusion/rearrangement. For the purposes of this protocol, “advanced/metastatic or inoperable” (as 
in the protocol title) is equivalent to “unresectable locally advanced or metastatic” (protocol-
defined study population). 
Subjects will be randomized in a 2:1 ratio to receive oral infigratinib administered once daily for 
the first 3 weeks (21 days) of a 28-day treatment cycle compared to a regimen of gemcitabine 
with cisplatin given on Days 1 and 8 of a 21-day cycle. Randomization will be stratified by 
locally advanced vs metastatic disease, geographic region (North America, Western Europe, 
Asia Pacific, and rest of the world), prior neoadjuvant/adjuvant treatment (yes/no), and received 
up to 1 cycle of prior gemcitabine-based chemotherapy for unresectable locally advanced or 
metastatic disease (yes/no).  
During the treatment period, subjects will be radiographically evaluated every 8 weeks ±7 days 
from the first dose of study drug, regardless of drug interruption, for tumor response 
(RECIST 1.1). When the decision is made to discontinue study drug, subjects will complete an 
End of Treatment (EOT) visit, no later than 8 days from the decision to discontinue study drug, 
and a Safety Follow-up visit no more than 30 days after last dose of study drug. If a subject 
discontinues study drug for reasons other than progressive disease (PD) confirmed by BICR, a 


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radiographic assessment should be conducted at the EOT visit, unless taken within the previous 
4 weeks.  
Subjects who discontinue study drug for radiographic PD confirmed by BICR will be followed 
approximately every 3 months (via telephone or office visit) for survival status and new 
anticancer therapy information (subsequent therapy and progression/PFS2) until End of Study 
(EOS), defined as the time when at least 224 OS events have been reached (for the primary OS 
analysis) and the last subject has completed study treatment. Subjects who discontinue study 
drug for reasons other than PD confirmed by BICR will continue to have radiographic 
assessments every 8 weeks ±7 days until radiographic PD confirmed by BICR. Thereafter, these 
subjects will be followed approximately every 3 months for survival status and use of anticancer 
therapy, as described above. 
Sparse PK blood samples will be collected from all subjects in the infigratinib group at multiple 
time points, predose (Cmin infigratinib) and 4 hours (±30 minutes) postdose (Cmax infigratinib). 
Plasma concentrations of infigratinib and its metabolites (including BHS697 and CQM157) will 
be measured. 
For a PK substudy, blood samples will be collected, at multiple time points (predose [Cmin 
infigratinib], 4 hours [±30 minutes] postdose, and 24 hours postdose [±1 hour]) from the first 
40 subjects who receive infigratinib. Plasma concentration of infigratinib and its active 
metabolites will be measured and PK parameters will be assessed. 
Following radiographic PD confirmed by BICR, subjects randomized to the gemcitabine with 
cisplatin group may be eligible to cross over and receive infigratinib; these subjects will be 
followed for safety and OS. 
Number of subjects (planned): Approximately 300 subjects with a likely or known activating 
FGFR2 fusion/rearrangement determined by a central laboratory or local laboratory are planned 
for study participation. 
Diagnosis and criteria for inclusion and exclusion: To be eligible for the study, subjects must 
meet all of the following criteria: 
1. Have histologically or cytologically confirmed unresectable locally advanced or metastatic 
cholangiocarcinoma. Subjects with gallbladder cancer or ampulla of Vater carcinoma are 
not eligible. 
2. Have written documentation of local laboratory or central laboratory determination of a 
known or likely activating FGFR2 fusion/rearrangement from a sample collected before 
randomization (refer to Section 10.3.1 for the definition of a known or likely activating 
FGFR2 fusion/rearrangement). Note: All subjects enrolled based on local molecular test 
results must have sufficient tumor tissue for confirmation of FGFR2 fusion/rearrangement 
by the central laboratory, but this central confirmation is not required prior to enrollment in 
the study. 
3. Have an archival tumor tissue sample available with sufficient tumor content for FGFR2 
fusion/rearrangement molecular testing by the central laboratory. However, if an archival 
tumor tissue sample is not available or does not meet requirements for central testing, a 
newly obtained (before randomization) tumor biopsy may be submitted instead. If a 
prestudy written documentation of FGFR2 fusion/rearrangement in tumor tissue is available 
from the central laboratory, an additional tumor sample does not need to be submitted. 
4. Have full recovery from the following permitted prior treatments (as applicable) such that 
the subject is reasonably expected to tolerate study treatment (gemcitabine/cisplatin or 
infigratinib) according to the investigator’s assessment: 


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a. A non-curative operation (ie, R2 resection [with macroscopic residual disease] or 
palliative bypass surgery only) 
b. Curative surgery with evidence of unresectable disease relapse requiring systemic 
chemotherapy 
c. Adjuvant radiotherapy (with or without radio-sensitizing low-dose chemotherapy) for 
localized disease provided there has been clear evidence of disease progression before 
inclusion in this study 
d. Adjuvant or neoadjuvant chemotherapy, provided recurrence occurred >6 months after 
the date of the last dose of adjuvant or neoadjuvant therapy and before randomization 
e. Gemcitabine-based chemotherapy (specified in Appendix 5 [Section 17.5]) for 
advanced/unresectable or metastatic cholangiocarcinoma (≤1 cycle) 
i. 
Recovery from acute toxicities to the extent that would allow initiation of cisplatin-
gemcitabine (absolute neutrophil count (ANC) ≥1,000/mm3 (≥1.0 × 109/L); platelets 
≥100,000/mm3 (≥100× 109/L) 
ii. Baseline tumor assessment at least 7 days after the last dose of chemotherapy and 
before randomization 
iii. The window between the last dose of chemotherapy and the start of randomized 
study treatment must be ≥14 days and ≤5 weeks 
f. Photodynamic treatment provided there is clear evidence of disease progression at the 
local site or at a new metastatic site 
5. Are ≥18 years of age of either gender. 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1.  
7. Have a life expectancy >3 months. 
8. Are able to read and/or understand the details of the study and provide written evidence of 
informed consent as approved by Institutional Review Board (IRB)/Independent Ethics 
Committee (IEC). 
9. Are able to swallow and retain oral medication. 
10. Are willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
11. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test within 
7 days of the first dose of study drug. A woman is not of childbearing potential if she has 
undergone surgical sterilization (total hysterectomy, or bilateral tubal ligation or bilateral 
oophorectomy at least 6 weeks before taking study drug) or if she is postmenopausal and 
has had no menstrual bleeding of any kind including menstrual period, irregular bleeding, 
spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is no 
other cause of amenorrhea (eg, hormonal therapy, prior chemotherapy). 
WOCBP and males whose sexual partners are WOCBP must agree to use barrier 
contraception and a second form of highly effective contraception (Clinical Trials 
Facilitation Group 2014; see Appendix 3 [Section 17.3]) while receiving study drug and for 
1 month following their last dose of infigratinib or 6 months following their last dose of 
gemcitabine/cisplatin (or according to local labeling and standard institutional practice). 
Alternatively, total abstinence is also considered a highly effective contraception method 
when this is in line with the preferred and usual lifestyle of the subject. Periodic abstinence 
(eg, calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
Sexually active males must use a condom during intercourse while taking drug and for 
1 month after the last dose of infigratinib or 6 months after their last dose of 


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gemcitabine/cisplatin (or according to local labeling and standard institutional practice) and 
should not father a child during this period. A condom is required to be used by 
vasectomized men and by men having intercourse with a male partner, to prevent delivery 
of the drug via seminal fluid. 
To be eligible for the study, subjects must not meet any of the following criteria: 
1. Have received treatment with any systemic anti-cancer therapy for unresectable locally 
advanced or metastatic cholangiocarcinoma, with the following exceptions:  
a. Prior neoadjuvant or adjuvant therapy is permitted if documented disease recurrence 
occurred ≥6 months after the last date of neoadjuvant or adjuvant therapy 
b. One cycle of gemcitabine-based chemotherapy (specified in Appendix 5 [Section 17.5]) 
for locally advanced or metastatic cholangiocarcinoma is permitted before 
randomization 
2. Have history of a liver transplant. 
3. Have previously or currently is receiving treatment with a mitogen-activated protein kinase 
(MEK) or selective FGFR inhibitor.  
4. Have neurological symptoms related to underlying disease requiring increasing doses of 
corticosteroids. Note: Steroid use for management of central nervous system tumors is 
allowed but must be at a stable or decreasing dose of corticosteroids for at least 2 weeks 
preceding randomization.  
5. Have a history of another primary malignancy within 3 years except adequately treated in 
situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any other curatively 
treated or surveilled malignancy (eg, localized low-risk prostate cancer) that is not expected 
to require treatment for recurrence during the course of the study. 
6. Have any other medical condition that would, in the investigator’s judgment, prevent the 
subject’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures. 
7. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited 
to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis, or diabetic 
retinopathy, confirmed by ophthalmic examination. Subjects with asymptomatic ophthalmic 
conditions assessed by the investigator to pose minimal risk for study participation may be 
enrolled in the study. 
8. Have a history and/or current evidence of extensive tissue calcification including, but not 
limited to, the soft tissue, kidneys, intestine, myocardium, vascular system, and lung with 
the exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, and 
asymptomatic coronary calcification.  
9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of oral infigratinib (eg, ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection). 
10. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, eg, 
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, etc. 
11. Are currently receiving or are planning to receive during participation in this study, 
treatment with agents that are known moderate or strong inducers or inhibitors of CYP3A4 
and medications which increase serum phosphorus and/or calcium concentration. Subjects 
are not permitted to receive enzyme-inducing anti-epileptic drugs, including carbamazepine, 
phenytoin, phenobarbital, and primidone. See Appendix 2 (Section 17.2) for details. 


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12. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, 
pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to 
first dose of study drug. 
13. Have insufficient bone marrow function: 
a. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L) 
b. Platelets <100,000/mm3 (<100× 109/L) 
c. Hemoglobin <8.5 g/dL; transfusion support is allowed if >1 week before randomization 
and hemoglobin remains stable 
14. Have insufficient hepatic and renal function: 
a. Total bilirubin >1.5 × upper limit of normal (ULN) (for patients with documented 
Gilbert syndrome, direct bilirubin must be ≤1. 5 × ULN and enrollment requires 
approval by the medical monitor) 
b. Aspartate aminotransferase/serum glutamic-oxaloacetic transaminase (AST/SGOT) and 
alanine aminotransferase/serum glutamic-pyruvic transaminase (ALT/SGPT) 
>2.5 × ULN (AST and ALT >5 × ULN in the presence of liver involvement of 
cholangiocarcinoma) 
c. Calculated (using the Cockcroft-Gault formula [Cockcroft and Gault 1976]) or 
measured creatinine clearance of <45 mL/min (or value ≥45 mL/min that excludes 
administration of cisplatin per local label and institutional guidelines) 
15. Have amylase or lipase >2.0 × ULN 
16. Have elevated phosphorus or abnormal serum calcium, or calcium-phosphorus product 
≥55 mg2/dL2 (refer to Section 9.3 for guidance on calculation): 
a. Inorganic phosphorus >1.1 × ULN 
b. Total corrected serum calcium >11 mg/dL or <8 mg/dL 
17. Have clinically significant cardiac disease including any of the following: 
a. Congestive heart failure requiring treatment (New York Heart Association Grade ≥2B) 
or uncontrolled hypertension (refer to the European Society of Cardiology and 
European Society of Hypertension guidelines [Williams et al 2018]) 
b. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction 
abnormality 
c. Unstable angina pectoris or acute myocardial infarction ≤3 months prior to first dose of 
study drug 
d. QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first 
electrocardiogram (ECG), a total of 3 ECGs separated by at least 5 minutes should be 
performed. If the average of these 3 consecutive results for QTcF is ≤470 msec, the 
subject meets eligibility in this regard 
e. Known history of congenital long QT syndrome 
18. Have had a recent (≤3 months prior to first dose of study drug) transient ischemic attack or 
stroke. 
19. CTCAE (v5.0) Grade ≥2 hearing loss. 
20. CTCAE (v5.0) Grade ≥2 neuropathy. 


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21. If female, is pregnant or nursing (lactating), where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
human chorionic gonadotrophin urine or blood laboratory test. 
22. Have known microsatellite instability-high (MSI-H) disease and the decision is made by the 
treating investigator that an alternative, non-study therapy is warranted according to 
standard of care. 
23. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents, 
infigratinib, or their excipients. 
24. Have any contraindication to cisplatin or gemcitabine treatment according to local labeling 
or standard institutional practice. 
25. Have taken any Chinese herbal medicine or Chinese patent medicine treatments with 
anticancer activity within 14 days of the first dose of study drug. 
26. Have received a live vaccine within 30 days before the first dose of study drug or are 
planning to receive a live vaccine during participation in this study. 
Investigational product, dosage and mode of administration: Subjects randomized to the 
infigratinib group will receive hard gelatin capsules for oral infigratinib 125 mg QD 
(administered as one 100-mg capsule and one 25-mg capsule) using a “3 weeks on, 1 week off” 
schedule for each 28-day treatment cycle (FMI IV formulation). 
Reference therapy, dosage and mode of administration: Subjects randomized to the 
gemcitabine plus cisplatin group will receive intravenous infusions of gemcitabine 
(1000 mg/m2) and cisplatin (25 mg/m2) on Days 1 and 8 of each 21-day treatment cycle 
according to each country’s respective labeling and local institutional practices. It is 
recommended to have cisplatin infused over 1 hour in 1000 mL of 0.9% saline containing 
20 mmol potassium chloride and 8 mmol magnesium sulfate, followed by 500 mL of 0.9% 
saline over an additional 30 minutes before initiation of the gemcitabine infusion. The cisplatin 
infusion should be performed with adequate hydration according to the institution’s practice. 
After cisplatin administration, gemcitabine, diluted in 0.9% saline according to local labeling, 
will be infused over approximately 30 minutes.  
Duration of treatment: Treatment will continue until radiographic PD confirmed by BICR, 
unacceptable toxicity, or other reason listed in Section 8.1.1. 
If a subject in the gemcitabine and cisplatin group cannot tolerate cisplatin, they can remain on 
gemcitabine alone. However, if gemcitabine is discontinued due to toxicity then all study 
treatment must be discontinued. The subject will have an EOT visit and then continue on study 
for PFS, PFS2, and OS follow-up (even if the subject starts new anticancer treatment). 
After radiographic PD confirmed by BICR, subjects randomized to gemcitabine with cisplatin 
may be eligible to cross over and receive infigratinib. Subjects who cross over to infigratinib 
will continue until unacceptable toxicity or other criterion listed in Section 8.1.1 has been met. 
Criteria for evaluation: 
Efficacy: Tumor response will be evaluated by BICR and by the investigator according 
RECIST Version 1.1 (Eisenhauer et al 2009). Subject management will be based upon 
investigator evaluations; subjects should remain on study drug until PD is confirmed by BICR.  
Survival status and use of new anticancer medications will be followed approximately every 
3 months once PD has been documented and confirmed by BICR. Survival status, use of 
anticancer therapy, and PFS2 will be followed until EOS. 


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Safety: Assessments will be performed at Screening and visits throughout the treatment period 
(Section 2): AEs and SAEs, clinical laboratory tests (blood and urine), vital signs, physical 
examinations, ECOG performance status, and electrocardiograms (ECGs), and ophthalmic 
assessments. AEs and SAEs will be assessed through 30 days post-treatment. 
QOL: Subject QOL will be evaluated using the EQ-5D, which measures 5 dimensions of 
health, including mobility, self-care, usual activities, pain/discomfort, anxiety, and general 
health; the EORTC QLQ-C30, a reliable and valid measure of QOL in subjects with cancer; and 
the EORTC QLQ-BIL21, a disease-specific module for subjects with cholangiocarcinoma and 
gallbladder cancer. 
PK (infigratinib group only): All subjects in the infigratinib group will have PK blood 
samples collected on Day 21 of Cycles 1 through 4 at 0 (predose) and 4 hours (±30 minutes) 
postdose. The PK parameters Cmax, Cmin, and Racc, will be calculated. 
In addition, a PK substudy will be conducted on the first 40 subjects enrolled who receive 
infigratinib. These subjects will have PK blood samples collected at the following time points in 
Cycle 1: Day 1 (0 [predose] and 4 hours [±30 minutes] postdose), Day 2 (24 hours [±1 hour] 
after the Day 1 dose prior to Day 2 dosing), Day 21 (0 [predose] and 4 hours [±30 min] 
postdose), Day 22 (24 hours [±1 hour] after the Day 21 dose), and the same as all other subjects 
in the infigratinib group: Day 21 of Cycles 2 through 4 at 0 (predose) and 4 hours (±30 minutes) 
postdose.   
For any subject in the infigratinib group who permanently discontinues study drug for any 
reason, attempts should be made to collect a PK blood sample from the subject at the time of 
discontinuation, if the sample can be collected within 24 hours of last dose. 
Blood samples will be collected to measure plasma concentrations of infigratinib and its 
metabolites (eg, BHS697 and CQM157). On days of PK sampling, subjects should bring their 
study drug with them to the clinic and take it after the predose PK sample is taken.  
Biomarkers: Archival or newly obtained tumor samples will be collected to evaluate 
biomarkers related to cholangiocarcinoma biology and their potential correlation to efficacy, 
disease progression, and resistance to study medications using genetic and protein analysis of 
the tumor. Blood samples will also be collected for assessment of cell-free DNA. 
Statistical methods:  
Sample Size: Approximately 300 subjects with FGFR2 fusion/rearrangement determined by a 
central laboratory or local laboratory will be randomized in the study (2:1 randomization, with 
200 in the infigratinib group and 100 in gemcitabine with cisplatin group) and stratified by 
unresectable locally advanced vs metastatic disease, geographic region (North America, 
Western Europe, Asia Pacific, and rest of the world), prior neoadjuvant/adjuvant treatment 
(yes/no), and received up to 1 cycle of prior gemcitabine-based chemotherapy for unresectable 
locally advanced or metastatic disease (yes/no). 
The primary endpoint is PFS assessed by BICR. Assuming a PFS hazard ratio (HR) of 0.67 
(median PFS 11.9 vs 8 months) (Valle et al 2010) comparing infigratinib to gemcitabine with 
cisplatin, with 228 PFS events required, the study will provide approximately 80% power to 
determine if infigratinib improves PFS assessed by BICR compared to treatment with 
gemcitabine and cisplatin at a 2-sided significance level of 0.05. Assuming the test on PFS is 
significant, with 224 deaths observed, the study will provide 66% power to demonstrate 
infigratinib improves OS compared to treatment with gemcitabine and cisplatin assuming an OS 
HR of 0.7 (median OS 16.7 vs 11.7 months) (Valle et al 2010). 
The study employs a group sequential design with one interim analysis for futility on PFS, 
which will be conducted when approximately 50% of the PFS events (114) are observed. The 
primary analysis for PFS will be conducted after approximately 228 PFS events have been 


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observed. A fixed 2-sided significance level of 0.0001 will be spent at the interim analysis for 
PFS. A Lan-DeMets alpha spending function approximating O’Brien Fleming boundaries will 
be used for the interim non-binding futility and final boundary.  
One interim analysis and one primary analysis for OS are planned. The interim analysis for OS 
will be conducted at the PFS primary analysis, and the primary analysis for OS will be 
conducted after approximately 224 deaths have been observed. OS will be tested only if PFS is 
found to be significant. The Lan-DeMets spending function approximating the O'Brien-Fleming 
spending function will be used to calculate the significance boundaries. 
With 42-month uniform enrollment, the study is projected to reach the planned number of PFS 
events assessed by BICR (228) in approximately 54 months from randomization of the first 
subject. The OS event goal of 224 deaths is projected to be reached approximately 66 months 
from randomization of the first subject. The required sample size is estimated to be a total of 
300 subjects, considering that approximately 10% of subjects will drop out per year before a 
PFS or OS event. 
Efficacy Analyses: The efficacy analyses will be conducted on the ITT population unless 
otherwise specified. This population will include all subjects who are randomized. Subjects will 
be analyzed according to the treatment group to which they are randomized. The stratified log-
rank test (using the randomization stratification factors) will be used to compare the treatment 
arms with respect to PFS assessed by BICR and OS. The HR and the corresponding 2-sided 
95% confidence interval (CI) will be derived from a stratified Cox proportional hazards 
regression model using randomization stratification factors for PFS assessed by BICR and OS. 
The Kaplan-Meier (K-M) medians (if estimable) will be derived, along with their 2-sided 95% 
CIs. Sensitivity analyses will be conducted on OS to address the impact of subjects’ crossover. 
The primary endpoint, PFS assessed by BICR, will be tested first at 2-sided significance level of 
0.05. The key secondary endpoint, OS, will only be tested if the test on PFS assessed by BICR 
is significant. 
The 2-sided 95% CI will be calculated for the difference in ORR between the 2 treatment 
groups based on the Wilson method for subjects in the ITT population. PFS based on 
investigator assessment will be analyzed using a stratified log-rank test and corresponding 2-
sided 95% CI for the HR from the stratified Cox proportional hazards regression model. 
Response duration will be summarized by the K-M method, and descriptive summaries will be 
provided for BOR and disease control rate (PR+CR+SD). PFS2 will be analyzed using the same 
approaches as for investigator-assessed PFS. 
Safety Analyses: All reported AEs will be assigned a system organ class and preferred term, 
according to the Medical Dictionary for Regulatory Activities (MedDRA) dictionary. All AEs 
(including serious and drug-related) of subjects who receive at least one dose of study drug will 
be tabulated from first dose through 30 days after last dose of study drug. 
Interim Analysis: One formal interim analysis of PFS based on BICR will be performed when 
approximately 114 PFS events have occurred across both treatment arms in the ITT population. 
One interim analysis for OS will be conducted at the time of the PFS primary analysis.  
The study may be stopped due to futility at the interim PFS analysis if the futility boundary for 
testing PFS is crossed. The futility stopping boundary is non-binding to allow for additional 
considerations. Though efficacy boundaries are specified for PFS assessed by BICR at the time 
of the interim PFS analysis, the trial will not stop for efficacy at the interim analysis for PFS 
even if the efficacy boundary is crossed for PFS. 
Other Information: An independent Data Monitoring Committee (DMC) will review safety 
and efficacy data at the interim analyses. In addition, the DMC will periodically review safety 
data at regularly scheduled meetings, according to a prespecified DMC charter. 
Full details of the planned statistical analyses will be included in the Statistical Analysis Plan. 


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2 SCHEDULE OF ASSESSMENTS 
Schedules of assessments to be performed during the study are presented in Table 2 
(infigratinib group), Table 4 (gemcitabine plus cisplatin group), and Table 5 (subjects in 
the gemcitabine plus cisplatin group who cross over to infigratinib). Table 3 outlines 
pharmacokinetics (PK) sampling times for subjects in the PK substudy, which will be 
composed of the first 40 subjects enrolled in the infigratinib group . 
All data obtained from these assessments must be supported in the subject’s source 
documentation.  
Baseline/screening assessments must be conducted within 28 days before randomization. 
Note: for subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before 
randomization, the baseline imaging assessment must be conducted ≥7 days after the last 
dose of chemotherapy and before randomization.  
In the event that subjects have a baseline/screening laboratory assessment that excludes 
them from the study, the assessment can be repeated. Baseline/screening assessments that 
are conducted within 3 days prior to first treatment can be used to satisfy the Day 1 
requirement. Every effort must be made to follow the schedule outlined. 
Whenever feasible vaccinations should be administered at least 30 days prior to 
randomization. Live vaccines are prohibited within 30 days before the first dose of study 
drug, for the duration of study participation, and for a period of time (approximately 
3-6 months) after the last dose of chemotherapy according to local guidelines (see also 
Section 7.7). 
Unless otherwise indicated, there is a ±3-day window on assessments. For post-baseline 
imaging and ophthalmic assessments, a ±7 day window is allowed, except for the first 
post-baseline assessment (+7 day window permitted). The EOT visit is to be conducted 
no later than 8 days from the decision to discontinue study drug. In the PK substudy, 
there are no visit windows for the trough PK sampling days (Cycle 1 Day 2 and 
Cycle 1 Day 22). 
Subjects without central confirmation of FGFR2 fusion/rearrangement will be able to 
continue study drug at the investigator’s discretion; these subjects will follow the same 
study schedules as previously described. 
Each subject will be tested for microsatellite instability (MSI) status as part of central 
testing for FGFR2 fusion/rearrangement. Subjects may randomize to the study prior to 
MSI results being available. If the subject is determined to be MSI-H prerandomization, 
then the investigator should decide if the subject is an appropriate candidate. If the 
subject is determined to be MSI-H postrandomization, the subject may continue on study 
treatment, but this requires joint decision by the subject and investigator and 
documentation of subject consent to continue on study treatment. 


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Table 2: 
Schedule of Assessments: Subjects in the Infigratinib Group 
 
Molecular Pre 
screening a 
Screening a 
Visits during Treatment Period  
(28-day Treatment Cycles: 3 Weeks on, 1 Week off) 
EOT 
 
30-day Safety Follow-up 
Survival 
Follow-up 
 
Every 3 mo 
After Disease 
Progression c 
Wk1 
D1 
Wk2 
D1 
Wk3 
D1 
Wk3 
D7 
 
Each 
Additional 
Cycle 
Time of Study b 
 
-28 to -1 
Cycle 1 
Cycles 2-4 
Cycle 5+ 
No Later 
than 8d 
from 
Decision 
to DC 
Study 
Drug 
 
D1 
D8 
D15 
D21 
D1 
D21 
D1 
Prescreening IC if FGFR2 data not 
available 
X 
 
 
 
 
 
 
 
 
 
 
 
Prescreening molecular testing if FGFR2 
data not available 
X 
 
 
 
 
 
 
 
 
 
 
 
FGFR2 fusion/rearrangement 
documentation and confirmation of tumor 
availability for central testing  d 
 
X 
 
 
 
 
 
 
 
 
 
 
Collection of archival or a newly obtained 
tumor sample AND pathology report, if 
archival paraffin blocks/slides and 
pathology report not available 
X 
X e 
 
 
 
 
 
 
 
 
 
 
Main Study IC 
 
X 
 
 
 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
 
 
 
I/E criteria 
 
X 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
 
 
X 
 
X 
X 
X 
 
Relevant medical history/current medical 
conditions 
 
X 
 
 
 
 
 
 
 
 
 
 
Diagnosis, primary location, and extent of 
cancer 
 
X 
 
 
 
 
 
 
 
 
 
 
Prior anticancer therapy 
 
X 
 
 
 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
 
 
 
Weight f 
 
X 
X  
 
 
 
X 
 
X 
X 
 
 
Randomization (within 5 days before 
Cycle 1 Day 1 [C1D1]) 
 
X 
 
 
 
 
 
 
 
 
 
 


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Molecular Pre 
screening a 
Screening a 
Visits during Treatment Period  
(28-day Treatment Cycles: 3 Weeks on, 1 Week off) 
EOT 
 
30-day Safety Follow-up 
Survival 
Follow-up 
 
Every 3 mo 
After Disease 
Progression c 
Wk1 
D1 
Wk2 
D1 
Wk3 
D1 
Wk3 
D7 
 
Each 
Additional 
Cycle 
Time of Study b 
 
-28 to -1 
Cycle 1 
Cycles 2-4 
Cycle 5+ 
No Later 
than 8d 
from 
Decision 
to DC 
Study 
Drug 
 
D1 
D8 
D15 
D21 
D1 
D21 
D1 
Infigratinib Dose Administration 
 
 
Daily dosing using a “3 weeks on, 1 week off” schedule for each 28-day 
treatment cycle; C1D1 and C1-4 D21o doses are administered in the clinic. 
 
 
 
Adverse Events  
Continuous g 
 
Prior/concomitant medications 
 
Continuous 
 
Pregnancy test f 
 
X 
X  
 
 
 
X 
 
X 
X 
 
 
Vital signs f 
 
X 
X  
X 
X 
X 
X 
 
X 
X 
 
 
Hematology f 
 
X 
X  
 
X 
 
X 
 
X 
X 
 
 
Chemistry f 
 
X 
X  
X 
X 
X 
X 
 
X 
X 
 
 
12-lead ECG h 
 
X 
X  
 
 
 
X h 
 
 
X 
 
 
Coagulation 
 
X 
If clinically indicated 
 
 
 
Urinalysis (micro- and macroscopic) 
 
X 
If clinically indicated 
 
 
 
Physical examination  
 
X 
Symptom-directed exams, as needed 
X 
 
 
Ophthalmic assessment (performed by an 
ophthalmologist) 
 
X 
 
 
 
 
C2D1, C4D1, and every 3 months 
after i 
X i 
 
 
CT/MRI scans of the chest, abdomen, and 
pelvis (also brain if clinically indicated) 
 
X j 
Tumor response will be assessed at Wk9D1 and every 8 wk (±1wk) thereafter until PD confirmed by BICR, 
regardless of drug interruption (RECIST 1.1). After PD is confirmed by BICR, tumor assessments will be completed 
only according to investigator assessment (no longer BICR-assessed). k 
EQ-5D, EORTC QLQ-C30, EORTC 
QLQ-BIL21 l 
 
 
QOL assessments are every 4 weeks through Wk17D1 i.e, Wk1D1, Wk5D1, 
Wk9D1, Wk13D1, Wk17D1, and every 8 wk (±1wk) from last assessment, 
regardless of drug interruption 
X 
 
 
Blood sample for assessment of cell-free 
tumor DNA (all samples are predose) 
 
 
Xm 
Every 8 wk (±1wk) coinciding with CT/MRI scans, regardless of 
drug interruption m 
X (if not 
done 
within 
28 d prior) 
 
 
Blood sample for PK assessment (all 
subjects receiving infigratinib) n 
 
 
 
 
 
X  
(0 and 4 
 
X  
(0 and 4 
 
Xn 
 
 


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Molecular Pre 
screening a 
Screening a 
Visits during Treatment Period  
(28-day Treatment Cycles: 3 Weeks on, 1 Week off) 
EOT 
 
30-day Safety Follow-up 
Survival 
Follow-up 
 
Every 3 mo 
After Disease 
Progression c 
Wk1 
D1 
Wk2 
D1 
Wk3 
D1 
Wk3 
D7 
 
Each 
Additional 
Cycle 
Time of Study b 
 
-28 to -1 
Cycle 1 
Cycles 2-4 
Cycle 5+ 
No Later 
than 8d 
from 
Decision 
to DC 
Study 
Drug 
 
D1 
D8 
D15 
D21 
D1 
D21 
D1 
hr 
postdose) 
hr 
postdose) 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
 
X 
Anticancer therapies since discontinuation 
of study drug 
 
 
 
 
 
 
 
 
 
 
X 
X 
Newly obtained tumor sample (if 
medically feasible) 
 
 
X (upon disease progression)-optional 
 
 
Abbreviations: AE, adverse event; BICR, blinded independent central review; CT, computed tomography; d, day; DC, discontinue; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of treatment; EQ-5D, 
EuroQOL five dimensions questionnaire; FGFR2, fibroblast growth factor receptor 2; IC, informed consent; I/E, inclusion/exclusion; MRI, magnetic resonance imaging; NaF, 
sodium fluoride; OCT, optical coherence tomography; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PFS2, PFS on subsequent 
therapy; PK, pharmacokinetic; QLQ, quality of life questionnaire; RECIST, Response Evaluation Criteria in Solid Tumors;TC99, technetium-99. 
a  After prescreening ICF, molecular prescreening assessments can be done any time prior to the initiation of the screening. All baseline/screening assessments must be performed 
within 28 days before randomization. For subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before randomization, the baseline imaging assessment must 
be conducted ≥7 days after the last dose of chemotherapy and before randomization. Baseline/screening assessments that are conducted within 3 days prior to first treatment 
can be used to satisfy the Day 1 requirement. Every effort must be made to follow the schedule outlined.  
b  Unless otherwise indicated, there is a ±3-day window on assessments. For post-baseline imaging and ophthalmic assessments, a ±7 day window is allowed, except for the first 
post-baseline assessment (+7 day window permitted). The EOT visit is to be conducted no later than 8 days from the decision to discontinue study drug.  
c  Once radiographic PD is confirmed by BICR and documented, survival status, use of anticancer therapy (names and dates of therapies, response, and reason for 
discontinuation), and date of subsequent progression (PFS2) will be followed approximately every 3 months (via telephone or office visit) until the End of Study, defined as the 
time when at least 224 OS events have been reached (for the primary OS analysis) and the last subject has completed study treatment.  
d  Central laboratory testing for FGFR2 fusion/rearrangement will include microsatellite instability status.  
e  If written documentation of FGFR2 fusion/rearrangement is determined by a local laboratory, archival or fresh biopsy tumor tissue sample must be submitted to the central 
laboratory within approximately 14 days of start of study treatment for the confirmation of FGFR2 fusion/rearrangement. Refer to the Laboratory Manual for the sample 
requirements and processing instructions for central laboratory testing of FGFR2 fusion/rearrangement. 
f  To be conducted within 3 days before the first dose of study drug is administered; all subsequent assessments may be conducted at any time relative to dosing (pre- or 
postdose), unless specified otherwise. If a subject is not dosed at a visit where dosing is scheduled, then the procedures specified for that visit must be completed/repeated on 
the actual dosing day. 


