Clinical trial NCT04197986
Conditions: Upper Tract Urothelial Carcinomas Urothelial Bladder Cancer
Keywords: FGFR3 Genetic Alterations Upper Tract Urothelial Carcinomas UTUC Muscle Invasive Urothelial Carcinoma Fibroblast Growth Factor Receptor Inhibitor BGJ398 FGFR3 Urothelial Bladder Cancer UBC Infigratinib Phosphate Infigratinib Adjuvant Nephroureterectomy Distal ureterectomy Cystectomy
Sponsor: QED Therapeutics, Inc., a Bridgebio company
Start date: 2020-03-11; Completion date: 2023-02-28
Enrollment: 39 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the efficacy of infigratinib (an oral targeted FGFR1-3 inhibitor) versus placebo, as adjuvant treatment following surgery in adult subjects with invasive urothelial carcinoma and susceptible FGFR3 genetic alterations (mutations, and gene fusions or rearrangements) who have disease that is considered at high risk for recurrence with surgery alone. The study enrolls subjects with either bladder cancer post radical cystectomy or upper tract urothelial cancer post distal ureterectomy and/or nephrectomy. Study treatment is randomized 1:1 between infigratinib or placebo with treatment up to 1 year or until invasive local, distal, or metastatic disease recurrence confirmed by independent imaging reviewer.

Detailed description:

Arms: arm 1: Participants will be randomly assigned (1:1) to receive oral infigratinib administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks arm 2: Participants will be randomly assigned (1:1) to receive oral placebo administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks
Interventions: intervention 1: Infigratinib intervention 2: Placebo
Intervention descriptions: intervention 1: Participants randomly assigned to infigratinib will receive hard gelatin capsules for oral administration of infigratinib 125 mg once a day (administered as one 100-mg capsule and one 25-mg capsule) using a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule. intervention 2: Participants randomly assigned to placebo will receive placebo matching in appearance the investigational product (infigratinib), which will be provided as hard gelatin capsules for oral use and will be administered once daily on a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing schedule.

Protocol documents:
Prot_000.pdf: 
Infigratinib
QED Therapeutics
Protocol QBGJ398-302 Amendment 1.0 (Version 1.0)
Confidential
19 May 2021
Page 1 of 113 
Clinical Development
Protocol QBGJ398-302 
Phase 3, Multicenter, Double-Blind, Randomized, Placebo-
Controlled Trial of Infigratinib for the Adjuvant Treatment of 
Subjects with Invasive Urothelial Carcinoma with Susceptible 
FGFR3 Genetic Alterations (PROOF 302)
Investigational Product:
Infigratinib (BGJ398) 
Phase of Development
3 
Medical Monitor:
 MD
Executive Director, Clinical Development
QED Therapeutics, Inc. 
Sponsor:
QED Therapeutics, Inc. 
8000 Marina Boulevard, Suite 400 
Brisbane, CA 94005 
US IND Number:
144,007
EudraCT Number:
2019-003248-63 
Protocol Version / Date: 
0.0 (original protocol) 03 September 2019 
1.0 (Amendment 1) 19 May 2021
Property of QED Therapeutics, Inc.
Confidential
May not be used, divulged, published, or otherwise disclosed without the consent of QED Therapeutics, Inc.
PPD
PPD
PPD


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INVESTIGATOR’S AGREEMENT 
I have read Protocol QBGJ398-302 titled “Phase 3, multicenter, double-blind, randomized, 
placebo-controlled trial of infigratinib for the adjuvant treatment of subjects with invasive 
urothelial carcinoma with susceptible FGFR3 genetic alterations (PROOF 302)” 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, 
investigator agrees to give access to all relevant data and records to QED Therapeutics monitors, 
auditors, QED Therapeutics Clinical Quality Assurance representatives, designated agents of 
QED Therapeutics, 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 
Medical Monitor 
 MD 
email: 
 
Telephone: 
 
Pharmacovigilance/ 
Safety Management 
Covance Safety 
email: SAEintake@covance.com 
 
 
 
 
PROTOCOL VERSION HISTORY 
Protocol Version Number 
Amendment Number 
Date 
0.0 (original protocol) 
NA 
03 September 2019 
1.0 (Amendment 1) 
1.0 
19 May 2021 
Abbreviations: NA=not applicable. 
 
 
 
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TABLE OF CONTENTS 
INVESTIGATOR’S AGREEMENT ............................................................................................2 
TRIAL CONTACTS ......................................................................................................................3 
PROTOCOL VERSION HISTORY ............................................................................................3 
TABLE OF CONTENTS ..............................................................................................................4 
LIST OF TABLES .........................................................................................................................7 
LIST OF FIGURES .......................................................................................................................7 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................................8 
1 
SYNOPSIS .............................................................................................................................11 
2 
SCHEDULE OF ASSESSMENTS ......................................................................................20 
3 
BACKGROUND ...................................................................................................................26 
3.1 
Overview of Disease Pathogenesis, Epidemiology and Current Treatment ...............26 
3.1.1 
Upper Tract Urothelial Carcinomas ........................................................................26 
3.1.2 
Invasive Urinary Bladder Carcinomas ....................................................................27 
3.1.3 
Overview of the FGFR Family and FGFR Genetic Alterations in Human 
Malignancies ...............................................................................................................27 
3.2 
Overview of Infigratinib ..................................................................................................28 
3.3 
Nonclinical Experience with Infigratinib.......................................................................28 
3.4 
Clinical Experience with Infigratinib.............................................................................29 
3.4.1 
Clinical Pharmacokinetics and Phase 1 Data ..........................................................29 
3.4.2 
Clinical Safety .............................................................................................................30 
3.4.3 
Clinical Efficacy .........................................................................................................31 
3.5 
Rationale ...........................................................................................................................32 
3.5.1 
Study Rationale and Purpose ....................................................................................32 
3.5.2 
Rationale for the Study Design .................................................................................33 
3.5.3 
Rationale for Dose and Regimen Selection ..............................................................34 
3.6 
Benefit/Risk Assessment of Study Participation ...........................................................34 
4 
OBJECTIVES AND ENDPOINTS .....................................................................................35 
5 
INVESTIGATIONAL PLAN ..............................................................................................37 
5.1 
Overall Study Design .......................................................................................................37 
5.2 
Number of Subjects..........................................................................................................39 
5.3 
Time on Study and End of Study Definition .................................................................39 
6 
STUDY POPULATION .......................................................................................................39 
6.1 
Inclusion Criteria .............................................................................................................39 
6.2 
Exclusion Criteria ............................................................................................................42 
7 
TREATMENTS ....................................................................................................................45 
7.1 
Treatments Administered ...............................................................................................45 
7.2 
Information on Dosing with Study Drug .......................................................................45 
7.2.1 
Subject Instructions for Dosing ................................................................................45 
7.2.2 
Description of Test Article ........................................................................................46 
7.2.3 
Packaging and Labeling ............................................................................................46 
7.2.4 
Study Drug Accountability, Handling, and Disposal ..............................................46 
7.2.5 
Dose Modifications for Study Drug ..........................................................................47 
7.2.5.1 
Dose Modifications and Delays ...........................................................................47 
7.2.5.2 
Follow-up for Toxicities .......................................................................................56 


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7.2.6 
Anticipated Risks and Safety Concerns for Infigratinib ........................................56 
7.3 
Randomization and Blinding ..........................................................................................56 
7.4 
Compliance .......................................................................................................................58 
7.5 
Supportive Care Guidelines ............................................................................................58 
7.5.1 
Hematopoietic Growth Factors ................................................................................58 
7.5.2 
Management of Hyperphosphatemia .......................................................................58 
7.5.3 
Management of Diarrhea ..........................................................................................59 
7.5.4 
Management of Alopecia, Palmar-Plantar Erythrodysesthesia Syndrome, 
Paronychia, and Stomatitis .......................................................................................59 
7.5.5 
Management of Dry Eye and Blurred Vision ..........................................................61 
7.6 
Prior and Concomitant Medications ..............................................................................61 
7.6.1 
Permitted Concomitant Therapy Requiring Caution and/or Action ....................62 
7.6.2 
Prohibited Concomitant Therapy ............................................................................63 
7.6.3 
COVID-19 Vaccinations ............................................................................................64 
7.7 
Non-drug Therapies .........................................................................................................64 
8 
SUBJECT DISCONTINUATION AND STUDY TERMINATION ................................64 
8.1 
Subject Discontinuation...................................................................................................64 
8.1.1 
Discontinuation of Study Drug .................................................................................64 
8.1.2 
Discontinuation from Study ......................................................................................66 
8.2 
Study Termination ...........................................................................................................67 
9 
STUDY VISITS AND PROCEDURES ..............................................................................67 
9.1 
Molecular Prescreening ...................................................................................................67 
9.2 
Main Study Informed Consent .......................................................................................68 
9.3 
Screening (Day −28 to −1) ...............................................................................................68 
9.4 
Study Drug Dosing During Treatment Period (Days 1-28, Cycles 1-13) ....................69 
9.5 
Study Visits During Treatment Period (Cycle 1 Day 1 to Cycle 13 Day 21) ..............70 
9.6 
Cycle 13 Day 28 or EOT Visit (±5 Days) ........................................................................72 
9.7 
30-day Post-treatment Follow-up (±5 Days) ..................................................................73 
9.8 
Follow-up Every 6 Months (±7 Days) after EOT and at EOS .....................................73 
9.9 
Survival Follow-up and New Antineoplastic Therapies ...............................................75 
9.10 
End of Treatment and End of Study ..............................................................................75 
10 STUDY ASSESSMENTS .....................................................................................................76 
10.1 
Efficacy Assessments .......................................................................................................76 
10.2 
Pharmacokinetic Assessments ........................................................................................79 
10.3 
Assessment of Biomarkers and Eligible FGFR3 Alterations .......................................80 
10.4 
Quality of Life ..................................................................................................................82 
10.5 
Safety Assessments ...........................................................................................................83 
10.5.1 
Adverse Events ...........................................................................................................83 
10.5.1.1 
Definitions .............................................................................................................83 
10.5.1.2 
Clarifications for AE Definitions ........................................................................84 
10.5.1.3 
Recording Adverse Events ..................................................................................84 
10.5.1.4 
Reporting Serious Adverse Events .....................................................................85 
10.5.1.5 
Adverse Events of Special Interest .....................................................................86 
10.5.1.6 
Follow up of Adverse Events ...............................................................................86 
10.5.2 
Pregnancies .................................................................................................................87 
10.5.3 
Laboratory Parameters .............................................................................................87 


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10.5.4 
Vital Signs ...................................................................................................................88 
10.5.5 
Physical Examinations ...............................................................................................88 
10.5.6 
Electrocardiograms....................................................................................................88 
10.5.7 
Ophthalmic Assessments ...........................................................................................89 
10.5.8 
Eastern Cooperative Oncology Group Performance Status ..................................89 
10.5.9 
Early Stopping Guidelines and Data Monitoring Committee ...............................89 
11 STATISTICAL METHODOLOGY ...................................................................................90 
11.1 
General Considerations ...................................................................................................90 
11.2 
Sample Size Determination .............................................................................................92 
11.3 
Statistical Hypothesis, Model, and Method of Analysis ...............................................92 
11.3.1 
Disposition of Subjects ...............................................................................................92 
11.3.2 
Demographics, Medical History, Baseline Characteristics, and 
Concomitant Medications .........................................................................................92 
11.3.3 
Efficacy Analyses .......................................................................................................92 
11.3.4 
Pharmacokinetic Analyses ........................................................................................95 
11.3.5 
Biomarker Analyses ...................................................................................................95 
11.3.6 
Analyses of Quality of Life Assessments ..................................................................96 
11.3.7 
Interim Analysis .........................................................................................................96 
11.3.8 
Safety Analyses ...........................................................................................................96 
11.3.8.1 
Treatment Exposure ............................................................................................96 
11.3.8.2 
Adverse Events .....................................................................................................97 
11.3.8.3 
Other Safety Findings ..........................................................................................97 
12 DATA COLLECTION AND MANAGEMENT ................................................................97 
12.1 
Data Confidentiality.........................................................................................................97 
12.2 
Study Center Monitoring ................................................................................................98 
12.3 
Data Collection .................................................................................................................99 
12.4 
Database Management and Quality Control .................................................................99 
12.5 
Study Documentation, Record Keeping and Retention of Documents .......................99 
12.6 
Audits and Inspections ..................................................................................................100 
13 REGULATORY AND ETHICAL CONSIDERATIONS ...............................................100 
13.1 
Regulatory and Ethical Compliance ............................................................................100 
13.2 
Responsibilities of the Investigator and IRB/IEC/REB .............................................100 
13.3 
Informed Consent Procedures ......................................................................................101 
13.4 
Confidentiality of Study Documents and Subject Records ........................................101 
14 FINANCIAL CONSIDERATIONS AND INSURANCE ................................................102 
15 PUBLICATION POLICY ..................................................................................................102 
16 REFERENCE LIST............................................................................................................103 
17 APPENDICES .....................................................................................................................108 
17.1 
Appendix 1: List of Concomitant Medications ...........................................................108 
17.2 
Appendix 2: List of Prohibited Medications ...............................................................109 
17.3 
Appendix 3: List of Highly Effective Methods of Contraception ..............................110 
17.4 
Appendix 4: Recommended Standards for Lymph Node Dissection (LND) at 
the Time of Selected Definitive Surgeries for Urothelial Carcinoma ........................111 
17.5 
Appendix 5: Instructions for Optimal Tumor Specimens for FGFR3 testing .........112 
 


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LIST OF TABLES 
Table 1: 
Trial Contact Information ....................................................................................3 
Table 2: 
Schedule of Assessments ......................................................................................21 
Table 3: 
Schedule of Assessments: Pharmacokinetic and Blood and Urine 
cfDNA Sample Collection, Laboratory Parameters, and Adverse 
Event and Concomitant Medication Assessments ............................................25 
Table 4: 
Objectives and Endpoints ...................................................................................36 
Table 5: 
Dose Reduction Scheme .......................................................................................48 
Table 6: 
Criteria for Interruption and Re-initiation of Study Drug for Adverse 
Events Considered to be Possibly Related to Study Drug ................................49 
Table 7: 
Management of Skin Toxicity .............................................................................60 
Table 8: 
Definitions of Recurrence by Site .......................................................................77 
Table 9: 
Pharmacokinetic Parameters ..............................................................................80 
Table 10: 
Safety Laboratory Parameters ...........................................................................88 
Table 11: 
Drugs to be Used with Caution While on Study .............................................108 
Table 12: 
List of Prohibited Medications and Substancesa While on Study ..................109 
Table 13: 
Recommendations for Tumor Nuclei Percentage ...........................................113 
 
LIST OF FIGURES 
Figure 1: 
Study Design .........................................................................................................38 
 


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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 
BCG 
Bacillus Calmette-Guerin 
BCRP 
breast cancer resistance protein  
BGJ398 
Infigratinib 
BICR 
blinded independent central review 
BMI 
body mass index 
BUN 
blood urea nitrogen 
cfDNA 
cell-free DNA 
CI 
confidence interval 
Cmax 
maximum observed plasma concentration after drug administration 
C-G 
Cockcroft-Gault 
Ctrough 
trough observed plasma concentration (before drug administration) 
 COVID-19 
 Coronavirus disease 2019 
CR 
complete response 
CRF 
case report form 
CRO 
contract research organization 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CXD1 
first day of Cycle number  
CYP 
cytochrome P450 
DFS 
disease-free survival 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form  
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 
EQ-5D-5L 
EuroQOL 5 dimensions, 5 levels questionnaire 
ESMO 
European Society of Medical Oncology 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 


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Abbreviation 
Term/Definition 
FGFR1 
fibroblast growth factor receptor 1 
FGFR2 
fibroblast growth factor receptor 2 
FGFR3 
fibroblast growth factor receptor 3 
FGFR3 alterations 
FGFR3 genetic alterations (mutations, and gene fusions or translocations 
[ie, rearrangements]) 
FGFR4 
fibroblast growth factor receptor 4 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
glomerular filtration rate 
GI 
gastrointestinal 
GMP 
Good Manufacturing Practice 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
GSM 
global study manager  
HDPE 
High-density polyethylene 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonization 
IEC 
Independent Ethics Committee 
IHC 
immunohistochemistry 
IRB 
Institutional Review Board 
IRT 
Interactive response technology 
ITT 
intent-to-treat 
IV 
intravenous 
LC-MS/MS 
liquid chromatography-tandem mass spectrometry 
LLN 
lower limit of normal 
LLOQ  
lower limit of quantification 
LND 
lymph node dissection 
MFS 
metastasis-free survival 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen-activated protein kinase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
NCBI RefSeq 
National Center for Biotechnology Information reference sequence  
NCCN 
National Comprehensive Cancer Network 
NK-1 
neurokinin-1 
NMIBC 
nonmuscle invasive bladder cancer 
NYHA 
New York Heart Association 
OCT 
optical coherence tomography 
ORR 
overall response rate 
OS 
overall survival  
PD 
pharmacodynamic 
PD-L1 
programmed death-ligand 1 
PFS 
progression-free survival  


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Abbreviation 
Term/Definition 
PK 
pharmacokinetics 
pNx 
post-lymphadenectomy or no lymphadenectomy 
PPES 
palmar-plantar erythrodysesthesia syndrome 
PR 
partial response 
PT 
Prothrombin time 
PTT 
Partial thromboplastin time 
QD 
once a day 
QED 
QED Therapeutics, Inc. 
QLQ-C30 
quality of life questionnaire core 30 
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 
QTcF 
QT interval corrected by Fridericia's formula 
RBC 
red blood cell  
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 
RNU 
radical nephroureterectomy 
RPTD 
recommended Phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
SUSAR 
suspected unexpected serious adverse reaction 
TdP 
Torsades de Pointes  
Tmax 
time at which the maximum observed concentration (Cmax) occurs 
UBC 
urothelial carcinoma of the bladder/urinary bladder cancer 
UC 
urothelial carcinoma 
ULN 
upper limit of normal 
UTUC 
upper tract urothelial carcinoma 
WBC 
white blood cell  
WOCBP 
woman of childbearing potential 
WHO 
World Health Organization 
 
 
 
 


I nfi grati ni b 
Q E D T hera pe utics  
Pr ot oc ol Q B GJ 3 9 8 -3 0 2 A me n d me nt 1 . 0 ( Versi o n 1. 0 ) 
C o nfi de ntial  
1 9 Ma y 2 0 2 1  
Pa ge 1 1  of 1 1 3     
 
 
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 , I nc. 
N a me of I n vesti g ati o n al Pr o d uct:  Infi grati ni b ( als o k n o w n as B GJ 3 9 8 , B B P -8 3 1 , a n d i nfi grati ni b p h os p hate; 
hereafter referre d t o as i nfi grati ni b)  
N a me of Acti ve I n gre die nt: I nfi grati ni b 
Title of St u d y: P hase 3 , M ultice nter, D o u ble -Bli n d, Ra n d o mize d, Place b o -C o ntr olle d Trial of I nfi grati ni b f or t he 
A dj u va nt Treat me nt of S u bjects wit h I n vasi ve Ur ot helial Carci n o ma wit h S usce pti ble F G F R 3 Ge n etic 
Alterati o ns  ( P R O O F 3 0 2) 
St u d y ce nters: 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 6 5 st u d y ce nters w orl d wi de. 
Me dic al M o nit or: 
 M D  
St u die d peri o d ( ye ars):  
Esti mate d date first s u bject e nr olle d: Dece m ber 2 0 1 9  
Esti mate d date last s u bject c o m plete d: 2 0 2 4  
P h ase of de vel o p me nt:  3  
 
O bjecti ves  a n d E n d p oi nts :  
O bjecti ves  
E n d p oi nts  
Pri m ary:  
•  
T o deter mi ne if treat me nt wit h i nfi grati ni b 
i m pr o ves ce ntrall y re vie we d disease -free 
s ur vi val (D F S ) c o m pare d wit h place b o 
treat me nt i n s u bjects wit h i n vasi ve ur ot helial 
carci n o ma wit h susce pti ble F G F R 3 alterati o ns 
after  ne p hr o ureterect o m y, distal  ureterect o m y, 
or c ystect o m y  
 
•  
Ce ntrall y re vie we d D F S, fr o m date of 
ra n d o mizati o n t o l ocal/re gi o nal or c o ntralateral 
i n vasi ve or metastatic rec urre nce, or deat h d ue t o 
a n y ca use, w hic he ver occ urs earlier  
Sec o n d ary : 
 
•  
T o c o m pare D F S i ncl u di n g i ntral u mi nal l o w -
ris k (n o ni n vasi ve, l o w -gra de, or hi g h -gra de) 
rec urre nce i n s u bjects treate d wit h i nfi grati ni b 
vs place b o  
•  
I n vesti gat or-re vie we d D F S i ncl u di n g i ntral u mi nal 
l o w-ris k ( n o ni n vasi ve, l o w-gra de, or hi g h -gra de)  
rec urre nce, fr o m date of ra n d o mizati o n t o a n y 
rec urre nce or deat h d ue t o a n y ca use, w hic he ver 
occ urs earlier  
•  
T o c o m pare metasta sis-free s ur vi val (M F S ) of 
s u bjects treate d wit h i nfi grati ni b vs place b o 
•  
I n vesti gat or-re vie we d M F S , fr o m date of 
ra n d o mizati o n t o metastatic rec urre nce  or deat h 
d ue t o a n y ca use, w hic he ver occ urs earlier  
 
•  
T o c o m pare O S i n s u bjects treate d wit h 
i nfi grati ni b vs place b o 
 
•  
O S (fr o m date of ra n d o mizati o n t o deat h) 
•  
T o c o m pare i n vesti gat or -re vie we d D F S i n 
s u bjects treate d wit h i nfi grati ni b vs place b o 
•  
I n vesti gat or-re vie we d DF S , fr o m date of 
ra n d o mizati o n t o l ocal/re gi o nal or c o ntralateral 
i n vasi ve or metastatic rec urre nce, or deat h d ue t o 
a n y ca use, w hic he ver occ urs earlier  
 
•  
T o c haracterize t he safet y a n d t olera bilit y of 
i nfi grati ni b w he n a d mi nistere d as p ost o perati ve 
a dj u va nt m o n ot hera p y  
•  
T y pe, fre q ue nc y, a n d se verit y of a d verse e ve nts 
a n d seri o us a d verse e ve nts , la b orat or y 
a b n or malities, a n d ot her safet y fi n di n gs  
E x pl or at ory : 
 
•  
T o c o m pare Q O L i n s u bjects treate d wit h 
i nfi grati ni b vs place b o 
 
•  
Q O L as meas ure d b y t he E Q -5 D -5 L  a n d t he 
E O R T C Q L Q C 3 0  
P P D


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• 
To evaluate the PK of infigratinib 
• 
PK parameters (trough and maximum plasma 
concentration).  
 
• 
To evaluate the overall genomic landscape in 
subjects with invasive urothelial carcinoma  
 
• 
Determine the prevalence of genomic alterations 
and their correlations with available 
clinicopathologic and demographic features in 
subjects with invasive urothelial carcinoma.  
 
• 
To evaluate biomarkers related to the biology 
of urothelial carcinoma and their potential 
association with efficacy, disease recurrence, 
and resistance to study medication. 
• 
Genomic and proteomic assessments of tumor 
tissue and cell-free DNA samples from baseline to 
disease recurrence and the determination of the 
prognostic and/or predictive value of biomarkers. 
Abbreviations: DFS=disease-free survival; EORTC=European Organization for Research and Treatment of 
Cancer; EQ-5D-5L=EuroQOL 5-dimensions, 5-levels questionnaire; FGFR3=fibroblast growth factor 
receptor 3; MFS=metastasis-free survival; PK=pharmacokinetics; QLQ=quality of life questionnaire; 
QOL=quality of life; OS=overall survival. 
Study Design: This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the 
efficacy of infigratinib in approximately 218 adult subjects with invasive urothelial carcinoma with susceptible 
fibroblast growth factor receptor 3 (FGFR3) genetic alterations (mutations, and gene fusions or rearrangements; 
hereafter referred to collectively as “FGFR3 alterations”) who are within 120 days following 
nephroureterectomy, distal ureterectomy, or cystectomy and ineligible for or refuse cisplatin-based (neo)adjuvant 
chemotherapy or with residual disease after neoadjuvant therapy. The sample size can be increased up to a total 
of 328 subjects based on interim analysis result using an adaptive design promising zone approach. Subjects with 
invasive urothelial carcinoma includes subjects with invasive upper tract urothelial carcinoma (UTUC) and 
urothelial carcinoma of the bladder (UBC). 
Subjects who meet eligibility criteria will be randomly assigned (1:1) to receive oral infigratinib or placebo 
administered once daily for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 52 weeks 
(13 cycles), or until local/regional or contralateral invasive or metastatic recurrence (whichever occurs first) is 
confirmed by BICR, or until other criteria specified in the protocol are met, whichever occurs first.  
Subjects will be evaluated for tumor recurrence radiographically, by urine cytology, and for subjects with UTUC 
(ie, subjects with a bladder), cystoscopy will also be performed. Radiography, urine cytology, and cystoscopy 
will continue until metastatic recurrence by blinded independent central review (BICR) or metastatic recurrence 
by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. 
Use of anticancer therapy will be collected for all subjects, including from the time of study treatment 
discontinuation, regardless of reason for discontinuation. After metastatic recurrence by BICR or metastatic 
recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already 
occurred, subjects will be followed for survival status and use of anticancer therapy until 1 year after the final 
disease-free survival (DFS) event goal is reached (ie, End of Study [EOS]). After the EOS (1 year after the DFS 
primary analysis), subjects will continue to be followed for overall survival (OS) (under a separate protocol) for 
approximately 14 years, or until all of the subjects die or drop from this follow up, whichever is earlier, referred 
to as long-term OS follow up. 
Subjects should remain on study treatment until local/regional or contralateral invasive or metastatic recurrence is 
confirmed by BICR. If BICR confirms recurrence (local/regional or contralateral invasive or metastatic 
recurrence, whichever occurs first), the subject must be permanently discontinued from study treatment. BICR 
diagnosis of a local/regional or contralateral invasive or metastatic recurrence, independently from and 
undiagnosed by local team, will not be communicated to the clinical site. 