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g  See Section 10.5.1.3 for details on the collection and recording of adverse events (including serious adverse events).  
h  For each subject, 12-lead ECGs are to be performed at the Screening visit; on Day 1 (predose) of Cycle 1, Day 1 of Cycle 2; at the EOT visit, and otherwise as clinically 
indicated. 
i  
Ophthalmic assessment (performed by an ophthalmologist) will be done on C2D1, C4D1, and every 3 months after that. Ophthalmic assessment includes visual acuity testing 
(including corrected distance acuity), slit lamp examination of the anterior eye segment, intraocular pressure, retinal OCT, and dilated fundoscopy. Additional examination 
methods such as specular microscopy and corneal pachymetry will be done as clinically indicated. Retinal OCT scan images will be collected centrally for potential review. 
Refer to the Study Manual for details regarding image collection and transfer or shipment. Ophthalmic assessment will be conducted at EOT visit unless performed within 
previous 4 weeks. 
j  
For subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before randomization, the baseline imaging assessment must be conducted ≥7 days after the last 
dose of chemotherapy and before randomization. For subjects with skeletal lesions suspected at screening, whole-body bone imaging should be obtained either with a TC99 
bone scan or alternatively a NaF CT/ MRI PET scan, with local CT of any identified lesions. Of note, the CT or MRI portion of the scan should only be substituted for the 
required chest, abdomen, and pelvic CT scans if the CT or MRI is of diagnostic quality and meets all requirements as described in the study imaging guide (ie, oral and IV 
contrast, slice thickness, and anatomic coverage). Postbaseline, if skeletal lesions are identified at screening, which are not visible on the chest, abdomen or pelvis CT/MRI 
scan, bone imaging with either a TC99 bone scan or NaF CT/MRI PET is required at all postbaseline imaging timepoints (every 8 weeks). In all cases that postbaseline bone 
imaging is required, the same modality that was used at screening should be used for all postbaseline imaging when possible. 
k  During the treatment period, subjects will be evaluated every 8 weeks from the first dose of study drug, regardless of drug interruption. For postbaseline imaging and 
ophthalmic assessments, a ±7 day window is allowed, except for the first post-baseline assessment (+7 day window permitted). If a subject discontinues study drug for reasons 
other than PD confirmed by BICR, a radiographic assessment should be conducted at the EOT visit, unless taken within the previous 4 weeks. Subjects who discontinue study 
drug for reasons other than PD confirmed by BICR will continue to have radiographic assessments every 8 weeks ±7 days until radiographic PD confirmed by BICR (even if 
subjects start new anticancer treatment). After PD is confirmed by BICR, tumor assessments will be completed only according to investigator assessment (no longer BICR-
assessed). 
l  
Quality of life assessments should be conducted prior to all other study procedures and in order of EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BIL21. Assessments do not 
need to be administered at the EOT visit if they were completed within the previous 7 days at a regularly scheduled visit.  
m  Blood for cell-free DNA should be collected on Day 1 of Cycle 1 (predose) and then every 8 wk (±1wk) at the same visit as CT/MRI scans. For subjects who discontinue 
therapy without radiographic PD confirmed by BICR, a blood sample for cell-free DNA should be taken once progression is confirmed by BICR and/or investigator.  
n  For all subjects in the infigratinib group, blood samples will be collected on Day 21 of Cycles 1 through 4 at 0 (predose) and 4 hours (±30 minutes) postdose. In addition, for 
any subject in the infigratinib group who permanently discontinues study drug for any reason, attempts should be made to collect a PK blood sample from the subject at the 
time of discontinuation, if the sample can be collected within 24 hours of last dose.  
NOTE: On the days of PK dosing, subjects should not take their study drug dose at home; subjects should take their study drug with them to the study center where dosing of 
infigratinib will be supervised and administration time recorded. 
 
 


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Table 3: 
Schedule of Assessments: PK Sampling in a Substudy of 40 Subjects in the Infigratinib Group 
 
 
 
Visits during Treatment Period 
(28-day Treatment Cycles: 3 Weeks on, 1 Week off) 
EOT 
 
No Later than 8d 
from Decision to 
DC Study Drug 
Wk1 
D1 
Wk1 
D2 
Wk3 
D7 
Wk4 
D1 
Wk7 
D7 
Wk11 
D7 
Wk15 
D7 
Study Day: 
1 
2 
21 
22 
49 
77 
105 
Time of Study  
 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
D1 
D2 
D21 
D22 
D21 
D21 
D21 
Blood sample for PK assessment a   
 
X  
(0 and 4 hr 
postdose) 
X  
(24 hr post 
Day 1 dose) 
X  
(0 and 4 hr 
postdose) 
X  
(24 hr post 
Day 21 dose) 
X  
(0 and 4 hr 
postdose) 
X  
(0 and 4 hr 
postdose) 
X  
(0 and 4 hr 
postdose) 
Xb 
Abbreviations: AE, adverse event; d, day; DC, discontinue; EOT, end of treatment; PK, pharmacokinetic. 
a  For the first 40 subjects in the infigratinib group, blood samples will be collected at the following time points for PK analysis for Cycle 1: Cycle 1: Day 1 (0 [predose] and 
4 hours [±30 minutes] postdose), Day 2 (24 hours [±1 hour] after the Day 1 dose prior to Day 2 dosing), Day 21 (0 [predose] and 4 hours [±30 min] postdose), and Day 22 
(24 hours [±1 hour] after the Day 21 dose). For Cycles 2 through 4, blood samples will be collected on Day 21 (0 [predose] and 4 hr [±30 min] postdose) of each respective 
cycle.  
b 
For any subject in the infigratinib group who permanently discontinues study drug for any reason, attempts should be made to collect a PK blood sample from the subject at the 
time of discontinuation, if the sample can be collected within 24 hours of last dose.  
 
NOTE: There are no visit windows for the trough PK sampling days (Cycle 1 Day 2 and Cycle 1 Day 22). On the days of PK sampling, subjects should not take their study drug 
dose at home; subjects should take their study drug with them to the study center where dosing of infigratinib will be supervised and administration time recorded. 
 
 


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Table 4: 
Schedule of Assessments: Subjects in the Gemcitabine plus Cisplatin Group 
 
Molecular Pre 
screening a 
Screening a 
Visits during Treatment Period  
(21-day Treatment Cycles: Infusions on Day 1 and Day 8 
of each Cycle) 
EOT 
 
30-day Safety Follow-up 
Survival 
Follow-up 
 
Every 3 mo 
After Disease 
Progression c 
 
Wk1 
D1 
Wk2 
D1 
Each Additional Cycle 
Time of Study b 
 
-28 to -1 
Cycle 1 
Cycle 2-8+ 
No Later than 8d 
from Decision to 
DC Study Drug 
 
D1 
D8 
D1 
D8 
Prescreening IC if FGFR2 data not available 
X 
 
 
 
 
 
 
 
 
Prescreening molecular testing if FGFR2 data not available 
X 
 
 
 
 
 
 
 
 
FGFR2 fusion/rearrangement documentation and 
confirmation of tumor availability for central testing  d 
 
X 
 
 
 
 
 
 
 
Collection of archival or a newly obtained tumor sample 
AND pathology report, if archival paraffin blocks/slides 
and pathology report not available 
X 
X e 
 
 
 
 
 
 
 
Main Study IC 
 
X 
 
 
 
 
 
 
 
Demography 
 
X 
 
 
 
 
 
 
 
I/E criteria 
 
X 
 
 
 
 
 
 
 
ECOG Performance Status 
 
X 
X 
 
X 
 
X 
X 
 
Relevant medical history/current medical conditions 
 
X 
 
 
 
 
 
 
 
Diagnosis, primary location, and extent of cancer 
 
X 
 
 
 
 
 
 
 
Prior anticancer therapy 
 
X 
 
 
 
 
 
 
 
Height 
 
X 
 
 
 
 
 
 
 
Weight h 
 
X 
X 
 
X 
 
X 
 
 
Randomization (within 5 days before Cycle 1 Day 1) 
 
X 
 
 
 
 
 
 
 
Gemcitabine/ Cisplatin Dose Administration f 
 
 
X 
X 
X 
X 
 
 
 
Adverse Events  
Continuous g 
 
Prior/concomitant medications 
 
Continuous 
 
Pregnancy test h 
 
X 
X  
 
X 
 
X 
 
 
Vital signs h 
 
X 
X  
X 
X 
X 
X 
 
 
Hematology h 
 
X 
X  
X  
X  
X  
X 
 
 
Chemistry h 
 
X 
X  
X  
X  
X  
X 
 
 
12-lead ECG h 
 
X 
X  
 
X 
 
X 
 
 
Coagulation 
 
X 
If clinically indicated 
 
 
 
Urinalysis (micro- and macroscopic) 
 
X 
If clinically indicated 
 
 
 
Physical examination  
 
X 
Symptom-directed exams, as needed 
X 
 
 


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Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
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Molecular Pre 
screening a 
Screening a 
Visits during Treatment Period  
(21-day Treatment Cycles: Infusions on Day 1 and Day 8 
of each Cycle) 
EOT 
 
30-day Safety Follow-up 
Survival 
Follow-up 
 
Every 3 mo 
After Disease 
Progression c 
 
Wk1 
D1 
Wk2 
D1 
Each Additional Cycle 
Time of Study b 
 
-28 to -1 
Cycle 1 
Cycle 2-8+ 
No Later than 8d 
from Decision to 
DC Study Drug 
 
D1 
D8 
D1 
D8 
Ophthalmic assessment (performed by an ophthalmologist) 
i 
 
X 
 
 
C2D8, C5D1, and every 
3 months after j 
X j 
 
 
CT/MRI scans of the chest, abdomen, and pelvis (also brain 
if clinically indicated) 
 
X k 
Tumor response will be assessed at Wk9D1 and every 8 wk (±1wk) thereafter until PD confirmed by 
BICR, regardless of drug interruption (RECIST 1.1). After PD is confirmed by BICR, tumor 
assessments will be completed only according to investigator assessment (no longer BICR-assessed). l 
EQ-5D, EORTC QLQ-C30, EORTC QLQ-BIL21 m 
 
 
QOL assessments are every 4 weeks through Wk17D1 i.e, 
Wk1D1, Wk5D1, Wk9D1, Wk13D1, Wk17D1, and every 8 
wk (±1wk) from last assessment, regardless of drug 
interruption 
X 
 
 
Blood sample for assessment of cell-free tumor DNA (all 
samples are predose) 
 
 
X n 
Every 8 wk (±1wk) coinciding with CT/MRI 
scans, regardless of drug interruption n   
X  
(if not done 
within 28 d prior) 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
X 
Anticancer therapies since discontinuation of study drug 
 
 
 
 
 
 
 
X 
X 
Newly obtained tumor sample (if medically feasible) 
 
 
X (upon disease progression)-optional 
 
 
Abbreviations: AE, adverse event; BICR, blinded independent central review; CT, computed tomography; d, day; DC, discontinue; DNA, deoxyribonucleic acid; ECG, 
electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for Research and Treatment of Cancer; EOT, end of treatment; EQ-5D, 
EuroQOL five dimensions questionnaire; FGFR2, fibroblast growth factor receptor 2; IC, informed consent; I/E, inclusion/exclusion; MRI, magnetic resonance imaging; NaF, 
sodium fluoride; OCT, optical coherence tomography; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; PFS2, PFS on subsequent 
therapy; PK, pharmacokinetic; QLQ, quality of life questionnaire; RECIST, Response Evaluation Criteria in Solid Tumors;TC99, technetium-99.  
a  After prescreening ICF, molecular prescreening assessments can be done any time prior to the initiation of the screening. All baseline/screening assessments must be performed 
within 28 days before randomization. For subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before randomization, the baseline imaging assessment must 
be conducted ≥7 days after the last dose of chemotherapy and before randomization. Baseline/screening assessments that are conducted within 3 days prior to first treatment 
can be used to satisfy the Day 1 requirement. Every effort must be made to follow the schedule outlined.  
b  Unless otherwise indicated, there is a ±3-day window on assessments. For post-baseline imaging and ophthalmic assessments, a ±7 day window is allowed, except for the first 
post-baseline assessment (+7 day window permitted). The EOT visit is to be conducted no later than 8 days from the decision to discontinue study drug. 
c  Once radiographic PD is confirmed by BICR and documented, survival status, use of anticancer therapy (names and dates of therapies, response, and reason for 
discontinuation) and date of subsequent progression (PFS2) will be followed approximately every 3 months (via telephone or office visit) until the End of Study, defined as the 
time when at least 224 OS events have been reached (for the primary OS analysis) and the last subject has completed study treatment. 
d  Central laboratory testing for FGFR2 fusion/rearrangement will include microsatellite instability status. 


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27 July 2021 
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e  If written documentation of FGFR2 fusion/rearrangement is determined by a local laboratory, archival or fresh biopsy tumor tissue sample must be submitted to the central 
laboratory within approximately 14 days of start of study treatment for the confirmation of FGFR2 fusion/rearrangement. Refer to the Laboratory Manual for the sample 
requirements and processing instructions for central laboratory testing of FGFR2 fusion/rearrangement. 
f  
Subjects will receive gemcitabine plus cisplatin on Day 1 and Day 8 of each 21-day treatment cycle until radiographic PD confirmed by BICR; unacceptable toxicity; or other 
reason listed in Section 8.1.1. Following radiographic PD confirmed by BICR, subjects randomized to the gemcitabine with cisplatin group may be eligible to cross over and 
receive infigratinib (see Section 7.1). If one or more toxicities result in delay of cycle start, the cycle will be considered to start on the first day when any chemotherapy is 
administered. Subjects who cannot start a cycle within 21 days of the scheduled Day 1 (ie, within 42 days of the previous cycle Day 1) must permanently discontinue all 
chemotherapy unless approved by the sponsor medical monitor. If Day 8 dosing can’t be given by Day 15 of a 21-day cycle, the subject should skip the Day 8 dose and dosing 
will resume on Day 1 of the next scheduled cycle.  
g 
See Section 10.5.1.3 for details on the collection and recording of adverse events (including serious adverse events).  
h  
To be conducted within 3 days before the first study treatment is administered; all subsequent assessments may be conducted at any time relative to treatment (pre- or 
post-treatment), unless specified otherwise. For each subject, 12-lead ECGs are to be performed at the Screening visit; on Day 1 (predose) of Cycle 1, Day 1 of Cycle 2, at the 
EOT visit, and otherwise as clinically indicated. 
i 
If a subject is not dosed at a visit where dosing is scheduled, then the procedures specified for that visit must be completed/repeated on the actual dosing day, with the 
exception of ophthalmic assessment (performed by an ophthalmologist). 
j  
Ophthalmic assessment (performed by an ophthalmologist) will be done C2D8, C5D1, and every 3 months after that. Ophthalmic assessment includes visual acuity testing 
(including corrected distance acuity), slit lamp examination of the anterior eye segment, intraocular pressure, retinal OCT, and dilated fundoscopy. Additional examination 
methods such as specular microscopy and corneal pachymetry will be done as clinically indicated. Retinal OCT scan images will be collected centrally for potential review. 
Refer to the Study Manual for details regarding image collection and transfer or shipment. Ophthalmic assessment will be conducted at EOT visit unless performed within 
previous 4 weeks. 
k 
For subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before randomization, the baseline imaging assessment must be conducted ≥7 days after the last 
dose of chemotherapy and before randomization. For subjects with skeletal lesions suspected at screening, whole-body bone imaging should be obtained either with a TC99 
bone scan or alternatively a NaF CT/ MRI PET scan, with local CT of any identified lesions. Of note, the CT or MRI portion of the scan should only be substituted for the 
required chest, abdomen, and pelvic CT scans if the CT or MRI is of diagnostic quality and meets all requirements as described in the study imaging guide (ie, oral and IV 
contrast, slice thickness, and anatomic coverage). Postbaseline, if skeletal lesions are identified at screening, which are not visible on the chest, abdomen or pelvis CT/MRI 
scan, bone imaging with either a TC99 bone scan or NaF CT/MRI PET is required at all postbaseline imaging timepoints (every 8 weeks). In all cases that postbaseline bone 
imaging is required, the same modality that was used at screening should be used for all postbaseline imaging when possible. 
l 
During the treatment period, subjects will be evaluated every 8 weeks from the first dose of study drug, regardless of drug interruption. For post-baseline imaging 
andophthalmic assessments, a ±7 day window is allowed, except for the first post-baseline assessment (+7 day window permitted). If a subject discontinues study drug for 
reasons other than PD confirmed by BICR, a radiographic assessment should be conducted at the EOT visit, unless taken within the previous 4 weeks. Subjects who 
discontinue study drug for reasons other than PD confirmed by BICR will continue to have radiographic assessments every 8 weeks ±7 days until radiographic PD confirmed 
by BICR (even if subjects start new anticancer treatment). After PD is confirmed by BICR, tumor assessments will be completed only according to investigator assessment (no 
longer BICR-assessed). 
m  Quality of life assessments should be conducted prior to all other study procedures and in order of EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BIL21. Assessments do not 
need to be administered at the EOT visit if they were completed within the previous 7 days at a regularly scheduled visit.  
n 
Blood for cell-free DNA should be collected Day 1 of Cycle 1 (predose) and then every 8 wk (±1wk) at the same visit as CT/MRI scans. For subjects who discontinue therapy 
without radiographic PD confirmed by BICR, a blood sample for cell-free DNA should be taken once progression is confirmed by BICR and/or investigator.  


Infigratinib 
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Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
Page 30 of 120
 
 
Table 5: 
Schedule of Assessments: Subjects in the Gemcitabine plus Cisplatin Group who Cross Over to 
Infigratinib 
Time of Study a 
Visits during Treatment Period 
(To be Followed Once a Subject in the Gemcitabine plus Cisplatin Group has PD 
Confirmed by BICR and Crosses Over to Infigratinib) b 
EOT 
No Later than 
8 d from 
Decision to DC 
Study Drug 
30-day Safety 
Follow-up
Survival 
Follow-
up 
 
Every 
3 mo c 
Wk1 
D1 
Wk2 
D1 
Wk3 
D1 
Wk4 
D1 
Wk5 
D1 
Wk9 
D1 
Wk13 
D1 
Each Additional 
Cycle 
Cycle 1 
Cycle 2 
Cycle 3 
Cycle 4 
Cycle 5+ 
D1 
D8 
D15 
D22 
D1 
D1 
D1 
D1 
I/E criteria 
X d 
 
 
 
 
 
 
 
 
 
 
ECOG Performance Status 
X 
 
 
 
X 
X 
X 
X 
X 
X 
 
Infigratinib (Crossover) 
Daily dosing using a “3 weeks on, 1 week off” schedule for each 28-day treatment cycle 
 
 
 
Adverse Events 
Continuous 
 
Prior/ concomitant medications 
Continuous 
 
Pregnancy test e 
X 
 
 
 
X 
X 
X 
X 
X 
 
 
Vital signs e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
Hematology e 
X 
 
X 
 
X 
X 
X 
X 
X 
 
 
Chemistry e 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
12-lead ECG e, f 
X 
 
 
 
X 
 
 
 
X 
 
 
Coagulation 
If clinically indicated 
 
 
 
Urinalysis (micro- and macroscopic) 
If clinically indicated 
 
 
 
Physical examination 
Symptom-directed exams, as needed 
X 
 
 
Ophthalmic assessment (performed by an 
ophthalmologist) e 
C2D1, C4D1, and every 3 months after g 
X g 
 
 
CT/MRI scans of the chest, abdomen, and 
pelvis (also brain if clinically indicated) 
Tumor response will be assessed at Wk9D1 and every 8 wk (±1wk) thereafter until PD confirmed by BICR, regardless of drug 
interruption (RECIST 1.1). After PD is confirmed by BICR, tumor assessments will be completed only according to investigator 
assessment (no longer BICR-assessed).h 
Blood sample for assessment of cell-free 
tumor DNA (all samples are predose) 
X 
Every 8 wk (±1wk) coinciding with CT/MRI scans, regardless of drug interruption i 
X  
(if not done 
within 28 d prior) 
 
 
Survival follow-up 
 
 
 
 
 
 
 
 
 
 
X 
Abbreviations: d, day; DC, discontinue; DNA, deoxyribonucleic acid; ECG, electrocardiogram; ECOG, Eastern Cooperative Oncology Group; EORTC, European Organization for 
Research and Treatment of Cancer; EOT, end of treatment; FGFR2, fibroblast growth factor receptor 2; I/E, inclusion/exclusion; MRI, magnetic resonance imaging; NaF, sodium 


Infigratinib 
QED Therapeutics
Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
Page 31 of 120
 
 
fluoride; OCT, optical coherence tomography; PD, progressive disease; PET, positron emission tomography; PFS, progression-free survival; QLQ, quality of life questionnaire; 
RECIST, Response Evaluation Criteria in Solid Tumors; TC99, technetium-99. 
a  For all visits, there is a ±3-day window on assessments, if not explicitly specified otherwise. The EOT visit is to be conducted no later than 8 days from the decision to 
discontinue study drug. 
b  Subjects randomized to the gemcitabine with cisplatin group who cross over to receive infigratinib must complete their 30-day Safety Follow-up visit for gemcitabine with 
cisplatin before receiving any infigratinib.  
c  Survival status will be followed approximately every 3 months (via telephone or office visit) until the End of Study, defined as the time when at least 224 OS events have been 
reached (for the primary OS analysis) and the last subject has completed study treatment. 
d  Before subjects in the gemcitabine/cisplatin cross over and receive any infigratinib, the following exclusion criteria must be rechecked: Exclusion Criteria 4, 7-10, 13, 14, 
16-18. Assessments performed within the past 30 days may be used to check these criteria. If the subject is receiving ondansetron, its use must be discontinued with a washout 
period of at least 24 hours before receiving any infigratinib. 
e  If a subject is not dosed at a visit where dosing is scheduled, then the procedures specified for that visit must be completed/repeated on the actual dosing day, with the 
exception of ophthalmic assessment (performed by an ophthalmologist). 
f  For each subject, 12-lead ECGs are to be performed on Days 1 (predose) and 15 of Cycle 1; on Day 1 of Cycle 2; at the EOT visit, and otherwise as clinically indicated. 
g 
Ophthalmic assessment (performed by an ophthalmologist) will be done on C2D1, C4D1, and every 3 months after that. Ophthalmic assessment includes visual acuity testing 
(including corrected distance acuity), slit lamp examination of the anterior eye segment, intraocular pressure, retinal OCT, and dilated fundoscopy. Additional examination 
methods such as specular microscopy and corneal pachymetry will be done as clinically indicated. Retinal OCT scan images will be collected centrally for potential review. 
Refer to the Study Manual for details regarding image collection and transfer or shipment. Ophthalmic assessment will be conducted at EOT visit unless performed within 
previous 4 weeks. 
h 
For subjects with existing or suspected new skeletal lesions, whole-body bone imaging should be obtained either with a TC99 bone scan or alternatively a NaF CT/ MRI PET 
scan, with local CT of any identified lesions. Of note, the CT or MRI portion of the scan should only be substituted for the required chest, abdomen, and pelvic CT scans if the 
CT or MRI is of diagnostic quality and meets all requirements as described in the study imaging guide (ie, oral and IV contrast, slice thickness, and anatomic coverage). 
Postbaseline, if skeletal lesions are identified at screening, which are not visible on the chest, abdomen or pelvis CT/MRI scan, bone imaging with either a TC99 bone scan or 
NaF CT/MRI PET is required at all postbaseline imaging timepoints (every 8 weeks). In all cases that postbaseline bone imaging is required, the same modality that was used 
at screening should be used for all postbaseline imaging when possible.  
 i 
Blood for cell-free DNA should be collected at Day 1 of Cycle 1 (predose) of starting infigratinib treatment and then every 8 wk (±1wk) from last assessment, regardless of 
drug interruption. For subjects who discontinue therapy without radiographic PD confirmed by BICR, a blood sample for cell-free DNA should be taken once progression is 
confirmed by BICR and/or investigator. 
 
 


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3 BACKGROUND 
3.1 
Overview of Disease Pathogenesis, Epidemiology and Current 
Treatment 
Cholangiocarcinoma is the most common biliary tract malignancy with approximately 
5,000 new cases diagnosed each year in the United States (Ghouri et al 2015). The 
average age at presentation is 50 years, with the majority of cases in the Western world 
diagnosed at or after the age of 65 years (Ghouri et al 2015). Based on its location, it is 
classified as intrahepatic, perihilar or extrahepatic cholangiocarcinoma. Extrahepatic and 
perihilar cholangiocarcinoma are the most common types, with 6–8% of 
cholangiocarcinomas being intrahepatic, 50–67% perihilar and 27–42% distal 
extrahepatic (Nakeeb et al 1996; DeOliveira et al 2007).  
Histologically, 90% of cholangiocarcinomas are adenocarcinomas with other variants 
including signet-ring type, clear cell type, papillary adenocarcinoma, intestinal type 
adenocarcinoma, oat cell carcinoma, adenosquamous carcinoma and squamous cell 
carcinoma (Olnes and Erlich 2004).  
No predisposing factors are identified in most patients with cholangiocarcinoma, 
although there is evidence the presence of chronic inflammation, such as primary 
sclerosing cholangitis, hepatolithiasis, choledochal, and liver fluke infections, might be 
associated with the disease in some patients (National Comprehensive Cancer Network 
[NCCN] Guideline Version 1, 2021). Other risk factors for intrahepatic 
cholangiocarcinoma have been found to include infections with hepatitis C virus and/or 
hepatitis B virus, obesity, cirrhosis, diabetes, alcohol, non-alcoholic fatty liver disease 
and tobacco (Welzel et al 2007).  
The clinical presentation of cholangiocarcinoma patients is unspecific. Patients with 
intrahepatic masses may present with abdominal pain, malaise, night sweats, weight loss 
and loss of appetite. Patients with extrahepatic cholangiocarcinoma tend to present with 
symptoms of obstructive jaundice and sometimes with complications like cholangitis 
(Ghouri et al 2015). There is no effective screening for cholangiocarcinoma, hence most 
patients with cholangiocarcinoma are diagnosed at an advanced stage. 
Surgical treatments are the only potentially curative therapeutic options. For patients not 
amenable to curative surgical treatment, the current standard of care is combination 
chemotherapy with gemcitabine plus cisplatin, which has been shown to significantly 
increase progression free survival compared with the gemcitabine-only regimen, based on 
the ABC-02 trial (Valle et al 2010; Ghouri et al 2015; NCCN Guideline Version 1, 2021). 
In the ABC-02 trial, the median overall survival (OS) was 11.7 months in the 
gemcitabine with cisplatin group and 8.1 months in the gemcitabine only group. The 
median progression-free survival (PFS) was 8.0 months in the gemcitabine with cisplatin 
group and 5.0 months in the gemcitabine only group. Other gemcitabine-based and 
fluoropyrimidine-based combination chemotherapy regimens, including gemcitabine with 


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oxaliplatin or capecitabine, capecitabine with cisplatin or oxaliplatin, fluorouracil with 
cisplatin or oxaliplatin, and single-agent fluorouracil, capecitabine, and gemcitabine 
might be used (NCCN Guideline Version 1, 2021). None of these regimens are approved 
by the Food and Drug Administration (FDA) primarily for use in biliary tract cancers. 
In the palliative setting, local ablative therapies, such as radiofrequency ablation, 
transarterial chemoembolization (TACE), drug eluting bead-TACE (DEB-TACE), 
selective intra-arterial radiotherapy with Y microspheres or external beam radiation 
therapy for intrahepatic cholangiocarcinoma, and photodynamic therapy with or without 
stents for perihilar cholangiocarcinoma, have been considered. No studies have been 
conducted to show the survival benefit for most of these mentioned local therapies 
(Ghouri et al 2015). Thus, there is a real need to develop novel therapeutic strategies for 
cholangiocarcinoma based on exploiting select molecular targets that would significantly 
impact clinical outcomes. Molecular alterations implicated in the dysregulation of 
cholangiocarcinoma cell growth and survival, aberrant gene expression, and invasion and 
metastasis have been considered potential therapeutic targets (Sirica 2005). 
The fibroblast growth factor receptor (FGFR) family (FGFR 1-4) plays an important role 
in the pathology of cholangiocarcinoma (Jain et al 2018). Using reverse-transcriptase 
polymerase chain reaction screening, the FGFR2 fusion was detected in 8.9% of the 
patients with cholangiocarcinoma (9/102 patients), and 13.6% (9/66 patients) exclusively 
in the intrahepatic subtype (Borad et al 2014). Using ribonucleic acid (RNA) sequencing, 
Sia et al (2015) reported that FGFR2 fusions are frequent molecular aberrations in 
intrahepatic cholangiocarcinomas, occurring in about 16% (17/107) of patients with 
intrahepatic cholangiocarcinomas, and represent a recurrent targetable alteration for 
potential therapy. 
3.2 
Overview of Infigratinib 
Infigratinib (formerly BGJ398, also known as BBP-831, and infigratinib phosphate) is an 
orally bioavailable, potent and selective ATP-competitive inhibitor of FGFRs 1-3, which 
has demonstrated anti-tumor activity in nonclinical in vitro and in vivo tumor models 
harboring FGFR genetic alterations (data on file). Infigratinib is a tyrosine kinase 
inhibitor and its chemical name is 3-(2,6-dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-
ethylpiperazin-1-yl)phenylamino]-pyrimidin-4-yl}-1-methylurea phosphate (1:1). 
Please refer to the current Investigator’s Brochure for the most recent information on 
infigratinib. 
3.3 
Nonclinical Experience with Infigratinib 
At the cellular level, infigratinib selectively inhibits the kinase activity of FGFR1, 
FGFR2 and FGFR3, as measured by inhibition of receptor autophosphorylation, with half 
maximal inhibitory concentration (IC50) values of 1.1, 1.0, and 2.0 nM, respectively. 
Infigratinib also inhibits FGFR4 (IC50 61 nM), but not at clinically relevant 
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Consistent with inhibition of FGFR autophosphorylation, infigratinib inhibits FGFR 
downstream signaling and proliferation of human cancer cell lines harboring genetic 
alterations of the FGFRs. These include, among others, lung and breast cancer cell lines 
with FGFR1 gene amplification, gastric cancer with FGFR2 gene amplification, 
endometrial cancer with FGFR2 mutations and bladder cancer with FGFR3 mutations or 
FGFR3 rearrangements (Wesche et al 2011; Guagnano et al 2012; Konecny et al 2013). 
In vivo, infigratinib is widely distributed to tissues in the rat. A battery of in vivo safety 
pharmacology studies in rats and dogs did not reveal any effects on central nervous or 
respiratory systems and on hemodynamic or electrocardiographic parameters, 
respectively. 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, infigratinib did lead to 
increases in serum fibroblast growth factor 23 and serum phosphorous associated with 
partially reversible ectopic mineralization (kidney, vascular and digestive systems) along 
with largely reversible changes in renal function parameters and bone growth plate 
thickening / retention of the primary spongiosa in rats (≥10 mg/kg/day) and dogs 
(≥10 mg/kg/day). These effects were deemed to be on-target effects mediated by 
pharmacological inhibition of FGFR.  
The no observed adverse effect level in the dog and rat was 1 mg/kg. 
3.4 
Clinical Experience with Infigratinib 
Please refer to the current Investigator’s Brochure for the most recent clinical safety and 
efficacy information on infigratinib. 
3.4.1 
Clinical Pharmacokinetics and Phase 1 Data 
The pharmacokinetics (PK) of infigratinib and its active metabolites have been evaluated 
following single and repeat daily doses in a Phase 1 study (CBGJ398X2101).  
Following a single dose, median Tmax was approximately 3-4 hours. Infigratinib had a 
relatively short median elimination half-life ranging from 2.69 to 5.71 hours on Day 1. 
Despite the relatively short half-life on Day 1, accumulation was observed with daily 
dosing at doses ≥60 mg, likely due to auto-inhibition of CYP3A4 mediated clearance 
pathways (data on file). Mean accumulation ratio (Racc) ranged from 3 to 8 on Days 15 
and 28. The interpatient variability was high for infigratinib. 
In vitro studies indicated that infigratinib inhibits CYP3A4; therefore, a clinical drug-
drug interaction study (QBGJ389-106) was conducted to assess the effects of multiple 
doses of infigratinib on midazolam (a sensitive CYP3A4 substrate). Midazolam exposure 
in terms of AUCinf and Cmax was minimally reduced (11% and 1%, respectively). For the 
active metabolite, 1-hydroxymidazolam, exposure increased by 19% and 26% for AUCinf 
and Cmax, respectively. Overall, these results indicate that infigratinib had a small effect 
on the metabolism of midazolam and can be considered a weak CYP3A4 inhibitor. As 
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by CYP3A4. However, due to the weak inhibition, drugs that are CYP3A4 substrates and 
have a narrow therapeutic index should be co-administered with caution. 
In the single agent, first-in-human Phase 1 study (CBGJ398X2101), infigratinib was 
evaluated at 9 different dose levels and 3 different dose schedules, ranging from 
5 mg/day to 150 mg/day. Eight dose levels were administered on the once daily 
continuous 28-day cycle schedule, and one dose level was administered on a twice a day 
continuous 28-day cycle schedule. One subject at 100 mg experienced Grade 3 alanine 
aminotransferase (ALT) and aspartate aminotransferase (AST) elevation, 1 subject at 
125 mg daily experienced hyperphosphatemia, and 2 subjects at 150 mg experienced 
Grade 1 corneal toxicity (1 subject) and Grade 3 ALT and AST elevation (1 subject). The 
dose of infigratinib 125 mg once daily continuously was declared as the maximum 
tolerated dose (MTD).  
While dose levels of 100 mg QD and higher were tolerated by subjects, the majority of 
subjects experienced reversible hyperphosphatemia, which led to study drug interruptions 
(data on file). An evaluation of the drug administration records for subjects prior to 
receiving prophylactic phosphate-lowering therapy indicated that the median time until 
first dose interruption was approximately 22 days and the median duration of interruption 
was 7 days. This observation led to the introduction of an expansion arm to evaluate the 
administration of 125 mg QD on a 3 week on (21 days) / 1 week off (7 days) schedule in 
28-day cycles. Subjects treated with this alternative dosing schedule required less dose 
interruption (n=24, 49.0%) compared with subjects treated with 125 mg continuously 
(n=40, 70.2%). Thus, infigratinib 125 mg once daily on a 3 weeks on/1 week off schedule 
was declared as the recommended Phase 2 dose (RPTD).  
In the dose escalation cohort of 92 subjects, no complete response (CR) was observed, 
and 4 subjects had partial response (PR) (1 subject at 100 mg; 3 subjects at 125 mg 
continuous dose).  
Of the 173 subjects treated at the 125 mg continuous or intermittent schedule, CR was 
observed in 2 subjects (1.2%), and 22 subjects (12.7%) had PR. The overall response rate 
(ORR) (95% confidence interval [CI]) and disease control rate (95% CI) were 13.9% 
(9.10, 19.94) and 49.1% (41.47, 56.83), respectively.  
The median PFS for all subjects treated at the MTD/RPTD was 3.12 months (95% CI: 
2.10, 3.65 months). 
3.4.2 
Clinical Safety 
Based on Investigator’s Brochure (Edition 11), a total of 480 patients and 134 healthy 
volunteers had received infigratinib, alone or in combination, in 4 healthy volunteer, two 
Phase 1, one Phase 1b, and three Phase 2 trials. All trials have completed with the 
exception of the ongoing Phase 2 CBGJ398X2204 study of infigratinib in patients with 
advanced or metastatic cholangiocarcinoma with FGFR2 fusions/rearrangements or other 
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A safety analysis was completed for CBGJ398X2204 on a data cutoff of 01 June 2017. 
As of 01 June 2017, 63 patients had been treated in CBGJ398X2204 which included 
50 patients with FGFR2 fusions and 13 patients with other FGFR alterations. The most 
commonly reported treatment emergent adverse event (AE) of any grade was 
hyperphosphatemia, reported in 82.5% of patients. Other frequently reported AE include 
fatigue (49.2%), constipation (41.3%), stomatitis (38.1%), alopecia (38.1%), dysgeusia 
(31.7%), blood creatinine increased (27.0%), hypophosphatemia (27.0%), nausea 
(27.0%), diarrhea (25.4%), dry eye (25.4%), arthralgia (23.8%), dry mouth (23.8%), dry 
skin (23.8%), palmar plantar erythrodysesthesia syndrome (23.8%), aspartate 
aminotransferase increased (22.0%), decreased appetite (20.6%), hypercalcemia (20.6%), 
alanine aminotransferase increased (19.0%), vision blurred (19.0%), anemia (17.5%), 
dyspepsia (17.5%), vomiting (17.5%), weight decreased (17.5%), epistaxis (17.5%), 
onychomadesis (17.5%), myalgia (17.5%), pain in extremity (16.1%), and cough 
(16.1%).  
Forty-one of 63 patients (65.1%) experienced at least one grade 3 or 4 event regardless of 
the relationship to infigratinib. Grade 3 or 4 events that occurred in at least 5% of patients 
were hyperphosphatemia (15.9%), hypophosphatemia (6.3%), hyponatremia (12.7%), 
lipase increased (7.9%), and stomatitis (7.9%).  
Twenty-nine of 63 patients (46.0%) experienced at least one grade 3 or 4 suspected to be 
related to infigratinib. Grade 3 or 4 events that occurred in at least 5% of patients were 
hyperphosphatemia (15.9%) and stomatitis (7.9%).  
Overall, most AEs reported have been mild to moderate in severity, reversible, and 
unrelated to infigratinib.  
No effect of infigratinib on electrocardiogram (ECG) intervals, including QTc, has been 
noted. Reversible and largely asymptomatic decreases in left ventricular ejection fraction 
(LVEF) have been noted in subjects enrolled on study, as measured by serial 
transthoracic echocardiography or multiple gated acquisition (MUGA) scans. 
3.4.3 
Clinical Efficacy 
Preliminary anti-tumor activity was seen in the Phase 1 first-in-human trial in subjects 
treated at doses of ≥100 mg of infigratinib in FGFR1-amplified squamous non-small cell 
lung cancer and urothelial carcinoma with FGFR3 genetic alterations.  
As of 08 August 2018, 83 subjects with advanced or metastatic cholangiocarcinoma 
containing FGFR genetic alterations were enrolled in Study CBGJ398X2204, of whom 
71 had FGFR2 fusions or rearrangements. Of 71 evaluable subjects with the potential for 
confirmation of response (subject completed or discontinued prior to 6 cycles) 
(preliminary data with a cutoff date of 08 August 2018), the investigator-assessed ORR 
was 26.9% (95% CI: 16.8-39.1%). The disease control rate (CR + PR + stable disease 
[SD]) was 83.6% (95% CI: 72.5-91.5%), with a median duration of response of 
5.4 months (95% CI: 3.7-7.4 months). The median PFS was 6.8 months (95% CI: 
5.3-7.6 months) (Javle et al 2018). 


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3.5 
Rationale 
3.5.1 
Study Rationale and Purpose 
The growing understanding of the genetic alterations involved in the tumorigenesis of 
cholangiocarcinoma provides new therapeutic options for molecular targets. Among other 
genetic alterations, recurrent fusions involving the FGFRs are an important class of driver 
mutations in a number of tumor types, including cholangiocarcinoma.  
Wu et al (2013) reported 24 primary tumors or cell lines with FGFR1, FGFR2, or FGFR3 
fusions among other targetable fusions. These FGFR fusions involve numerous protein 
partners with various functions that maintain kinase activity after formation. The 
identified fusions expressed an FGFR family member as a 5’ or 3’ fusion partner with an 
intact kinase domain, suggesting that these may serve as potential therapeutic targets via 
kinase inhibition. Cancer types harboring FGFR fusions were quite diverse and included 
cholangiocarcinoma (n=2), breast cancer (n=4), prostate cancer (n=1), thyroid cancer 
(n=1), lung squamous cell carcinoma (n=6), bladder cancer (n=5), oral cancer (n=1), head 
and neck squamous cell carcinoma (n=2), and glioblastoma (n=2). Two 
cholangiocarcinoma patients were reported to harbor FGFR2-bicaudal c homolog 1 
(BICC1) fusions. Cells harboring FGFR fusions showed enhanced sensitivity to the 
FGFR inhibitors PD173074 and pazopanib, suggesting that patients with cancer with 
FGFR fusions may benefit from targeted FGFR kinase inhibition.  
In a second study (Arai et al 2014), two fusion kinase genes, FGFR2-AHCYL1 and 
FGFR2-BICC1 were identified in 2 of 8 cholangiocarcinoma tumor samples by massive-
parallel whole transcriptome sequencing. Further, reverse transcription polymerase chain 
reaction and Sanger sequencing analysis of 102 cholangiocarcinoma specimens (66 
intrahepatic cholangiocarcinomas and 36 extrahepatic cholangiocarcinomas) identified 
seven FGFR2-AHCYL1-positive and two FGFR2-BICC1-positive cases, which were 
identified as oncogenic in an NIH3T3 transformation assay. Treatment with FGFR 
inhibitors, including infigratinib, reversed the transformed phenotype. In a third study 
(Jiao et al 2013), somatic mutations in FGFR2 were identified in 4 of 32 (12.5%) 
intrahepatic cholangiocarcinomas. Thus, FGFR fusions or activating mutations could 
potentially identify a subset of cholangiocarcinoma patients who would benefit from 
targeted FGFR kinase inhibition. 
Infigratinib has been shown to specifically inhibit proliferation of cancer cells with FGFR 
genetic alterations; infigratinib did not alter cell growth in cells that did not express 
FGFR or where FGFR was not altered (data on file). In vivo, infigratinib significantly 
inhibited growth of tumors in a dose-dependent manner in various mouse and rat 
xenograft subcutaneous or orthotopic models. These include models of bladder cancer 
with FGFR3 chromosomal rearrangement or FGFR3 mutation (RT112, MGHU3), 
endometrial cancer with FGFR2 mutation (AN3CA), lung cancer with FGFR1 
amplification (NCI-H1581) and gastric cancer with FGFR2 amplification (SNU16) (data 
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On the basis of the activity of infigratinib in a variety of cancer models harboring FGFR 
genetic alterations (Guagnano et al 2012), including rearrangements, the Phase 2 study 
CBGJ398X2204 was conducted. As described above, the single arm study demonstrated 
clinically meaningful activity of infigratinib in subjects with refractory 
cholangiocarcinoma containing FGFR2 fusions or other rearrangements. 
3.5.2 
Rationale for the Study Design 
The ABC-02 trial established gemcitabine with cisplatin as standard of care for first line 
treatment of cholangiocarcinoma (Valle et al 2010). Still, the median PFS was 8.0 months 
and median OS was 11.7 months. Study CBGJ398X2204 suggested that infigratinib 
could offer a targeted, chemotherapy-free therapeutic option for first line treatment of 
patients with advanced or metastatic cholangiocarcinoma with FGFR2 fusions.  
The current Phase 3 study is being conducted to evaluate the efficacy and safety of 
infigratinib specifically in subjects with unresectable locally advanced or metastatic 
cholangiocarcinoma with FGFR2 fusion/rearrangement. Further, PK estimates will be 
evaluated to gain further understanding of the PK of infigratinib and its metabolites. In 
addition to the companion diagnostic detection of molecular alterations, longitudinal 
tumor and blood samples from treated subjects will be analyzed. Molecular 
characterization of tumors at baseline and at the time of progression may allow for 
increased understanding of potential treatment combinations, as well as primary and 
acquired resistance mechanisms. 
The study is of parallel-group design, comparing orally administered infigratinib with 
infusion of gemcitabine plus cisplatin (recommended by the NCCN as first line treatment 
of advanced biliary tract cancer [NCCN Guideline Version 1, 2021]). The study is 
stratified and randomized to prevent bias. The study is open-label, as a double-dummy 
design is not ethically feasible.  
3.5.3 
Rationale for Dose and Regimen Selection 
In this study, subjects randomized to the infigratinib group will receive 125 mg QD of 
infigratinib on a 3 week on (21 day) /1 week off (7 day) schedule in 28-day cycles. This 
dose level and regimen is based on experiences from the Phase 1 CBGJ398X2101 and 
Phase 2 CBGJ398X2204 trials, described in Section 3.4. Subjects with mild/moderate 
renal or hepatic impairment should have their dose adjusted because the relative potency 
adjusted steady state AUC of infigratinib and its metabolites is increased in these subjects 
compared with that for subjects with normal organ function; see Section 7.2.1 for dosing 
recommendations, and see the current Investigator’s Brochure for recent clinical safety 
updates. 
Subjects in the gemcitabine plus cisplatin group will receive intravenous (IV) infusions of 
gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2), according to each country’s 
respective labeling, local institutional practices, the ABC-02 trial (Valle et al 2010), and 
as recommended by the NCCN and European Society of Medical Oncology (ESMO) 
guidelines as first line treatment of advanced biliary tract cancer. Subjects who 


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experience progressive disease (PD) in the gemcitabine plus cisplatin group will be 
offered the opportunity to receive infigratinib upon PD confirmed by BICR (NCCN 
Guideline Version 1, 2021; Valle et al 2016).  
3.6 
Benefit/Risk Assessment 
Cholangiocarcinoma harboring FGFR2 fusion/rearrangement, for which standard 
anticancer therapies are still not available, represent a targetable disease for potential 
therapy with infigratinib. Novel chemotherapy-free, oral treatment options with durable, 
clinically meaningful benefit would be a significant improvement over available 
treatments for patients with cholangiocarcinoma harboring FGFR2 
fusions/rearrangements. 
The nonclinical pharmacologic, PK, and toxicologic properties of infigratinib have been 
thoroughly evaluated and support the use of infigratinib in patients with advanced cancer. 
These nonclinical data support investigation of infigratinib as a therapy for tumors with 
oncogenic FGFR2 activation, including cholangiocarcinoma. 
Infigratinib has shown evidence of clinical activity in adult patients with unresectable 
locally advanced or metastatic cholangiocarcinoma, supporting its efficacy (as described 
in Section 3.4.3 and in the Investigator’s Brochure), and infigratinib had an acceptable 
safety profile in this population. Reported adverse events across the infigratinib 
development program are consistent with its mechanism of action and can be adequately 
managed/reversed through dose modification and supportive care, thus minimizing risk to 
study subjects who receive infigratinib. Available clinical data support investigation of 
the safety and efficacy of infigratinib in cholangiocarcinoma. 
Subjects will be closely monitored for safety. For adult patients with cancer who were 
treated with infigratinib, hyperphosphatemia and ocular events are important identified 
risks. Safety assessments consist of complete ophthalmic exams including optical 
coherence tomography (OCT) and performance status assessments. Serum phosphorus 
will be monitored. Based on the mechanism of action and findings in animal reproduction 
studies, infigratinib may cause embryo-fetal harm or loss of pregnancy when 
administered to a pregnant woman. Pregnant women and females of reproductive 
potential are advised of the potential risk to a fetus. Pregnancy status in females of 
reproductive potential will be verified prior to initiating infigratinib. Females of 
reproductive potential will be advised to use effective contraception during treatment 
with infigratinib and for 1 month after the last dose. Males that are partnered with 
females of reproductive potential will be advised to use effective contraception during 
treatment with infigratinib and for 1 month after the last dose. 
More detailed information about the known and expected benefits and risks and 
reasonably expected adverse events of infigratinib may be found in the current 
Investigator’s Brochure. 


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Taking into account the measures taken to minimize risk to subjects participating in this 
study, the potential risks identified in association with infigratinib are justified by the 
anticipated benefits that may be afforded to subjects with cholangiocarcinoma. 
4 OBJECTIVES AND ENDPOINTS 
4.1 
Objectives 
The primary objective is to determine if treatment with infigratinib improves PFS as 
assessed by BICR compared to treatment with gemcitabine and cisplatin in subjects with 
unresectable locally advanced or metastatic cholangiocarcinoma with FGFR2 
fusion/rearrangement. 
The secondary objectives are to 
• Determine if treatment with infigratinib improves OS compared to treatment with 
gemcitabine and cisplatin in subjects with unresectable locally advanced or metastatic 
cholangiocarcinoma with FGFR2 fusion/rearrangement. 
• Evaluate the efficacy of infigratinib treatment compared to gemcitabine and cisplatin 
in terms of investigator assessed PFS. 
• Further evaluate the efficacy in subjects treated with infigratinib versus gemcitabine 
and cisplatin by ORR, best overall response (BOR), duration of response and disease 
control rate determined by BICR and by the investigator. 
• Characterize the safety and tolerability of single agent infigratinib. 
The exploratory objectives are to 
• Evaluate the efficacy of infigratinib treatment compared to gemcitabine and cisplatin 
in terms of investigator assessed PFS after subsequent therapy (PFS2). 
• Compare quality of life (QOL) in subjects treated with infigratinib or gemcitabine and 
cisplatin. 
• Assess the PK of infigratinib and its active metabolites including BHS697 and 
CQM157. 
• Evaluate the overall genomic landscape of subjects with cholangiocarcinoma. 
• Evaluate biomarkers related to cholangiocarcinoma biology and their potential 
correlation to efficacy, disease progression, and resistance to study medications. 


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4.2 
Endpoints 
The primary endpoint is PFS (from date of randomization until date of progression as 
determined by blinded independent central review [BICR] or death due to any cause, 
whichever is earlier). 
The secondary endpoints are:  
• OS (from date of randomization until date of death) 
• PFS as determined by the investigator 
• ORR assessed by BICR according to Response Evaluation Criteria in Solid Tumors 
(RECIST) Version 1.1 
• ORR assessed by the investigator according to RECIST Version 1.1 
• BOR, disease control rate (PR + CR + SD), and duration of response (only for 
subjects who have a response) assessed by BICR and by the investigator according to 
RECIST 1.1 
• Type, frequency, and severity of AEs and serious AEs (SAEs), laboratory 
abnormalities, and other safety findings. 
The exploratory endpoints are:  
• PFS2 (from date of randomization until date of progression on the subsequent therapy 
or death due to any cause, whichever is earlier) as determined by the investigator 
• QOL as measured by the European Organization for Research and Treatment of 
Cancer (EORTC) quality of life questionnaire (QLQ) C30, EORTC QLQ-BIL21, and 
EuroQOL five dimensions questionnaire (EQ-5D) 
• PK parameters (Cmax, Cmin, and Racc) 
• The prevalence of genomic alterations and their correlations with available 
clinicopathologic and demographic features in subjects with cholangiocarcinoma 
• Genomic and proteomic assessments of tumor biopsies and cell-free DNA (blood) at 
baseline, during treatment, and at disease progression; and determination of the 
prognostic and/or predictive value of biomarkers to the clinical endpoints. 


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5 INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is a multi-center, open label, randomized, controlled Phase 3 study to determine if 
treatment with infigratinib improves PFS assessed by BICR (primary objective) and OS 
(key secondary objective) compared to treatment with gemcitabine and cisplatin in 
subjects with unresectable locally advanced or metastatic cholangiocarcinoma with 
FGFR2 fusion/rearrangement. The study will be conducted at approximately 145 study 
centers worldwide. 
For the purposes of this protocol, “advanced/metastatic or inoperable” (as in the protocol 
title) is equivalent to “unresectable locally advanced or metastatic” (protocol-defined 
study population). 
A study schematic is presented in Figure 1. 
Subjects will be randomized in a 2:1 ratio to receive oral infigratinib administered once 
daily for the first 3 weeks (21 days) of a 28-day treatment cycle compared to a regimen of 
gemcitabine with cisplatin given on Days 1 and 8 of a 21-day treatment cycle (see 
Section 7.1 for details). Randomization will be stratified by unresectable locally 
advanced vs metastatic disease, geographic region (North America, Western Europe, 
Asia Pacific, and rest of the world), prior neoadjuvant/adjuvant treatment (yes/no), and 
received up to 1 cycle of prior gemcitabine-based chemotherapy for unresectable locally 
advanced or metastatic disease (yes/no).  
During the treatment period, subjects will be radiographically evaluated every 8 weeks 
±7 days from the first dose of study drug, regardless of drug interruption, for tumor 
response using the RECIST 1.1 criteria. When the decision is made to discontinue study 
drug (see Section 8.1.1 for details), subjects will complete an End of Treatment (EOT) 
visit, no later than 8 days from the decision to discontinue study drug, and a Safety 
Follow-up visit no more than 30 days after last dose of study drug. If a subject 
discontinues study drug for reasons other than radiographic PD confirmed by BICR, a 
radiographic assessment should be conducted at the EOT visit, unless taken within the 
previous 4 weeks. 
Subjects who discontinue study drug for radiographic PD confirmed by BICR will be 
followed approximately every 3 months (via telephone or office visit) for survival status 
and new anticancer therapy information (subsequent therapy and progression/PFS2) until 
End of Study (EOS), defined as the time when at least 224 OS events have been reached 
(for the primary OS analysis) and the last subject has completed study treatment. Subjects 
who discontinue study drug for reasons other than PD confirmed by BICR will continue 
to have radiographic assessments every 8 weeks ±7 days until radiographic PD confirmed 
by BICR. Thereafter, these subjects will be followed approximately every 3 months for 
survival status and use of anticancer therapy, as described above. 


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Sparse PK blood samples will be collected from all subjects in the infigratinib group at 
multiple time points, predose (Cmin infigratinib) and 4 hours (±30 minutes) postdose (Cmax 
infigratinib). Plasma concentrations of infigratinib and its metabolites (including BHS697 
and CQM157) will be measured. 
For a PK substudy, blood samples will be collected, at multiple time points (predose 
[Cmin infigratinib], 4 hours [±30 minutes] postdose, and 24 hours postdose [±1 hour]) 
from the first 40 subjects who receive infigratinib. Plasma concentrations of infigratinib 
and its active metabolites (including BHS697 and CQM157) will be measured. 
Subjects randomized to the gemcitabine with cisplatin group may be eligible to cross 
over and receive infigratinib following radiographic PD confirmed by BICR; these 
subjects will be followed for safety and OS (according to the schedule of assessments in 
Table 5). 
 


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Figure 1: 
Study Design 
  
 
Abbreviations: BICR, blinded independent central review; EOT, end of treatment; N, no; OS, overall survival; PD, progressive disease; PFS, progression-free 
survival; PFS2, PFS on subsequent therapy; PO, oral; QD, once daily; Y, yes. 
 
 
Pretreatment 
(Prescreening/Screening)
Long-term Follow-up 
(Survival and Safety)
Randomization                     
2:1
Stratification by:
1.
Disease state (locally advanced vs. metastatic)
2.
Geographic region (North America, Western Europe, Asia Pacific, rest of the world)
3.
Prior neoadjuvant/adjuvant treatment (Y/N)
4.
Received up to 1 cycle of prior gemcitabine-based chemotherapy for unresectable locally 
advanced or metastatic cholangiocarcinoma (Y/N)
Infigratinib
125 mg QD PO, 3 weeks on/ 
1 week off, 28-day cycle
Gemcitabine (1000 mg/m2)
+ Cisplatin (25 mg/m2), on 
Days 1 and 8, 21-day cycle
​PFS: PD
confirmed by 
BICR
EOT
option to cross over 
to infigratinib
EOT
Option to receive up 
to 1 cycle of 
gemcitabine-based 
chemotherapy
1st Subsequent therapy
PFS2 
investigator-
assessed PD
OS


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5.2 
Number of Subjects and Time on Study 
Approximately 300 subjects with a likely or known activating FGFR2 
fusion/rearrangement determined by a central laboratory or local laboratory are planned 
for study participation. Note: Central laboratory determination of FGFR2 
fusion/rearrangement is required for all subjects but local determination of FGFR2 
fusion/rearrangement may be obtained and used for eligibility and randomization prior to 
central laboratory results being available. If available FGFR2 fusion/rearrangement 
determination is from the central laboratory being used in the study, a tumor sample does 
not need to be submitted for central FGFR2 fusion/rearrangement molecular testing. 
The duration of time spent on study will vary by subject. Each subject will have a 
Screening visit, conducted up to 28 days prior to first dose of study drug. Thereafter, 
subjects will receive study drug until radiographic PD confirmed by BICR, unacceptable 
toxicity, or other reason listed in Section 8.1.1. Following radiographic PD confirmed by 
BICR, subjects in the gemcitabine with cisplatin group may be eligible to cross over and 
receive infigratinib. 
Once study drug is discontinued, subjects are to complete an EOT visit, followed by 
30-day Safety Follow-up visit. Thereafter, subjects will be followed for disease 
progression and/or survival status, as previously described. 
6 STUDY POPULATION 
6.1 
Inclusion Criteria 
To be eligible for the study, subjects must meet all of the following criteria: 
1. Have histologically or cytologically confirmed unresectable locally advanced or 
metastatic cholangiocarcinoma. Subjects with gallbladder cancer or ampulla of Vater 
carcinoma are not eligible. 
2. Have written documentation of local laboratory or central laboratory determination of 
a known or likely activating FGFR2 fusion/rearrangement from a sample collected 
before randomization (refer to Section 10.3.1 for the definition of a known or likely 
activating FGFR2 fusion/rearrangement). Note: All subjects enrolled based on local 
molecular test results must have sufficient tumor tissue for confirmation of FGFR2 
fusion/rearrangement by the central laboratory, but this central confirmation is not 
required prior to enrollment in the study. 
3. Have an archival tumor tissue sample available with sufficient tumor content for 
FGFR2 fusion/rearrangement molecular testing by the central laboratory. However, if 
an archival tumor tissue sample is not available or does not meet requirements for 
central testing, a newly obtained (before randomization) tumor biopsy may be 
submitted instead. If a prestudy written documentation of FGFR2 


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fusion/rearrangement in tumor tissue is available from the central laboratory, an 
additional tumor sample does not need to be submitted.  
4. Have full recovery from the following permitted prior treatments (as applicable) such 
that the subject is reasonably expected to tolerate study treatment 
(gemcitabine/cisplatin or infigratinib) according to the investigator’s assessment: 
a. A non-curative operation (ie, R2 resection [with macroscopic residual disease] or 
palliative bypass surgery only) 
b. Curative surgery with evidence of unresectable disease relapse requiring systemic 
chemotherapy 
c. Adjuvant radiotherapy (with or without radio-sensitizing low-dose chemotherapy) 
for localized disease provided there has been clear evidence of disease 
progression before inclusion in this study 
d. Adjuvant or neoadjuvant chemotherapy, provided recurrence occurred >6 months 
after the date of the last dose of adjuvant or neoadjuvant therapy and before 
randomization 
e. Gemcitabine-based chemotherapy (specified in Appendix 5 [Section 17.5]) for 
advanced/unresectable or metastatic cholangiocarcinoma (≤1 cycle) 
i. Recovery from acute toxicities to the extent that would allow initiation of 
cisplatin-gemcitabine (absolute neutrophil count (ANC) ≥1,000/mm3 
(≥1.0 × 109/L); platelets ≥100,000/mm3 (≥100× 109/L) 
ii. Baseline tumor assessment at least 7 days after the last dose of chemotherapy 
and before randomization 
iii. The window between the last dose of chemotherapy and the start of 
randomized study treatment must be ≥14 days and ≤5 weeks 
f. Photodynamic treatment provided there is clear evidence of disease progression at 
the local site or at a new metastatic site 
5. Are ≥18 years of age of either gender. 
6. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤1.  
7. Have a life expectancy >3 months. 
8. Are able to read and/or understand the details of the study and provide written 
evidence of informed consent as approved by IRB/IEC. 
9. Are able to swallow and retain oral medication. 
10. Are willing and able to comply with scheduled visits, treatment plan and laboratory 
tests. 