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An interim analysis for adaptation and futility for centrally reviewed DFS will be conducted after approximately 
35 confirmed DFS events by BICR (independent of investigator assessment) (ie, half of the planned number) 
have been reached. Based on the results of the interim analysis on DFS, if a sample size increase is deemed 
necessary using the promising zone approach, the sample size/centrally reviewed DFS event goal will be 
increased by a maximum of 50% (328/105). If sample size is increased and event goal is adjusted, then the 
subsequent analyses will be adjusted accordingly time-wise when the adjusted event goal is reached. The details 
of the sample size adaptation method will be prespecified in the adaptation plan. 
Subjects will be stratified according to lymph node involvement (yes vs no), prior neoadjuvant cisplatin 
chemotherapy (yes vs no), Stage (pT2 vs >pT2), and disease (UTUC vs UBC). 
Number of subjects (planned): Approximately 218 subjects are initially planned for study participation. The 
sample size can be increased up to a total of 328 subjects based on interim analysis result using an adaptive 
design promising zone approach. No more than 15% of the population will be enrolled with UBC, and ≤25% of 
UTUC subjects will have Stage pT2 UTUC (limit will be based on stratification). The number of subjects 
refusing cisplatin-based perioperative therapy will be capped at approximately 10% of the total population 
(approximately 22 subjects). 
Diagnosis and criteria for inclusion: To be eligible for the study, subjects must meet all of the following 
criteria: 
1. Are ≥18 years of age (≥20 years of age in Taiwan) of either sex. 
2. Have signed informed consent. 
3. Are randomized within 120 days following nephroureterectomy, distal ureterectomy, or cystectomy.  
Note: at the time of definitive surgery, lymph node dissection (LND) should be performed in cases of 
suspected lymph node invasion based on preoperative imaging or intraoperative findings. In other cases, 
LND is to be performed in accordance with surgeon preferences/local standard practices. Additional details 
on recommended standards for LND are provided in the protocol. 
4. Have histologically or cytologically confirmed, invasive urothelial carcinoma with susceptible FGFR3 
alterations. Variant histology is allowed provided urothelial carcinoma is predominant (>50%). 
Neuroendocrine (including small and large cell), sarcomatoid, and plasmacytoid variants are excluded (any 
component): 
a. 
Regarding samples and documentation of FGFR3 alterations: 
i. 
FGFR3 mutation is confirmed if: FGFR3 gene is mutated in Exon 7 (R248C, S249C), Exon 10 
(G370C, A391E, Y373C), or Exon 15 (K650M/T, K650E/Q)  
OR 
ii. FGFR3 gene fusion or FGFR3 rearrangement is confirmed based on the following genomic criteria: 
(1) Any fusion/rearrangement with a literature-derived known partner gene regardless of strand or 
frame.  
(2) Fusion/rearrangements in the same strand that are in frame with a novel partner gene.  
(3) Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot region and the 
other breakpoint in an intergenic region or another gene. This rule excludes 3′ duplications 
comprising only exon 18. 
iii. The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 isoform 1 
(NP_000133.1) that is the NCBI Refseq ID used to report genetic alterations in FGFR3 by the 
FoundationOne® CDx test (F1CDx, Foundation Medicine, USA). 
iv. Written documentation of central laboratory determination by F1CDx testing of FGFR3 alterations 
is required for study eligibility. 
v. For subjects who require molecular prescreening to confirm the presence of the FGFR3 alteration to 
meet the inclusion criteria, a tumor sample with a pathology report must be sent to Foundation 
Medicine USA for F1CDx testing. (Instructions for optimal tumor specimens are provided in the 
protocol). 
(1) The tumor sample to be used should be from the definitive surgical resection (cystectomy, 
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(2) An archival biopsy of confirmed invasive urothelial carcinoma (≥pT2) can be used if (1) tissue 
from definitive surgery cannot be submitted, (2) the biopsy sample is not older than 4 months 
prior to surgery date and (3) the subject did not receive any type of systemic anticancer 
treatment since the biopsy was obtained. If more than one biopsy is available, the most recent 
one is to be sent. 
b. 
If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be Stage ≥ ypT2 
and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based 
chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received less than this or 
non-cisplatin-based neoadjuvant treatment are not excluded. If enrolled, they will be stratified as having 
received no neoadjuvant chemotherapy. 
c. 
If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based adjuvant 
chemotherapy based on Galsky (2011): 
i. 
Creatinine clearance ≤60 mL/minute, or 
ii. Common Terminology Criteria for Adverse Events (CTCAE version 5.0) Grade ≥2 hearing loss, or 
iii. CTCAE Grade ≥2 neuropathy. 
d. 
 Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receive cisplatin-based 
chemotherapy based on Galsky (2011), must also meet the following criteria: 
i. 
UTUC should be Stage ≥pT2 pN0-2 (post-lymphadenectomy or no lymphadenectomy [pNx]), or 
pN+, M0 
ii. UBC should be Stage ≥pT3 or pN+, M0.  
e. 
Must have a centrally reviewed negative postoperative computed tomography (CT) (defined as lymph 
nodes with short axis <1.0 cm and without growth and no distant metastases according to Response 
Evaluation Criteria in Solid Tumors [RECIST] v1.1) or negative biopsy within 28 days before 
randomization to confirm absence of disease at baseline. 
5. If have had adverse events (AEs) associated with prior surgery or neoadjuvant chemotherapy, they have 
stabilized or resolved to Grade ≤2 before randomization. 
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
7. If a woman of childbearing potential, 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 ≥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 ≥12 months, and there is no other cause of amenorrhea (eg, hormonal therapy, 
prior chemotherapy). 
Women of childbearing potential and males whose sexual partners are women of childbearing potential must 
agree to use barrier contraception and a second form of contraception (Clinical Trials Facilitation Group 
2020) while receiving study drug and for 1 month following their last dose of study drug. 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, postovulation 
methods) and withdrawal are not acceptable methods of contraception. (Highly effective contraception 
methods are specified in the protocol.)  
Sexually active males must use a condom during intercourse while taking study drug and for 1 month after 
the last dose of study drug and should not father a child during this period. A condom is required to be used 
also by vasectomized men as well as during intercourse with a male partner to prevent delivery of the study 
drug via seminal fluid. Study subjects must agree to refrain from donating sperm and eggs during the study 
and for 1 month following their last dose of study drug. 
8. Are willing and able to comply with study visits and study procedures. 
Criteria for exclusion: To be eligible for the study, a subject must not meet any of the following criteria: 
1. Presence of positive invasive surgical margins following nephroureterectomy, distal ureterectomy, or 
cystectomy. In subjects not eligible for further surgery, radiotherapy, or other efficacious treatment, 
microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease are allowed. 
2. Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for nonmuscle invasive bladder 
cancer (NMIBC) within the previous 30 days. 


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3. 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 
antiepileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone.  
Prior anticancer or other therapies are restricted as follows: 
a. 
Prior adjuvant treatment for urothelial cancer is not allowed. 
b. 
Prior neoadjuvant therapy (eg, chemotherapy, immunotherapy, or investigational) is allowed if inclusion 
criterion #4 is met.  
Prior neoadjuvant chemotherapy must have been completed within a period of time that is greater than 
the cycle length used for that treatment before the first dose of study drug. 
c. 
 Prior biologic, immunotherapy, or investigational therapy should have been completed within a period 
that is ≥5 half-lives or 30 days, whichever is shorter, before the first dose of study drug. 
4. Are planning to receive other systemic therapies intended to treat invasive urothelial carcinoma while on this 
study. 
5. Have previously or currently is receiving treatment with a mitogen-activated protein kinase (MEK) or 
selective FGFR inhibitor. 
6. Have a history of primary malignancy within the past 3 years other than (1) invasive UBC or UTUC (ie, 
disease under study), (2) noninvasive urothelial carcinoma, (3) any adequately treated in situ carcinoma or 
non-melanoma carcinoma of the skin, (4) any other curatively treated malignancy that is not expected to 
require treatment for recurrence during participation in the study, or (5) an untreated cancer on active 
surveillance that may not affect the subject’s survival status for ≥3 years based on clinician 
assessment/statement and with medical monitor approval. For any other cancers that do not meet the criteria 
above, and for which the natural history or treatment do not have the potential to interfere with the safety or 
the efficacy assessments of the study, written approval is required by the medical monitor.  
7. Have current evidence of corneal keratopathy or retinal disorder including, but not limited to, bullous/band 
keratopathy, inflammation or ulceration, keratoconjunctivitis, macular degeneration, 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, vasculature, myocardium, and lung with the exception of calcified lymph nodes, 
minor pulmonary parenchymal calcifications, small renal cyst or stone calcifications, and asymptomatic 
coronary calcification. 
9. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the absorption of oral 
infigratinib (eg, active 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), unless well controlled. 
11. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, pomelos, or Seville 
oranges or products containing juice of these fruits within 7 days before the first dose of study drug; have 
taken any Chinese herbal medicine or Chinese patent medicine treatments with anticancer activity within 
14 days of the first dose of study drug. 
12. Have insufficient bone marrow function: 
a. 
Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L). 
b. 
Platelets <75,000/mm3 (<75 × 109/L). 
c. 
Hemoglobin<8.5 g/dL; transfusion support is allowed if >1 week before randomization and hemoglobin 
remains stable. 
13. Have insufficient hepatic and renal function: 
a. 
Total bilirubin >1.5 × upper limit of normal (ULN) of the testing laboratory (for subjects with 
documented Gilbert syndrome, direct bilirubin must be ≤1.5× ULN and enrollment requires approval by 
the medical monitor). 
b. 
AST/SGOT and ALT/SGPT >2.5× ULN of the testing laboratory. 
c. 
Serum creatinine >1.5 × ULN or a calculated (using the Cockcroft-Gault [C-G] formula [Cockcroft 
1976]) or measured creatinine clearance of <30 mL/min. 


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14. Have amylase or lipase >2.0 × ULN. 
15. Have abnormal calcium or phosphorus: 
a. 
Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory. 
b. 
Total serum calcium (can be corrected) higher than 1.02 × ULN of the testing laboratory. 
16. Have clinically significant cardiac disease including any of the following: 
a. 
New York Heart Association (NYHA) Class ≥2B; subjects with known history or current symptoms of 
cardiac disease, or history of treatment with cardiotoxic agents, should have a clinical risk assessment of 
cardiac function using the NYHA classification.  
b. 
Uncontrolled hypertension (refer to European Society of Cardiology and European Society of 
Hypertension guidelines [Williams 2018]). 
c. 
Presence of CTCAE (version 5.0) Grade ≥2 ventricular arrhythmias, atrial fibrillation, bradycardia, or 
conduction abnormality. 
d. 
Unstable angina pectoris or acute myocardial infarction ≤3 months before the first dose of study drug. 
e. 
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 ≥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. 
f. 
History of congenital long QT syndrome. 
17. Have had a recent (≤3 months before the first dose of study drug) transient ischemic attack or stroke. 
18. If female, are 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. 
19. Have a known allergy/hypersensitivity reaction to any components of the study drug. 
20. Have any other concurrent disease or condition that, in the view of the investigator, would interfere with 
study participation. 
Investigational product, dosage and mode of administration: Subjects randomly assigned to infigratinib will 
receive hard gelatin capsules for oral administration of infigratinib 125 mg once daily (administered as one 
100-mg capsule and one 25-mg capsule) using a 3 weeks on (Days 1-21) /1 week off (Days 22-28) dosing 
schedule. Subjects with mild/moderate renal or hepatic impairment should have their dose adjusted as described 
in the protocol. 
Reference therapy, dosage and mode of administration: Subjects randomly assigned to placebo will receive 
placebo matching in appearance the investigational product (infigratinib), which will be provided as hard gelatin 
capsules for oral use and will be administered once daily on a 3 weeks on (Days 1-21) /1 week off (Days 22-28) 
dosing schedule. Subjects with mild/moderate renal or hepatic impairment should have their dose adjusted as 
described in the protocol. 
Duration of treatment: Up to 52 weeks  


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Criteria for evaluation: 
Efficacy: Assessments will consist of CT/magnetic resonance imaging (MRI) scans performed at baseline within 
28 days before randomization, every 3 months up to 24 months after start of treatment, and annually thereafter or 
until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred. Scan images will be sent for BICR. Cystoscopy 
(for subjects with a bladder) and urine cytology will be performed at Screening; 3 (C4), 6 (C7), 9 (C10), and 12 
(C13) months; at C13D28 or End of Treatment (EOT); every 6 months up to 24 months after start of treatment, 
and then annually or until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if 
local/regional or contralateral invasive recurrence by BICR has already occurred. After metastatic recurrence by 
BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by 
BICR has already occurred, subjects will be followed up for use of anticancer therapy and survival status 
approximately every 6 months up to 1 year, then annually thereafter until 1 year after the final DFS event goal is 
reached. Use of anticancer therapy will be collected for all subjects, including from the time of study treatment 
discontinuation, regardless of reason for discontinuation. For subjects started on a non-study related anticancer 
therapy after discontinuing from study treatment, imaging assessment of disease status should continue , until 
metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred. Subjects who come off treatment before the end 
of the year of treatment for reasons other than recurrence (as stated above) should continue efficacy assessments 
according to the Schedule of Assessments, including survival follow-up for 1 year after final DFS event goal is 
reached (ie, EOS). After the EOS (1 year after the DFS primary analysis), subjects will continue to be followed 
for long-term OS follow-up for approximately 14 years (under a separate protocol). 
QOL: Subject quality of life (QOL) will be evaluated at Screening and at every visit through the first 6-month 
follow-up visit after discontinuation of study drug using the European Organization for Research and Treatment 
of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30) and EuroQOL 5 dimensions, 5 levels 
questionnaire (EQ-5D-5L). 
PK: Blood samples will be collected on Cycle 1 Day 1 predose and 4 hours (±30 min) postdose; on Cycle 1 
Day 21 predose and 4 hours (±30 min) postdose; and on Cycle 2 and all subsequent cycles on Day 21 predose 
and 4 hours (±30 min) postdose. Plasma concentrations of infigratinib and its active metabolites will be 
measured. The pharmacokinetic (PK) parameters of Ctrough and Cmax will also be calculated. 
Safety: Assessments will be performed at Screening and visits throughout the treatment period: adverse events 
(AEs and serious AEs [SAEs]), clinical laboratory tests (blood and urine), physical examinations, vital signs, 
ECGs (screening, C1D1, C2D1, and C13D28 or EOT only), ECOG performance status, and ophthalmic 
assessments. Retinal optical coherence tomography (OCT) scan images will be read locally and the scans will be 
sent to the OCT imaging vendor. AEs and SAEs will be assessed until 30 days post EOT. 
Statistical methods:  
Sample Size: Approximately 218 subjects will be initially randomly assigned to treatment in this study in a 
double-blind fashion. The sample size can be increased up to a total of 328 subjects based on interim analysis 
result using an adaptive design promising zone approach. The study will start with a group sequential design with 
1 interim analysis at approximately 35 confirmed DFS events by BICR (independent of investigator assessment) 
(50% of the initial event goal). A Haybittle-Peto boundary will be used for the efficacy boundary with a fixed 
one-sided alpha of 0.00005 spent at the interim analysis for centrally reviewed DFS, and the rest of the alpha 
(one-sided alpha=0.025) spent at the primary centrally reviewed DFS analysis. Though an efficacy boundary is 
specified for the interim centrally reviewed DFS analysis, the trial will not stop at the interim analysis if the 
efficacy boundary is crossed. A Lan DeMets spending function approximating O’Brien-Fleming boundaries will 
be used for the non-binding futility boundary. Assuming disease will recur in 46% of subjects in the first 2 years 
and a 5% yearly recurrence rate in the third year and beyond for the placebo group, the required sample size with 
initial group sequential design is approximately 218 subjects to reach 70 confirmed DFS events by BICR 
(independent of investigator assessment). This is assuming with 3-year uniform enrollment, 1-year follow-up, 
10% yearly drop-out rate, and a hazard ratio (HR) of 0.5. The sample size will provide approximately 80% power 
to detect a difference in DFS assuming an HR of 0.5, based on a log-rank test controlling type I error at one-sided 
0.025. 