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11. If a woman of childbearing potential (WOCBP), must have a negative pregnancy test 
within 7 days of the first dose of study drug. A woman is not of childbearing potential 
if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal 
ligation or bilateral oophorectomy at least 6 weeks before taking study drug) or if she 
is postmenopausal and has had no menstrual bleeding of any kind including menstrual 
period, irregular bleeding, spotting, etc., for at least 12 months, with an appropriate 
clinical profile, and there is no other cause of amenorrhea (eg, hormonal therapy, 
prior chemotherapy). 
WOCBP and males whose sexual partners are WOCBP must agree to use barrier 
contraception and a second form of highly effective contraception (Clinical Trials 
Facilitation Group 2014; see Appendix 3 [Section 17.3]) while receiving study drug 
and for 1 month following their last dose of infigratinib or 6 months following their 
last dose of gemcitabine/cisplatin (or according to local labeling and standard 
institutional practice). Alternatively, total abstinence is also considered a highly 
effective contraception method when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (eg, calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
Sexually active males must use a condom during intercourse while taking drug and 
for 1 month after the last dose of infigratinib or 6 months after their last dose of 
gemcitabine/cisplatin (or according to local labeling and standard institutional 
practice) and should not father a child during this period. A condom is required to be 
used by vasectomized men and by men having intercourse with a male partner, to 
prevent delivery of the drug via seminal fluid. 
6.2 
Exclusion Criteria 
To be eligible for the study, subjects must not meet any of the following criteria: 
1. Have received treatment with any systemic anti-cancer therapy for unresectable 
locally advanced or metastatic cholangiocarcinoma, with the following exceptions:  
a. Prior neoadjuvant or adjuvant therapy is permitted if documented disease 
recurrence occurred ≥6 months after the last date of neoadjuvant or adjuvant 
therapy 
b. One cycle of gemcitabine-based chemotherapy (specified in Appendix 5 
[Section 17.5]) for locally advanced or metastatic cholangiocarcinoma is 
permitted before randomization 
2. Have history of a liver transplant. 
3. Have previously or currently is receiving treatment with a mitogen-activated protein 
kinase (MEK) or selective FGFR inhibitor.  
4. Have neurological symptoms related to underlying disease requiring increasing doses 
of corticosteroids. Note: Steroid use for management of central nervous system 


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tumors is allowed but must be at a stable or decreasing dose of corticosteroids for at 
least 2 weeks preceding randomization.  
5. Have a history of another primary malignancy within 3 years except adequately 
treated in situ carcinoma of the cervix or non-melanoma carcinoma of the skin or any 
other curatively treated or surveilled malignancy (eg, localized low-risk prostate 
cancer) that is not expected to require treatment for recurrence during the course of 
the study. 
6. Have any other medical condition that would, in the investigator’s judgment, prevent 
the subject’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures. 
7. Have current evidence of corneal or retinal disorder/keratopathy including, but not 
limited to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis, 
or diabetic retinopathy, confirmed by ophthalmic examination. Subjects with 
asymptomatic ophthalmic conditions assessed by the investigator to pose minimal 
risk for study participation may be enrolled in the study. 
8. Have a history and/or current evidence of extensive tissue calcification including, but 
not limited to, the soft tissue, kidneys, intestine, myocardium, vascular system, and 
lung with the exception of calcified lymph nodes, minor pulmonary parenchymal 
calcifications, and asymptomatic coronary calcification.  
9. Have impairment of gastrointestinal (GI) function or GI disease that may significantly 
alter the absorption of oral infigratinib (eg, ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, small bowel resection). 
10. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, eg, 
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, 
etc. 
11. Are currently receiving or are planning to receive during participation in this study, 
treatment with agents that are known moderate or strong inducers or inhibitors of 
CYP3A4 and medications which increase serum phosphorus and/or calcium 
concentration. Subjects are not permitted to receive enzyme-inducing anti-epileptic 
drugs, including carbamazepine, phenytoin, phenobarbital, and primidone. See 
Appendix 2 (Section 17.2) for details. 
12. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star 
fruits, pomelos, Seville oranges or products containing juice of these fruits within 
7 days prior to first dose of study drug. 
13. Have insufficient bone marrow function: 
a. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L) 
b. Platelets <100,000/mm3 (<100× 109/L) 


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c. Hemoglobin <8.5 g/dL; transfusion support is allowed if >1 week before 
randomization and hemoglobin remains stable 
14. Have insufficient hepatic and renal function: 
a. Total bilirubin >1.5 × upper limit of normal (ULN) (for patients with documented 
Gilbert syndrome, direct bilirubin ≤1.5 × ULN and enrollment requires approval 
by the medical monitor) 
b. AST/ serum glutamic-oxaloacetic transaminase (SGOT) and ALT/ serum 
glutamic-pyruvic transaminase (SGPT) >2.5 × ULN (AST and ALT >5 × ULN in 
the presence of liver involvement of cholangiocarcinoma) 
c. Calculated (using the Cockcroft-Gault formula [Cockcroft and Gault 1976]) or 
measured creatinine clearance of <45 mL/min (or value ≥45 mL/min that 
excludes administration of cisplatin per local label and institutional guidelines) 
15. Have amylase or lipase >2.0 × ULN  
16. Have elevated phosphorus or abnormal serum calcium, or calcium-phosphorus 
product ≥55 mg2/dL2 (refer to Section 9.3 for guidance on calculation): 
a. Inorganic phosphorus >1.1 × ULN 
b. Total corrected serum calcium >11 mg/dL or <8 mg/dL 
17. Have clinically significant cardiac disease including any of the following: 
a. Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥2B) or uncontrolled hypertension (refer to the European Society of 
Cardiology and European Society of Hypertension guidelines [Williams et al 
2018]) 
b. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 
Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction 
abnormality 
c. Unstable angina pectoris or acute myocardial infarction ≤3 months prior to first 
dose of study drug 
d. QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first 
ECG, a total of 3 ECGs separated by at least 5 minutes should be performed. If 
the average of these 3 consecutive results for QTcF is ≤470 msec, the subject 
meets eligibility in this regard 
e. Known history of congenital long QT syndrome 
18. Have had a recent (≤3 months prior to first dose of study drug) transient ischemic 
attack or stroke  
19. CTCAE (v5.0) Grade ≥2 hearing loss 
20. CTCAE (v5.0) Grade ≥2 neuropathy 


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21. If female, is pregnant or nursing (lactating), where pregnancy is defined as the state of 
a female after conception and until the termination of gestation, confirmed by a 
positive human chorionic gonadotrophin urine or blood laboratory test. 
22. Have known microsatellite instability-high (MSI-H) disease and the decision is made 
by the treating investigator that an alternative, non-study therapy is warranted 
according to standard of care. 
23. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents, 
infigratinib, or their excipients. 
24. Have any contraindication to cisplatin or gemcitabine treatment according to local 
labeling or standard institutional practice. 
25. Have taken any Chinese herbal medicine or Chinese patent medicine treatments with 
anticancer activity within 14 days of the first dose of study drug. 
26. Have received a live vaccine within 30 days before the first dose of study drug or are 
planning to receive a live vaccine during participation in this study. 
 
7 TREATMENTS 
7.1 
Treatments Administered 
Subjects randomized to the infigratinib group will receive hard gelatin capsules for oral 
infigratinib 125 mg QD (administered as one 100-mg capsule and one 25-mg capsule) 
using a “3 weeks on, 1 week off” schedule for each 28-day treatment cycle. Subjects with 
mild/moderate renal or hepatic impairment should have their dose adjusted; see 
Section 7.2.1 for dosing recommendations. Infigratinib treatment will continue until 
radiographic PD confirmed by BICR, unacceptable toxicity, or other reason listed in 
Section 8.1.1. Subjects who cross over to infigratinib will continue on treatment until a 
criterion listed in Section 8.1.1 is met. 
Subjects randomized to the gemcitabine with cisplatin group will receive IV infusions of 
gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) on an outpatient basis according to 
each country’s respective labeling and local institutional practices. The gemcitabine and 
cisplatin infusions will be administered on Days 1 and 8 of each 21-day treatment cycle 
until radiographic PD confirmed by BICR; unacceptable toxicity; or other reason listed in 
Section 8.1.1. Following radiographic PD confirmed by BICR, subjects randomized to 
the gemcitabine with cisplatin group may be eligible to cross over and receive 
infigratinib. 
If a subject cannot tolerate cisplatin, they can remain on gemcitabine alone. However, if 
gemcitabine is discontinued due to toxicity, then all study treatment must be 
discontinued. The subject will have an EOT visit within 8 days of the decision to 
discontinue study drug, and a Safety Follow-up visit no more than 30 days after last dose 


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of study drug. Thereafter, subjects will be followed for disease progression and survival 
(as previously described). 
7.2 
Information on Infigratinib 
7.2.1 
Subject Instructions for Infigratinib Dosing 
Subjects with mild or moderate renal impairment (creatinine clearance 30 mL/min to 
≤89 mL/min) should be administered a starting dose of 100 mg QD infigratinib on a 
3 week on (21 day) /1 week off (7 day) schedule. Subjects with mild (total bilirubin 
>ULN to 1.5×ULN or AST >ULN) and moderate hepatic impairment (total bilirubin 
>1.5 to 3×ULN with any AST) should be administered a starting dose of 100 and 75 mg 
QD of infigratinib, respectively, on a 3 week on (21 day) /1 week off (7 day) schedule. 
For subjects with combined hepatic and renal impairment, the lower of the 2 starting 
doses should be administered. 
Subjects in the infigratinib group should be instructed to take the daily dose of 
infigratinib in the morning, at approximately the same time each day (24 ±4 hour 
interval). Subjects will take their first dose of infigratinib at the study center on Cycle 1 
Day 1. On the days of PK sampling, subjects should not take their study drug dose at 
home; subjects should take their study drug with them to the study center where dosing of 
infigratinib will be supervised and administration time recorded. On PK sampling days 
after Cycle 1 Day 1, the time of the previous infigratinib administration (ie, the prior day) 
before the pre-dose PK sample will be recorded in the eCRF. Administration may fall 
outside of the ±4 hour interval on the days of PK sampling. 
Infigratinib should be taken in the fasted state at least 1 hour before or 2 hours after a 
meal. It should be taken with a large glass of water (~250 mL) and consumed over as 
short a time as possible. Subjects should be instructed to swallow the capsules whole and 
not chew them. 
If the subject forgets to take the scheduled dose of infigratinib in the morning (other than 
on a day of PK sampling), he/she should not take the dose more than 4 hours after the 
usual time and should continue treatment the next day. Any such doses that are missed 
should be skipped altogether and should not be replaced or made up at the next scheduled 
dosing. 
If vomiting occurs following dosing with infigratinib, re-dosing is not permitted the same 
day. Dosing should resume the next day. If vomiting occurs on a PK sampling day within 
the first 4 hours postdosing, this event is to be noted on the Dose Administration page of 
the electronic case report form (eCRF), as well as on the AE page, as appropriate. 
Infigratinib is characterized by pH-dependent solubility; therefore, medicinal products 
that alter the pH of the upper GI tract may alter the solubility of infigratinib and limit 
bioavailability. These agents include, but are not limited to, proton pump inhibitors (eg, 
omeprazole), H2-antagonists (eg, ranitidine) and antacids. Proton pump inhibitors are 
prohibited due to their long pharmacodynamic effect and should be replaced with 


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H2-antagonists or antacids. Infigratinib should be taken at least 2 hours before or 
10 hours after dosing with H2-antagonists. Antacids, locally acting acid neutralizing 
agents, are to be separated from infigratinib doses by 2 hours.  
Subjects in the infigratinib group must avoid the consumption of grapefruits, grapefruit 
juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or juice 
within 7 days prior to the first dose of infigratinib and throughout the treatment period. 
This is due to a potential CYP3A4 interaction with study drug. Normal oranges and 
orange juice are allowed. 
7.2.2 
Description and Dispensing of Infigratinib 
Infigratinib will be supplied as hard gelatin capsules for oral use at dose strengths of 25 
and 100 mg. Excipients will include microcrystalline cellulose, lactose monohydrate, 
hypromellose 2910, crospovidone, colloidal silicon dioxide, magnesium stearate, and 
hard gelatin capsule. Infigratinib will be manufactured under Good Manufacturing 
Practice for investigational use. The color and appearance of the capsules are outlined 
below.  
Physical 
Attribute 
Appearance 
(color) 
Size 3 Capsule: White opaque body with gray opaque cap, 
imprinted with a green band on the body and a black band 
on the cap filled with white to greyish powder (25 mg) 
Size 1 Capsule: White opaque body with light orange 
opaque cap, imprinted with a green band on the body and a 
black band on the cap filled with white to greyish powder 
(100 mg) 
Infigratinib will be provided in 21-count bottles (FMI IV formulation). 
The site pharmacist or designee will dispense the correct number and dose strength of 
capsules to ensure the subject receives sufficient drug for each 28-day treatment cycle. 
Study drug will be dispensed to the subject by authorized trained site personnel only. 
7.2.3 
Packaging and Labeling 
Infigratinib capsules will be packaged in high density polyethylene bottles with intact 
induction seal child resistant closures. Study drug labels will be in the local language and 
comply with the legal requirements of each country. Labels will include storage 
conditions for the drug. 
7.2.4 
Study Drug Accountability, Handling, and Disposal 
Infigratinib capsules will be received by designated personnel at the study center, 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, infigratinib should 


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be stored according to the instructions specified on the drug label and in the 
Investigator’s Brochure. Refer to the Pharmacy Manual for further details. 
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of infigratinib in a drug accountability log. Subjects in the infigratinib group 
will be asked to return all used and unused bottles of infigratinib and packaging on a 
regular basis, at the end of the study, or at the time of study drug discontinuation. Drug 
accountability will be assessed by the investigator and/or study personnel, and captured 
in a subject drug accountability log. This information must be captured in the source 
document at each subject visit. Drug accountability will be completed by the field 
monitor during study center visits and at the completion of the study.  
At study close-out, and, as appropriate during the course of the study, the investigator 
will provide access to all used and unused bottles of infigratinib, packaging, drug labels, 
and a copy of the completed drug accountability log to the field monitor. 
At study close-out, infigratinib can be destroyed at the study center if permitted by local 
regulations. Alternatively, the study drug can be destroyed at a third party depot. 
7.2.5 
Dose Modifications for Infigratinib 
Subject management will be based upon investigator evaluations. 
7.2.5.1 
Dose Modifications and Delays 
For subjects who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the subject to continue infigratinib. For these subjects, the 
dosing guidelines outlined below will be followed. All dose modifications related to 
tolerability should be based on the worst preceding toxicity, as described in Table 7 (AEs 
considered possibly related to infigratinib) and Table 9 (skin toxicity). In addition, 
according to investigator’s medical judgment, dose modification (hold) can be applied for 
subject safety (eg, perioperatively); a sponsor medical monitor must be consulted for 
dose modifications that are not related to tolerability. Dosage changes must be recorded 
on the appropriate page of the eCRF. 
The following guidelines should be applied. 
• Each subject may be allowed up to 3 infigratinib dose reductions according to 
protocol specified dose modifications for AEs. Dose reductions below 50 mg are not 
allowed. Prospective sponsor medical monitor approval is required for the third dose 
reduction (Table 6). 
• Management of related toxicity, including during a period of infigratinib hold, will 
continue until the toxicity is stable at Grade ≤1, returns to baseline, or is in 
accordance with the assessment of the treating physician. 


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If treatment is resumed at the same dose of infigratinib, and the same toxicity recurs with 
the same or worse severity regardless of duration, dose must be reduced to the next lower 
dose level. If treatment is resumed at the lower dose of infigratinib, and the same toxicity 
recurs with the same or worse severity, the subject should have a second dose reduction. 
• Subjects who permanently discontinue infigratinib for a study related AE or an 
abnormal laboratory value must be followed as described in Section 7.2.5.2. 
• Study drug must be permanently discontinued for a delay of >14 days and may only 
be restarted with written permission of a sponsor medical monitor if (1) the delay was 
not due to an AE that requires permanent infigratinib discontinuation as provided in 
Table 7, and (2) the subject has not met other criteria requiring infigratinib 
discontinuation as provided in Section 8, and it is the Investigator’s opinion that no 
safety concerns are present. In situations where a delay of >14 days is needed for a 
treatment-related AE requiring permanent infigratinib discontinuation (see Table 7), 
with prospective sponsor medical monitor approval, the delay may be extended to a 
maximum of 28 days before permanent treatment discontinuation is required. 
• If infigratinib is on hold for ≤14 days, and the criteria for restarting treatment are met, 
infigratinib can be restarted on Day 1 to Day 21 of a cycle. Study drug should not be 
restarted on Day 22 to Day 28 of a cycle; in such cases, treatment restart must wait 
until Day 1 of the next cycle. 
Table 6: 
Dose Reduction Scheme for Infigratinib 
Dose Reduction  
 
 
 
 
 
Starting dose level 0 
Dose level -1 
Dose level -2 
Dose level -3 
Infigratinib 
125 mg 
100 mg 
75 mg 
50 mg a 
a  Dose reduction to 50 mg requires prospective sponsor medical monitor approval. Details are provided in the text 
above. 


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Table 7: 
Criteria for Interruption and Re-initiation of Infigratinib for 
Adverse Events Considered to be Possibly Related to 
Infigratinib 
Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
CARDIAC DISORDERS 
Cardiac - Prolonged QTc Interval 
Grade 2:  
Average QTc 481-500 msec 
Maintain dose level of infigratinib.  
Two additional ECGs separated by at least 5 minutes should be 
performed to confirm the finding. If the finding is confirmed, single 
ECG assessments should be performed for 2 additional cycles at the 
same frequency as in Cycle 1, or as clinically indicated. If abnormality 
is detected, 2 additional ECGs separated by at least 5 minutes should be 
performed to confirm the finding. 
• 
If ECG assessments show no QTcF ≥481 msec, for subsequent 
cycles ECG monitoring will be performed as according to the visit 
schedule. 
• 
If ECG assessments are still abnormal (QTcF ≥481 msec and 
≤500 msec), then ECG monitoring must continue at the same 
frequency as in Cycle 1 for all subsequent cycles. 
Grade 3:  
Average QTc ≥501 msec; 
>60 msec change from baseline  
 
Hold dose of infigratinib. Two additional ECGs separated by at least 
5 minutes should be performed to confirm the finding. If the finding is 
confirmed, monitor subject with hourly ECGs until the QTcF has 
returned to baseline and perform further monitoring as clinically 
indicated.  
• 
Exclude other causes of QTcF prolongation such as hypokalemia, 
hypomagnesaemia and decreased blood oxygenation. 
• 
Subjects should receive appropriate electrolyte replacement and 
should not receive further infigratinib until electrolytes are 
documented to be within normal limits.  
Once the QTcF prolongation has resolved to <481 msec, subjects may 
be re-treated at one lower dose level at the investigator’s discretion. If 
not determined to be clinically significant, the subject may resume at 
the current dose. 
Single ECG assessments should be performed for 2 additional cycles at 
the same frequency as in Cycle 1 or as clinically indicated. If 
abnormality is detected, 2 additional ECGs separated by at least 
5 minutes should be performed to confirm the finding. 
• 
If ECG assessments show no QTcF ≥481 msec, ECG monitoring 
will be performed as according to the visit schedule for subsequent 
cycles.  
• 
If ECG assessments are still abnormal (QTcF ≥481 msec and 
≤500 msec), then ECG monitoring must continue at the same 
frequency as in Cycle 1 or as clinically indicated, for all 
subsequent cycles. 
• 
Subjects who experience recurrent QTcF ≥501 msec after one dose 
reduction will be discontinued from infigratinib. 


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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Grade 4:  
Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia 
Discontinue infigratinib. 
INVESTIGATIONS-HEMATOLOGY 
Neutrophil Count Decreased (Neutropenia) 
Grade 3  
(ANC <1000-500/mm3 [<1.0–
0.5 × 109/L]) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 or 
baseline, then  
• 
If resolved within ≤7 days, maintain dose level of infigratinib  
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of 
infigratinib 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Grade 4  
(ANC <500/mm3 [<0.5 × 109/L]) 
Hold dose of infigratinib until resolved to CTCAE ≤Grade 1, then 
↓ 1 dose level of infigratinib 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Febrile Neutropenia 
Grade 3  
(ANC <1000 mm3 with a single 
temperature of >38.3°C [101.0°F] 
or a sustained temperature 
of ≥38.0°C [100.4°F] for >1 
hour) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1, then  
• 
If resolved within ≤14 days, ↓ 1 dose level of infigratinib 
• 
If not resolved within 14 days, discontinue infigratinib 
Grade 4 
Discontinue infigratinib 
Anemia 
Grade 3  
(hemoglobin <8.0 g/dL 
[<4.9 mmol/L; <80 g/L]; 
transfusion indicated) 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Grade ≤1 or baseline, then maintain dose level 
Grade 4 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Grade ≤1 or baseline, then ↓ 1 dose level 
Platelet Count Decreased (Thrombocytopenia) 
Grade 3  
(platelet <50,000-25,000/mm3 
[<50-25 × 109/L])  
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 or 
baseline, then  
• 
If resolved within ≤7 days, maintain dose level of infigratinib 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of 
infigratinib 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Grade 4  
(platelet <25,000/mm3 
[<25 × 109/L]) 
• 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 or 
baseline, then ↓ 1 dose level 
• 
If not resolved within ≤14 days, discontinue infigratinib 


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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
INVESTIGATIONS – RENAL 
Serum Creatinine 
Creatinine clearance <45 mL/min 
(calculated or measured) 
Hold dose of infigratinib until creatinine clearance is ≥45 mL/min 
regardless of grade. 
Serum creatinine increase 
Grade 2  
(≥1.5-3.0 × ULN or 
1.5-3.0 × baseline) 
Hold dose of infigratinib until resolved to Grade ≤1 or baseline, then 
• 
If resolved within ≤7 days, maintain dose level of infigratinib 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of 
infigratinib 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Serum creatinine increase 
Grade ≥2 
If serum creatinine CTCAE Grade ≥2 has been demonstrated in 
conjunction with hyperphosphatemia, serum creatinine levels must be 
repeated at least weekly until resolution. 24-hour urine collection 
should be obtained as clinically indicated for total phosphate, calcium, 
protein, and creatinine clearance. Ultrasound examination of the 
kidneys should be performed as indicated to evaluate de-novo 
calcifications until resolution or stabilization of creatinine. 
Serum creatinine increase 
Grade ≥3 (>3.0 × ULN or 
>3 × baseline) 
Discontinue infigratinib 
INVESTIGATIONS – HEPATIC 
Blood bilirubin increase (For subjects with Gilbert Syndrome, these dose modifications apply to 
changes in direct bilirubin only) 
Grade 2  
(bilirubin >1.5-3.0 × ULN if 
baseline was normal; 
>1.5-3.0 × baseline if baseline 
was abnormal) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1, then 
• 
If resolved within ≤7 days, maintain dose level of infigratinib. 
• 
If not resolved within ≤7 days, ↓ 1 dose level of study drug 
Grade ≥3  
(bilirubin >3.0 × ULN if baseline 
was normal; >3.0 × baseline if 
baseline was abnormal) 
Discontinue infigratinib. 
Note: If CTCAE Grade 3 or 4 hyperbilirubinemia is due to hemolysis, 
then ↓ 1 dose level of infigratinib and continue treatment at the 
discretion of the investigator. 
AST or ALT Increase 
 
Grade 3  
(>5.0-20.0 × ULN if baseline was 
normal; >5.0-20.0 × baseline if 
baseline was abnormal) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 or 
baseline, then  
• 
If resolved within ≤7 days ↓, 1 dose level of infigratinib 
• 
If not resolved within ≤7 days, discontinue infigratinib 
Grade 4  
(>20.0 × ULN if baseline was 
normal; >20.0 × baseline if 
baseline was abnormal)  
Discontinue infigratinib 


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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
AST or ALT and Bilirubin Increase 
AST or ALT >3.0 – 5.0 × ULN 
and total bilirubin >2.0 × ULN 
without liver metastasis or 
evidence of disease progression 
in the liver 
Hold dose of infigratinib until both transaminases and bilirubin 
resolved to CTCAE Grade ≤1 or baseline, then 
• 
If resolved within ≤7 days, ↓ 1 dose level of infigratinib 
• 
If not resolved within ≤7 days, discontinue infigratinib 
AST or ALT >5.0 × ULN and 
total bilirubin >2.0 × ULN 
Discontinue infigratinib 
LABORATORY / METABOLIC DISORDERS 
Amylase and/or Lipase Increase 
General Comment: 
A CT scan or other imaging study to assess the pancreas, liver, and 
gallbladder should be performed as clinically indicated within 1 week 
of the first occurrence of any CTCAE Grade ≥3 amylase and/or lipase. 
Grade 3  
(amylase or lipase >2.0 - 
5.0 × ULN with signs or 
symptoms; >5.0 × ULN and 
asymptomatic) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤2, then 
• 
↓ 1 dose level of infigratinib  
• 
If not resolved within ≤14 days, discontinue infigratinib 
For recurrent Grade 3 asymptomatic lipase or amylase elevation despite 
dose reduction, drug should be held and continuation of therapy should 
be discussed with the medical monitor following resolution to 
≤Grade 2. 
Grade 4  
(amylase or lipase >5.0 × ULN 
and with signs or symptoms) 
For any Grade 4 lipase or amylase elevation, drug should be held and 
continuation of therapy should be discussed with the medical monitor 
following resolution to ≤Grade 2. 
Hypophosphatemia 
Serum phosphate 
<LLN-2.0 mg/dL (0.6 mmol/L) 
Maintain dose level of infigratinib; decrease or hold dose of phosphate 
binder and optimize standard diet or medical therapy as clinically 
indicated to increase phosphate level. 
Serum phosphate <2.0-1.0 mg/dL 
(<0.6-0.3 mmol/L) 
 
Hold dose of infigratinib until resolved to >2.0 mg/dL (>0.6 mmol/L), 
then 
• 
↓ 1 dose level of infigratinib. 
• 
If not resolved within ≤14 days, discontinue infigratinib. 
Serum phosphate <1.0 mg/dL 
(<0.3 mmol/L)  
(life threatening consequences) 
Discontinue infigratinib. 
Hyperphosphatemia 
General Comment: 
Optimize dose and schedule of phosphate lowering therapy in 
accordance with the package insert, or local or institutional guidelines 
Serum phosphate >5.5–
≤7.5 mg/dL 
Maintain dose level of infigratinib and optimize phosphate lowering 
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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Serum phosphate >7.5 mg/dL for 
more than 7 days despite 
maximal phosphate-lowering 
therapy  
• 
Hold dose of infigratinib until resolved to serum 
phosphate ≤5.5 mg/dL. 
• 
Restart infigratinib at the same dose level with maximal phosphate 
binder dosing if the subject did not receive maximal phosphate 
binder dosing for serum phosphate >7.5 mg/dL for >7 days. 
Or, single serum phosphate 
>9.0 mg/dL regardless of 
duration or dose of phosphate 
lowering therapy 
 
• 
Reduce one dose level of infigratinib if the subject had received 
maximal phosphate lowering therapy for serum phosphate 
>7.5 mg/dL for >7 days or if subject had a one-time serum 
phosphate of >9.0 mg/dL. Restart infigratinib with maximal 
phosphate binder dosing.  
It is recommended that phosphate binder dosing continues during 
infigratinib dose interruptions for hyperphosphatemia and that serum 
phosphate values be monitored frequently, eg, every 2-3 days. 
Phosphate binder dosing should be held during the week off infigratinib 
therapy each cycle (Days 22-28) unless serum phosphate is not 
normalized and during infigratinib dose interruptions for non-
hyperphosphatemia AEs. 
Serum phosphate with life-
threatening consequences; urgent 
intervention indicated (eg, 
dialysis) 
• 
Discontinue infigratinib 
Hypercalcemia 
Serum calcium Grade 2 
Corrected serum calcium 
(>11.5-12.5 mg/dL 
[>2.9-3.1 mmol/L]) 
Ionized calcium 
(>1.5-1.6 mmol/L), symptomatic 
Hold dose of infigratinib until resolved to Grade 1 or baseline, then 
• 
If resolved within ≤7 days after suspending infigratinib, maintain 
dose level 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level 
• 
If not resolved within ≤14 days, discontinue infigratinib 
 
Serum calcium Grade ≥3 
Corrected serum calcium 
(>12.5 mg/dL [>3.1 mmol/L])  
Ionized calcium (>1.6 mmol/L), 
hospitalization indicated 
Discontinue infigratinib 
GASTROINTESTINAL SYSTEM DISORDERS 
Pancreatitis 
Grade 2 (asymptomatic enzyme 
elevation with radiologic findings 
only) 
 Hold dose of infigratinib until resolved to CTCAE Grade <2, then 
• 
↓ 1 dose level of infigratinib  
• 
If not resolved within ≤14 days, discontinue infigratinib 
For recurrent Grade 2 asymptomatic radiologic pancreatitis despite 
dose reduction, discontinue infigratinib. 
Grade 3 or Grade 4 
Discontinue infigratinib 


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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Diarrhea 
General Comment:  
Antidiarrheal medication is recommended at the first sign of abdominal 
cramping, loose stools or overt diarrhea. 
Grade 1  
(increase of <4 stools/day over 
baseline; mild increase in ostomy 
output compared to baseline) 
Maintain dose level of infigratinib, initiate anti-diarrheal treatment 
Grade 2  
(increase of 4-6 stools/day over 
baseline; moderate increase in 
ostomy output compared to 
baseline; limiting instrumental 
activities of daily living [ADL]) 
• 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 
• 
Optimize anti-diarrheal treatment 
• 
For reoccurrence of diarrhea CTCAE Grade 2, hold dose of 
infigratinib until resolved to CTCAE Grade ≤1, then ↓ infigratinib 
by 1 dose level 
Grade 3  
(increase of ≥7 stools/day over 
baseline; hospitalization 
indicated; severe increase in 
ostomy output compared to 
baseline; limiting self care ADL) 
• 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1 
• 
Optimize anti-diarrheal treatment 
• 
↓ infigratinib by 1 dose level 
• 
For reoccurrence of diarrhea CTCAE Grade 3, despite optimal 
antidiarrheal treatment, discontinue infigratinib 
Grade 4 
Discontinue infigratinib 
Vomiting 
 
Grade 2 (outpatient IV hydration; 
medical intervention indicated) 
not controlled by optimal anti-
emetic therapy 
Hold dose of infigratinib until ≤Grade 1, then ↓ 1 dose level 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Grade 3 (tube feeding, TPN, or 
hospitalization indicated) not 
controlled by optimal anti-emetic 
therapy or Grade 4 
Discontinue infigratinib 
EYE DISORDERS (CONFIRMED BY OPHTHALMIC EXAMINATION) 
Retinal Disorders 
Grade 2 or 3 central serous 
retinopathy and central serous 
retinopathy-like events 
Hold dose of infigratinib until resolved to ≤Grade 1 and continue 
ophthalmic evaluations 
• 
If resolved within ≤14 days, ↓ infigratinib by 1 dose level 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Grade ≥1 retinal vein occlusion, 
Grade 4 central serous 
retinopathy and central serous 
retinopathy-like events 
Discontinue infigratinib 


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Worst Toxicity CTCAEa (v5.0) 
Grade (Unless Otherwise 
Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Other Ocular/Visual Toxicity 
Grade ≥3 
Hold dose of infigratinib until resolution to ≤Grade 1 
• 
If resolution within ≤14 days, ↓ 1 dose level 
• 
If not resolved within ≤14 days, discontinue infigratinib 
OTHER CLINICALLY SIGNIFICANT AEs 
Grade 3 
Hold dose of infigratinib until resolved to CTCAE Grade ≤1, then ↓ 1 
dose level of infigratinib 
• 
If not resolved within ≤14 days, discontinue infigratinib 
Grade 4 
Discontinue infigratinib 
Abbreviations: ADL, activities of daily living; AE, adverse event; ALT, alanine aminotransferase; ANC, 
absolute neutrophil count; AST, aspartate aminotransferase; CT, computed tomography; CTCAE, Common 
Terminology Criteria for Adverse Events; ECG, electrocardiogram; QT, measure of time between the start 
of the Q wave and the end of the T wave (QT interval) in the heart’s electrical cycle; QTc, QT interval 
corrected for heart rate; QTcF, QTc corrected by Fridericia's formula; ULN, upper limit of normal. 
a CTCAE (v5.0) general guidelines:  
Grade 1 Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; intervention 
not indicated. 
Grade 2 Moderate; minimal, local or noninvasive intervention indicated; limiting age-appropriate 
instrumental ADL. 
Grade 3 Severe or medically significant but not immediately life-threatening; hospitalization or 
prolongation of hospitalization indicated; disabling; limiting self care ADL. 
Grade 4 Life-threatening consequences; urgent intervention indicated. 
Grade 5 Death related to AE. 
NOTE: All dose modifications should be based on the worst preceding toxicity. Subjects may have a third 
dose reduction only with prospective approval of a sponsor medical monitor. 
 
 


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7.2.5.2 
Follow-up for Toxicities 
Subjects whose infigratinib treatment is interrupted or permanently discontinued due to 
an AE or clinically significant laboratory value, must be followed up at least once a week 
(or more frequently if required by institutional practices, or if clinically indicated) for 4 
weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Clinical experts or specialists, such as an ophthalmologist, 
endocrinologist, or dermatologist, should be consulted as deemed necessary. Further 
guidelines and dose modifications for the management of specific infigratinib-induced 
toxicities (hyperphosphatemia, diarrhea) are provided in Table 7. All subjects must be 
followed up for AEs and SAEs for 30 days following last dose of infigratinib. 
7.2.6 
Anticipated Risks and Safety Concerns for Infigratinib 
Eligibility criteria as well as specific dose modification and stopping rules are included in 
this protocol. Guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of infigratinib-induced AEs (eg, hyperphosphatemia, renal 
toxicities) are provided in Table 7 and Section 7.6.1. For more information, refer to the 
nonclinical toxicity and/or clinical data presented in the infigratinib Investigator’s 
Brochure. 
Treatment of adverse events or laboratory abnormalities should follow the protocol where 
specified. If not specified in the protocol, treatment of AEs or laboratory abnormalities 
should be according to local institutional guidelines. 
7.3 
Information on Gemcitabine with Cisplatin 
The active comparator in this study, gemcitabine with cisplatin, will be obtained locally 
by the study centers or provided centrally by the sponsor, depending on local country 
operational or regulatory requirements. Drug product will be stored according to the 
product labels.  
For any commercially available product provided by the study center, every attempt will 
be made to source these supplies from a single lot/batch number. The study center is 
responsible to record the lot number, manufacturer, and expiry date for any locally 
purchased product as according to local guidelines, unless instructed otherwise by the 
sponsor.   
The investigator shall take responsibility for and shall take all steps to maintain 
appropriate records and ensure appropriate supply, storage, handling, distribution, and 
usage of treatments in accordance with the protocol and any applicable laws and 
regulations.  
Intravenous infusions of gemcitabine (1000 mg/m2) and cisplatin (25 mg/m2) will be 
administered according to each country’s respective labeling and/or local institutional 
practices.  


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It is recommended to have cisplatin infused over 1 hour in 1000 mL of 0.9% saline 
containing 20 mmol potassium chloride and 8 mmol magnesium sulfate, followed by 
500 mL of 0.9% saline over an additional 30 minutes before initiation of the gemcitabine 
infusion. The cisplatin infusion should be performed with adequate hydration according 
to the institution’s practice. After cisplatin administration, gemcitabine, diluted in 0.9% 
saline according to local labeling, will be infused over approximately 30 minutes (Valle 
et al 2010).  
The gemcitabine and cisplatin infusions will be administered on Days 1 and 8 of each 
21-day treatment cycle. If one or more toxicities result in delay of cycle start, the cycle 
will be considered to start on the first day when any chemotherapy is administered. 
Subjects who cannot start a cycle within 21 days of the scheduled Day 1 (ie, within 42 
days of the previous cycle Day 1) must permanently discontinue all chemotherapy unless 
prospectively approved by the sponsor medical monitor. If Day 8 dosing can’t be given 
by Day 15 of a 21-day cycle, the subject should skip the Day 8 dose and dosing will 
resume on Day 1 of the next scheduled cycle.  
Management of AEs including gemcitabine and/or cisplatin dose modification and 
supportive therapy (ie, growth factor administration) should follow the respective 
gemcitabine or local cisplatin labels and institutional guidelines. 
Additional laboratory testing (not specified in the protocol), including pregnancy testing 
and audiometry, for either surveillance or emerging AEs should be done according to the 
local gemcitabine or cisplatin label and institutional standard practice. 
Table 8 presents dose reduction guidelines for gemcitabine and cisplatin for neutropenia 
and/or thrombocytopenia.  
If a subject cannot tolerate cisplatin, they can remain on gemcitabine alone. However, if 
gemcitabine is discontinued due to toxicity then all study treatment must be discontinued. 
The subject will have an EOT visit and then continue on study for PFS, PFS2, and OS 
follow-up (even if the subject starts new anticancer treatment). 
Table 8: 
Dose Reduction/Interruption Guidelines for Gemcitabine and 
Cisplatin 
Neutrophils 
(×106/L) 
 
Platelet Count 
(×106/L) 
% of Full Dose 
(Gemcitabine) 
% of Full Dose 
(Cisplatin) 
≥1000  
(≥1.0×109/L) 
And 
≥100,000 
(≥100×109/L) 
100 
100 
500-999  
(0.50-
0.99×109/L) 
Or 
50,000-99,000 
(50-99×109/L) 
75 
100 
<500 
(<0.50×109/L) 
Or 
<50,000 
(<50×109/L) 
Hold 
Hold 
 


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General guidelines for non-hematologic toxicity for gemcitabine include: 
• Hold or decrease gemcitabine dose by 50% for the following: severe (Grade 3 or 4) 
non-hematologic toxicity until resolved (excludes nausea, vomiting, or alopecia [no 
dose modifications recommended]) 
• Permanently discontinue gemcitabine for any of the following: unexplained dyspnea 
(or other evidence of severe pulmonary toxicity), severe hepatotoxicity, hemolytic 
uremic syndrome, capillary leak syndrome, posterior reversible encephalopathy 
syndrome 
Subjects should be monitored for signs of dehydration, kidney function, ototoxicity, 
neuropathy and hypersensitivity reaction with cisplatin administration, and adjust 
cisplatin treatment according to local labeling and institution standard.  
Subjects whose treatment is interrupted or permanently discontinued due to an AE or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first. Clinical experts or specialists should be consulted as deemed necessary. All 
subjects must be followed up for AEs and SAEs for 30 days following last dose of study 
drug.  
7.4 
Randomization  
Subjects will be randomized in a 2:1 ratio to one of the two treatment groups. 
Randomization should occur within 5 days before Cycle 1 Day 1. Randomization will be 
stratified by unresectable locally advanced vs metastatic disease, geographic region 
(North America, Western Europe, Asia Pacific, and rest of the world), prior 
neoadjuvant/adjuvant treatment (yes/no), and received up to 1 cycle of prior 
gemcitabine-based chemotherapy for unresectable locally advanced or metastatic disease 
(yes/no). Documented medical monitor approval is required prior to randomization. 
Interactive Response Technology will be used to assign subjects to treatment based on 
the randomization stratification factors entered into the system. Site personnel will be 
given a unique subject number for each subject, consisting of a unique center number 
followed by a sequential subject number suffixed to it. 
This is an open-label study; all study drugs will be administered in an open label fashion. 
7.5 
Compliance 
The investigator or responsible site personnel should instruct the subject to take 
infigratinib exactly as prescribed to promote compliance. All dosages prescribed and 
dispensed to the subject and all dose changes or missed doses during the study must be 
recorded on the appropriate eCRF as outlined in the Case Report Completion Guidelines. 
Subject re-training for infigratinib dosing non-compliance should be conducted and 
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For subjects in the gemcitabine plus cisplatin group, administration of study drugs will be 
captured in the appropriate eCRF and source documents. 
7.6 
Supportive Care Guidelines 
7.6.1 
Infigratinib Group 
Any palliative and supportive care for disease related symptoms, including any 
medication or therapy for a concurrent medical condition are permitted, except if 
specifically prohibited below. 
Hematopoietic Growth Factors  
Hematopoietic growth factors (eg, erythropoietin [EPO], granulocyte colony-stimulating 
factor (G-CSF), granulocyte-macrophage colony-stimulating factor [GM-CSF]) and 
blood transfusions are not to be administered prophylactically or to be used to meet 
eligibility criteria. However, these drugs may be administered as according to the label of 
these agents or as dictated by local practice or guidelines established by the American 
Society of Clinical Oncology (ASCO), ESMO, or other appropriate regional societies. 
Management of Hyperphosphatemia 
Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of 
the FGFR pathway. While on infigratinib, subjects should avoid foods that are especially 
high in phosphate and, if possible, should restrict dietary phosphate to 600 – 800 mg/day. 
High-phosphate foods include dairy products; meats, nuts, and other high-protein foods; 
processed foods; and dark colas.  
Subjects who have experienced hyperphosphatemia should take a phosphate binder such 
as sevelamer, sucroferric oxyhydroxide, lanthanum carbonate, ferric citrate, etc. within 
30 minutes of a meal on the day while taking infigratinib. Once the subject has had 
hyperphosphatemia, the subject should remain on a low phosphate diet, if possible, and 
take phosphate binder on the days infigratinib is taken, even if the serum phosphate is 
normalized. Unless otherwise specified by the local prescribing information or 
institutional practice, the following regimen should be used to manage 
hyperphosphatemia: 
• For serum phosphate >5.5 – <7.5 mg/dL 
• Start sevelamer 800 mg three times a day with meals 
• Increase the dose of sevelamer up to 1200 mg every 8 hours 
• For serum phosphate ≥7.5 mg/dL 
• Increase the dose of sevelamer up to 1600 mg (2 tablets per meal) every 8 hours 
• Consider adding acetazolamide two to three 250 mg tablets per day. 


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During the infigratinib cycle, subjects do not need to be on a low phosphate diet or take a 
phosphate binder during their 1-week off period unless serum phosphate is not 
normalized. Other dose modification recommendations are provided in Table 7, but 
should be modified according to country or institutional practice. 
Management of Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of 
poorly formed or loose stool or an increased frequency of bowel movements. 
Administration of antidiarrheal/anti-motility agents is recommended at the first sign of 
diarrhea as initial management. Some subjects may require concomitant treatment with 
more than one antidiarrheal agent. When therapy with antidiarrheal agents does not 
control the diarrhea to tolerable levels, infigratinib should be temporarily interrupted or 
dose reduced according to Table 7. 
Management of Bone Metastatic Disease 
Treatment of bone metastatic disease with symptomatic standard of care therapy 
according to institutional guidelines, including prophylactic treatment with 
bisphosphonates, palliative localized radiation therapy, and symptomatic treatment with 
steroids and pain medications is allowed. Initiation of other systemic anticancer therapy 
as described in Section 7.7.1.2 is not allowed and requires permanent discontinuation of 
study treatment. 
Management of Alopecia, Palmar-Plantar Erythrodysesthesia, Paronychia, and 
Stomatitis 
Recommendations for management (not required per protocol) of alopecia, palmar-
plantar erythrodysesthesia syndrome, paronychia (adapted from Segaert 2005), and 
stomatitis (adapted from Rugo et al 2017) are provided in Table 9. These are guidelines 
only and institutional guidelines should be followed where applicable. 


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Table 9: 
Recommendations for Management of Alopecia, Palmar-
Plantar Erythrodysesthesia Syndrome, Paronychia, and 
Stomatitis 
Alopecia 
Grade 1 
Continue study drug  
• 
Minoxidil 5% (OTC) solution or foam once daily to scalp 
Grade 2 
Continue study drug  
• 
Minoxidil 5% (OTC) solution or foam twice daily to scalp 
• 
Fluocinonide 0.05% solution daily to scalp 
Palmar-plantar erythrodysesthesia syndrome 
Grade 1 
Continue study drug  
• 
Urea 20% or ammonium lactate 12% lotions BID to hands and feet 
Grade 2 
Continue study drug  
• 
Urea 20% or ammonium lactate 12% BID to hands and feet 
• 
Fluocinonide 0.05% cream BID to hands and feet 
Grade 3 
Hold study drug until resolved to Grade ≤1  
• 
Urea 20% or ammonium lactate 12% BID to hands and feet 
• 
Fluocinonide 0.05% cream BID to hands and feet 
Paronychia 
Grade 1 
Continue study drug  
• 
Clindamycin 1% solution around and under nails TID 
• 
Soak for 15 minutes daily in white vinegar in tap water (1:1) 
Grade 2 
Continue study drug  
• 
Obtain bacterial cultures to confirm sensitivity to antimicrobial 
• 
Cefadroxil 500 mg BID or TMP/SMX DS BID for 14 days 
• 
Soak for 15 minutes daily in white vinegar in tap water (1:1) 
• 
Dermatology consultation 
Grade 3  
Hold study drug until resolved to Grade ≤1  
• 
Obtain bacterial cultures to confirm sensitivity to antimicrobial 
• 
Cefadroxil 500 mg BID or TMP/SMX DS BID for 14 days 
• 
Dermatology consultation 
Stomatitis 
Grade 1/2 Continue study drug  
• 
Dexamethasone elixir 0.5 mg/5 mL swish and spit 1 teaspoon (5mL) TID. 
Grade 3 
Hold study drug until resolved to Grade ≤1  
• 
Dexamethasone elixir 0.5 mg/5 mL swish and spit 1 teaspoon (5 mL) TID. 
• 
Clotrimazole 10 mg lozenges 3-5 times/day 
BID=2 times daily; OTC=over-the-counter; TID=3 times daily; TMP/SMX DS=sulfamethoxazole and 
trimethoprim 
 
7.6.2 
Gemcitabine with Cisplatin Group 
Subjects in the gemcitabine with cisplatin group can receive any palliative and supportive 
care for disease related symptoms, as clinically indicated and in accordance with standard 
of care. 
Cisplatin is associated with a high emetic potential; anti-emetics are recommended to 
prevent nausea and vomiting. 


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Hematopoietic growth factors (eg, EPO, G-CSF, GM-CSF) and blood transfusions are 
not to be used to meet eligibility criteria. However, these drugs may be administered as 
according to the label of these agents or as dictated by local practice or guidelines 
established by the ASCO, ESMO, or other appropriate regional societies. 
7.7 
Prior and Concomitant Medications 
At Screening, subjects are to be asked about their history of prior therapies (including 
prior anticancer therapy); investigators are to check for use of any disallowed prior 
medications, as outlined in the exclusion criteria for the study (Section 6.2).  
Live vaccines are prohibited within 30 days before the first dose of study drug, for the 
duration of study participation, and for a period of time (approximately 3-6 months) after 
the last dose of chemotherapy according to local guidelines. 
For each subject enrolled in the study, all anticancer therapies ever taken for 
cholangiocarcinoma and other medications taken within 28 days of first dose of study 
drug are to be recorded on the appropriate page of the eCRF. 
All prescription and non-prescription medications administered from the time of first 
dose of study drug through 30 days after last dose are to be recorded for each subject on 
the appropriate page of the eCRF. Dates for the start and stop of each concomitant 
medication are to be recorded, as well as the reason for administration (particularly if 
administered for an AE). Any changes in dose of concomitant medications are to also be 
recorded. 
Cancer medications taken by the subject after last dose of study drug are to be recorded 
on the Post Study Anticancer Medications page of the eCRF, and non-medication cancer 
therapies and surgeries are to be recorded on the Post Anticancer Therapies page of the 
eCRF. 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as 
well as estrogen replacement hormone treatment. 
7.7.1 
Infigratinib Group 
7.7.1.1 
Permitted Concomitant Therapy Requiring Caution and/or Action 
Details for specific medications which require action and/or caution while on study in 
subjects taking infigratinib are provided in Appendix 1 (Section 17.1). The rationale for 
these medications is provided below. 
Infigratinib is characterized by pH-dependent solubility, and therefore, medicinal 
products that alter the pH of the upper GI tract may alter the solubility of infigratinib, and 
limit bioavailability. These agents include, but are not limited to, proton pump inhibitors 
(eg, omeprazole), H2-antagonists (eg, ranitidine) and antacids. Proton pump inhibitors are 
prohibited due to their long PD effect and should be replaced with H2-antagonists or 


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antacids. Infigratinib should be taken ≥2 hours before or 10 hours after dosing with 
H2-antagonists. Antacids, locally acting acid neutralizing agents, are to be separated from 
infigratinib doses by 2 hours. 
Infigratinib is a substrate of CYP3A4. If anticoagulation is required, heparin and/or low-
molecular-weight heparins or direct thrombin inhibitors and/or Factor Xa inhibitors that 
are not metabolized by CYP3A4 (eg, dabigatran, edoxaban) are to be used. 
Anticoagulants that are CYP3A4 substrates and have a narrow therapeutic index (eg, 
warfarin sodium or any other coumadin-derivative anticoagulants or certain direct 
thrombin inhibitors [eg, argatroban] or Factor Xa inhibitors [eg, rivaroxaban]) should be 
used with caution. Refer to Section 7.7.1.2 for further information on CYP3A4. 
Infigratinib was shown in vitro to inhibit the drug transporter breast cancer resistance 
protein (BCRP), with an IC50 of 210 nM. While the clinical relevance of this inhibition is 
unknown, drugs transported by BCRP should be used with caution. 
Anti-emetics are recommended as clinically appropriate at the first sign of nausea and 
vomiting or as prophylaxis to prevent emesis, along with supportive care according to 
clinical practice guidelines, with the following considerations: 
• Ondansetron has a known risk for Torsade de Pointes, and therefore should be used 
with caution. Palonosetron may be used as an alternative. 
• Aprepitant (brand name: Emend) is both a sensitive substrate and a moderate 
CYP3A4 inhibitor and is prohibited with infigratinib. Similarly, the use of other 
agents in the neurokinin-1 (NK-1) receptor antagonist class (casopitant and 
fosaprepitant) is limited by drug interactions and is prohibited with infigratinib. 
It is recommended to avoid using drugs that are known to cause QT prolongation. See 
Appendix 1 (Section 17.1) for list of drugs that need to be used with caution.  
Preliminary clinical data have shown that infigratinib has no effect on cardiac conduction 
or ECG intervals (see current version of the infigratinib Investigator’s Brochure). 
However, medications that have the potential to prolong the QT/QTc interval or induce 
Torsade de Pointes (possible and conditional risk of TdP/QT prolongation) are allowed 
with caution. Investigators at their discretion may co-administer such medications, but 
subjects should be carefully monitored. See Appendix 1 (Section 17.1) for list of drugs 
that need to be used with caution. Please note that the list might not be comprehensive. 
7.7.1.2 
Prohibited Concomitant Therapy 
A concomitant medication is considered prohibited if it appears on any of the prohibited 
medication lists for any clinical pharmacology property of the drug (eg, CYP, BCRP). 
Details for specific medications prohibited while on study are provided in Appendix 2 
(Section 17.2). The rationale for the restricted medications is provided below. 


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Other investigational therapies must not be used while the subject is on the study. 
Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) other than 
the study drug must not be given to subjects while the subject is on study drug. If such 
agents are required, then the subject must be discontinued from study drug. The only 
exception is palliative localized radiation therapy for bone metastases with approval by 
the sponsor medical monitor.  
Proton pump inhibitors are prohibited; see Section 7.7.1.1 for rationale. 
Infigratinib is a substrate of CYP3A4. Therefore, strong and moderate inhibitors and 
inducers should be avoided. Strong and moderate inhibitors of CYP3A4 such as the ones 
listed in Appendix 2 (Section 17.2) are prohibited because infigratinib is a likely substrate 
of this isoenzyme; these include the anti-emetic aprepitant (brand name: Emend) and 
other agents in the NK-1 receptor antagonist class (casopitant and fosaprepitant), as 
described in Section 7.7.1.1. Strong inducers of CYP3A4 are prohibited because their 
usage may decrease the exposure of infigratinib. Therefore, agents such as those listed in 
Appendix 2 (Section 17.2) are prohibited. Please note that the list may not be exhaustive. 
Subjects in the infigratinib group must also avoid the consumption of grapefruits, 
grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, Seville oranges or 
juice within 7 days prior to the first dose of infigratinib and throughout the treatment 
period due to a potential CYP3A4 interaction with study drug. 
Medications that increase the serum levels of phosphate and/or calcium are prohibited.  
7.7.2 
Gemcitabine with Cisplatin Group 
Subjects in the gemcitabine with cisplatin group cannot receive any investigational 
therapies while the subject is on gemcitabine and cisplatin. Anticancer therapy 
(chemotherapy, biologic or radiation therapy, and surgery) other than study drug 
(gemcitabine with cisplatin) must not be given to subjects while the subject is on study 
drug. If such agents are required, then the subject must be discontinued from study drug. 
The only exception is palliative localized radiation therapy for bone metastases with 
approval by the sponsor medical monitor. 
Antiemetic therapy, including premedications prior to chemotherapy, and anti-diarrheal 
medications can be used as clinically indicated and in accordance with standard of care. 
7.7.3 
COVID-19 Vaccinations 
The effect of COVID-19 vaccines has not been studied in combination with infigratinib; 
hence the safety and efficacy of either agent when used in combination are unknown 
(ie, vaccination before, during, or after infigratinib treatment has not been studied, and 
the efficacy and safety of COVID-19 vaccines in the presence of infigratinib, as well as 
the efficacy and safety of infigratinib in the presence of a COVID-19 vaccine, are 
unknown). Similarly, the safety and efficacy of combining COVID-19 vaccinations with 
gemcitabine and cisplatin are unknown. 


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There is no detailed or conclusive information on studies conducted with the COVID-19 
vaccines in patients receiving any anticancer therapies, or in patients with cancer. In 
general, COVID-19 vaccines may be administered before, during, and after study 
participation, if determined to be safe in the clinical judgement of the treating 
physician/study investigator. The treating physician/study investigator should assess the 
risk for each individual study subject for receiving the vaccine in the context of the study. 
Whenever feasible, vaccinations should be administered at least 30 days prior to 
randomization. Live vaccines are prohibited as specified in Section 7.7. 
All applicable guidelines should be followed, and vaccinations should adhere to the 
manufacturer’s guidelines for eligibility and contraindications to receive the vaccine 
(ASCO 2021; Garassino 2020; Pergam 2021). Subjects vaccinated for COVID-19 should 
be closely monitored, and any observed AEs/SAEs should be reported as outlined in 
Section 10.5.1. 
7.8 
Non-drug Therapies 
Any significant non-drug therapies (including physical therapy, herbal/natural 
medications, and blood transfusions) administered from the time of first dose of study 
drug through 30 days after last dose are to be recorded for each subject on the appropriate 
page of the eCRF. Dates for the start and stop of each therapy are to be recorded, as well 
as the reason for administration (particularly if administered for an AE). 
Non-drug therapies are prohibited if they appear on any of the prohibited medication lists 
for any clinical pharmacology or PK property of the drug (eg, CYP, BCRP) (see 
Appendix 2 [Section 17.2]). 
8 SUBJECT DISCONTINUATION AND STUDY TERMINATION 
8.1 
Subject Discontinuation 
8.1.1 
Discontinuation of Study Drug 
In rare instances, it may be necessary for a subject to permanently discontinue study 
treatment. If study treatment is permanently discontinued, the subject will remain in the 
study to be evaluated for safety follow-up and follow-up of disease progression and 
survival status. See Section 2 for data to be collected at the time of discontinuation of 
study treatment and follow-up and for any further evaluations that need to be completed. 
Subjects must be discontinued from study drug for:  
• Radiographic PD confirmed by BICR.  
• Pregnancy 
• AE that leads to substantial changes in individual risk-benefit considerations 


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• Dose delay of >14 days for infigratinib or >21 days for chemotherapy, with 
exceptions noted in Section 7.2.5.1 and Section 7.3, respectively, and approval by the 
sponsor medical monitor.  
• Death 
In addition, subjects may be discontinued from study drug for any of the following 
reasons:  
• Treatment phase complete (gemcitabine plus cisplatin arm) 
• New medical condition that does not allow continuation of study drug compliance 
• Protocol deviation, including non-compliance with dosing regimen 
• Lost to follow-up (defined as no contact after 3 documented attempts by telephone 
followed by 1 attempt via letter [eg, certified mail, if available])  
• Subject request 
• Investigator request 
• Central finding does not confirm FGFR2 fusion or rearrangement and the investigator 
elects to discontinue study treatment (subjects in the infigratinib arm) 
• Subject is found to be MSI-H and the investigator elects to discontinue study 
treatment. 
Of note: postrandomization, if the subject is determined to be MSI-high and/or does 
not have FGFR2 fusion or rearrangement confirmed by molecular testing by the 
central laboratory, the subject may continue on study treatment. This requires a joint 
decision by the subject and investigator and documentation of subject consent to 
continue on study treatment. 
If a subject is discontinued from study drug, the investigator is to notify the sponsor. At 
the time of discontinuation of study drug, subjects are to complete the EOT visit, 
followed 30 days later by the 30-day Follow-up visit. Thereafter, subjects will be 
followed for disease progression and survival (as previously described). Subjects who 
discontinue study drug for reasons other than PD confirmed by BICR will continue to 
have radiographic assessments every 8 weeks ±7 days until radiographic PD confirmed 
by BICR. 
The reason for discontinuation of study drug is to be documented in the eCRF. Further, if 
a subject is withdrawn from treatment due to protocol deviation or investigator’s request, 
specifics are to be recorded in the eCRF. 


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8.1.2 
Discontinuation from Study 
Subjects have the right to withdraw from the study at any time and their request without 
prejudice or may be withdrawn at any time at the discretion of the investigator for safety, 
behavioral, or compliance reasons. This is expected to be uncommon. At the time of 
discontinuing from the study, if possible, an EOT visit should be conducted, as shown in 
Section 2. See Section 2 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed.  
Subjects may be discontinued from the study for the following reasons: 
• Subject’s formal withdrawal of informed consent: 
• If the subject withdraws consent for disclosure of future information, the sponsor 
may retain and continue to use any data collected before such a withdrawal of 
consent. 
• If a subject withdraws from the study, the subject may request destruction of any 
samples taken and not tested, and the investigator must document this in the study 
records and notify the sponsor immediately. 
• Investigator request 
• Lost to follow-up (defined as no contact after 3 documented attempts by telephone 
followed by 1 attempt via certified letter) 
• Discontinuation of the study by the sponsor 
• Protocol deviation 
• Study complete 
• Death 
• Other 
The reason for discontinuation from the study is to be documented in the eCRF. The 
investigator should make every effort to determine why a subject is lost to follow-up or 
withdraws consent and record this information in the eCRF. Further, if a subject is 
withdrawn due to protocol deviation or investigator’s request, specifics are to be recorded 
in the eCRF. 
8.2 
Study Termination 
The study can be terminated at any time for any reason by the sponsor. Should this be 
necessary, every effort is to be made to ensure that the subject completes certain 
assessments, depending on where they are in the study. If a subject is still on study drug, 


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the subject is to complete the EOT visit. If the subject has already discontinued study 
drug, he/she is to complete the 30-day Safety follow-up visit (if not already completed). 
EOS reasons will be recorded for all subjects.  
The investigator may be informed of additional procedures to be followed in order to 
ensure that adequate consideration is given to the protection of the subject’s interests. The 
investigator will be responsible for informing Institutional Review Boards (IRBs) and/or 
Independent Ethics Committees (IECs) of the early termination of the trial. 
9 STUDY VISITS AND PROCEDURES 
See Section 2 for the Schedules of Assessments (Table 2, Table 3, Table 4, and Table 5). 
9.1 
Molecular Prescreening 
The sponsor must review and approve local tests for FGFR2 status to determine that the 
local laboratory result complies with the study protocol and definition of a known or 
likely activating FGFR2 fusion/rearrangement (refer to Section 10.3.1). If the FGFR2 
fusion/rearrangement status from a local test performed on tumor tissue that is compliant 
with local requirements for laboratory-developed tests or in vitro diagnostic devices 
(IVDs) is not available, molecular prescreening is required to confirm the presence of 
FGFR2 fusion/rearrangement from tumor tissue. If archival tumor tissue is available with 
a pathology report, molecular prescreening will be done using this sample. Otherwise, 
newly obtained tumor tissue collected before randomization will be required. The 
archival or newly obtained tumor tissue will be sent to a sponsor-designated central 
laboratory. Results of the analysis will be communicated to each respective study center.  
For China, all molecular prescreening will be performed by the contracted laboratory in 
China to determine the FGFR2 status. 
If FGFR2 data are not available prior to consent and molecular prescreening is required, 
subjects must provide written informed consent for molecular prescreening 
(Section 13.3). Molecular prescreening assessments can be done any time prior to the 
initiation of screening for the study. 
For subjects who sign the prescreening informed consent form (ICF), AEs which occur 
after signature of this consent and prior to signing the main informed consent will be 
captured if they meet the definition of serious and are reported to be causally related with 
study procedures (eg, an invasive procedure such as biopsy) (Section 10.5.1.3).  
For all subjects undergoing molecular prescreening, data collected as part of the 
assessment for FGFR2 fusion/rearrangement, including the following, will be collected 
and used for analysis of the exploratory objectives: (1) other genetic alterations identified 
on the F1CDx gene panel as well as tumor mutational burden, and microsatellite 
instability (MSI); (2) primary tumor site; (3) anatomic site of specimen collection 
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(FFPE block or FFPE slides); (6) gender; (7) age at the time of informed consent; and 
(8) country. 
9.2 
Main Informed Consent 
The subject will sign the main study ICF to begin screening procedures (Section 13.3). 
Informed consent must be obtained before conducting any study-specific procedures. A 
copy of the ICF must be given to the subject or to the person signing the form. The 
investigator or designee must record the date when the study informed consent was 
signed in the medical records of the subject. 
9.3 
Screening (Day −28 to −1) 
After the main ICF is signed, screening activities will include the following:   
• Collection of written documentation of local or central laboratory determination of 
known or likely activating FGFR2 fusions/rearrangements (see Section 9.1). Note: 
Central confirmation is not required prior to enrollment in study. Subjects 
with/without central confirmation of FGFR2 fusions/rearrangements are expected to 
follow the same study procedures. 
• Demography 
• I/E criteria assessment 
• ECOG performance status 
• Relevant medical history/current medical conditions 
• Diagnosis, primary location, and extent of cancer 
• Prior anticancer therapy 
• Height and weight 
• AEs (see Section 10.5.1.3)  
• Prior medication use 
• Physical examination 
• Vital signs 
• Ophthalmic assessment (performed by an ophthalmologist)  
• Blood draw for hematology, chemistry, and coagulation assessment 


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o To calculate calcium-phosphorus product (as noted in Exclusion Criterion #16): 
multiply the serum value of calcium in mg/dL by the serum phosphate in mg/dL. 
The calcium level used for this calculation and assessment of whether the subject 
has an abnormal calcium level should be corrected for serum albumin (Block 
2004; Young 2004; Young 2005). 
• Urinalysis (micro- and macroscopic) 
• Pregnancy test (blood or urine) for WOCBP 
• 12-lead ECG 
• Computed tomography (CT)/ magnetic resonance imaging (MRI) scans (chest, 
abdomen, and pelvis), unless available within 28 days prior to randomization (for 
subjects who receive up to 1 cycle of gemcitabine-based chemotherapy before 
randomization, the baseline imaging assessment must be conducted ≥7 days after the 
last dose of chemotherapy and before randomization) 
• Sufficient archival or newly obtained tumor sample for central confirmation of 
FGFR2 fusions/rearrangements by central laboratory (only if a tumor sample was not 
sent for central molecular prescreening) (see the Laboratory Manual for sample 
requirements for the central laboratory).  
In the event that subjects have a baseline/screening laboratory assessment that excludes 
them from the study, the baseline/screening laboratory assessment can be repeated. 
9.4 
Treatment Period: Cycle 1 Day 1 
Before the start of dosing on Cycle 1 Day 1, the following assessments are to be 
performed. Baseline/screening assessments that are conducted within 3 days prior to first 
treatment can be used to satisfy the Day 1 requirement.  
• ECOG performance status 
• Weight 
• Prior and concomitant medication use 
• Symptom-directed physical examination (if needed) 
• Vital signs 
• Blood draw for hematology, chemistry; blood draw for coagulation, if clinically 
indicated 
• Blood sample for PK assessment (first 40 subjects enrolled in the infigratinib group) 


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• Blood sample for assessment of cell-free tumor DNA  
• Urinalysis (micro- and macroscopic), if clinically indicated 
• Pregnancy test (blood or urine) for WOCBP 
• 12-lead ECG 
• AEs (see Section 10.5.1.3) 
• EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BIL21 prior to all other study 
procedures (and in order of EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BIL21) 
Note: Audiometry should be done for subjects assigned to gemcitabine/cisplatin, as 
required by the cisplatin local label or standard institutional guidelines. 
Subjects will then receive their first dose of infigratinib or gemcitabine plus cisplatin, 
depending on their treatment assignment.  
For the first 40 subjects enrolled in the infigratinib group, a blood sample will be 
collected 4 hours (±30 minutes) after infigratinib dosing for PK analysis. A sample will 
also be collected on Day 2 of Cycle 1 (24 hours [±1 hour] after the Day 1 dose prior to 
Day 2 dosing). 
Subjects in the infigratinib group will be dispensed study drug and instructed on daily 
dosing using a “3 weeks on, 1 week off” schedule for each 28-day treatment cycle. 
Subjects in the gemcitabine plus cisplatin group will be instructed to return to the study 
center on Day 8 to receive their next scheduled dose of study drug. 
9.5 
Rest of Treatment Period 
Subjects will continue to receive infigratinib or gemcitabine with cisplatin, as described 
in Section 7.1.  
During the treatment period, CT/MRI scans (chest, abdomen, and pelvis) will be taken 
every 8 weeks from the first dose of study drug, regardless of treatment interruption. For 
post-baseline imaging and ophthalmic assessments, a ±7 day window is allowed, except 
for the first post-baseline assessment (+7 day window permitted). 
Blood samples for assessment of cell-free tumor DNA will be collected every 8 weeks 
(±1 week) at the same visit as CT/MRI scans, regardless of treatment interruption. All 
samples are to be collected predose on dosing days.  
QOL assessments (EQ-5D, EORTC QLQ-C30, EORTC QLQ-BIL21) will be done every 
4 weeks (±1week) from last assessment through Cycle 3; then every 8 weeks (±1 week), 
regardless of treatment interruption. These assessments should be completed on the 


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specified visit day prior to all other study procedures and in order of EQ-5D, EORTC 
QLQ-C30, and EORTC QLQ-BIL21. 
Tumor samples may be collected during the treatment period upon disease progression 
and will be used to explore mechanisms of disease progression. Such sample collection 
requires documented subject informed consent. 
All subjects in the infigratinib group will have blood samples collected on Day 21 of 
Cycles 1 through 4 at 0 (predose) and 4 hour (±30 minutes) postdose for PK analysis.  
In addition, a PK substudy will be conducted on the first 40 subjects enrolled who receive 
infigratinib. These subjects will have PK blood samples collected at the following time 
points in Cycle 1: Day 1 (0 [predose] and 4 hours [±30 minutes] postdose), Day 2 
(24 hours [±1 hour] after the Day 1 dose prior to Day 2 dosing), Day 21 (0 [predose] and 
4 hours [±30 min] postdose), Day 22 (24 hours [±1 hour] after the Day 21 dose) of 
Cycle 1, and the same as all other subjects in the infigratinib group: Day 21 of Cycles 2 
through 4 at 0 (predose) and 4 hours (±30 minutes) postdose. If PK results are not 
evaluable for a subject, then that subject will be replaced with a subject treated with 
infigratinib to a total of 40 subjects enrolled in the PK substudy. 
Throughout the treatment period, subjects will be monitored for AEs and concomitant 
medication use. Other safety assessments, including symptom-directed physical 
examinations; vital signs; ophthalmic assessments (performed by an ophthalmologist); 
laboratory measures (hematology, blood chemistry, coagulation, pregnancy) and 
urinalysis; and 12-lead ECG will be conducted at the times indicated in Table 2 and 
Table 4.  
In addition, for subjects assigned to gemcitabine/cisplatin, audiometry should be done for 
subjects assigned to gemcitabine/cisplatin, as required by the cisplatin local label and 
standard institutional guidelines. 
Of note, if a subject has a dose delay and cannot receive study treatment for a visit, all 
safety labs must be conducted on the dosing visits that are listed in the schedule of 
assessments (Section 2) for the intended dosing day. In the event of missed/delayed 
infigratinib doses, a PK blood sample should be collected if the sample can be collected 
within 24 hours of the last dose. 
Weight will be taken, and ECOG performance status will be assessed, at the times 
indicated in Table 2 and Table 4. 
9.6 
EOT Visit 
When the decision is made to discontinue study drug, subjects will complete an EOT 
visit, no later than 8 days from the decision to discontinue study drug.  