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At the interim analysis, the study uses an adaptive design promising zone approach to adjust sample size and 
event goal as needed. The details of the sample size adaptation method will be prespecified in the adaptation 
plan. If no sample size adaption is needed at the interim analysis, the study is projected to reach the planned 
number of confirmed DFS events by BICR (70 events) 4 years from the randomization of the first subject. If a 
sample size increase is deemed necessary based on the interim result and the promising zone approach, the 
sample size/event goal will be increased by maximum of 50% (328/105). If sample size is increased and event 
goal is adjusted, then the subsequent analyses will be adjusted accordingly time-wise when the adjusted event 
goal is reached, and the boundary to test centrally reviewed DFS when the adjusted event goal is reached will be 
based on the original boundary from the initial group sequential design. 
Efficacy Analyses: The primary efficacy analysis will be conducted on the intent-to-treat (ITT) population, 
which will include all subjects who are randomly assigned to treatment. Subjects will be analyzed according to 
the treatment arm to which they are randomly assigned.  
For the primary efficacy endpoint, CHW statistics based on stratified log-rank test (using randomization 
stratification factors except disease type [UTUC or UBC]) will be used to control type I error in case of sample 
size increase at the interim analysis. Conventional stratified log-rank test will be used for the inference on 
centrally reviewed DFS if sample size is not adjusted at interim. Repeated confidence interval (CI) will be 
provided for the estimated HR based on stratified Cox proportional hazard model.  
For the secondary efficacy endpoints DFS (including intraluminal low-risk [noninvasive, low-grade, or 
high-grade] recurrence), MFS, and OS, a fixed sequence testing procedure will be followed to control the family-
wise type I error at a level of one-sided 0.025. 
DFS including intraluminal low-risk (noninvasive, low -grade, or high-grade), recurrence will be tested first if the 
test on centrally reviewed DFS is significant, followed by the test on MFS if both DFS and DFS including 
intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence are significant. OS will be tested finally 
if DFS, DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence, and MFS are all 
significant. 
A Haybittle-Peto boundary will be used for the secondary efficacy endpoints. A fixed one-sided type I error with 
alpha=0.00005 will be spent at the interim analysis, and the rest of the type I error will be spent at the time of the 
primary analysis. 
For DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence and MFS, 1 interim 
analysis will be conducted at the time of interim analysis for centrally reviewed DFS, and the primary analysis 
will be conducted at the primary analysis for centrally reviewed DFS when the DFS event goal is reached. There 
will be 2 interim analyses for OS, one at the interim centrally reviewed DFS analysis and the other one at the 
primary centrally reviewed DFS analysis. The primary analysis for OS will be conducted at approximately 1 year 
after the DFS event goal is reached. For OS analyses, a fixed one-sided type I error with alpha=0.00005 will be 
spent at each of the interim analyses, and the rest of the type I error will be spent at the time of the primary OS 
analysis. After EOS (1 year after the primary DFS analysis), subjects will continue to be followed for long-term 
OS follow up (under a separate protocol) for approximately 14 years or all of the subjects die or drop from this 
follow up, whichever is earlier. The data for this long-term OS follow-up will be reported in a separate study 
report. 
The same analysis methodology described for centrally reviewed DFS will be applied for statistical analyses for 
DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence, MFS, and OS with 
corresponding efficacy boundaries.  
Sensitivity analyses may be conducted to evaluate the potential effect on efficacy outcomes due to enrollment of 
subjects refusing cisplatin-based chemotherapy (yes vs no) and reasons why a subject did not receive cisplatin-
based chemotherapy (ineligible or refusal) in the 2 treatment arms (active vs placebo), using the Cox regression 
model with this factor as a covariate. The number of subjects refusing cisplatin-based perioperative therapy will 
be capped at approximately 10% of the total population (approximately 22 subjects). If sufficient numbers of 
subjects are enrolled with a component of variant histology, or with microscopic positive noninvasive margins 
(eg, carcinoma in situ) without gross residual disease, sensitivity analysis will be conducted to account for 
variations in response. Further details are provided in the Statistical Analysis Plan (SAP). 


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Safety Analyses: All reported AEs will be assigned to a system organ class and preferred term according to 
Medical Dictionary for Regulatory Activities (MedDRA). The number and percentage of subjects reporting 
treatment-emergent AEs (all, serious, related, and deaths within 30 days) will be tabulated by treatment arm 
graded using CTCAE (version 5.0). Summary tables also will be provided for treatment-emergent AEs leading to 
study drug modification (discontinuation, hold or reduction). 
Interim Analysis: One formal interim analysis of centrally reviewed DFS will be performed when a total of 
35 confirmed DFS events by BICR (independent of investigator assessment) has occurred.  
At the interim analyses, the study will not be stopped for efficacy if the efficacy boundary for centrally reviewed 
DFS is crossed. 
The study may be stopped due to futility at the interim DFS analysis if the futility boundary for testing centrally 
reviewed DFS is crossed. The futility stopping boundary is non-binding to allow for additional considerations. 
If a sample size increase is deemed necessary based on the interim result on centrally reviewed DFS using the 
promising zone approach, the sample size/event goal will be increased by a maximum of 50% (328/105). The 
details of sample size adaptation method will be prespecified in a separate adaptation plan. 
Other Information: An independent Data Monitoring Committee (DMC) will review safety and efficacy data at 
the interim analysis and make recommendations regarding sample size adaptation.  
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 SAP. 
 


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2 SCHEDULE OF ASSESSMENTS 
Table 2 is a schedule of assessments to be performed during the study. Table 3 outlines detailed 
sampling times for pharmacokinetic (PK), urine and blood plasma cell-free DNA (cfDNA), and 
other laboratory parameters. All data obtained from these assessments must be supported in the 
subject’s source documentation.  
Molecular prescreening for susceptible fibroblast growth factor receptor 3 (FGFR3) genetic 
alterations (mutations, and gene fusions or rearrangements; hereafter referred to collectively as 
“FGFR3 alterations”) testing can be conducted any time before the Screening visit.  
All baseline/screening assessments, including screening cystoscopy (for subjects with a bladder) 
and imaging assessments must be conducted within 28 days before randomization. Baseline 
scans must be sent for blinded independent central review (BICR) to confirm absence of residual 
or metastatic disease before randomization. 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 to re-check their eligibility.  
Whenever feasible, vaccinations should be administered at least 30 days prior to randomization.  
Baseline/Screening assessments that are conducted within 3 days before the first treatment can 
be used to satisfy the Day 1 requirement. Every effort must be made to follow the schedule 
outlined. 
Unless otherwise indicated, for Treatment Period there is a minus-3-day window on assessments 
(study visits on C1D1, C1D4, C1D7, C1D14 and C2D1) or a minus-5-day window (study visits 
on C4D1, C7D1, C10D1, and C13D1) on assessments to take into account scheduling over 
weekends and holidays. For study visits on Day 21 of all cycles (C1 to C13) there is a 
minus-2-day window. For postbaseline imaging assessments, a ±7-day window is allowed, 
except for the first postbaseline assessment (+7-day window permitted). The end of treatment 
(EOT) visit is to be conducted no later than 5 days from the decision to discontinue study drug. 
For visits that occur every 6 months after the EOT or the End of Study (EOS) visit, a ±7-day 
window is allowed. For Survival Follow-up visits that occur annually after EOT or the EOS, a 
±14-day window is allowed (see Section 9.9 for details on long-term overall survival [OS] 
follow-up after the EOS).  


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Table 2: 
Schedule of Assessments 
Assessment 
Molecular 
Prescreening b 
Screening b 
Treatment Period Clinic Visits (Cycle and Day) a 
30-Day Post-
Treatment 
Follow-Up 
Every 
6 Months 
after EOT c 
and at EOS 
Survival 
Follow-Up d 
C1 
D1 
C2 
D1 
C4 
D1 
C7 
D1 
C10 
D1 
C13 
D1 
C13 
D28 
or 
EOT c 
Visit Window (days) e  
 
–28 to −1 
-3 
-3 
-5 
-5 
-5 
-5 
±5 
±5 
±7 
±14 
Informed consent for molecular prescreening 
X 
 
 
 
 
 
 
 
 
 
 
 
Prescreening FGFR3 alteration testing by 
F1CDx b 
X 
 
 
 
 
 
 
 
 
 
 
 
FGFR3 alteration documentation  
 
X 
 
 
 
 
 
 
 
 
 
 
PD-L1 testing f 
 
 
X f 
 
 
 
 
 
 
 
 
 
Informed consent g 
 
X 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion criteria g 
 
X 
 
 
 
 
 
 
 
 
 
 
Demographics  
 
X 
 
 
 
 
 
 
 
 
 
 
ECOG performance status 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Medical history 
 
X 
 
 
 
 
 
 
 
 
 
 
Diagnosis & extent of cancer 
 
X 
 
 
 
 
 
 
 
 
 
 
Prior medication and antineoplastic therapy 
 
X 
 
 
 
 
 
 
 
 
 
 
Ophthalmic assessment h 
 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination i 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Weight and BMI (height at screening only) 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
Vital signs 
 
X 
X 
X 
X 
X 
X 
X 
X 
 
X 
 
12-Lead ECG j 
 
X 
X 
X 
 
 
 
 
X 
 
 
 
QOL assessment k 
 
 
X 
X 
X 
X 
X 
X 
X 
 
X k 
 
Blood samples:  
 
Hematology l,m 
 
X 
Refer to Table 3 for specific schedule 
X 
 
 
 
Clinical chemistry l,m 
 
X 
Refer to Table 3 for specific schedule 
X 
 
 
 
Coagulation  
 
X 
As clinically indicated 
 
 
 
Pharmacokinetics 
 
 
Refer to Table 3 for specific schedule 
 
 
 
cfDNA 
 
 
Refer to Table 3 for specific schedule n 
 
X n 
 


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Assessment 
Molecular 
Prescreening b 
Screening b 
Treatment Period Clinic Visits (Cycle and Day) a 
30-Day Post-
Treatment 
Follow-Up 
Every 
6 Months 
after EOT c 
and at EOS 
Survival 
Follow-Up d 
C1 
D1 
C2 
D1 
C4 
D1 
C7 
D1 
C10 
D1 
C13 
D1 
C13 
D28 
or 
EOT c 
Visit Window (days) e  
 
–28 to −1 
-3 
-3 
-5 
-5 
-5 
-5 
±5 
±5 
±7 
±14 
Urine samples: 
 
Urinalysis 
 
X 
(subjects 
with a 
bladder) 
As clinically indicated (all subjects) 
 
 
 
Cytology  
 
X 
 
 
X 
X 
X 
X 
X 
 
X 
 
cfDNA 
 
 
Refer to Table 3 for specific schedule n  
 
X 
 
Pregnancy test in WOCBP o 
 
X 
Monthly (refer to Table 3 for schedule) 
X 
 
 
 
Chest, Abd/Pelvis CT or MRI scan p  
 
X 
 
 
X 
X 
X 
X 
X 
 
X  
(every 3M) p 
 
Cystoscopy (subjects with a bladder) q 
 
X 
 
 
X 
X 
X 
X 
X  
 
X 
 
Randomization r 
 
X 
 
 
 
 
 
 
 
 
 
 
Administer study drug (3 weeks on [Days 1-21] 
/1 week off [Days 22-28] s 
 
 
X 
 
 
 
 
AEs 
 
X t 
X (Refer to Table 3 for additional schedule) 
X 
X 
 
 
Concomitant medications 
 
 
X (Refer to Table 3 for additional schedule) 
X 
X 
 
 
Antineoplastic therapies since discontinuation  
of study treatment 
 
 
 
 
 
 
 
 
 
X 
X 
X 
Newly obtained tumor sample 
(if medically feasible) 
 
 
 
Collect upon any disease recurrence u 
 
Survival follow up d 
 
 
 
 
 
 
 
 
 
 
X 
X 
Abbreviations: Abd=abdomen; AE=adverse event; BICR=blinded independent central review; BMI=body mass index; C=cycle; cfDNA=cell-free DNA; 
CRF=case report form; CT=computed tomography; D=day; DFS=disease-free survival; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; 
EDC=electronic data capture; EORTC=European Organization for Research and Treatment of Cancer; EOS=end of study; EOT=end of treatment; EQ-5D-
5L=EuroQOL 5 dimensions, 5 levels questionnaire; F1CDx=FoundationOne CDx test (from Foundation Medicine USA); FGFR3=fibroblast growth factor 
receptor 3; ICF=informed consent form; M=months; MRI=magnetic resonance imaging; OCT=optical coherence tomography; OS=overall survival; PD-
L1=programmed death-ligand 1; PK=pharmacokinetics; QLQ-Core 30=Quality Of Life Questionnaire Core 30; QOL=quality of life; UTUC=upper tract 
urothelial carcinoma; SAE=serious adverse event; WOCBP=women of childbearing potential. 
a 
Additional assessments, including sample collection for clinical laboratory assessments, PK and blood and urine cfDNA assessments, pregnancy testing, and 
collection of AEs and concomitant medications will be as detailed in Table 3.  


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b 
Molecular Prescreening: If F1CDx data are not available from testing that occurred as part of the subject’s standard of care, molecular prescreening 
assessments can be done (after signing Molecular Prescreening ICF) any time before the initiation of the Screening visit. Further details are provided in 
Section 9.1. 
 