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If a subject discontinues study drug for reasons other than radiographic PD confirmed by 
BICR, CT/MRI scans (chest, abdomen, and pelvis) should be taken at the EOT visit, 
unless taken within the previous 4 weeks.  
Other assessments will include the following: 
• ECOG performance status 
• Weight 
• Concomitant medication use 
• Physical examination 
• Vital signs 
• Ophthalmic assessment (performed by an ophthalmologist) 
• Blood draw for hematology, chemistry 
• Pregnancy test (blood or urine) for WOCBP 
• 12-lead ECG 
• EQ-5D, EORTC QLQ-C30, EORTC QLQ-BIL21 (prior to all other study procedures 
and in order of EQ-5D, EORTC QLQ-C30, and EORTC QLQ-BIL21); these 
assessments are not required if they were completed within the previous 7 days at a 
regularly scheduled visit. 
• AEs  
• Blood sample for assessment of cell-free tumor DNA (if not done within the previous 
28 days).  
For any subject in the infigratinib group who permanently discontinues study drug for 
any reason, attempts should be made to collect a PK blood sample from the subject at the 
time of discontinuation, if the sample can be collected within 24 hours of last dose. 
9.7 
30-day Safety Follow-up Visit 
All subjects must complete safety follow-up assessments 30 days after the last dose of the 
study drug, as outlined in Table 2 and Table 4. Information relating to anticancer 
therapies taken since discontinuation of study drug and AEs (including concomitant 
medication taken for ongoing AEs) will be collected for 30 days after the last dose of the 
study drug. 


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9.8 
Follow-up of Disease Progression and Survival Status 
Subjects who discontinue study drug for radiographic PD confirmed by BICR will be 
followed approximately every 3 months (via telephone or office visit) for survival status 
and new anticancer therapy information (subsequent therapy and progression/PFS2) until 
EOS, defined as the time when at least 224 OS events have been reached (for the primary 
OS analysis) and the last subject has completed study treatment. The following will be 
collected for new anticancer therapy information: 
• Name(s) of new anticancer therapy regimens. 
• New anticancer therapy dates of initiation and completion. 
• Date of radiographic progression to the first new anticancer therapy (PFS2). 
• Response to subsequent anticancer therapies and reason for discontinuation. 
Subjects who discontinue study drug for reasons other than radiographic PD confirmed 
by BICR will continue to have radiographic assessments every 8 weeks ±7 days until 
radiographic PD confirmed by BICR (even if subjects start new anticancer treatment). 
Thereafter, these subjects will be followed approximately every 3 months for survival 
status and use of anticancer therapy, as described above. 
At the time that PD is confirmed (by BICR and/or investigator), a blood sample will be 
collected for analysis of cell-free tumor DNA.  
For subjects assigned to gemcitabine/cisplatin, pregnancy testing every 4 weeks for 
6 months or other schedule should be done after the last infusion of gemcitabine and 
cisplatin if required according to the local gemcitabine or cisplatin label and local 
institutional practice. 
9.9 
Crossover to Infigratinib 
Subjects randomized to the gemcitabine with cisplatin group may be eligible to cross 
over and receive infigratinib following radiographic PD confirmed by BICR. Before 
these subjects receive any infigratinib, the following exclusion criteria must be 
rechecked: Exclusion Criteria 4, 7-10, 13, 14, 16-18 (see Section 6.2). Assessments 
performed within the past 30 days may be used to check these criteria. Crossover requires 
approval by the medical monitor. 
Subjects randomized to the gemcitabine with cisplatin group who cross over must 
complete their 30-day Safety Follow-up visit for gemcitabine with cisplatin before 
receiving any infigratinib. If a subject is receiving ondansetron, its use must be 
discontinued with a washout period of at least 24 hours before receiving any infigratinib. 
Crossover subjects will be dispensed study drug and instructed on daily dosing using a 
“3 weeks on, 1 week off” schedule for each 28-day treatment cycle.  


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Subjects who cross over to infigratinib will continue on treatment until unacceptable 
toxicity or other reason listed in Section 8.1.1. 
Subjects who cross over to infigratinib will be evaluated for safety, ECOG performance 
status, PFS2, OS and blood collection for cell-free DNA, as outlined in Table 5. 
9.10 End of Study 
EOS is defined as the time when 224 OS events have been reached (for the primary OS 
analysis) and the last subject has completed study treatment. At the EOS, the investigator 
is to document the primary reason for EOS for each subject, as defined in Section 8.1.2. 
10 STUDY ASSESSMENTS 
10.1 Efficacy Assessments 
Efficacy will be assessed by tumor response to study drug. To assess each subject’s 
response, CT/MRI scans will be performed.  
Chest, abdomen, and pelvic CT scans are required for all subjects at screening, unless 
available within 28 days prior to randomization. A contrast-enhanced MRI (if possible) 
of the chest, abdomen, and pelvis should be performed if a subject is known to have a 
contraindication to IV contrast at baseline or develops a contraindication during the trial. 
CT/MRI of the brain should be performed if clinically indicated. Details are provided in 
the Subject Scanning Guide. 
For subjects with skeletal lesions suspected at screening, whole-body bone imaging 
should be obtained either with a TC99 bone scan or alternatively a NaF CT/ MRI PET 
scan, with local CT of any identified lesions. Of note, the CT or MRI portion of the scan 
should only be substituted for the required chest, abdomen, and pelvic CT scans if the CT 
or MRI is of diagnostic quality and meets all requirements as described in the study 
imaging guide (ie, oral and IV contrast, slice thickness, and anatomic coverage). 
Postbaseline, if skeletal lesions are identified at screening, which are not visible on the 
chest, abdomen or pelvis CT/MRI scan, bone imaging with either a TC99 bone scan or 
NaF CT/MRI PET is required at all postbaseline imaging timepoints (every 8 weeks). In 
all cases that postbaseline bone imaging is required, the same modality that was used at 
screening should be used for all postbaseline imaging when possible. 
During the treatment period, CT/MRI scans (chest, abdomen, and pelvis) will be taken 
every 8 weeks from the first dose of study drug, regardless of treatment interruption. For 
post-baseline imaging assessments, a ±7 day window is allowed, except for the first 
post-baseline assessment (+7 day window permitted). 
If a subject discontinues study drug for reasons other than radiographic PD confirmed by 
BICR, CT/MRI scans (chest, abdomen, and pelvis) should be taken at the EOT visit, 
unless taken within the previous 4 weeks. Thereafter, these subjects will continue to have 
radiographic assessments every 8 weeks ±7 days until radiographic PD confirmed by 


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BICR (even if subjects start new anticancer treatment). Subjects who cross over from the 
gemcitabine-cisplatin group to receive infigratinib, after radiographic PD confirmed by 
BICR, will continue to have radiographic tumor assessments every 8 weeks for 
investigator assessment of efficacy. 
Subjects are to be evaluated for all potential sites of tumor lesions at each assessment 
time point. Any lesion that has been previously treated with radiotherapy should be 
considered as a non-target lesion. However, if a lesion previously treated with 
radiotherapy has clearly progressed since the radiotherapy, it can be considered as a 
target lesion. 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. 
Measurable disease according to RECIST v1.1 is not required for study entry (ie, a 
subject with non-target disease only may be enrolled into the study if they meet all other 
eligibility criteria). Tumor response will be evaluated by BICR and by the investigator 
according to RECIST Version 1.1 (Eisenhauer et al 2009). Summaries of the time point 
responses for target lesions (if applicable, Table 10), non-target lesions (Table 11), and 
overall response (Table 12) are provided below for reference.  
All radiographic assessments, including imaging obtained at unscheduled time points to 
determine disease progression, as well as imaging obtained for other reasons but captures 
radiographic progression, will be sent for BICR. Refer to the Study Manual for details 
regarding image collection and shipment. 
Once radiographic PD has been confirmed by BICR and documented, survival status and 
new anticancer therapy information (subsequent therapy and progression/PFS2) will be 
followed approximately every 3 months (via telephone or office visit) until EOS, defined 
as the time when at least 224 OS events have been reached (for the primary OS analysis) 
and the last subject has completed study treatment. 
For any subject with a centrally unreadable baseline scan, PD will be considered 
confirmed (for study conduct purposes, not analysis) when the study center submits their 
local PD notification for BICR.  


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Table 10: 
Response Criteria for Target Lesions  
Response criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes (whether 
target or non-target) must have reduction in short axis to <10 mm. 
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 diameters of target lesions, taking as 
reference the smallest sum on study (this includes the baseline sum if that is 
the smallest on study). In addition to the relative increase of 20%, the sum 
must also demonstrate an absolute increase of at least 5 mm.a 
Stable Disease (SD): 
Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Abbreviations: CR, complete response; PD, progressive disease; PR, partial response; SD, stable disease.  
a  The appearance of one or more new lesions is also considered progression. 
Source: Eisenhauer et al 2009 
 
Table 11: 
Response Criteria for Non-target Lesions  
Response criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor marker 
level. All lymph nodes must be non-pathological in size (<10 mm short axis). 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions or the appearance of 
one or more new lesions. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Abbreviations: CR, complete response; PD, progressive disease. 
Source: Eisenhauer et al 2009 
Note: Unequivocal progression in non-target lesions must be substantial and generally sufficient to require 
change in therapy. The increase in overall disease burden should be comparable in magnitude to the 
increase that would be required to declare PD for measurable disease: ie, an increase in tumor burden 
representing an additional 73% increase in ‘volume’ (which is equivalent to a 20% increase diameter in a 
measurable lesion).  
 


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Table 12: 
Overall Lesion Response at each Assessment  
Target lesions 
Non-target lesions 
New lesions 
Overall lesion 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated No 
PR 
SD 
Non-PD or not all evaluated No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbreviations: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; 
SD, stable disease. 
Source: Eisenhauer et al 2009 
 
10.2 Pharmacokinetic Assessments 
All subjects in the infigratinib group will have blood samples collected on Day 21 of 
Cycles 1 through 4 at 0 (predose) and 4 hours (±30 minutes) postdose for PK analysis 
(Table 2).  
In addition, a PK substudy will be conducted on the first 40 subjects enrolled who receive 
infigratinib. These subjects will have PK blood samples collected at the following time 
points in Cycle 1: Day 1 (0 [predose] and 4 hours [±30 minutes] postdose), Day 2 (24 
hours [±1 hour] after the Day 1 dose prior to Day 2 dosing), Day 21 (0 [predose] and 4 
hours [±30 min] postdose), Day 22 (24 hours [±1 hour] after the Day 21 dose), and the 
same as all other subjects in the infigratinib group: Day 21 of Cycles 2 through 4 at 0 
(predose) and 4 hours (±30 minutes) postdose (Table 3). If PK results are not evaluable 
for a subject, then that subject will be replaced with a subject treated with infigratinib to a 
total of 40 subjects enrolled in the PK substudy. 
For any subject in the infigratinib group who permanently discontinues study drug for 
any reason, attempts should be made to collect a PK blood sample from the subject at the 
time of discontinuation, if the sample can be collected within 24 hours of last dose.  
All blood samples will be taken from a central line, by direct venipuncture, or with an 
indwelling cannula inserted in a peripheral vein.  
On the days of PK sampling, subjects should take their study drug at the clinic after the 
predose PK sample is taken. Subjects who forget and take their study drug at home will 


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be excluded from PK analysis for that day and should not have blood samples collected 
for PK analysis.  
Complete dosing information, including the date and time of actual blood draw and time 
of the last study drug dose prior to the sampling, should be obtained on all sampling days 
and recorded on the appropriate blood collection eCRF. If any of the scheduled sampling 
times are missed or a sample is not drawn according to schedule, the actual collection 
date and time should be recorded, and the remaining samples should be collected on 
schedule whenever possible. 
Refer to the Laboratory Manual for complete instructions on PK sample collection, 
processing, handling, storage and shipment.  
Plasma concentrations of infigratinib and its active metabolites (including BHS697 and 
CQM157) will be measured by a central laboratory using a validated liquid 
chromatography-tandem mass spectrometry assay with a lower limit of quantification 
(LLOQ) of approximately 1.0 ng/mL. Concentrations below the LLOQ will be reported 
as below the quantification limit, and missing samples will be labeled accordingly.  
PK parameters listed in Table 13 will be estimated for infigratinib. Concentrations of 
metabolites will be reported and summary statistics (e.g. mean, standard deviation, %CV) 
calculated, as appropriate. 
Table 13: 
Pharmacokinetic Parameters for Infigratinib 
Term  
Definition 
Cmax 
Maximum observed plasma concentration after drug administration (defined as the 2 hour 
postdose concentration) 
Ctrough (min) 
Measured concentration at the end of a dosing interval (taken directly before next 
administration) 
Racc 
Accumulation ratio calculated as Cmin steady-state/Cmin (predose Day 2) 
 
10.3 Assessment of Biomarkers 
10.3.1 
Sample Collection Procedures and Requirements 
Biomarker assessments will be performed to confirm subject eligibility and to aid in 
understanding the effects of study medications (eg, infigratinib and gemcitabine/cisplatin) 
on biomarkers of cholangiocarcinoma disease and FGFR pathway regulation as related to 
clinical outcome. 
Options for determination of FGFR2 fusion/rearrangement results for eligibility (archival 
tumor tissue sample or new biopsy obtained before randomization) include: 


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• Central laboratory. 
• A known or likely activating FGFR2 fusion/rearrangement is defined as occurring 
when the breakpoint is within the FGFR2 intron 17/exon 18 hotspot and the gene 
partner is: 1) known in the literature, in strand with FGFR2; or 2) is a novel 
partner that is predicted to be in strand and in frame with FGFR2; or 3) is within 
the FGFR2 intron 17/exon 18 hotspot but the partner gene is out of frame or out 
of strand with exon 17 of FGFR2; or 4) where the downstream end of the 
breakpoint may be in an intergenic region and not within another gene (designated 
as partner n/a) (FoundationOne Liquid CDx 2020). 
• If FGFR2 fusion/rearrangement status was determined by the central laboratory as 
part of routine clinical care, a tumor sample does not need to be submitted for 
central confirmation. 
• CLIA-certified (or equivalent) local laboratory using a clinically validated test as 
determined and approved by the sponsor Translational Medicine Department 
(approved local testing).  
All subjects must have documented FGFR2 fusion/rearrangement before randomization 
and all subjects must have adequate tumor tissue from a prerandomization biopsy sample 
to send to the central laboratory for confirmation of FGFR2 fusion/rearrangement either 
before or after enrollment.  
If eligibility is determined by a local laboratory, then a prerandomization tumor tissue 
sample must be sent to the central laboratory within approximately 14 days of start of 
study treatment for the confirmation of FGFR2 fusion/rearrangement. Refer to the 
Laboratory Manual for additional details on the amount of tumor tissue required for 
FGFR2 fusion/rearrangement testing by the central laboratory. 
Note: If a prestudy written documentation of FGFR2 fusion/rearrangement in tumor 
tissue is available from the central laboratory, an additional tumor sample does not need 
to be submitted. 
For China, all FGFR2 testing will be done by the contracted China central laboratory. For 
study centers in China, written documentation of FGFR2 fusion/rearrangement by the 
contracted central laboratory is required for study eligibility.  
Optional tumor samples may be collected upon disease progression to support 
exploratory objectives to evaluate potential biomarkers related to cholangiocarcinoma 
biology and their potential correlation to efficacy, disease progression, and resistance to 
study medications. Subject consent is required for this optional tumor biopsy.  
Archival or newly obtained tumor samples collected during the study will be used to 
evaluate potential biomarkers related to cholangiocarcinoma biology and their potential 
correlation to efficacy, disease progression, and resistance to study medications 
(infigratinib and gemcitabine/cisplatin). This research will be performed using a 


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combination of genomic, transcriptomic and proteomic technology, which may include 
profiling of mutation, amplification and/or modification in DNA, RNA, or protein levels 
in tumor tissue. 
Blood samples for assessment of cell-free DNA will be collected as outlined in Table 2, 
Table 4, Table 5. Blood will be collected at Day 1 of Cycle 1 (predose), and every 
8 weeks (±1week) at the same visit as CT/MRI scans, regardless of treatment 
interruption; at the EOT, if not done within the previous 28 days; and at the time that PD 
is confirmed (by BICR and/or investigator). These samples will be used for analysis of 
DNA to explore whether genetic alterations found in tumor samples may also be 
observed in blood, and if any alterations found are associated with efficacy, disease 
progression, and development of resistance to study medications. 
Sponsor-designated lab(s) will be used for processing of all tumor and blood samples 
collected. The sponsor will provide kits to collect and ship these samples to sponsor-
designated lab(s) for analysis. Refer to the Lab Manual for additional instructions on the 
collection, handling, storage, and shipment of samples. Sample collection must be 
captured on the appropriate eCRF and requisition page(s). The samples may be stored 
under the control of the sponsor or its authorized agents. Samples collected will be stored 
until the end of the study, or 3 years after the PFS primary analysis, whichever is longer. 
Samples may be stored longer if the sponsor is required to answer questions from a 
regulatory or governmental agency. The data may be shared with Health Authorities 
worldwide, at medical meetings, or in medical publications. 
10.3.2 
Potential Use for Future Research 
Subjects will have an opportunity to consent to use of their remaining tissue or blood 
samples for additional research related to FGFR genetic alterations and other cancers. A 
decision to perform such future research studies would be based on new scientific 
findings related to FGFR genetic alterations and disease, as well as reagent and assay 
availability. 
Future research will use genetic testing (DNA, RNA, protein) of tissue and plasma 
samples (for cell-free DNA) that are left over from the exploratory objectives analysis.  
The investigators and subjects will not receive the results from future research. The 
biological samples will be coded with unique numbers that do not link the samples to the 
study subject in the study database as part of de-identification of the samples.  
The leftover samples for future research may be stored under the control of the sponsor or 
its authorized agents. The samples will be stored up to 15 years. The period of time that 
data derived from future research may be used is not specified and these data may be 
used indefinitely. The data may be shared with Health Authorities worldwide, at medical 
meetings, or in medical publications. 
Participation in future research using leftover tissue and blood is optional. Subjects can 
request that the sponsor not use their stored samples for future research, to the extent that 


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they are able to locate the sample after it has been de-identified. Subjects who fail 
prescreening and fail screening will not have their samples stored for future research. 
10.4 Quality of Life 
Subject QOL will be evaluated using the EQ-5D, which measures 5 dimensions of health, 
including mobility, self-care, usual activities, pain/discomfort, anxiety, and general 
health; the EORTC QLQ-C30, a reliable and valid measure of QOL in cancer subjects; 
and the EORTC QLQ-BIL21, a disease-specific module for subjects with 
cholangiocarcinoma and gallbladder cancer. QOL instruments (ie, EQ-5D, EORTC QLQ-
C30, and EORTC QLQ-BIL21 questionnaires) appear in Appendix 4 (Section 17.4). 
QOL will be evaluated at the times outlined in Table 2 and Table 4. QOL will not be 
evaluated for subjects in the gemcitabine plus cisplatin group if and after they cross over 
to infigratinib. 
At each time point, the EQ-5D is to be completed first, followed sequentially by the 
EORTC QLQ-C30 and EORTC QLQ-BIL21.  
If a subject cannot complete a QOL instrument because of illiteracy or other documented 
reason, the instrument should be omitted. Reasons for missing data will be documented 
and incorporated into the analysis as necessary. 
EQ-5D 
The EQ-5D is a standardized instrument for use as a measure of general health states 
preferences and provides a simple descriptive profile and index value for health status 
and measures 5 dimensions of health including mobility, self-care, usual activities, 
pain/discomfort, anxiety, and general health is measured via a vertical visual analog scale 
(Rabin et al 2001). Applicable to a wide range of health conditions and treatments, it 
provides a simple descriptive profile and a single index value for health status. 
The subject-reported assessments are for the purpose of exploring the subject’s own 
perceptions about their symptoms and health-related QOL and thus a proxy (ie, a 
caregiver or study personnel) should not complete the questionnaires. Additionally, the 
investigator must not influence the subject’s assessments. Every effort should be made to 
maintain an unbiased assessment.  
At each scheduled assessment, the EQ-5D should be administered prior to all other study 
procedures. If assessments were completed within the previous 7 days at a regularly 
scheduled visit, assessments do not need to be administered at the EOT visit.  
Details of the algorithms that generate summary derived scores on each of the above 
health related QOL scales and the statistical approach for each will be provided in the 
Statistical Analysis Plan (SAP). 


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EORTC QLQ-C30 
The EORTC QLQ-C30 was developed to assess the QOL of subjects with cancer 
(Aaronson et al 1993). It has been translated and validated into 8 languages. It contains 5 
functioning scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, nausea and vomiting, pain) and additional single symptom items. It is scored on 
a 4 point scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The EORTC QLQ -
C30 instrument also contains 2 global scales that use 7 point scale scoring with anchors 
(1=very poor and 7=excellent). 
EORTC QLQ-BIL21 
The EORTC QLQ-BIL21 is a disease-specific module to be used with the EORTC QLQ-
C30 tool. It was been validated in subjects with cholangiocarcinoma and cancer of the 
gallbladder (Kaupp-Roberts et al 2016). The QLQ-BIL21 consists of 21 questions: 3 
single-item assessments relating to treatment side effects, difficulties with drainage 
bags/tubes and concerns regarding weight loss, in addition to 18 items grouped into 5 
scales: eating symptoms, jaundice symptoms, tiredness symptoms, pain symptoms, and 
anxiety symptoms. The items are scored on a 4-point Likert scale, as described above. 
10.5 Safety Assessments 
The safety evaluation will be based on AE reporting, laboratory parameters, vital signs, 
physical examinations, 12-lead ECGs, and ophthalmic assessments. Tolerability will be 
assessed by the incidence of AEs leading to study drug interruption, dose reduction, or 
discontinuation. 
10.5.1 
Adverse Events 
10.5.1.1 
Definitions 
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s). 
An 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, ie, defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 


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• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition  
• Elective or preplanned treatment for a pre-existing condition that is unrelated to 
the indication under study and has not worsened since signing the informed 
consent 
• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
In addition, any suspected transmission of an infectious agent via a medicinal product 
will be considered an SAE at study centers in the EU. 
10.5.1.2 
Clarifications for AE Definitions 
Abnormal laboratory values or test results constitute AEs only if they induce clinical 
signs or symptoms, are considered clinically significant, require therapy (eg, hematologic 
abnormality that requires transfusion or hematological stem cell support), or require 
changes in study drug(s). 
Progression of underlying malignancy is not considered as an AE if it is clearly consistent 
with the suspected progression of the underlying cancer as defined by RECIST criteria 
v1.1, or other criteria as determined by protocol. Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as an SAE. 
Clinical symptoms of progression may be reported as AEs if the symptom cannot be 
determined as exclusively due to the progression of the underlying malignancy, or does 
not fit the expected pattern of progression for the disease under study. 
Symptomatic deterioration may occur in some subjects. In this situation, progression is 
evident in the subject’s clinical symptoms, but is not supported by the tumor 
measurements. Or, the disease progression is so evident that the investigator may elect 
not to perform further disease assessments. In such cases, the determination of clinical 
progression is based on symptomatic deterioration. These determinations should be a rare 
exception as every effort should be made to document the objective progression of 
underlying malignancy. 
Overdose of infigratinib is to be reported as an AE when drug is administered or taken at 
a dose ≥200 mg and the overdose is associated with signs or symptoms potentially related 
to study drug (see also Section 10.5.1.5).  
If there is any uncertainty about an AE being due to progression of the disease under 
study, it should be reported as an AE or SAE. 


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10.5.1.3 
Recording Adverse Events 
After a subject signs the molecular prescreening ICF and/or the main study ICF and until 
a subject is randomized, AEs will only be captured if they meet the definition of serious 
and are reported to be causally related with study procedures (eg, an invasive procedure 
such as biopsy). Any other appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) should be recorded as medical history.  
Before randomization, any SAEs reported as causally related with study procedures will 
be captured on a paper SAE Report form. After randomization, all AEs and all SAEs will 
be captured and reported in the eCRF.  
Conditions already present at the time of informed consent should be recorded in the 
Medical History eCRF.  
AEs (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 AE. 
The following information is to be captured in the eCRF for each AE: severity grade 
(CTCAE v5.0, Grade 1-5); duration (start and end date); relationship to study drug 
(infigratinib, gemcitabine, and/or cisplatin); action taken with respect to study drug; 
whether medication or therapy was given; outcome; and whether the event was serious 
and seriousness criteria. 
AE monitoring should be done from the time of informed consent and continue through 
30 days after the last dose of study drug.  
10.5.1.4 
Reporting Serious Adverse Events 
Before randomization, any SAEs causally related with study procedures will be captured 
on a paper SAE Report Form and must be reported to Covance Safety via email 
(SAEintake@covance.com) or FAX (refer to the Study Manual for country-specific FAX 
numbers) within 24 hours of learning of its occurrence.  
Every SAE, regardless of suspected causality, occurring after the subject has been 
randomized through 30 days after the subject has taken his/her last dose of study drug 
must be reported in the SAE eCRF immediately, and under no circumstances later than 
24 hours of learning of its occurrence. If there are any issues with EDC, please send a 
completed paper SAE report form to Covance Safety via email 
(SAEintake@covance.com) or FAX. Refer to the Study Manual for country-specific 
FAX numbers. Any SAEs experienced after this 30-day period should be reported to 
Covance Safety if the investigator suspects a causal relationship to the study drug.  
Any additional information for the SAE including recurrent episodes, complications, or 
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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. 
Follow-up information is submitted in the same way as the original SAE Report. Each 
reoccurrence, 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, and 
whether the subject continued or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study drug, a Covance Safety 
Associate may urgently require further information from the investigator for Health 
Authority reporting. Covance Safety may need to issue an investigator notification, to 
inform all investigators involved in any study with the same drug that this SAE has been 
reported. Suspected Unexpected Serious Adverse Reactions will be collected and 
reported to the competent authorities and relevant ethics committees in accordance with 
Directive 2001/20/EC or according to national regulatory requirements in participating 
countries. 
More detailed information on SAE Reporting can be found in the Study Reference 
Manual. 
10.5.1.5 
Adverse Events of Special Interest 
The following AEs, if otherwise not qualified as an SAE, are to be reported within 
24 hours in the electronic data capture (EDC) system. 
• Potential drug induced liver injury that meets the following criteria (elevation of 
bilirubin and ALT/AST that meet Hy’s Law criteria [FDA Guidance for Industry, 
2009]): 
• Treatment-emergent ALT or AST >3 × baseline value in combination with total 
bilirubin ≥2 × upper limit of normal (of which ≥35% is direct bilirubin) 
• Treatment-emergent ALT or AST >3 × baseline value in combination with 
clinical jaundice. 
• Retinal detachment of Grade 3 or higher, regardless of relationship to study drug 
• Keratitis Grade 3 or higher with suspected relationship to study drug 
• Pathological fractures, defined as fractures potentially related or related to metastatic 
tumor to bone and/or study drug 
• Vascular calcifications accompanied by ischemic AEs 
• Overdose, defined as a dose ≥200 mg of infigratinib, and that is associated with an 
AE which is potentially related to study drug. 


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10.5.1.6 
Follow up of Adverse Events 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy 
is given, this action should be recorded on the appropriate page of the eCRF. 
Once an AE 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 drug, the 
interventions required to treat it, and the outcome. 
All SAEs should be followed according to standard of care until resolution or stability. 
Also see Section 7.2.5.2 (infigratinib group) and Section 7.3 (gemcitabine plus cisplatin 
group) for follow up information on toxicities. 
10.5.2 
Pregnancies 
All WOCBP are to undergo pregnancy testing (blood or urine) at the times specified in 
Table 2, Table 4, and Table 5. Female subjects must be discontinued from study drug in 
the event of pregnancy. In addition, for subjects assigned to gemcitabine/cisplatin, 
pregnancy testing every 4 weeks for 6 months or other schedule should be done after the 
last infusion of gemcitabine and cisplatin if required according to the local gemcitabine 
or cisplatin label and local institutional practice. 
To ensure subject safety, each pregnancy of a subject or partner of a male subject 
occurring while the subject is on study drug (and for 30 days after the last study drug 
dose) must be reported to Covance Safety 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. Consent to 
report information regarding pregnancy and pregnancy outcomes should be obtained 
from the partner of the male subject. 
Pregnancy of a subject or partner of a male subject should be entered on the Pregnancy 
Notification eCRF. Pregnancy follow-up should be documented on a paper Pregnancy 
Follow-up Form and reported to Covance Safety via email (SAEintake@covance.com) or 
FAX Refer to the Study Manual for country-specific FAX numbers. 
Any SAE experienced by a subject during pregnancy must be reported as an SAE, as 
outlined in Section 10.5.1.4. 
10.5.3 
Laboratory Parameters 
Clinical laboratory analyses are to be performed at the times specified in Table 2, 
Table 4, and Table 5. Parameters included in the panel are listed in Table 14. 


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Laboratory tests will be collected and analyzed on the scheduled day, even if study drug 
is being withheld. More frequent assessments may be performed at the discretion of the 
investigator and if medically indicated, and should be recorded on the unscheduled visit 
eCRFs. 
At any time during the study, abnormal laboratory parameters which are clinically 
relevant (eg, require dose modification and/or interruption of study drug, lead to clinical 
symptoms or signs, or require therapeutic intervention), whether specifically requested in 
the protocol or not, will be recorded on the AE eCRF page. Laboratory data will be 
summarized using the CTCAE v5.0. 
Table 14: 
Safety Laboratory Parameters 
Test Category 
Test Name 
Hematology 
Hematocrit, hemoglobin, RBC counts, WBC counts with differentials, platelets 
Biochemistry 
Albumin, alkaline phosphatase, ALT (SGPT), AST (SGOT), calcium (can be 
corrected), chloride, creatinine, blood urea nitrogen or urea, potassium, sodium, 
magnesium, phosphate 
Direct bilirubin, indirect bilirubin, total bilirubin, total protein, uric acid, amylase, 
lipase 
Urinalysis 
Macroscopic panel (dipstick) (blood, glucose, ketones, pH, protein, specific 
gravity). 
Microscopic panel (RBC, WBC) 
Coagulation 
Prothrombin time or international normalized ratio, partial thromboplastin time 
Abbreviations: ALT, alanine aminotransferase; AST, aspartate aminotransferase; RBC, red blood cell; 
SGOT, serum glutamic-pyruvic transaminase; SGPT, serum glutamic-oxaloacetic transaminase; WBC, 
white blood cell 
 
10.5.4 
Vital Signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed in the same 
position, either sitting or supine, before dosing at the times specified in Table 2, Table 4, 
and Table 5. Vital signs should be assessed on the scheduled day, even if study drug is 
being withheld. More frequent examinations may be performed at the discretion of the 
investigator and if medically indicated. 
10.5.5 
Physical Examinations 
A complete physical examination (including height and weight) must be performed at the 
Screening and EOT visits. At all other times indicated in Table 2, Table 4, and Table 5, 
targeted, symptom-based physical examinations are to be performed, as needed. 
The complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 


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lymph nodes, extremities, vascular and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. 
Information about the physical examination must be present in source documentation at 
the study center. Clinically significant findings that are present prior to randomization 
should be included in the Medical History eCRF. Significant new findings must be 
recorded on the AE eCRF. 
10.5.6 
Electrocardiograms  
For each subject, 12-lead ECGs are to be performed at the times indicated in Table 2, 
Table 4, and Table 5. 
Clinically significant ECG findings must be discussed with the sponsor medical monitor 
prior to enrolling the subject. Clinically significant ECG abnormalities present prior to 
randomization should be reported on the Medical History eCRF page. Significant new 
findings post randomization from initiation of study drug until 30 days after permanent 
discontinuation of study drug must be recorded as an AE on the AE eCRF. 
10.5.7 
Eastern Cooperative Oncology Group (ECOG) Performance 
Status 
ECOG performance status are to be assessed at the times indicated in Table 2, Table 4, 
and Table 5, according to the following scoring: 
 
Grade 
ECOG Performance 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, eg, light house work, office work 
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities; up and 
about more than 50% of waking hours 
3 
Capable of only limited selfcare; confined to bed or chair more than 50% of waking hours 
4 
Completely disabled; cannot carry on any selfcare; totally confined to bed or chair 
5 
Dead 
Source: https://ecog-acrin.org/resources/ecog-performance-status 
10.5.8 
Ophthalmic Assessments 
For each subject, ophthalmic examinations are to be performed by an ophthalmologist at 
the times indicated in Table 2, Table 4, and Table 5 and with any new onset of visual 
disturbance. For postbaseline assessments, a ±7 day window is allowed, except for the 
first post-baseline assessment (+7 day window permitted).  


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These assessments will include visual acuity testing (including corrected distance acuity), 
slit lamp examination of the anterior eye segment, intraocular pressure, retinal OCT, and 
dilated fundoscopy. Additional examinations such as specular microscopy and corneal 
pachymetry will be performed as clinically indicated. 
Retinal OCT scan images will be collected centrally for potential review. Refer to the 
Study Manual for details regarding image collection and transfer or shipment. 
10.5.9 
Early Stopping Guidelines and Data Monitoring Committee 
One formal interim analysis of PFS based on BICR will be performed when 
approximately 114 PFS events have occurred across both treatment arms in the ITT 
population.  
The study may be stopped due to futility at the interim PFS analysis when the futility 
boundary for testing PFS is crossed. The futility stopping boundary is non-binding to 
allow for additional considerations. Though efficacy boundaries are specified for PFS 
assessed by BICR and OS at the time of the interim PFS analysis, the trial will not stop 
for efficacy at the interim analysis for PFS even if the efficacy boundary is crossed for 
PFS. 
An independent Data Monitoring Committee (DMC) will periodically monitor the 
interim data at regularly scheduled meetings, according to a prespecified DMC charter 
and at the interim PFS analysis (see Section 11.2). The voting members of the committee 
will be external to the sponsor and must not be involved with the trial in any other 
capacity (ie, they cannot be trial investigators) and must have no competing interests that 
could affect their role with respect to the trial.  
The DMC will review interim trial results, consider the overall risk and benefit to trial 
participants and make recommendations to the sponsor whether the trial should continue 
in accordance with the protocol and regarding steps to ensure both subject safety and 
ethical integrity of the trial. 
In the event that the study is terminated early based on a DMC recommendation, the 
sponsor will notify the appropriate regulatory authorities.  
The DMC or sponsor study team may request an ad hoc meeting for any reason, 
including significant unexpected safety event or follow-up of an observation during a 
planned DMC meeting.  
At each review, subject incidence rates of AEs (including all serious, treatment-related, 
serious treatment-related and events requiring the discontinuation of study drug) will be 
tabulated by system organ class, preferred term and severity grade. Listings and/or 
narratives of “on-study” deaths, deaths within 30 days of receiving study drug and serious 
and significant AEs, including any early discontinuations due to AEs will be provided.  


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Records of all meetings will be archived. The DMC will communicate major safety 
concerns and recommendations regarding study modification or termination to the 
sponsor.  
Further details will be provided in the DMC charter. 
11 STATISTICAL METHODOLOGY 
11.1 General Considerations 
Data will be analyzed by the sponsor and/or designated contract research organization 
(CRO).  
Categorical data will be presented as frequencies and percentages. For continuous data, 
mean, standard deviation, median, 25th and 75th percentiles, minimum, and maximum will 
be presented.  
The primary efficacy analyses will be conducted on the intent-to-treat (ITT) population, 
defined as all subjects who were randomized; subjects will be analyzed according to their 
randomized treatment group assignment.  
A sensitivity analysis for efficacy will be conducted for subjects who have centrally 
confirmed FGFR fusion/rearrangement in the ITT population. The safety analysis 
population will include all subjects who receive at least one dose of study drug and will 
be analyzed according to the treatment they receive. Detailed definitions of the analysis 
populations will be provided in the SAP.  
The primary endpoint is PFS based on BICR. The primary analysis for PFS will be 
performed when 228 PFS events have been reached. A formal interim analysis of PFS 
based on BICR will be also performed when approximately 114 PFS events have 
occurred in the ITT population. 
PFS assessed by BICR will be tested at a 2-sided significance level of 0.05. The key 
secondary endpoint, OS, will only be tested if the test on PFS assessed by BICR is 
significant. One interim analysis and one primary analysis for OS are planned. The 
interim analysis for OS will be conducted at the time of the PFS primary analysis. The 
primary analysis for OS will be conducted after approximately 224 deaths have been 
observed. 
Any deviations from the protocol or SAP-specified analyses will be described in the 
clinical study report.  
11.2 Sample Size Determination 
Approximately 300 subjects with FGFR2 fusion/rearrangement determined by a central 
laboratory or local laboratory will be randomized in this study (2:1 randomization, with 
200 in the infigratinib group and 100 in gemcitabine with cisplatin group) and stratified 


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by unresectable locally advanced vs metastatic disease, geographic region (North 
America, Western Europe, Asia Pacific, and rest of the world), prior 
neoadjuvant/adjuvant treatment (yes/no), and received up to 1 cycle of prior gemcitabine-
based chemotherapy for unresectable locally advanced or metastatic disease (yes/no).  
The primary endpoint is PFS assessed by BICR. 
Assuming a PFS hazard ratio (HR) of 0.67 (median PFS 11.9 vs 8 months) (Valle et al 
2010) comparing infigratinib to gemcitabine with cisplatin, with 228 PFS events 
required, the study will provide approximately 80% power to determine if treatment with 
infigratinib improves PFS assessed by BICR compared to treatment with gemcitabine and 
cisplatin at a 2-sided significance level of 0.05. Assuming the test on PFS is significant, 
with 224 deaths observed, the study will provide 66% power to demonstrate infigratinib 
improves OS compared to treatment with gemcitabine and cisplatin assuming an OS HR 
of 0.7 (median OS 16.7 vs 11.7 months) (Valle et al 2010). 
The study employs a group sequential design with one interim analysis for futility on 
PFS, which will be conducted when approximately 50% of the PFS events (114) are 
observed. The primary analysis for PFS will be conducted after approximately 228 PFS 
events have been observed. A fixed 2-sided significance level of 0.0001 will be spent at 
the interim analysis for PFS. A Lan-DeMets alpha spending function approximating 
O’Brien Fleming boundaries will be used for the non-binding futility boundary.  
One interim analysis and one primary analysis for OS are planned. The interim analysis 
for OS will be conducted at the time of the PFS primary analysis, and the primary 
analysis for OS will be conducted after approximately 224 deaths have been observed. 
OS will be tested only if PFS is found to be significant. The Lan-DeMets spending 
function approximating the O'Brien-Fleming spending function will be used to calculate 
the significance boundaries. 
With 42-month uniform enrollment, the study is projected to reach the planned number of 
PFS events assessed by BICR (228) in approximately 54 months from randomization of 
the first subject. The OS event goal of 224 deaths is projected to be reached 
approximately 66 months from randomization of the first subject. The required sample 
size is estimated to be a total of 300 subjects, considering that approximately 10% of 
subjects will drop out per year before a PFS or OS event. 
11.3 Statistical Hypothesis, Model, and Method of Analysis 
11.3.1 
Disposition of Subjects 
The number and percentage of subjects entering and completing study drug and the study 
will be presented by arm. Reason for discontinuation of study drug and study withdrawal 
will also be summarized.  


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11.3.2 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications 
Demographic data, medical history, baseline characteristics, prior anticancer therapy, and 
concomitant medications will be summarized by treatment arm.  
11.3.3 
Efficacy Analyses 
The primary objective of the study is to determine if treatment with infigratinib improves 
PFS as assessed by BICR compared to treatment with gemcitabine and cisplatin in 
subjects with unresectable locally advanced or metastatic cholangiocarcinoma with 
FGFR2 fusion/rearrangement. 
The primary endpoint, PFS assessed by BICR, will be tested first at 2-sided significance 
level of 0.05. The key secondary endpoint, OS, will only be tested if the test on PFS 
assessed by BICR is significant.  
PFS assessed by BICR is defined as the time from randomization to PD confirmed by 
BICR or death due to any cause, whichever is earlier (including PD/death that occurs 
after other anticancer treatment) (FDA Guidance for Industry 2015; FDA Guidance for 
Industry 2018). If there is no documented PD confirmed by BICR or death, PFS assessed 
by BICR will be censored at the last valid tumor assessment. If the first PD confirmed by 
BICR or death occurs after 2 or more missing assessments, PFS assessed by BICR will be 
censored at the last valid tumor assessment. Sensitivity analysis of PFS assessed by BICR 
will be conducted, in which PFS assessed by BICR will be censored at the last valid 
tumor assessment before the start of subsequent anticancer therapy if PD confirmed by 
BICR or death occurs after subsequent anticancer therapy. 
The primary analysis of PFS based on BICR will be performed when approximately 
228 PFS events have been reached in the ITT population. A data-cut will also be set for 
the interim analysis for PFS when approximately 114 PFS events assessed by BICR have 
been reached for the interim analysis on PFS. A fixed 2-sided significance level of 0.0001 
will be spent at the interim analysis for PFS. A Lan-DeMets alpha spending function 
approximating O’Brien Fleming boundaries will be used for the interim non-binding 
futility and final significance boundaries.  
OS time is time from randomization to death. Subjects who have not died (no record of 
death) or who are lost to follow up will be censored at the date they were last known to 
be alive. Subjects who withdraw consent for study participation, including consent to be 
followed up, will be censored on the date of withdrawal. OS will be tested at the primary 
PFS analysis (only if PFS is found to be significant) and at the OS primary analysis when 
224 deaths have been observed. The Lan-DeMets spending function approximating the 
O'Brien Fleming spending function will be used to calculate the significance boundaries. 
The primary endpoint, PFS as determined by BICR, and the key secondary endpoint OS 
will be tested using a log rank test stratified by randomization stratification factors. The 
HR and the corresponding 2-sided 95% confidence interval (CI) will be derived from a 


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Cox proportional hazards regression model stratified by randomization stratification 
factors for PFS assessed by BICR and OS. The Kaplan-Meier (K-M) medians (if 
estimable) will be derived, along with their 2-sided 95% CIs. 
Subjects randomized to gemcitabine with cisplatin may cross over to infigratinib, or other 
FGFR inhibitors. To incorporate the effect of such crossover on OS, sensitivity analyses, 
including inverse probability of censoring weighting (IPCW) (Robins 2000) and rank-
preserving structural failure time (RPSFT ) model (Robins 1991), may be conducted. The 
details of such sensitivity analyses will be provided in the SAP. 
PFS based on investigator reads and PFS2 (defined as time date of randomization until 
date of progression on the subsequent therapy or death due to any cause, whichever is 
earlier, as determined by the investigator) will be analyzed using the same approaches for 
PFS. 
ORR (PR and CR according to RECIST 1.1) will be summarized by treatment group. The 
2-sided 95% CI will be calculated for the difference in ORR between the 2 treatment 
groups based on the Wilson method for subjects in the ITT population. Descriptive 
statistics will be provided for best overall response prior to any other anticancer treatment 
for each treatment group. The number and proportion of subjects within each category of 
response (CR, PR, SD, and PD) and subjects with disease control (CR+PR+SD) will be 
presented. For duration of response (time from initiation of response to PD confirmed by 
BICR or death), K-M medians with 2-sided 95% CIs will be presented for responders in 
each treatment group.  
11.3.4 
Pharmacokinetic Analyses 
PK parameters will be summarized. For subjects with sparse PK samples, only Ctrough, and 
Cmax will be estimated (see Section 10.2). PK parameters will be summarized and listed 
using relevant statistics by study day, and descriptive statistics will be presented. 
Concentrations will be summarized as appropriate. 
Only PK blood samples with the date and time of collection and for which the last prior 
dose dates and times are adequately recorded will be included in the PK analyses. 
Samples taken from subjects who vomited within 4 hours of dosing will be excluded 
from the analysis. 
PK data generated from this study may be used in conjunction with PK data from other 
clinical studies (eg, healthy volunteers, advanced cholangiocarcinoma, solid tumors, etc) 
for population PK and PK/pharmacodynamic assessment. If a population PK model exists 
when data from this study becomes available, this data may be used to update an existing 
model and estimate Bayesian PK parameter estimates and exposures (Ctrough, Cmax, and 
AUC) of each analyte for each patient. The estimated PK exposures will also be used to 
develop or further expand exposure-response models for efficacy and measures of safety. 
Any population PK data generated will be reported separate from the clinical study 
report. These analyses will be defined in a stand-alone analysis plan document(s), as 
appropriate, prior to clinical database lock. Residual PK plasma samples from this study 


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may also be used for exploratory analysis to further characterize the PK of BGJ398 
and/or its metabolites. This may include using residual PK samples for protein binding 
analysis or metabolite profiling (eg, other metabolites and markers for metabolic enzyme 
activity such as 4-beta hydroxyl cholesterol levels), if sufficient samples remain. 
11.3.5 
Biomarker Analyses 
Correlative analysis of genomic biomarkers from molecular prescreening and available 
clinicopathologic and demographic data will be assessed to better understand the 
genomic landscape of cholangiocarcinoma. Genetic testing (DNA, RNA, protein) of 
tissue and plasma samples (for cell-free DNA) will be performed using available matched 
samples in order to detect changes from baseline in molecular profiles in tumor tissues 
and cell-free DNA from infigratinib-treated and gemcitabine-cisplatin-treated subjects, 
including those who have progressed. The difference in biomarker results from samples 
taken before and during treatment will be investigated. Tumor samples collected at 
disease progression will also undergo genetic and protein analysis to support exploratory 
objectives to evaluate potential biomarkers that correlate with efficacy and resistance to 
study medications.  
Correlation between biomarkers related to cholangiocarcinoma biology (eg, co-mutations 
in other genes) and clinical endpoints may also be assessed. Correlative analysis for 
tumor biomarkers identified at the time of diagnosis and disease progression will be 
performed. Analysis of genetic alterations and dysregulation of other tumor signaling 
pathways will be performed to better understand efficacy and resistance to study 
medications. 
As described in Section 10.3.1, concordance between the China central laboratory and the 
global central laboratory will be assessed using leftover tumor samples and commercially 
procured cholangiocarcinoma tumors. 
11.3.6 
Companion Diagnostic Assay Analyses 
Concordance rate between central assessment and local assessment on FGFR2 
fusion/rearrangement status will be summarized for all subjects who have local testing 
results and have central testing results available.  
As described in Section 10.3.1, samples submitted to the central laboratory may be used 
to validate a companion diagnostic for FGFR2 fusion/rearrangement testing as part of this 
study. Leftover tumor samples from enrolled subjects may be used in a bridging study to 
validate the companion diagnostic.  
11.3.7 
Analyses of Quality of Life Assessments 
QOL assessments (EORTC QLQ-C30, EORTC QLQ-BIL21, and EQ-5D) will be 
analyzed using a random effects mixed model controlling for baseline scores and 
randomization stratification factors to assess the difference in treatment arms. Two-sided 
95% CIs will be calculated for the difference between the two treatment arms.  


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In addition, descriptive summaries on the observed data (including change from baseline) 
will be summarized at each assessed time point. Compliance of quality of life 
assessments will be reported. QOL instruments are described in Appendix 4 
(Section 17.4). 
11.3.8 
Safety Analyses 
Safety analyses will be performed for all subjects who receive at least one dose of study 
drug according to the treatment they receive. For subjects randomized to gemcitabine 
with cisplatin who cross over to infigratinib, the safety data before and after crossover 
will be analyzed separately. 
11.3.8.1 
Treatment Exposure and Compliance 
Duration of treatment will be summarized by treatment arm. In addition, the actual 
cumulative dose and the relative dose intensity (actual cumulative dose/planned 
cumulative dose) will be summarized. The number of subjects with dose holds or dose 
reductions will be tabulated for each study drug by treatment group. 
11.3.8.2 
Adverse Events 
Study data will be monitored on an ongoing basis by the clinical study team to ensure 
subjects’ safety. Additional safety reviews will be performed by the DMC periodically 
throughout the study (Section 10.5.9). These reviews will include all available data on 
incidence of AEs, SAEs including deaths, and events leading to study drug 
discontinuation.  
All reported AEs will be assigned system organ class, and preferred term, according to 
the Medical Dictionary for Regulatory Activities (MedDRA).  
AEs will be considered to be treatment emergent if the event occurs on or after the first 
administration of protocol specified treatment and within last dose date +30 days. The 
subject incidence rates of AEs will be tabulated by system organ class, preferred term, 
and severity grade for all treatment emergent, serious, treatment related, and serious 
treatment related AEs. Each of these outputs will include tabulation by maximum 
severity for each system organ class and preferred term as reported by the investigator 
based on CTCAE, version 5.0. Summary tables will be provided separately for AEs 
leading to study drug discontinuation. All “on study drug” deaths, ie, deaths that occur 
within 30 days after last dose of study drug, will be summarized. Listings and/or 
narratives of “on study drug” deaths, serious AEs, and AEs leading to study drug 
discontinuation, will also be provided. 
The summaries of the subject incidence rates of treatment emergent AEs by system organ 
class and preferred term reported AEs will also be provided for subgroups defined by 
age, sex, and race (if feasible). 
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11.3.8.3 
Other Safety Findings 
Laboratory parameters for hematology and serum blood chemistry will be summarized at 
baseline, by visit, and at the last observed value. Additionally, the maximum and 
minimum observed post-baseline values will be summarized along with the change from 
baseline to the maximum observed value, minimum observed value and last observed 
value. Tables of shifts in severity (by CTCAE version 5.0) from baseline for selected 
laboratory parameters and selected time points may also be provided. Graphical 
representations of aggregate data may also be presented for parameters of interest. 
Exploratory analyses of selected laboratory parameters by phosphate binder use may be 
performed. 
Vital signs, physical examination results, ECOG performance status, ophthalmic 
assessment, and ECG results will be summarized by treatment group using descriptive 
statistics (including changes from baseline). 
12 DATA COLLECTION AND MANAGEMENT 
12.1 Data Confidentiality 
All records identifying the subject will be kept confidential and, in accordance with the 
applicable laws and/or regulations, will not be made publicly available.  
Subject names will not be supplied to the sponsor. Only the subject number will be 
recorded on the eCRF. If the subject name appears on any other document or trial 
materials, then that information must be redacted before a copy of the document is 
supplied to the sponsor. Trial data stored on a computer will be stored in accordance with 
local data protection laws and regulations. Subjects will be informed in writing that 
representatives of the sponsor, Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB), or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance 
with local data protection laws and regulations.  
If the results of the trial are published, the subjects’ identity will remain confidential.  
The investigator will maintain a list to enable subjects’ records to be identified in 
accordance with applicable laws and regulations. 
The data collection system for this study uses built-in security features to encrypt all data 
for transmission in both directions, preventing unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of 
individually assigned user identification codes and passwords, made available only to 
authorized personnel who have completed prerequisite training. 


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Either year of birth or exact date of birth (depending on local privacy regulations) will be 
recorded 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. 
12.2 Study Center Monitoring 
Before study initiation, at a study center initiation visit or at an investigator’s meeting, 
sponsor personnel (or designated CRO) will review the protocol and eCRFs with the 
investigators and their staff. During the study, the field monitor will visit the study center 
regularly to check the completeness of subject records, the accuracy of entries on the 
eCRFs, the adherence to the protocol and to Good Clinical Practice (GCP), the progress 
of enrollment, and to ensure that study drug 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 subject in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical information, laboratory data, ECGs, and the results of any other tests or 
assessments. All information recorded on eCRFs must be traceable to source documents 
in the subject's file. The exception is the QOL instrument (questionnaire) data collected 
in this study, which will be entered directly into a handheld device. The investigator must 
also keep the original signed ICF (a signed copy is given to the subject). 
The investigator must give the field monitor access to all relevant source documents to 
confirm their consistency with the eCRF entries. Sponsor monitoring standards require 
full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria and documentation of SAEs. Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-
specific monitoring plan. 
12.3 Data Collection 
The designated investigator staff will enter the data required by the protocol into the 
eCRFs. The eCRFs have been built using fully validated secure web-enabled software 
that conforms to 21 CFR Part 11 requirements. The investigator and 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’s staff. 
The principal investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
PK and biomarker (blood and tissue) samples and imaging scans obtained during the 
course of the study will be collected from the study centers and analyzed by a sponsor-
designated laboratory. Designated study center staff will enter the information required 
by the protocol into the appropriate eCRF and/or designated laboratory requisition forms. 
Field monitors will review the eCRFs and laboratory paper requisition forms for accuracy 


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and completeness and instruct site personnel to make any required corrections or 
additions. One copy of the requisition form will be forwarded to each analytical 
laboratory with the respective sample(s) by the field monitor or by the designated study 
center staff; and one copy will be retained at the study center. 
12.4 Database Management and Quality Control 
Sponsor personnel (or designated CRO) will review the data entered into eCRFs 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 study center via the EDC system. Designated investigator 
site staff are required to respond promptly to queries and to make any necessary changes 
to the data. 
Prior medications, concomitant treatments, and post-treatment anti-cancer medications 
entered into the database will be coded using the World Health Organization (WHO) 
Drug/Anatomical Therapeutic Chemical classification system. Medical history/current 
medical conditions and AEs will be coded using the MedDRA terminology. 
PK and biomarker samples will be processed centrally and the results will be sent 
electronically to the sponsor (or a designated CRO). 
The occurrence of any protocol deviations will be determined. Once the data has been 
verified to be complete and accurate, the database will be declared locked and made 
available for data analysis. Appropriate sponsor authorization is required prior to making 
any database changes to locked data. 
After database lock, the investigator will receive a copy of his/her subjects’ data for 
archiving at the study center. 
12.5 Study Documentation, Record Keeping and Retention of Documents 
Each participating study center will maintain appropriate medical and research records 
for this trial, in compliance with Section 4.9 of the International Council for 
Harmonisation (ICH) E6 GCP, and regulatory and institutional requirements for the 
protection of confidentiality of subjects. As part of participating in a sponsored study, 
each study center will permit authorized representatives of the sponsor(s) and regulatory 
agencies to examine (and when required by applicable law, to copy) clinical records for 
the purposes of quality assurance reviews, audits and evaluation of the study safety and 
progress. 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Examples of these original documents and data records include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated instruments, copies or transcriptions certified after verification as being 


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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 study center under the 
supervision of the investigator. The study eCRF is the primary data collection instrument 
for the study. The investigator should ensure the accuracy, completeness, legibility, and 
timeliness of the data reported in the eCRFs and all other required reports. Data reported 
on the eCRF that are derived from source documents should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF 
must be recorded. Any missing data must be explained. For eCRFs an audit trail will be 
maintained by the system.  
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. 
The investigator must maintain all documentation relating to the study as outlined in 
local/regional requirements. 
The sponsor will retain records in accordance with ICH E6 GCP, Section C.05.012 of 
Division 5 of the Food and Drug Regulations (FDR), and other applicable regional 
regulatory requirements. 
12.6 Audits and Inspections 
Source data/documents must be available for inspection by the sponsor, its designees, or 
Health Authorities. 
13 REGULATORY AND ETHICAL CONSIDERATIONS 
13.1 Regulatory and Ethical Compliance 
This clinical study was designed, shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for GCP, 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. 
13.2 Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed ICF 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 sponsor monitors, auditors, 


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sponsor Clinical Quality Assurance representatives, designated agents of the sponsor, 
IRBs/IECs/REBs and regulatory authorities as required. 
The investigator will be responsible for informing IRBs and/or IECs in the event of early 
termination of the trial. 
13.3 Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent.  
Informed consent must be obtained before conducting any study-specific procedures (ie, 
all of the procedures described in the protocol). Study subjects will be informed in 
writing and orally before the start of the study about the nature and scope of the planned 
study procedures, in particular about the possible benefits and risks of participating in the 
study. Consent will be documented by signature on the ICF. The process of obtaining 
informed consent should be documented in the subject source documents. The date when 
a subject’s informed consent is actually obtained must be captured in the eCRF and the 
medical records for the subject. 
A copy of the ICF must be given to the subject or to the person signing the form. 
The sponsor will provide to investigators, in a separate document, a proposed ICF that is 
considered appropriate for this study and complies with the ICH GCP E6 guideline and 
regulatory requirements. Any changes to this ICF suggested by the investigator must be 
agreed to by the sponsor before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the sponsor monitor after IRB/IEC/REB approval. 
Women of childbearing potential and sexually active males should be informed that 
taking the study drug may involve unknown risks to the fetus if pregnancy were to occur 
during the study and agree that in order to participate in the study they must adhere to the 
contraception requirement for the duration of the study. If there is any question that the 
subject will not reliably comply, they should not be entered in the study. 
13.4 Confidentiality of Study Documents and Subject Records 
The investigator must ensure pseudonymization of the subjects by replacing names with 
the study-specific subject identification number); subjects must not be identified by 
names in any documents submitted to the sponsor. The names of study subjects and all 
other confidential information are subject to medical confidentiality and the provisions of 
the General Data Protection Regulation (GDPR) and other applicable regulations or laws. 
Subject data may only be passed on in pseudonymized form beyond the study center. 
Third parties do not have access to original documents.  
Signed ICFs and subject enrollment log kept at the study center to enable subject 
identification must be kept strictly confidential. 


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14 FINANCIAL CONSIDERATIONS AND INSURANCE 
Financial disclosures and insurance for the sponsor will be provided in a separate 
document. 
15 PUBLICATION POLICY 
The sponsor 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. The sponsor assures that the key design 
elements of this protocol will be posted on a publicly accessible database, eg, 
www.clinicaltrials.gov before study start. In addition, results of interventional clinical 
trials will be posted publicly according to local regulations.  
The sponsor follows the International Committee of Medical Journal Editors 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 the sponsor or through a 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, the sponsor 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. 
Any data analysis carried out independently by the investigator must be submitted to the 
sponsor before publication or presentation. 
 


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17 APPENDICES 
17.1 Appendix 1: List of Concomitant Medications (Infigratinib Treatment) 
In general, the use of any concomitant medication deemed necessary for the care of the 
subject is permitted in this study, except as specifically prohibited below. Combination 
administration of study drugs could result in drug-drug interactions that could potentially 
lead to reduced activity or enhanced toxicity of the concomitant medication and/or 
infigratinib. 
The following lists in Table 15 are based on the Indiana University School of Medicine’s 
“Clinically Relevant” Table (Flockhart Table™; Flockhart 2007) and supplemented with 
the FDA draft guidance and the online database Drugbank.ca. Note: this may not be an 
exhaustive list of medications, investigator should use this list as a guide. 
Table 15: 
Drugs to be used with Caution While on Study 
Category 
Drug Names 
CYP3A substrates with 
narrow therapeutic index 
alfentanil, cyclosporine, diergotamine, dihydroergotamine, 
ergotamine, fentanyl, sirolimus, tacrolimus, terfenadine, 
warfarin sodium or any other coumadin-derivative 
anticoagulants, direct thrombin inhibitors (eg, argatroban), and 
Factor Xa inhibitors (eg, rivaroxaban) 
Medications which alter the 
pH of the GI tract a,b 
antacids, H2-antagonists (eg, ranitidine) 
Medications that have possible 
risk of TdP/QT prolongation 
alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, eribulin, famotidine, felbamate, fingolimod, 
foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, 
granisertron, iloperidone, indapamide, isradipine, lapatinib, 
lithium, moexipril, nicardipine, nilotinib, octreotide, ofloxacin, 
oxytocin, paliperidone, pasireotide, quetiapine, ranolazine, 
risperidone, roxithromycin, sertindole, sunitinib, tamoxifen, 
tizanidine, vardenafil, venlafaxine, ziprasidone 
Medications that have 
conditional risk of TdP/QT 
prolongation 
amitriptyline, amisulpride, ciprofloxacin, clomipramine, 
desipramine, diphenhydramine, doxepin, fluoxetine, 
galantamine, imipramine, nortriptyline, paroxetine, 
protriptyline, sertraline, solifenacin, trazodone, trimethoprim-
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Category 
Drug Names 
Medications with established 
potential for QT prolongation 
or TdP 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US 
market), azithromycin, bepridil (off US market), chloroquine, 
chlorpromazine, cisapride (off US market), citalopram, cocaine, 
disopyramide, dofetilide, domperidone (off US market), 
dronedarone, droperidol, erythromycin, escitalopram, 
flecainide, halofantrine, haloperidol, ibutilide, levofloxacin, 
levomethadyl (off US market), mesoridazine (off US market), 
methadone, moxifloxacin, ondansetron, pentamidine, pimozide, 
probucol (off US market), procainamide (oral off US market), 
quinidine, sevoflurane, sotalol, sparfloxacin (off US market), 
sulpiride (off US market), terfenadine (off US market), 
thioridazine, vandetanib 
BCRP substrates 
atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin, 
sulfasalazine, topotecan 
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome p; FDA, Food and Drug 
Administration; GI, gastrointestinal; TdP, Torsades de Pointes 
a  
Infigratinib should be dosed at least 2 hours before or 10 hours after dosing with a H2 receptor agonist, 
or separated by 2 hours with acid neutralizing agents (antacids).  
b  
Proton pump inhibitors are prohibited due to their long pharmacodynamic effect and should be 
replaced with H2-antagonists or antacids. 
Sources: FDA Guidance for Industry, 2017; Flockhart 2007; drugbank.ca. 