Screening: All baseline/screening assessments, including baseline imaging assessments and screening cystoscopy (for subjects with a bladder) must be 
conducted within 28 days before randomization. Baseline/screening assessments that are conducted within 3 days before the first treatment can be used to 
satisfy the C1D1 requirement. Every effort must be made to follow the schedule outlined. 
c 
After EOT, subjects will be followed up every 6 months until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if 
local/regional or contralateral invasive recurrence by BICR has already occurred. The EOT visit should be no later than 5 days after treatment 
discontinuation. See footnote p regarding schedule of imaging assessments. 
d 
After metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has 
already occurred, subjects will be followed up for survival every 6 months for 1 year, then annually thereafter (via phone or office visit) for 1 year after the 
final DFS event goal is reached (ie, EOS). See Section 9.9 for details on long-term OS follow-up (under a separate protocol). 
e 
C1D1 has a minus-3-day window to account for scheduling over weekends and holidays. During study treatment, there is a minus-3-day window on C2D1 
assessments and a minus-5-day window on C4D1, C7D1, C10D1, and C13D1 assessments to take into account scheduling over weekends and holidays, if 
not explicitly specified otherwise. For postbaseline imaging assessments, a ±7-day window is allowed, except for the first postbaseline assessment (+7-day 
window is permitted). 
f 
If local PD-L1 test has been completed and status is available, enter the status information in EDC. If local PD-L1 is not already known, PD L1 testing can 
be initiated at C1D1 or at any time after the subject is deemed eligible. See Section 10.3 for additional details for PD-L1 testing. 
g 
Written informed consent is required before performing any study-specific tests or procedures and may be obtained at any time before such test or 
procedure. Results of standard-of-care tests or examinations and review of inclusion/exclusion criteria performed before obtaining informed consent and 
within 28 days before randomization may be used for screening assessments rather than repeating such tests. If the subject did not receive platinum-based 
chemotherapy in the perioperative setting (see inclusion criterion #4, Section 6.1), the reason must be documented in the CRF. 
h 
Ophthalmic assessment (performed by an ophthalmologist) will also be done as clinically indicated. 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 scans will be read 
locally and images will be provided to the OCT imaging vendor. Refer to the Study Manual for details regarding image collection and transfer or shipment. 
Ophthalmic assessment will be conducted at C13D28 or EOT visit unless performed within previous 4 weeks. 
i 
Full physical examination at screening, C1D1, and C13D28/EOT; abbreviated or symptom-directed physical examination at C2D1, C4D1, C7D1, C10D1, 
C13D1, every 6 months after EOT, and at the EOS visit. 
j 
For each subject, 12-lead ECGs will be done at Screening; predose on Day 1 of Cycles 1 and 2; and at C13D28 or EOT visit.  
k 
QOL assessments should be conducted before study drug administration, AE evaluation, and disease status notification, and preferably in order of EQ-5D-
5L then EORTC QLQ-C30. Subjects should complete QOL assessments for 18 months; for subjects who complete all 52 weeks of study drug treatment, the 
last assessment will be at the first 6-month follow-up visit after discontinuation of study drug. 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.  
l 
Laboratory tests will be collected and analyzed on the scheduled day, even if study drug treatment is being withheld. Laboratory tests must be conducted 
within the windows specified in the protocol.  
m 
Hematology will be assessed at C1D1, C2D21, C4D21, C7D21, C10D21, C13D21, and C13D28 or EOT (refer to Table 3). 
Clinical chemistry will be assessed at C1D1, C1D4, C1D7, C1D14, C1D21; Cycles 2-13 (Day 21); and C13D28 or EOT (refer to Table 3).  


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The schedules for these clinical laboratory tests coincide, as closely as possible, with the blood draws specified for PK and cfDNA (refer to Table 3). Every 
attempt should be made to collect the clinical chemistry sample at the same time as the PK sample taken at 4 hours after study drug administration. 
n 
At the time of local/regional or contralateral invasive or metastatic recurrence, a blood and urine sample will be collected for analysis of cfDNA. 
o 
Serum or urine pregnancy test within 7 days before the first dose of study drug; thereafter, pregnancy tests should be conducted monthly (at study visit on 
Day 21 of each cycle [per Table 3]) and may be serum or urine based on standard at the institution. Where required while the subject is receiving study drug, 
more frequent urine pregnancy tests may be conducted. 
p 
Baseline CT/MRI scans must be performed within 28 days before randomization and must be submitted for BICR to confirm absence of residual or 
metastatic disease before randomization. For an individual subject, whichever modality (CT or MRI) is used at screening, that same modality should be used 
for radiographic assessment throughout the study. Refer to the Study Manual for details regarding image collection and transfer or shipment. For 
postbaseline imaging assessments, a ±7-day window is allowed, except for the first postbaseline assessment (+7-day window permitted). Perform CT/MRI 
scans every 3 months for a total of 24 months since start of treatment, then annually until metastatic recurrence by BICR or metastatic recurrence by 
investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. Subjects who discontinue study drug for reasons 
other than metastatic recurrence by BICR (as stated in the previous sentence) will continue to have radiographic assessments every 3 months for a total of 
24 months since start of treatment, then annually until metastatic recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred. A radiographic assessment should be conducted at the EOT visit, unless taken within the 
previous 4 weeks. CT/MRI scans indicating unequivocal recurrence (as defined in Table 8) must be read locally and submitted for BICR as well as any 
supporting report (including pathology and cytology reports) if a biopsy was conducted at the time of recurrence. Refer to the Study Manual for details 
regarding image collection and transfer or shipment. 
q 
Perform cystoscopy (for UTUC subjects with a bladder) at Screening, within 28 days before randomization, and at C4D1, C7D1, C10D1, C13D1, and 
C13D28 or EOT, and then every 6 months for a total of 24 months since start of treatment; then annually until metastatic recurrence by BICR or metastatic 
recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. Subjects who discontinue study 
drug for reasons other than recurrence (as stated in the previous sentence) will continue to have cystoscopy/cytology as described until metastatic recurrence 
by BICR or metastatic recurrence by investigator assessment if local/regional or contralateral invasive recurrence by BICR has already occurred. Conduct 
cystoscopy/cytology at the EOT visit, unless done within the previous 4 weeks.  
r 
Randomization will occur after the subject completes the Screening visit and is deemed eligible for study (including documented medical monitor approval) 
and before C1D1. Treatment starts within 1 week of randomization. Note: only under certain unforeseen circumstances that are not caused by 
noncompliance or inappropriate planning [eg, adverse weather], randomization may occur after day 120 from definitive surgery but window for 
randomization and dosing should be 127 days total (120 days +7 days). 
s 
Study drug may be dispensed at study visits on Day 1 of C1, C2, C4, C7, C10, and C13 and/or monthly at study visits per local standard practice. 
t 
Only report protocol-mandated procedure-related AEs. See Sections 10.5.1.3 and 10.5.1.4 for details on collection and reporting of AEs and SAEs. 
u 
Histologic/cytologic confirmation is the preferred criterion to determine unequivocal recurrence, and new lesions should be biopsied to confirm recurrence 
when safe and feasible. All CT/MRI scans and biopsy reports (including pathology and cytology reports) must be submitted for BICR assessment. 
 


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Table 3: 
Schedule of Assessments: Pharmacokinetic and Blood and Urine cfDNA 
Sample Collection, Laboratory Parameters, and Adverse Event and 
Concomitant Medication Assessments 
Cycle 
Day 
Parameters 
PKa 
cfDNAa 
 
 
 
 
Predose 
(hrs before 
dose) 
Postdose 
(hrs ±30 min) 
Blood and 
Urine 
(predose) 
Clinical 
Chemistryb Hematologyb 
Pregnancy 
Testc 
AEs and  
Conmeds 
1 
1 
0 
4 
X 
X 
X 
 
X 
1 
4 
 
 
 
X 
 
 
 
1 
7 
 
 
 
X 
 
 
 
1 
14 
 
 
 
X 
 
 
 
1 
21 d 
0 
4 
X 
X 
 
X 
X 
2 
21 d 
0 
4 
 
X 
X 
X 
X 
3 
21 d 
0 
4 
X 
X 
 
X 
X 
4 
21 d 
0 
4 
 
X 
X 
X 
X 
5 
21 d 
0 
4 
X 
X 
 
X 
X 
6 
21 d 
0 
4 
 
X 
 
X 
X 
7 
21 d 
0 
4 
X 
X 
X 
X 
X 
8 
21 d 
0 
4 
 
X 
 
X 
X 
9 
21 d 
0 
4 
X 
X 
 
X 
X 
10 
21 d 
0 
4 
 
X 
X 
X 
X 
11 
21 d 
0 
4 
X 
X 
 
X 
X 
12 
21d 
0 
4 
 
X 
 
X 
X 
13 
21 d 
0 
4 
X 
X 
X 
X 
X 
13 
28(or 
EOT) e 
If within 
24 hrs of last 
dose 
NA 
If not done 
within 28 days 
prior 
X 
X 
X 
X 
Abbreviations: AEs=adverse events; C=cycle; cfDNA=cell-free DNA; Conmeds=concomitant medications; D=day; 
eCRF=electronic case report form; EOT=end of treatment; hrs=hours; NA=not applicable; PK=pharmacokinetic(s).  
NOTE 1: On the days of PK and cfDNA 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 will be supervised and administration time 
recorded.  
NOTE 2: If a subject is not on study drug, then no PK or cfDNA sample will be collected. PK and cfDNA sampling will 
resume once the subject is back on study drug. 
a 
On PK sampling days after C1D1, the time of the last study drug dose (ie, time of infigratinib/placebo administration 
on the previous day) before the predose PK sample will be recorded in the eCRF. For any subject who permanently 
discontinues study drug, attempts should be made to collect PK and blood (2 tubes, 16-20 mL) and urine cfDNA 
samples from the subject at the time of discontinuation, if the samples can be collected within 24 hours of last dose. 
b 
Samples for clinical laboratory tests (including hematology, clinical chemistry, and pregnancy) will be collected and 
analyzed on the scheduled day even if study drug is being withheld; where applicable, every attempt should be made 
to collect samples for clinical laboratory tests on the same day as PK and cfDNA sample collection (window is 
minus-3 days for C1D1, C1D4, C1D7, and C1D14). Every attempt should be made to collect the clinical chemistry 
sample at the same time as the PK sample taken at 4-hours after study drug administration.  
c 
Pregnancy test may be serum or urine based on standard at the institution. Where required while the subject is 
receiving study drug, more frequent urine pregnancy tests may be conducted.  
d 
A minus-2-day window before Day 21 is allowed (specifically on Days 19, 20, or 21).  
e 
Blood (2 tubes, 16-20 mL) and urine cfDNA samples will be collected at C13D28 or EOT if not done within 28 days 
before. At the time of local/regional or contralateral invasive or metastatic recurrence, blood (2 tubes, 16-20 mL) and 
urine samples will be collected for analysis of cfDNA. Sample for PK to be collected if within 24 hours of last dose 
of study drug. 


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3 BACKGROUND 
3.1 
Overview of Disease Pathogenesis, Epidemiology and Current Treatment 
3.1.1 
Upper Tract Urothelial Carcinomas 
In 2018, it was estimated that 150,350 new patients would be diagnosed with urinary system 
cancer: 81,190 urinary bladder; 65,340 kidney and renal pelvis; and 3820 ureter and other 
urinary organs. Excluding non-urothelial kidney cancers, approximately 5% to 10% of all 
urothelial carcinomas are upper tract urothelial carcinomas (UTUCs). The incidence of UTUC is 
2 to 3 times greater in men than women (Siegel 2018; Roupret 2015).  
In contrast to invasive urinary bladder cancer (UBC), UTUC has a more aggressive clinical 
course. At the time of diagnosis, 60% of patients with UTUC have invasive cancer compared to 
15% to 25% of patients with UBC (Margulis 2009; Roupret 2015). Thirty-six percent (36%) 
have regional disease and 9% have distant disease (Raman 2010). A large retrospective review of 
1363 patients with UTUC who underwent radical nephroureterectomy (RNU) at 12 centers 
demonstrated that 28% of the total population had recurrence outside of the bladder after RNU 
(Margulis 2009).  
Standard-of-care neoadjuvant, adjuvant, and metastatic disease treatment is based on urothelial 
histology common to UBC and UTUC. Neoadjuvant and adjuvant treatment regimens containing 
cisplatin in combination with other cytotoxic agents are administered for 3 to 4 cycles. These 
regimens are: dose-dense methotrexate, vinblastine, doxorubicin, and cisplatin (DDMVAC); 
gemcitabine and cisplatin; and cisplatin, methotrexate, and vinblastine (CMV; National 
Comprehensive Cancer Network [NCCN] Guidelines Version 3 2018; European Society of 
Medical Oncology [ESMO] Guidelines [Bellmunt 2014]).  
The peak incidence of UTUC occurs predominantly in 70- to 90-year-old patients who, if 
eligible for RNU, have 1 remaining kidney following surgery and often have other significant 
co-morbid conditions making cisplatin-based treatment a challenge (Roupret 2015). Renal 
function before and after RNU greatly limits the number of patients with UTUC who are eligible 
for platinum-based neoadjuvant or adjuvant therapy. Retrospective review of 336 patients with 
UTUC treated with RNU at the Cleveland Clinic using an estimated glomerular filtration rate 
(eGFR) cutoff of 60 mL/min/1.73 m2 determined the percentage of patients eligible for platinum-
based therapy. The median age was 72 years and the median preoperative eGFR was 
59 mL/min/1.73m2. Before RNU, 48% of patients were eligible for platinum-based therapy and 
after RNU 22% were eligible; for patients with Stage pT2 to pT4 and/or pN1 to pN3 disease 
these proportions were 40% and 24%, respectively (Lane 2010; Birtle 2018).  
The POUT study, a large randomized trial in UTUC supports the use of standard-of-care 
adjuvant platinum-based chemotherapy (Birtle 2020). Patients with histologically confirmed 
Stage pT2 to T4, N0-3, M0 UTUC, World Health Organization (WHO) performance status 0-1, 
≤90 days post RNU were randomly assigned (1:1) to 4 cycles gemcitabine and cisplatin (or 
gemcitabine and carboplatin if their glomerular filtration rate (GFR) was 30-49 mL/min) versus 
surveillance. There were 260 patients (131 chemotherapy and 129 surveillance patients) in the 