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17.2 Appendix 2: List of Prohibited Medications and Substances 
(Infigratinib Treatment) 
Table 16: 
List of Prohibited Medications and Substancesa While on 
Study 
Category 
Drug Names 
Moderate inhibitors of 
CYP3A4 b 
ACT-178882, ACT-539313, amprenavir, aprepitant, 
atazanavir, atazanavir/ritonavir, casopitant, cimetidine, 
ciprofloxacin, crizotinib, darunavir, darunavir/ritonavir, 
diltiazem, dronedarone, duvelisib, erythromycin, faldaprevir, 
fedratinib, FK1706, fluconazole, fosaprepitant, GSK2647544, 
imatinib, isavuconazole, istradefylline, lefamulin, letermovir, 
netupitant, nilotinib, primidone, ravuconazole, Schisandra 
sphenanthera, tofisopam, verapamil, voxelotor 
Moderate inducers of CYP3A4 b Asunaprevir/beclabuvir/daclatasvir, bosentan, cenobamate, 
dabrafenib, efavirenz, elagolix, etravirine, lersivirine, 
lesinurad, lopinavir, lorlatinib, modafinil, nafcillin, PF-
06282999, rifabutin, semagacestat, talviraline, telotristat 
ethyl, thioridazine, tipranavir/ritonavir 
Strong inhibitors of CYP3A4 b 
boceprevir, ceritinib, clarithromycin, cobicistat (GS-9350), 
conivaptan, danoprevir/ritonavir, elvitegravir/ritonavir, 
idelalisib, indinavir, indinavir/ritonavir, itraconazole, 
josamycin, ketoconazole, LCL161, lopinavir/ritonavir, 
mibefradil, mifepristone, nefazodone, nelfinavir, 
posaconazole, ribociclib, ritonavir, saquinavir, 
saquinavir/ritonavir, telaprevir, telithromycin, 
troleandomycin, tipranavir/ritonavir, tucatinib, voriconazole 
grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, 
star fruits, pomelos, Seville oranges or products containing 
juice of these fruits   
Strong inducers of CYP3A4 b 
apalutamide, avasimibe, carbamazepine, enzalutamide, 
ivosidenib, lumacaftor, mitotane, phenobarbital, phenytoin, 
rifampin, rifapentine, St. John's wort extract 
Medications which alter the pH 
of the GI tract 
proton-pump inhibitors (eg, omeprazole, esomeprazole, 
lansoprazole, pantoprazole, rabeprazole) 
Medications which increase 
serum phosphate and/or calcium 
calcium, parathyroid hormone, phosphate, vitamin D 
(including multivitamins containing vitamin D) 
Chinese herbal and patent 
medicines for cancer treatment 
Chinese herbal medicine and Chinese patent medicines for 
the treatment of cancer are not allowed during the treatment 
period. 
Abbreviations: CYP, cytochrome p; US, United States 
a 
This may not be an exhaustive list of prohibited medications. Use this list as a guide and refer to the 
prescribing information for any medication to determine unacceptable interactions and/or contact the 
sponsor. 
b Sources: University of Washington 2021a; University of Washington 2021b 


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17.3 Appendix 3: List of Highly Effective Methods of Contraception  
The following is from the Clinical Trials Facilitation Group 2014 (Section 4.1). 
Methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods. Such methods 
include: 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 1: 
• oral 
• intravaginal 
• transdermal 
• progestogen-only hormonal contraception associated with inhibition of ovulation 1: 
• oral 
• injectable 
• implantable 2 
• intrauterine device (IUD) 2 
• intrauterine hormone-releasing system (IUS) 2 
• bilateral tubal occlusion 2 
• vasectomised partner 2,3 
• sexual abstinence 4 
 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy 
of the contraception method (see Clinical Trials Facilitation Group 2014, section 4.3). 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical 
assessment of the surgical success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 


Infigratinib 
QED Therapeutics
Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
Page 118 of 120
 
 
17.4 Appendix 4: QOL Instruments 
This appendix describes the QOL instruments used in the study.  
EQ-5D-5L Scoring 
The EQ-5D-5L consists of 6 items: 5 dimensions (mobility, self-care, usual activity, 
pain/discomfort, and anxiety/depression) and a health state score. Each of the 
5 dimensions has 5 levels. The combination of 1 level from each of the 5 dimensions (eg, 
12234) will be used to obtain the health index score.  
The EQ-5D-5L cross-walk value set for United Kingdom (UK) will be used in the 
derivation of health index scores.  
Details of analysis will be described in the SAP. 
QLQ-C30 Scoring 
The EORTC QLQ-C30 has been translated and validated into 8 languages. It contains 
5 functioning scales (physical, role, cognitive, emotional, and social), 3 symptom scales 
(fatigue, nausea, pain) and additional single symptom items. It is scored on a 4-point 
scale (1=not at all, 2=a little, 3= quite a bit, 4=very much). The EORTC QLQ-C30 
instrument also contains 2 global scales that use 7-point scale scoring with anchors 
(1=very poor and 7=excellent). The scoring for each functioning scales and symptom 
scales follows the algorithms below.  
The EORTC QLQ-C30 Summary Score is calculated from the mean of 13 of the 
15 QLQ-C30 scales (the Global Quality of Life scale and the Financial Impact scale are 
not included). Prior to calculating the mean, the symptom scales need to be reversed to 
obtain a uniform direction of all scales. QLQ-C30 Summary Score = (Physical 
Functioning+ Role Functioning+ Social Functioning+ Emotional Functioning+ Cognitive 
Functioning+ 100-Fatigue+ 100-Pain+ 100-Nausea_Vomiting+ 100-Dyspnoea+ 100-
Sleeping Disturbances+ 100-Appetite Loss+ 100-Constipation+ 100-Diarrhoea). 
Details of analysis will be described in the SAP. 
EORTC QLQ-BIL21 
The QLQ-BIL21 module has been found to be a reliable and valid measure to assess the 
QOL of patients with cholangiocarcinoma and cancer of the gallbladder. It contains 
21 items that comprise 5 multi-item symptom scales and 3 items that should be scored as 
individual items. It is scored on a 4-point scale (1=not at all, 2=a little, 3=quite a bit, 4-
very much). Specific instructions regarding the scoring of the BIL21 are provided below: 
 


Infigratinib 
QED Therapeutics
Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
Page 119 of 120
 
 
Symptom Scales/Items 
Scale 
Number of 
items 
Item range* 
Item numbers 
Eating Symptoms 
ES 
4 
3 
31, 32, 33, 34 
Jaundice Symptoms 
JS 
3 
3 
35, 36, 37 
Tiredness 
T 
3 
3 
38, 39, 40 
Pain Symptoms 
PS 
4 
3 
41, 42, 43, 44 
Anxiety Symptoms 
AS 
4 
3 
45, 46, 47, 48 
Treatment Side Effects 
TSE 
1 
3 
49 
Difficulties with drainage 
D 
1 
3 
50 
Concerns re: Weight Loss 
WL 
1 
3 
51 
* Item range is the difference between the possible maximum and the minimum response to individual 
items; all items take values from 1 to 4, giving range = 3. 
For all scales, the Raw Score, RS, is the mean of the component items 
 
Raw Score = RS= (I1 + I2 +…In)/n 
For all Symptom Items or Scales, the score is calculated as follows: 
 
Score = [(RS – 1)/range] * 100% 
For example, if a subject has response value of 1, 2, 2, 4 for item 31, 32, 33 and 34, 
respectively, the Raw Score (RS) for Eating Symptoms would be calculated as follows: 
RS = (1+2+2+4)/4 = 2.25 
ES Score = (2.25 – 1)/3 = 41.7% 
Details of analysis will be described in the SAP. 


Infigratinib 
QED Therapeutics
Protocol QBGJ398-301 Amendment 4.0 (Version 4.0) 
Confidential
27 July 2021 
Page 120 of 120
 
 
17.5 Appendix 5: Acceptable Prestudy Gemcitabine-based Chemotherapy 
The following gemcitabine-based chemotherapies are acceptable for prestudy treatment 
(NCCN Guideline Version 1, 2021): 
• Gemcitabine + cisplatin  
• Gemcitabine + cisplatin + nab-paclitaxel  
• Gemcitabine + cisplatin + S-1 (Kanai 2015; Sakai 2018) 
• Gemcitabine + S-1 
• Gemcitabine + capecitabine 
• Gemcitabine + nab-paclitaxel  
• Gemcitabine monotherapy 
 

SAP_001.pdf: 
B GJ 3 9 8  (I nfi grati ni b) 
Q B GJ 3 9 8 -3 0 1  Statistical  A nal ysis  Pla n  
2 9 A pril  2 0 2 2  
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P P D


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 3 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................................... 3 
LIST OF TABLES ............................................................................................................................. 5 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ................................................... 6 
1 
INTRODUCTION ....................................................................................................................... 8 
2 
OBJECTIVES ............................................................................................................................. 8 
2.1 
Primary objective ............................................................................................................. 8 
2.2 
Secondary objectives ........................................................................................................ 8 
2.3 
Exploratory Objectives .................................................................................................... 8 
3 
STUDY DESIGN ......................................................................................................................... 9 
3.1 
Sample Size Considerations ........................................................................................... 10 
4 
STUDY ENDPOINTS AND COVARIATES .......................................................................... 11 
4.1 
Endpoints ........................................................................................................................ 11 
5 
HYPOTHESES.......................................................................................................................... 11 
6 
DEFINITIONS .......................................................................................................................... 11 
6.1 
General ............................................................................................................................ 11 
6.1.1 
Investigational Product/Study Treatment/Study Drug ............................................... 11 
6.1.2 
Study Day 1 and Study Day ........................................................................................... 11 
6.1.3 
Baseline ............................................................................................................................ 12 
6.1.4 
Subsequent anti-cancer therapy .................................................................................... 12 
6.1.5 
On Treatment Period ..................................................................................................... 12 
6.1.6 
Initial Treatment Phase ................................................................................................. 12 
6.2 
Efficacy ............................................................................................................................ 12 
6.2.1 
Overall Survival Time (OS) ........................................................................................... 12 
6.2.2 
Progression free survival (PFS) ..................................................................................... 12 
6.2.3 
Best Overall Response (BOR)........................................................................................ 13 
6.2.4 
Overall Response Rate (ORR) ....................................................................................... 13 
6.2.5 
Disease Control Rate (DCR) .......................................................................................... 13 
6.2.6 
Duration of Response (DOR) ........................................................................................ 13 
6.2.7 
Progression Free Survival on Subsequent Therapy (PFS2) ....................................... 13 
6.3 
Safety ............................................................................................................................... 13 
6.3.1 
Concomitant Therapies .................................................................................................. 13 
6.3.2 
Treatment Duration ....................................................................................................... 14 
6.3.3 
Cumulative dose ............................................................................................................. 14 
6.3.4 
Relative dose intensity .................................................................................................... 14 
6.3.5 
Treatment-emergent Adverse Event ............................................................................ 14 
7 
ANALYSIS POPULATION ..................................................................................................... 14 
7.1 
Intent to Treatment population ..................................................................................... 14 
7.2 
Safety Analysis Population ............................................................................................ 14 
7.3 
Central Confirmed FGFR2 Fusion/ Rearrangement Population .............................. 15 
7.4 
Subgroup Analyses ......................................................................................................... 15 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 4 
 
 
8 
STATISTICAL METHODS OF ANALYSIS ......................................................................... 15 
8.1 
General Principles .......................................................................................................... 15 
8.2 
Handling of Missing Data .............................................................................................. 15 
8.3 
Subject Accountability and Disposition ........................................................................ 16 
8.4 
Demographic and Baseline Characteristics ................................................................. 16 
8.5 
Medical history ............................................................................................................... 16 
8.6 
Prior Anti-cancer therapy ............................................................................................. 16 
8.7 
Protocol deviations ......................................................................................................... 17 
8.8 
Efficacy Analyses ............................................................................................................ 17 
8.8.1 
Sensitivity Analysis for PFS per BICR ......................................................................... 17 
8.8.2 
Sensitivity Analysis for OS ............................................................................................ 17 
8.9 
Safety Analyses ............................................................................................................... 17 
8.9.1 
Adverse Events ............................................................................................................... 18 
8.9.2 
Concomitant Medications .............................................................................................. 19 
8.9.3 
Treatment Exposure ....................................................................................................... 19 
8.9.4 
Laboratory Data Summary ........................................................................................... 20 
8.9.5 
Ophthalmic assessment .................................................................................................. 20 
8.9.6 
Left Ventricular Ejection Fraction (LVEF) ................................................................. 21 
8.9.7 
ECG ................................................................................................................................. 21 
8.9.8 
Vital signs and ECOG performance status .................................................................. 22 
8.9.9 
Summary of Data After Cross-over .............................................................................. 22 
9 
LITERATURE CITATIONS  REFERENCES ..................................................................... 23 
10 APPENDIX ................................................................................................................................ 25 
10.1 
Imputation of AE Start Date ......................................................................................... 25 
10.2 
TFL Shell ......................................................................................................................... 25 
 
 
 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 5 
 
 
 
LIST OF TABLES 
Table 1. Boundary for PFS and OS at interim and primary analyses .......... Error! Bookmark not 
defined. 
Table 2. Pharmacokinetic Parameters for Infigratinib ................................................................ 31 
Table 3. Imputation of treatment emergent AE start dates ......................................................... 39 
 
 
 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 6 
 
 
 
 
 
 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
 
Term 
Definition 
AE 
adverse event 
AESI 
adverse event of special interest 
ALT/SGPT 
alanine aminotransferase/serum glutamic-pyruvic transaminase 
AST/SGOT 
aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
BICR 
blinded independent central review 
BOR 
best overall response 
CI 
confidence interval 
Cmin 
minimum observed concentration 
Cmax 
maximum observed concentration 
CR 
complete response 
DCR 
disease control rate 
DMC 
Data Monitoring Committee 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
End of Study 
EOT 
End of Treatment 
EQ-5D 
EuroQOL five dimensions questionnaire 
FGFR2 
fibroblast growth factor receptor 2 
HR 
hazard ratio 
IPCW 
inverse probability of censoring weighting 
ITT 
intent-to-treat 
K-M 
Kaplan-Meier 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MSI 
microsatellite instability 
OCT 
Optical coherence tomography 
ORR 
overall response rate 
OS 
overall survival 
PD 
progressive disease 
PFS 
progression-free survival 
PFS2 
PFS on subsequent therapy 
PK 
pharmacokinetic 
PR 
partial response 
PT 
preferred term 
QLQ 
quality of life questionnaire 
QOL 
quality of life 
QT 
measure of time between the start of the Q wave and the end of the T wave (QT 
interval) in the heart’s electrical cycle 
QTc 
QT interval corrected for heart rate 
QTcB 
QTc corrected by Bazett's formula 
QTcF 
QTc corrected by Fridericia's formula 
RECIST 
Response Evaluation Criteria in Solid Tumors 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 7 
 
 
RPSFT 
rank-preserving structural failure time 
SAE 
serious adverse event 
SD 
stable disease 
SOC 
system organ class 
TEAE 
treatment-emergent adverse events 


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BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 9 
 
 
 
3 STUDY DESIGN 
This is a multi-center, open label, randomized, controlled Phase 3 study to determine if treatment 
with infigratinib improves PFS per BICR with supportive key secondary endpoint of OS compared 
to treatment with gemcitabine and cisplatin in subjects with advanced/metastatic or inoperable 
cholangiocarcinoma with FGFR2 fusion/ rearrangement. 
 
Subjects will be randomized in a 2:1 ratio to receive oral infigratinib administered once daily for 
the first 3 weeks (21 days) of a 28-day treatment cycle compared to a regimen of gemcitabine with 
cisplatin given on Days 1 and 8 of a 21-day cycle. Randomization will be stratified by locally 
advanced vs metastatic disease, geographic region (North America vs Western Europe vs Asia 
Pacific vs rest of the world), prior neoadjuvant/adjuvant treatment (yes/no), and received up to 1 
cycle of prior gemcitabine-based chemotherapy for unresectable locally advanced or metastatic 
disease (yes/no). 
 
During the treatment period, subjects will be radiographically evaluated every 8 weeks ±7 days 
from the first dose of study drug, regardless of drug interruption, for tumor response (Response 
Evaluation Criteria in Solid Tumors [RECIST] 1.1). When the decision is made to discontinue 
study drug, subjects will complete an End of Treatment (EOT) visit, no later than 8 days from the 
decision to discontinue study drug, and a Safety Follow-up visit no more than 30 days after last 
dose of study drug. If a subject discontinues study drug for reasons other than centrally confirmed 
progressive disease (PD), a radiographic assessment should be conducted at the EOT visit, unless 
taken within the previous 4 weeks. 
 
Subjects who discontinue study drug for centrally confirmed radiographic PD confirmed by BICR 
will be followed approximately every 3 months (via telephone or office visit) for survival status and 
new anticancer therapy information (subsequent therapy and progression/PFS2) until End of Study 
(EOS), defined as the time when at least 224 OS events have been reached (for the primary OS 
analysis) and the last subject has completed study treatment. Subjects who discontinue study drug 
for reasons other than centrally confirmed PD will continue to have radiographic assessments 
every 8 weeks ±7 days until centrally confirmed radiographic PD. Thereafter, these subjects will 
be followed approximately every 3 months for survival status and use of anticancer therapy, as 
described above. 
 
Sparse PK blood samples will be collected from all subjects in the infigratinib group at multiple 
time points, predose (Cmin infigratinib) and 4 hours (±30 minutes) postdose (Cmax infigratinib). 
Plasma concentrations of infigratinib and its metabolites (including BHS697 and CQM157) will 
be measured. 
 
For a PK substudy, blood samples will be collected, at multiple time points (predose [Cmin 
infigratinib], 4 hours [±30 minutes] postdose, and 24 hours postdose [±1 hour]) from the first 40 
subjects who receive infigratinib. Plasma concentration of infigratinib and its active metabolites  


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
29 April 2022 
QED Therapeutics 
Confidential 
Page 10 
 
 
 
will be measured, and PK parameters will be assessed. 
 
Following radiographic PD confirmed by BICR, subjects randomized to the gemcitabine with 
cisplatin group may be eligible to cross over and receive infigratinib. Before these subjects 
receive any infigratinib, certain exclusion criteria must be rechecked (Protocol Section 6.2). 
Assessments performed within the past 30 days may be used to check these criteria. Subjects 
who cross over to infigratinib will evaluated for safety and OS.  
 
3.1 
Sample Size Considerations 
 
Approximately 300 subjects with a likely or known activating FGFR2 fusion/ rearrangement 
determined by a central laboratory or local laboratory will be randomized in the study (2:1 
randomization, with approximately 200 in the infigratinib group and 100 in gemcitabine with 
cisplatin group) and stratified by locally advanced vs metastatic disease, geographic region (North 
America, Western Europe, Asia Pacific, and rest of the world), prior neoadjuvant/adjuvant 
treatment (yes/no), and received up to 1 cycle of prior gemcitabine-based chemotherapy for 
unresectable locally advanced or metastatic disease (yes/no). 
 
The primary endpoint is centrally reviewed PFS (ie, PFS assessed by BICR). Assuming a PFS 
hazard ratio (HR) of 0.67 (median PFS 11.9 vs 8 months) (Valle 2010) comparing infigratinib to 
gemcitabine with cisplatin, with 228 PFS events required, the study will provide approximately 
80% power to demonstrate that infigratinib improves the PFS per BICR compared to treatment 
with gemcitabine and cisplatin at a 2-sided significance level of 0.05. Assuming the test on PFS is 
significant, with 224 deaths observed, the study will provide 66% power to demonstrate that 
infigratinib improves OS compared to treatment with gemcitabine and cisplatin assuming an OS 
HR of 0.7 (median OS 16.7 vs 11.7 months) (Valle 2010). 
 
The study employs a group sequential design with one interim analysis for futility planned for PFS. 
The primary analysis for PFS will be conducted after approximately 228 PFS events have been 
observed and the interim will be conducted when approximately 114 PFS events (~50% of 228) 
are observed. A fixed 2-sided significance level of 0.0001 will be spent at the interim analysis for 
PFS. A Lan-DeMets alpha spending function approximating O’Brien Fleming boundaries will be 
used for the interim non-binding futility and final boundaries. 
 
One interim analysis and one primary analysis for OS are planned. The interim analyses for OS 
will be conducted at the primary analysis for PFS. The primary analysis for OS will be conducted 
after approximately 224 deaths have been observed. OS will only be tested if PFS is found to be 
significant. The Lan-DeMets spending function approximating the O'Brien-Fleming spending 
function will be used to calculate the significance boundaries.  
 
With 42-month uniform enrollment, the study is projected to reach the planned number of PFS events 
(228) per BICR in approximately 54 months from randomization of the first subject. The OS event 
goal of 224 deaths is projected to be reached approximately 66 months from randomization of the 
first subject. The required sample size is estimated to be a total of 300 subjects, assuming that 
approximately 10%  of subjects will drop out per year before a PFS or OS event. 
 


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BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 12 
 
 
 
6.1.3 
Baseline 
 
In general, the baseline value will be considered as the last measurement observed prior to taking 
the first dose of study treatment. For ECG, if a set of triplet ECG are the last ECG collected prior 
to taking the first dose of study treatment, the average of the triplet ECG will be considered as 
baseline. 
 
For subjects who are randomized and never receive study treatment, the baseline value will be the 
last assessment before randomization (on the day of or before randomization). 
 
6.1.4 
Subsequent anti-cancer therapy 
 
Subsequent anti-cancer therapy includes any other anti-cancer therapy for cholangiocarcinoma that 
are received after a subject has ended study treatment. Subjects who are randomized to receive the 
treatment of gemcitabine and cisplatin and continue receiving gemcitabine only treatment are not 
considered to have received subsequent anti-cancer therapy. For subjects treated by gemcitabine 
with cisplatin, if cisplatin was dropped from the regimen and patients continue to be treated by 
gemcitabine only, it should not be considered as subsequent anti-cancer therapy. However, if 
cisplatin is replaced with another medication and patients are treated by this medication with or 
without gemcitabine, this should be considered as subsequent anti-cancer therapy. 
 
6.1.5 
On Treatment Period 
On treatment period is defined as first administration of study treatment through 30 days after the 
last administration of study treatment inclusively.  
 
6.1.6 
Initial Treatment Phase 
Initial treatment phase is defined as first administration of initial study treatment through the end 
of study for non-crossover subjects. For crossover subjects, initial treatment phase is defined as 
first administration of initial study treatment through the day before the first Infigratinib taken. 
This period phase is applied to all time to event endpoints, such as OS and PFS. 
 
 
6.2 
Efficacy 
 
6.2.1 
Overall Survival Time (OS) 
 
OS is defined as the number of months from randomization to death (date of death - date of  
randomization + 1)/(365.25/12). Subjects who have not died (no record of death) or are lost to  
follow-up will be censored at the date of last known to be alive. Subjects who died or lost to 
follow-up during Crossover Period are censored at the start date of Crossover. 
 
6.2.2 
Progression free survival (PFS) 
 
PFS are limited to the initial treatment phase. It is defined as the number of months from 
randomization to disease progression (PD) or death  due to any cause, whichever is earlier. Events 
after subsequent anti-cancer therapy will still be included. Subjects who are still alive without 
documented PD will be censored at their last valid tumor assessment. For subjects who have a PFS 
event after missing  two or more consecutive scheduled tumor evaluation (i.e., the previous valid 
tumor assessment is >18 weeks prior to the event), their PFS will be censored at their last valid 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 13 
 
 
tumor assessment. Subjects who have no qualified PFS event or any qualified post-baseline tumor 
assessment will be censored on their randomization date. PFS will be calculated per BICR and per 
investigator; PFS per BICR is the primary endpoint. 
 
6.2.3 
Best Overall Response (BOR) 
 
BOR is defined as the best response a subject ever achieved after study treatment prior to any 
subsequent anti-cancer therapy, in descending order of precedence by confirmed CR, confirmed 
PR, SD, and PD. Confirmed CR and PR will be claimed only if the criteria for each are met at a 
subsequent time point at least 4 weeks apart. In the case of SD, measurements must have met the 
SD criteria at least once post-baseline no less than 6 weeks from the randomization date. 
BOR will be derived per central imaging review and per investigator. 
 
6.2.4 
Overall Response Rate (ORR) 
 
ORR is defined as the proportion of subjects with BOR of either confirmed PR or confirmed CR 
among ITT population with measurable disease at baseline. All subjects who do not achieve BOR 
of either confirmed PR or confirmed CR will be considered non-responders. 
ORR will be derived per central imaging review and per investigator. 
 
6.2.5 
Disease Control Rate (DCR) 
 
DCR is defined as the proportion of subjects with BOR of either confirmed PR/CR or SD or non- 
CR/non-PD. DCR will be derived per central imaging review and per investigator. 
 
6.2.6 
Duration of Response (DOR) 
 
DOR is defined as time from initiation of response (CR or PR) to PD or death. If subjects do not 
reach PD or death, the DOR is censored at the last valid tumor assessment. Subjects who never 
reach the response are not included in DOR analysis.  DOR will be derived per BICR. 
 
6.2.7 
Progression Free Survival on Subsequent Therapy (PFS2) 
 
PFS2 is calculated as the number of months from randomization to the disease progression on the 
subsequent therapy or death due to any cause, whichever is earlier, as determined by the 
investigator. Subjects who are still alive without documented disease progression on the 
subsequent therapy and subjects who are still alive without subsequent therapy will be censored at 
their last valid tumor assessment. For subjects who have a PFS2 event (PD or deaths) after missing 
two or more consecutive scheduled tumor evaluation (i.e., the previous valid tumor assessment is 
>18 weeks prior to the event), their PFS2 will be censored at their last valid tumor assessment. 
Subjects who have no qualified PFS2 event or any qualified post-baseline tumor assessment will 
be censored on their randomization date. 
 
6.3 
Safety 
 
6.3.1 
Concomitant Therapies 
 
Concomitant therapies are defined as any medications (other than study treatment) and significant 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 14 
 
 
other therapies (including surgery and radiotherapy) administered on or after the first 
administration day of study drug and up to last study administration day of study drug + 30 days 
(ie, during the on-treatment period). 
 
6.3.2 
Treatment Duration 
 
Treatment 
duration 
will 
be 
calculated 
separately 
for 
each 
study 
treatment 
(gemcitabine/cisplatin/infigratinib). Treatment duration is defined as last dose date of the 
corresponding study treatment – first dose date of the corresponding study treatment +1 day. 
 
6.3.3 
Cumulative dose 
 
The planned/actual cumulative dose will be calculated separately for each study treatment 
(gemcitabine/cisplatin/infigratinib). 
The 
planned 
cumulative 
dose 
for 
gemcitabine/cisplatin/infigratinib refers to the total originally assigned dose as per the protocol 
over the duration for which the subject is on the corresponding study treatment as documented in 
the Dose Administration eCRF (first dose date to the last dose date of the corresponding study 
treatment). The actual cumulative dose refers to the total actual dose administered. 
 
6.3.4 
Relative dose intensity 
 
The relative dose intensity will be calculated separately for each study treatment 
(gemcitabine/cisplatin/infigratinib). 
The 
relative 
dose 
intensity 
for 
gemcitabine/cisplatin/infigratinib is defined as cumulative actual dose a subject received divided 
by the planned cumulative dose for the corresponding study treatment. For example, a subject 
takes infigratinib from day 1 to day 21 at 125 mg/day; then from day 29 to day 30 at 100mg/day, 
and end treatment afterward. The cumulative actual dose =21*125+100*2=2825 mg; the planned 
cumulative dose =21*125+125*2=2875 mg. The relative dose intensity = 2825/2875=98.3%. 
 
6.3.5 
Treatment-emergent Adverse Event 
 
A treatment-emergent adverse event (TEAE) is defined as an adverse event that occurs on or after 
the first administration of study treatment and within 30 days after the last administration of study 
treatment. 
 
7 ANALYSIS POPULATION 
The primary analyses for the efficacy endpoints will be based on the intent-to-treat (ITT) 
population. Safety analyses will be performed on the safety analysis. 
7.1 
Intent to Treatment population 
 
The ITT population includes all subjects who are randomized. Subjects will be analyzed by the 
treatment group randomized to, regardless of the treatment received. This ITT analysis set will be 
the primary analysis set for efficacy. 
 
7.2 
Safety Analysis Population 
 
The safety analysis population includes all subjects who are randomized and receive at least one 
dose of study treatment. Subjects will be analyzed by the treatment received. 
 


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BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 16 
 
 
complete missing dates. An AE should be considered as on-treatment as long as there is no clear 
evidence to indicate otherwise. 
 
Partial dates for AE where the start day is missing will be imputed as the first day of the month 
unless the start month of the AE is the same as the month when the study treatment is initiated. In 
this case, the start day will be imputed as first dose date unless the AE ends before the date of the 
first study treatment administration, where the AE start date will still be imputed to the first day of 
the month (Appendix 10.1). 
 
In general, unless otherwise specified, for all other partial missing dates, if assessment day is 
missing, day 15 will be imputed; if start day is missing, day 1 will be imputed; and if end day is 
missing, last day of the month will be imputed. No other imputation will be done if month or year 
is missing. 
 
Any AEs with partial/missing dates will be displayed as such in the data listings. 
 
8.3 
Subject Accountability and Disposition 
 
The number of subjects randomized into the study by treatment group and by stratum, in addition 
to the number of subjects included in each analysis set, will be summarized. 
 
The number of subjects who have received study treatment in the ITT population, have ended the 
treatment, and the reason for ending treatment will be presented. The reason for discontinuing 
study will also be summarized. 
 
8.4 
Demographic and Baseline Characteristics 
 
Summary statistics will be provided for demographics (age, sex, race, age group [<65 vs. 65 and 
<75 vs. ≥75], region and other baseline disease characteristics including FGFR2 fusion/ 
rearrangement status and fusion partner both by central and local, lymph node involvement, stage 
at initial diagnosis, time from initial diagnosis to randomization, and histology. 
 
8.5 
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. Medical history will also be summarized by system organ class and preferred term. 
 
8.6 
Prior Anti-cancer therapy 
 
The number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized. 
 
The summary of prior anti-neoplastic medications will include the total number of regimens (note: 
there can be more than one medication per regimen), setting at last regimen, whether subjects 
progress on or after last regimen. Prior antineoplastic medications will also be summarized by 
Anatomical Therapeutic Chemical (ATC) class, and preferred term. 
 
The summary of prior anti-neoplastic radiotherapy will include the total number of subjects who 
received prior anti-neoplastic radiotherapy, the radiotherapy locations, (including all locations 


BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 17 
 
 
recorded for each patient), setting at last radiotherapy, radiotherapy type at last radiotherapy and 
whether subjects progress on or after last radiotherapy. 
 
The summary of prior cancer-related surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment, and procedure at last surgery. 
 
8.7 
Protocol deviations 
 
The number (%) of subjects with any CSR-reportable protocol deviation will be tabulated by the 
deviation category for the ITT population. 
 
8.8 
Efficacy Analyses 
The primary efficacy analysis will be conducted on the intent to treat (ITT) population, which will 
include all subjects who are randomized. Subjects will be analyzed according to the treatment 
group that they are randomized to.  
All primary and secondary efficacy endpoints will be summarized as specified in General 
Principle Section 8.1. The analysis of time to event endpoints such as PFS, OS and DOR is 
specified in Section 8.1. 
 
All the efficacy analyses will be repeated for the central confirmed FGFR2 fusion/ rearrangement 
population as the sensitivity analyses. 
 
8.8.1 
Sensitivity Analysis for PFS per BICR 
 
 
As a sensitivity analysis, all tumor assessments per BICR and death after any subsequent anti- 
cancer therapy will be excluded from PFS per BICR derivation. PFS per BICR will be censored at 
last valid tumor assessment prior to any subsequent anti-cancer therapy if there is no PFS event 
prior to the subsequent anti-cancer therapy. The same analysis approach described in Section 8.8 
for PFS per BICR will be applied. 
 
 
8.8.2 
Sensitivity Analysis for OS 
 
Subjects in either arm may receive subsequent anti-cancer therapy other than the treatment they are 
randomized to. In this analysis, OS will be censored at the initialization of the first subsequent anti-
cancer therapy. 
 
8.9 
Safety Analyses 
 
Analysis of safety will be performed on the safety analysis population. In general, summaries will 
be provided only for the baseline and on-treatment safety assessments, which are the assessments 
taken during the on-treatment period. 
 
For subjects in gemcitabine/cisplatin arm who cross-over to infigratinib, the summary of safety 
assessments described in Section 8.9.1 to Section 8.9.9 will be limited to the assessments within 
last dose of gemcitabine and cisplatin plus 30 days and prior to the initiation of infigratinib. The 
assessments on or after the initialization of infigratinib will be summarized separately as described 


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BGJ398 (Infigratinib) 
QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 23 
 
 
 
 
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QBGJ398-301 Statistical Analysis Plan 
05 March 2020 
QED Therapeutics 
Confidential 
Page 24 
 
 
 
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