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intent-to-treat (ITT) population. The distribution of patients by stage was: 28% Stage pT2; 66% 
pT3; and 91% pN0. The 3-year disease-free survival (DFS) was 71% for chemotherapy patients 
(95% confidence interval [CI]: 61, 78) and 46% for surveillance patients (95% CI: 36, 56). The 
metastasis-free survival (MFS) also favored the chemotherapy patients (HR=0.48 [95% CI: 0.31, 
0.74; p=0.0007]). Subgroup analysis demonstrated benefit was greater for patients who received 
gemcitabine and cisplatin (HR 0.35 [95% CI: 0.20,0.61]) compared to patients who received 
gemcitabine and carboplatin (HR 0.66 [95% CI: 0.35,1.26]). The independent Data Monitoring 
Committee (DMC) recommended stopping enrollment because the study met the early stopping 
criteria for efficacy. Patients continue to be followed for OS.  
3.1.2 
 Invasive Urinary Bladder Carcinomas 
Approximately 20% of patients with urothelial carcinoma have invasive UBC at the time of 
diagnosis and only 15% to 25% of Stage T2 or higher invasive UBC tumors have activating 
FGFR3 alterations (Roupret 2015). Nonetheless, invasive UBC has a poor prognosis and 
approximately 50% of patients with invasive UBC will develop metastatic disease; 5-year 
mortality is approximately 50% (Knowles 2015). Phase 3 trials have demonstrated a survival 
benefit for neoadjuvant cisplatin-based chemotherapy; however, patients with residual disease 
following neoadjuvant therapy have a poor prognosis (Grossman 2003). In addition, studies 
suggest that patients with invasive UBC are unlikely to receive neoadjuvant or adjuvant 
cisplatin-based chemotherapy, in part due to cisplatin ineligibility (Porter 2011). Moreover, 
postoperative complications can preclude the use of adjuvant cisplatin-based therapy (Donat 
2009). Therefore, patients with invasive UBC harboring FGFR3 alterations and either residual 
disease following neoadjuvant therapy or who are ineligible to receive or refuse cisplatin-based 
adjuvant chemotherapy will be permitted to enroll into this study. Given the small patient 
population, it is expected that ≤15% of enrolled patients will have invasive UBC. (Note: No 
more than 15% of the population will be enrolled with UBC and ≤25% of UTUC patients will 
have Stage pT2 UTUC [limit will be based on stratification]). The number of subjects refusing 
cisplatin-based perioperative therapy will be capped at approximately 10% of the total 
population (approximately 22 subjects). 
3.1.3 
Overview of the FGFR Family and FGFR Genetic Alterations in Human 
Malignancies 
The fibroblast growth factor receptor (FGFR) family of receptor tyrosine kinases (RTKs) 
consists of 4 members (FGFR1, FGFR2, FGFR3, FGFR4) which serve as high affinity receptors 
for 22 different fibroblast growth factors (FGFs).  
Several lines of evidence support the association and the involvement of FGFRs in human 
cancer, where genetic alterations leading to abnormal activation and/or deregulated expression of 
FGFs and FGFRs family members has been found in diverse tumor types.  
Somatic activating mutations in FGFR3 have been identified in solid tumors, with high 
frequency in bladder carcinomas (Cappellen 1999), where FGFR3 overexpression is also 
reported (Tomlinson 2007). Activating point mutations of FGFR3 have been identified in 
approximately 40% of bladder tumors overall. Eleven different missense mutations in Exons 7, 


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10 and 15, have been identified (Knowles 2008). Some of these mutations lead to constitutive 
activation of the kinase activities of the receptor and downstream signaling, and activation of 
FGFR family members occurs also as fusion proteins that result from chromosomal 
rearrangements (eg, translocations) with other genes (Katoh 2019). FGFR1, FGFR2, and FGFR3 
gene fusions or translocations (ie, rearrangements) have been identified in diverse cancer types 
including cholangiocarcinoma, breast cancer, prostate cancer, thyroid cancer, lung squamous cell 
carcinoma, bladder cancer, oral cancer, head and neck squamous cell carcinoma, and 
glioblastoma at low frequency (Wu 2013). As noted above, FGFR3 alterations occur in up to 
two-thirds of patients with UTUC (Sfakianos 2015; Moss 2017; Bagrodia 2019). 
3.2 
Overview of Infigratinib 
Infigratinib (also known as BGJ398, BBP-831, and infigratinib phosphate) is an orally 
bioavailable, potent, and selective ATP-competitive inhibitor of FGFRs 1-3, which has 
demonstrated antitumor activity in nonclinical in vitro and in vivo tumor models harboring 
FGFR genetic alterations. 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 phosphate1 (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 4 to 5 nM for FGFR1, FGFR2, and FGFR3. Infigratinib is less 
potent in inhibiting FGFR4, with an IC50 of 168 nM. 
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 
urothelial cancer with FGFR3 mutations or FGFR3 fusions (Wesche 2011; Guagnano 2012; 
Konecny 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 or on hemodynamic or electrocardiographic parameters, respectively. 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, infigratinib did lead to increases in 
serum FGF23 and serum phosphorous associated with partially reversible ectopic mineralization 
(kidney, lung, 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. 


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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. 
This section focuses on results from the single agent, first-in-human Phase 1 study in subjects 
with advanced solid malignancies for which no further standard therapy existed 
(CBGJ398X2101). A total of 208 subjects were treated in this study. Infigratinib was evaluated 
at 9 different dose levels and 3 different dose schedules, ranging from 5 mg/day to 150 mg/day 
(CBGJ398X2101 Clinical Study Report). Eight dose levels were administered on the once daily 
(QD) continuous 28-day cycle schedule and 1 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 QD 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 before 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 QD on a 3 weeks on 
(Days 1-21)/1 week off (Days 22-28) 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 and 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 (DCR) (95% CI) were 13.9% (9.10, 
19.94) and 49.1% (41.47, 56.83), respectively. The median progression free survival (PFS) for 
all subjects treated at the MTD/RPTD was 3.12 months (95% CI: 2.10, 3.65 months). 
3.4.1 
Clinical Pharmacokinetics and Phase 1 Data 
The PK of infigratinib and its active metabolites (BHS697, CQM157) 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 cytochrome P450 3A4 (CYP3A4) mediated clearance 


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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 such, infigratinib is not 
expected to have a clinically relevant effect on drugs metabolized 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. 
3.4.2 
Clinical Safety 
The majority of Study CBGJ398X2101 subjects (99.0%) evaluable for safety experienced 
≥1 adverse event (AE), with a Grade 3/4 AE reported in 58.7%, regardless of study treatment 
relationship (CBGJ398X2101 Clinical Study Report; Pal 2018). The incidence of Grade 3/4 AEs 
was similar at the MTD (52.6%). The majority of these subjects (95.7%) experienced ≥1 AE 
suspected to be study treatment related, with Grade 3/4 AEs suspected to be study treatment 
related reported in 38.0%. The incidence of Grade 3/4 AEs suspected to be study treatment 
related (38.0%) was similar at the MTD (31.6%). 
The most common AEs (occurring in ≥30% of all subjects, all grades), regardless of study 
treatment relationship were: hyperphosphatemia (65.4%), constipation (39.9%), decreased 
appetite (37.5%), fatigue (36.1%), stomatitis (34.1%), and nausea (32.2%). The most common 
AEs suspected to be study treatment related (occurring in ≥30% of all subjects, all grades) were: 
hyperphosphatemia (63.5%) and stomatitis (33.7%). 
The most commonly reported Grade 3/4 AEs (in ≥4% of all subjects), regardless of study 
treatment relationship were: hyperlipasemia (6.7%), hypophosphatemia (6.3%), ALT elevation 
(5.3%), hyperphosphatemia (4.8%), and fatigue (4.8%). The most frequently occurring Grade 3/4 
AEs suspected to be study treatment related (in ≥4% of all subjects) were: hyperlipasemia 
(5.8%), hyperphosphatemia (4.8%), and ALT increased (4.8%). 
A total of 57 deaths (27.4%) occurred during the study, and most of these deaths were due to 
disease progression (24.0%). Of the total deaths, 11.1% were on-treatment deaths; of these, 8.6% 
subjects died due to disease progression, 2 subjects died due to sepsis, and 1 subject each died 
due to respiratory failure, cardiac arrest, and unknown reason. 
At least 1 serious adverse event (SAE) (occurring in ≥5% subjects) of any grade, regardless of 
study treatment relationship, was reported in a total of 37.5%, with a similar incidence reported 
at the MTD (40.4%). SAEs suspected to be drug-related were reported in 8.6% of subjects. The 
most commonly reported SAEs, by preferred term (occurring in ≥5% subjects) were: general 
physical health deterioration (2.9%); pneumonia (2.9%); vomiting (2.9%); dyspnea (2.4%); and, 
hypercalcemia (2.4%). 


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Adverse events leading to study drug discontinuation were reported in a total of 14.4%. Most 
commonly reported AEs leading to discontinuation of study drug, in all subjects, by preferred 
term were: visual impairment, hypercalcemia, hypercreatininemia, hyperlipasemia, and palmar-
plantar erythrodysethesia syndrome (PPES) in 1.0% each. Twenty-one subjects (10.1%) 
discontinued treatment due to AEs that were suspected to be related to study treatment. The 
common suspected related AEs leading to study treatment discontinuation were: visual 
impairment, hypercalcemia, hypercreatininemia, hyperlipasemia, and PPES in 1.0% each. 
AEs requiring dose interruption or reduction occurred in 68.3% of subjects. The most common 
AEs (incidence ≥10%) requiring dose adjustment or temporary interruptions regardless of study 
drug relationship were hyperphosphatemia (28.8%) and hypercreatininemia (15.9%). 
Overall, Grade 3 hematology abnormalities were reported in 13.9%, of which, 2 SAEs of anemia 
were reported in 2 subjects (1 subject had Grade 2 anemia and the other had Grade 3 anemia). 
New or worsened Grade 4 hematology abnormality of lymphocytes decrease was reported in 
1.5% of subjects. 
Eye-related AEs were reported in a total of 44.7% of subjects. Of these, AEs suspected to be 
study treatment related were reported in 33.7%. There was one Grade 2 SAE of keratitis reported 
which was suspected to be treatment related and led to study drug discontinuation. 
3.4.3 
Clinical Efficacy 
Efficacy data for all subjects in the dose escalation and dose expansion parts of Study 
CBGJ398X2101 are available in the Investigator’s Brochure. The following efficacy data 
presented are for subjects with urothelial carcinoma participating in the Arm 4 expansion part 
(ie, subjects with advanced/metastatic urothelial carcinoma, originating in the bladder, urethra, 
ureter, or renal pelvis with FGFR3 mutations). 
Arm 4 of the expansion part of Study CBGJ398X2101 included 67 subjects with 
advanced/metastatic urothelial carcinoma with FGFR3 mutations or FGFR fusions who had 
either progressed on or were intolerant of platinum-based chemotherapy, or had 
contraindications to platinum-based chemotherapy (Pal 2018). Permitted FGFR3 mutations 
included mutations in exon 7 (R248C, S249C), exon 10 (G372C, A393E, Y375C), or exon 15 
(K652M/T, K652E/Q). These amino acid numbers refer to the functional FGFR3 isoform 3 
(NP_001156685.1). All FGFR3 fusions were included. Subjects were treated with oral 
infigratinib 125 mg/day for 21 days followed by 7 days without treatment as 28-day cycles. 
All 67 subjects were evaluable for response. Seventeen subjects (25.4%) had responses (1 CR 
and 16 PR). Forty-three (43) subjects (64.2%) had disease control (CR + PR + stable disease 
[SD]). Sixteen subjects (23.9%) had progressive disease and 8 subjects (11.9%) had an 
indeterminate response. One subject with an indeterminate response by Response Evaluation 
Criteria in Solid Tumors (RECIST) criteria actually had a pathologic CR; however, due to 
changing imaging modalities between assessments, the response was reported as unknown (Pal 
2018). The subject had primary bladder cancer and a histologically confirmed metastasis in the 
humerus. During infigratinib treatment, the subject had surgical resection of a suspected 


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pathologic fracture of the humerus. Histologic assessment revealed no evidence of residual 
disease. 
3.5 
Rationale 
3.5.1 
Study Rationale and Purpose 
UTUC comprises approximately 5% to 10% of all urothelial carcinomas (Roupret 2015). At the 
time of diagnosis, 60% of patients with UTUC have invasive cancer (Roupret 2015), 36% have 
regional disease and 9% have distant disease (Raman 2010), and 28% have recurrence outside of 
the bladder after RNU (Margulis 2009). The peak incidence of UTUC occurs in 70- to 90-year-
old patients (Shariat 2011; Roupret 2015). To reduce the morbidity and mortality in patients with 
UTUC, neoadjuvant or adjuvant treatment is needed. The POUT study, a large randomized trial 
in UTUC supports the use of standard-of-care adjuvant cisplatin-based chemotherapy (Birtle 
2020). Because many patients with UTUC will have 1 remaining kidney following RNU and 
frequently have other significant co-morbid conditions, cisplatin-based therapy is not well 
tolerated (NCCN Guidelines Version 3.2018; ESMO Guidelines [Bellmunt 2014]). Renal 
function before and after RNU greatly limits the number of patients with UTUC who are eligible 
for platinum-based neoadjuvant or adjuvant therapy. Therefore, targeted therapies are needed 
(Lane 2010).  
Despite demonstrated survival benefit for neoadjuvant treatment of invasive UBC, many patients 
with invasive UBC are unlikely to receive (neo)adjuvant cisplatin-based chemotherapy, due in 
part to cisplatin ineligibility (Porter 2011). In addition, residual disease following neoadjuvant 
therapy is associated with a poor prognosis (Grossman 2003). Therefore, there remains an unmet 
need for a substantial proportion of patients with invasive UBC who are ineligible to receive 
cisplatin-based adjuvant chemotherapy or who have residual disease following neoadjuvant 
therapy. The proportion of cancer patients who refuse chemotherapy in general varies between 
3% and 19% (Frenkel 2013; Rehman 2013). Whereas the NCCN Guidelines for Bladder Cancer 
(Version 5.2020) recommend treatment with cisplatin-based peri-operative chemotherapy, there 
are no other recommended treatments with Level 1 evidence for neoadjuvant or adjuvant 
treatment for patients who refuse this therapy. Thus, for these patients, treatment options are 
limited to active surveillance or participation in clinical studies. To avoid unnecessarily 
excluding patients who are otherwise eligible but refuse treatment with cisplatin-based 
chemotherapy even after being informed of the limited options, these patients will be allowed to 
enroll in the study. 
The most frequent genetic alterations in UTUC affect the FGFR3 gene and occur in up to 
two-thirds of UTUC (Sfakianos 2015; Moss 2017; Bagrodia 2019). FGFR3 alterations are also 
identified in invasive UBC, although at a far lower rate (<20%) (Knowles 2015).  
Infigratinib is rationally designed to target cancers with susceptible FGFR3 alterations. Phase 2 
infigratinib data derived from Arm 4 of the expansion part of Study CBGJ398X2101 included 
67 subjects with advanced/metastatic urothelial carcinoma with susceptible FGFR3 alterations 
who had either progressed on or were intolerant of platinum-based chemotherapy, or had 
contraindications to platinum-based chemotherapy. Seventeen subjects (25.4%) had responses 


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(1 CR and 16 PR). Forty-three (43) subjects (64.2%) had disease control (CR + PR + SD). 
Sixteen subjects (23.9%) had progressive disease and 8 subjects (11.9%) had an indeterminate 
response. In addition, 1 subject with an indeterminate response by RECIST criteria actually had a 
pathologic CR (Pal 2018). Eight (8) of the 67 subjects had advanced UTUC and 4 of 8 (50%) 
subjects had confirmed responses (1 CR and 3 PR) (Dizman 2019). These Phase 2 data 
demonstrate significant activity in advanced/metastatic urothelial carcinoma with FGFR3 
mutations and support the use infigratinib in the adjuvant setting where subjects with less tumor 
burden are more likely to benefit for a targeted therapy. This Phase 3 study addresses this unmet 
need for an adjuvant therapy for subjects with UTUC who are ineligible or refuse to receive 
cisplatin-based adjuvant chemotherapy or who have residual disease following neoadjuvant 
chemotherapy. Although the population of subjects with susceptible FGFR3-altered invasive 
UBC is much smaller, subjects with invasive UBC who fit the same criteria will be permitted to 
enroll in the trial. 
3.5.2 
Rationale for the Study Design 
This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the 
efficacy of infigratinib in adult subjects with invasive urothelial carcinoma with susceptible 
FGFR3 alterations who are within 120 days following nephroureterectomy, distal ureterectomy, 
or cystectomy and ineligible for or refuse cisplatin-based (neo)adjuvant chemotherapy or who 
have residual disease following neoadjuvant therapy. The sample size can be increased up to a 
total of 328 subjects based on interim analysis result using an adaptive design promising zone 
approach (Mehta 2011). Subjects with invasive urothelial carcinoma includes subjects with 
invasive UTUC and UBC.  
Subjects will be stratified according to lymph node involvement, prior neoadjuvant cisplatin 
chemotherapy, Stage (pT2 vs >pT2), and disease (UTUC vs UBC), and then randomly assigned 
(1:1) to receive oral infigratinib or placebo administered QD for the first 3 weeks (21 days) of 
each 28-day cycle for a maximum of 52 weeks (13 cycles), or local/regional or contralateral 
invasive or metastatic recurrence (whichever occurs first) is confirmed by BICR, or other criteria 
specified in Section 8.1.1 are met, whichever occurs first.  
The use of a placebo control is justified because there is no standard-of-care adjuvant therapy for 
patients with invasive urothelial carcinoma who are ineligible to receive cisplatin-based adjuvant 
chemotherapy or who have residual disease following neoadjuvant therapy (NCCN Guidelines 
Version 3.2018; ESMO Guidelines [Bellmunt 2014]). Placebo comparator was chosen over 
surveillance to reduce unbalanced dropout in the comparator arm and to allow for determination 
of background rates of AEs, including ophthalmic events, in the population under study.  
Subjects who refuse cisplatin-based chemotherapy will be informed of available treatment 
options during a well-balanced risk-benefit discussion between the investigator and the subject; 
this will also be specified in the informed consent form (ICF) to ensure that subjects are fully 
informed and aware that they may be deferring a standard treatment by enrolling in this trial. The 
reason that a subject did not receive cisplatin-based chemotherapy in the perioperative setting 
will be clearly documented in the electronic case report form (eCRF). 


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Stratification before randomization is essential to ensure balance of significant prognostic 
variables between the infigratinib and placebo-treated groups. 
The surveillance plan is consistent with standard-of-care follow-up procedures (Table 2; NCCN 
Guidelines Version 3.2018; ESMO Guidelines [Bellmunt 2014]).  
An interim analysis will be conducted after approximately 35 confirmed DFS events by BICR 
(independent of investigator assessment) have occurred. Based on the results of the interim 
analysis, if a sample size increase is deemed necessary using the promising zone approach, the 
sample size/event goal will be increased by a maximum of 50% (328/105). If sample size is 
increased and event goal is adjusted, then the subsequent analyses will be adjusted accordingly 
time-wise when the adjusted event goal is reached. The details of the sample size adaptation 
method will be prespecified in the adaptation plan.  
3.5.3 
Rationale for Dose and Regimen Selection 
In this study, subjects randomly assigned to the infigratinib group will receive 125 mg QD of 
infigratinib on a 3 weeks on (Days 1-21)/1 week off (Days 22-28) schedule. This dose level and 
regimen is based on experience from the Phase 1 CBGJ398X2101 trial (Section 3.4.1). Subjects 
with mild/moderate renal or hepatic impairment should have their study drug 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. Refer to 
Section 7.2.1 for dosing recommendations and the current Investigator’s Brochure for recent 
clinical safety updates. 
3.6 
Benefit/Risk Assessment of Study Participation 
Subjects enrolled in this study have high unmet medical need, as described in Section 3. Current 
US and European Union (EU) guidelines do not recommend perioperative chemotherapy for 
patients who are not candidates for cisplatin (NCCN Guidelines Version 3, 2018; ESMO 
Guidelines [Bellmunt 2014]; Milowsky 2016). Participation in Study QBGJ398-302 offers the 
possibility of adjuvant treatment with infigratinib for these subjects. Study subjects will be 
randomly assigned (1:1) to either infigratinib or placebo.  
Infigratinib, which targets FGFR3 genetic alterations, has shown preliminary evidence of 
efficacy in subjects with urothelial carcinoma (Section 3.4.3) and has an acceptable safety profile 
in this study population (Section 3.4.2). Reported adverse effects across the infigratinib 
development program are consistent with its mechanism of action (eg, hyperphosphatemia, etc.), 
and can be adequately managed/reversed through dose modification/supportive care, thus 
minimizing risk to study subjects who receive infigratinib. 
Subjects will be closely monitored for safety. Safety assessments that will be performed at 
Screening and visits throughout the treatment period include: adverse events (AEs and SAEs), 
clinical laboratory tests (blood and urine), physical examinations, vital signs, and 
electrocardiograms (ECGs), Eastern Cooperative Oncology Group (ECOG) performance status, 
and ophthalmic assessments. In addition, AEs/SAEs will be collected up to 30 days after the last 
study dose. 


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This study offers subjects an opportunity to receive adjuvant therapy who would otherwise not 
be eligible for such treatment, outside of possibly another investigational treatment. Subjects, 
regardless of the treatment group to which they are randomly assigned, will receive close 
medical monitoring and care throughout their participation in the study. Subjects are required to 
comply with the study visit schedule and procedures in order to receive this potentially 
efficacious/beneficial investigational adjuvant therapy with infigratinib, and also to monitor, 
manage, and mitigate its safety risks. 
4 OBJECTIVES AND ENDPOINTS 
Table 4 presents the study objectives and endpoints defined in Section 10. 


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Table 4: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary:  
 
To determine if treatment with infigratinib improves 
centrally reviewed disease-free survival (DFS) 
compared with placebo treatment in subjects with 
invasive urothelial carcinoma with susceptible 
FGFR3 alterations after nephroureterectomy, distal 
ureterectomy, or cystectomy 
Centrally reviewed DFS, from date of randomization to 
local/regional or contralateral invasive or metastatic 
recurrence, or death due to any cause, whichever occurs 
earlier 
Secondary: 
 
To compare DFS including intraluminal low-risk 
(noninvasive, low-grade, or high-grade) recurrence 
in subjects treated with infigratinib vs placebo 
Investigator-reviewed DFS including intraluminal low-risk 
(noninvasive, low-grade, or high-grade) recurrence, from 
date of randomization to any recurrence or death due to any 
cause, whichever occurs earlier 
 
To compare metastasis-free survival (MFS) of 
subjects treated with infigratinib vs placebo 
Investigator-reviewed MFS, from date of randomization to 
metastatic recurrence or death due to any cause, whichever 
occurs earlier 
 
To compare OS in subjects treated with infigratinib 
vs placebo 
 
OS (from date of randomization to death) 
To compare investigator-reviewed DFS in subjects 
treated with infigratinib vs placebo 
Investigator-reviewed DFS, from date of randomization to 
local/regional or contralateral invasive or metastatic 
recurrence, or death due to any cause, whichever occurs 
earlier 
 
To characterize the safety and tolerability of 
infigratinib when administered as postoperative 
adjuvant monotherapy 
Type, frequency, and severity of adverse events and serious 
adverse events, laboratory abnormalities, and other safety 
findings 
Exploratory: 
 
To compare QOL in subjects treated with infigratinib 
vs placebo 
QOL as measured by the EQ-5D-5L and the EORTC QLQ 
C30 
 
To evaluate the PK of infigratinib 
 
PK parameters (trough and maximum plasma concentration) 
 
To evaluate the overall genomic landscape in 
subjects with invasive urothelial carcinoma  
 
Determine the prevalence of genomic alterations and their 
correlations with available clinicopathologic and 
demographic features in subjects with invasive urothelial 
carcinoma.  
To evaluate biomarkers related to the biology of 
urothelial carcinoma and their potential association 
with efficacy, disease recurrence, and resistance to 
study medication. 
Genomic and proteomic assessments of tumor tissue and 
cell-free DNA samples from baseline to disease recurrence 
and the determination of the prognostic and/or predictive 
value of biomarkers. 
Abbreviations: DFS=disease-free survival; EORTC=European Organization for Research and Treatment of 
Cancer; EQ-5D-5L=EuroQOL 5-dimensions, 5-levels questionnaire; FGFR3=fibroblast growth factor receptor 3; 
MFS=metastasis-free survival; OS=overall survival; PK=pharmacokinetics; QLQ-C30=Quality of Life 
Questionnaire Core 30; QOL=quality of life. 
 


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5 INVESTIGATIONAL PLAN 
5.1 
Overall Study Design 
This is a Phase 3 multicenter, double-blind, randomized, placebo-controlled study to evaluate the 
efficacy of infigratinib in approximately 218 adult subjects with invasive urothelial carcinoma 
with susceptible FGFR3 alterations who are within 120 days following nephroureterectomy, 
distal ureterectomy, or cystectomy and ineligible for or refuse cisplatin-based adjuvant 
chemotherapy or with residual disease following neoadjuvant therapy. The sample size can be 
increased up to a total of 328 subjects based on interim analysis result using an adaptive design 
promising zone approach. Subjects with invasive urothelial carcinoma includes subjects with 
invasive UTUC and UBC.  
Prior neoadjuvant therapy is defined as at least 3 cycles of neoadjuvant cisplatin-based 
chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received 
non-cisplatin-based neoadjuvant treatment should be considered as having received no 
neoadjuvant chemotherapy. 
A study schematic is presented in Figure 1  
Subjects who meet eligibility criteria will be randomly assigned 1:1 to receive oral infigratinib or 
placebo administered QD for the first 3 weeks (21 days) of each 28-day cycle for a maximum of 
52 weeks (13 cycles), or until BICR confirmed local/regional or contralateral invasive or 
metastatic recurrence (whichever occurs first) (see Section 10.1 for definitions of recurrence), or 
until other criteria specified in Section 8.1.1 are met, whichever occurs first.  
Subjects will be evaluated for tumor recurrence radiographically every 3 months for the first 
24 months after the start of treatment, and annually thereafter or until metastatic recurrence by 
BICR or metastatic recurrence by investigator assessment if local/regional or contralateral 
invasive recurrence by BICR has already occurred. Cystoscopy (for subjects with a bladder) and 
urine cytology/cfDNA will be performed at 3 (C4), 6 (C7), 9 (C10), and 12 (C13) months, then 
every 6 months up to 24 months after start of treatment, and then annually until metastatic 
recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred. After metastatic recurrence by 
BICR or metastatic recurrence by investigator assessment if local/regional or contralateral 
invasive recurrence by BICR has already occurred, subjects will be followed up for survival 
status and use of anticancer therapy approximately every 6 months (via phone or office visit) up 
to 1 year, then annually thereafter until 1 year after the final DFS event goal is reached (ie, EOS) 
(Section 9.9). (See Section 9.9 for details on long-term OS follow-up after EOS). Use of 
anticancer therapy will be collected for all subjects, including from the time of study treatment 
discontinuation, regardless of reason for discontinuation. For subjects started on a non-study 
related anticancer therapy after discontinuing from study treatment, imaging assessment of 
disease status should continue until metastatic recurrence by BICR or metastatic recurrence by 
investigator assessment if local/regional or contralateral invasive recurrence by BICR has 
already occurred.  


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Subjects should remain on study treatment until local/regional or contralateral invasive or 
metastatic recurrence is confirmed by BICR. If BICR confirms recurrence (local/regional or 
contralateral invasive or metastatic recurrence, whichever occurs first), the subject must be 
permanently discontinued from study treatment. BICR diagnosis of a local/regional or 
contralateral invasive or metastatic recurrence, independently from and undiagnosed by local 
team, will not be communicated to the clinical site (additional details are provided in 
Section 8.1.1). 
An interim analysis will be conducted after approximately 35 confirmed DFS events by BICR 
(independent of investigator assessment) have occurred, ie, half of the planned number of 70 
confirmed DFS events by BICR (independent of investigator assessment) (see Section 11.2). 
Based on results of the interim analysis, if a sample size increase is deemed necessary using the 
promising zone approach, the sample size/event goal will be increased by a maximum of 50% 
(328/105). If sample size is increased and event goal is adjusted, then the subsequent analyses 
will be adjusted accordingly time-wise when the adjusted event goal is reached. The details of 
the sample size adaptation method will be prespecified in the adaptation plan. 
Subjects will be stratified according to lymph node involvement (yes vs no), prior neoadjuvant 
cisplatin chemotherapy (yes vs no), Stage (pT2 vs >pT2), and disease (UTUC vs UBC). Staging 
is described by Amin (2017).  
Figure 1: 
Study Design 
Population: Adult 
subjects with invasive 
UC (85% UTUC and 
15% UBC) with 
susceptible FGFR3 
genetic alterations 
Stratified by: 
1. Lymph node 
involvement 
(Yes/No) 
2. Prior neoadjuvant 
cisplatin 
chemotherapy 
(Yes/No) a 
3. Stage 
pT2 vs >pT2  
4. Disease 
UTUC vs UBC 
 
 
 
 
 
 
 
 
 
 
 
Infigratinib 
125 mg QD for  
21 days/28-day 
cycle up to 
52 weeks or 
local/regional 
or contralateral 
invasive or 
metastatic 
recurrence b, c  
 
Radiology and 
cystoscopy/cytology 
until metastatic 
recurrence by BICR 
or metastatic 
recurrence by 
investigator 
assessment if 
local/regional or 
contralateral 
invasive recurrence 
by BICR has 
already occurred  
 
Survival  
Follow-
up 
 
Randomize  
1:1 
 
 
 
 
 
 
 
Placebo 
QD for  
21 days/28-day 
cycle up to 
52 weeks or 
local/regional 
or contralateral 
invasive or 
metastatic 
recurrence b, c 
 
 
Abbreviations: BICR=blinded independent central review; FGFR3=fibroblast growth factor receptor 3; QD=once 
daily; UBC=urothelial carcinoma of the bladder; UC=urothelial carcinoma; UTUC=upper tract urothelial carcinoma.  


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a 
Prior neoadjuvant cisplatin chemotherapy is defined as at least 3 cycles of neoadjuvant cisplatin-based 
chemotherapy with a planned cisplatin dose of 70 mg/m2/cycle. Subjects who received less than this or 
non-cisplatin-based neoadjuvant treatment will be considered as having received no neoadjuvant chemotherapy. 
b  Subjects with mild/moderate renal or hepatic impairment should have their dose adjusted; see Section 7.2.1 for 
dosing recommendations. 
c  
Refer to Section 8.1.1 for guidance on treatment when recurrence is not confirmed by BICR. 
 
5.2 
Number of Subjects 
Approximately 218 subjects with histologically confirmed invasive urothelial carcinoma with 
susceptible FGFR3 alterations within 120 days following nephroureterectomy, distal 
ureterectomy, or cystectomy and who are ineligible for or refuse cisplatin-based adjuvant 
chemotherapy or with residual disease following neoadjuvant therapy are planned for study 
participation. The sample size can be increased up to a total of 328 subjects based on interim 
analysis result using an adaptive design promising zone approach. 
5.3 
Time on Study and End of Study Definition 
End of study is defined as 1 year after the final number of confirmed DFS events by BICR is 
reached (planned number of confirmed DFS events is 70). The expected duration of the study is 
approximately 5 years.  
After the EOS (1 year after the DFS primary analysis), subjects will continue to be followed for 
OS (under a separate protocol) for approximately 14 years, or all of the subjects die or drop from 
this follow up, whichever is earlier, referred to as long-term OS follow-up (Section 9.9).  
The duration of time spent on study treatment will vary for individual subjects. Subjects will 
receive study treatment for a maximum of 52 weeks (13 cycles), or until BICR-confirmed 
local/regional or contralateral invasive or metastatic recurrence (whichever occurs first), or until 
other criteria specified in Section 8.1.1 are met, whichever occurs first. Subjects who complete 
52 weeks of treatment and subjects who discontinue study treatment for any reason (except 
withdrawal of consent) will remain in the study and will be followed up until metastatic 
recurrence, including after initiation of a non-study anticancer therapy, as described in 
Section 9.8. Use of anticancer therapy will be collected for all subjects, including from the time 
of study treatment discontinuation, regardless of reason for discontinuation. All subjects will be 
followed up for survival status and use of anticancer therapy for 1 year after the final number of 
DFS events are reached (ie, EOS) (see Section 9.9). After the final DFS goal is reached, subjects 
will continue to be followed for long-term OS follow up for approximately 14 years as described 
above and in Section 9.9.  
6 STUDY POPULATION 
6.1 
Inclusion Criteria 
To be eligible for the study, a subject must meet all of the following criteria: 
1. Are ≥18 years of age (≥20 years of age in Taiwan) of either sex. 


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2. Have signed informed consent. 
3. Are randomized within 120 days following nephroureterectomy, distal ureterectomy or 
cystectomy. Note: at the time of definitive surgery, lymph node dissection (LND) should be 
performed in cases of suspected lymph node invasion based on preoperative imaging or 
intraoperative findings. In other cases, LND is to be performed in accordance with surgeon 
preferences/local standard practices. Additional details on recommended standards for LND 
are provided in Appendix 4 (Section 17.4). 
4. Have histologically or cytologically confirmed, invasive urothelial carcinoma with 
susceptible FGFR3 alterations. Variant histology is allowed provided urothelial carcinoma is 
predominant (>50%). Neuroendocrine (including small and large cell), sarcomatoid, and 
plasmacytoid variants are excluded (any component).  
a. Regarding samples and documentation of FGFR3 alterations (see also Section 10.3): 
i. 
FGFR3 mutation is confirmed if: FGFR3 gene is mutated in Exon 7 (R248C, 
S249C), Exon 10 (G370C, A391E, Y373C), or Exon 15 (K650M/T, K650E/Q)  
OR 
ii. 
FGFR3 gene fusion or FGFR3 rearrangement is confirmed based on the following 
genomic criteria: if: 
(1)  
Any fusion/rearrangement with a literature-derived known partner gene 
regardless of strand or frame.  
(2) 
Fusion/rearrangements in the same strand that are in frame with a novel 
partner gene. 
(3) 
Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot 
region and the other breakpoint in an intergenic region or another gene. This 
rule excludes 3′ duplications comprising only exon 18.  
iii. 
The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 
isoform 1 (NP_000133.1) that is the NCBI Refseq ID used to report genetic 
alterations in FGFR3 by the FoundationOne® CDx test (F1CDx, Foundation 
Medicine, USA). 
iv. 
Written documentation of central laboratory determination by F1CDx of FGFR3 
alterations is required for study eligibility.  
v. 
For subjects who require molecular prescreening to confirm the presence of the 
FGFR3 alteration to meet the inclusion criteria, a tumor sample with a pathology 
report must be sent to Foundation Medicine USA for F1CDx testing. (See 
Appendix 5 [Section 17.5] for instructions for optimal tumor specimens). 
(1) 
The tumor sample to be used should be from the definitive surgical 
resection (cystectomy, nephroureterectomy, or distal ureterectomy).  


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(2) 
An archival biopsy of confirmed invasive urothelial carcinoma (≥pT2) can 
be used if (1) tissue from definitive surgery cannot be submitted, (2) the 
biopsy sample is not older than 4 months prior to surgery date and (3) the 
subject did not receive any type of systemic anticancer treatment since the 
biopsy was obtained. If more than one biopsy is available, the most recent 
one is to be sent. 
b. If status post neoadjuvant chemotherapy, pathologic stage at surgical resection must be 
Stage ≥ ypT2 and/or yN+. Prior neoadjuvant therapy is defined as at least 3 cycles of 
neoadjuvant cisplatin-based chemotherapy with a planned cisplatin dose of 
70 mg/m2/cycle. Subjects who received less than this or non-cisplatin-based neoadjuvant 
treatment are not excluded. If enrolled, they will be stratified as having received no 
neoadjuvant chemotherapy. 
c. If not status post neoadjuvant chemotherapy, is ineligible to receive cisplatin-based 
adjuvant chemotherapy based on Galsky (2011):  
i. 
Creatinine clearance ≤60 mL/minute, or 
ii. 
Common Terminology Criteria for Adverse Events (CTCAE version 5.0) 
Grade ≥2 hearing loss, or 
iii. 
CTCAE Grade ≥2 neuropathy. 
d. Subjects who refuse cisplatin-based chemotherapy or who are ineligible to receive 
cisplatin-based chemotherapy based on Galsky (2011), must also meet the following 
criteria: 
i. 
UTUC should be Stage ≥pT2 pN0-2 (post-lymphadenectomy or no 
lymphadenectomy [pNx]) , or pN+,  M0.  
ii. 
UBC should be Stage ≥pT3 or pN+, M0. 
e. Must have a centrally reviewed negative postoperative computed tomography (CT) 
(defined as lymph nodes with short axis <1.0 cm and without growth and no distant 
metastases according to Response Evaluation Criteria in Solid Tumors [RECIST] v1.1) or 
negative biopsy within 28 days before randomization to confirm absence of disease at 
baseline. 
5. If have had AEs associated with prior surgery or neoadjuvant chemotherapy, they have 
stabilized or resolved to Grade ≤2 before randomization. 
6. Have Eastern Cooperative Oncology Group (ECOG) performance status of ≤2. 
7. If a woman of childbearing potential, 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 
≥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 ≥12 


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months, and there is no other cause of amenorrhea (eg, hormonal therapy, prior 
chemotherapy). 
Women of childbearing potential and males whose sexual partners are women of 
childbearing potential must agree to use barrier contraception and a second form of 
contraception (Clinical Trials Facilitation Group 2020) while receiving study drug and for 
1 month following their last dose of study drug. 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, 
postovulation methods) and withdrawal are not acceptable methods of contraception. (Highly 
effective contraception methods are specified in Appendix 3 [Section 17.3].) 
Sexually active males must use a condom during intercourse while taking study drug and for 
1 month after the last dose of study drug and should not father a child during this period. A 
condom is required to be used also by vasectomized men as well as during intercourse with a 
male partner to prevent delivery of the study drug via seminal fluid. 
Study subjects must agree to refrain from donating sperm and eggs during the study and for 
1 month following their last dose of study drug. 
8. Are willing and able to comply with study visits and study procedures. 
6.2 
Exclusion Criteria 
To be eligible for the study, a subject must not meet any of the following criteria: 
1. Presence of positive invasive surgical margins following nephroureterectomy, distal 
ureterectomy, or cystectomy. In subjects not eligible for further surgery, radiotherapy, or 
other efficacious treatment, microscopic positive noninvasive margins (eg, carcinoma in situ) 
without gross residual disease are allowed.  
2. Have received Bacillus Calmette-Guerin (BCG) or other intravesical therapy for nonmuscle 
invasive bladder cancer (NMIBC) within the previous 30 days.  
3. 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).  
Prior anticancer or other therapies are restricted as follows: 
a. Prior adjuvant treatment for urothelial cancer is not allowed. 
b. Prior neoadjuvant therapy (eg, chemotherapy, immunotherapy, or investigational) is 
allowed if inclusion criterion #4 is met.  
Prior neoadjuvant chemotherapy must have been completed within a period of time that 
is greater than the cycle length used for that treatment before first dose of study drug.  


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c. Prior biologic, immunotherapy, or investigational therapy should have been completed 
within a period that is ≥5 half-lives or 30 days, whichever is shorter, before the first dose 
of study drug. 
4. Are planning to receive other systemic therapies intended to treat invasive urothelial 
carcinoma while on this study. 
5. Have previously or currently is receiving treatment with a mitogen-activated protein kinase 
(MEK) or selective FGFR inhibitor. 
6. Have a history of primary malignancy within the past 3 years other than (1) invasive UBC or 
UTUC (ie, disease under study), (2) noninvasive urothelial carcinoma, (3) any adequately 
treated in situ carcinoma or non-melanoma carcinoma of the skin, (4) any other curatively 
treated malignancy that is not expected to require treatment for recurrence during 
participation in the study, or (5) an untreated cancer on active surveillance that may not affect 
the subject’s survival status for ≥3 years based on clinician assessment/statement and with 
medical monitor approval. For any other cancers that do not meet the criteria above, and for 
which the natural history or treatment do not have the potential to interfere with the safety or 
the efficacy assessments of the study, written approval is required by the medical monitor.  
7. Have current evidence of corneal keratopathy or retinal disorder including, but not limited to, 
bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis, macular 
degeneration, 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, vasculature, myocardium, and lung with the 
exception of calcified lymph nodes, minor pulmonary parenchymal calcifications, small renal 
cyst or stone calcifications, and asymptomatic coronary calcification. 
9. Have impaired gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral infigratinib (eg, active 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), 
unless well controlled. 
11. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, 
pomelos, or Seville oranges or products containing juice of these fruits within 7 days before 
the first dose of study drug; have taken any Chinese herbal medicine or Chinese patent 
medicine treatments with anticancer activity within 14 days of the first dose of study drug. 
12. Have insufficient bone marrow function: 
a. Absolute neutrophil count (ANC) <1,000/mm3 (1.0 × 109/L). 
b. Platelets <75,000/mm3 (<75 × 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. 
13. Have insufficient hepatic and renal function: 
a. Total bilirubin >1.5 × upper limit of normal (ULN) of the testing laboratory (for subjects 
with documented Gilbert syndrome, direct bilirubin must be ≤1.5 × ULN and enrollment 
requires approval by the medical monitor). 
b. AST/SGOT and ALT/SGPT >2.5 × ULN of the testing laboratory. 
c. Serum creatinine >1.5 × ULN or a calculated (using the Cockcroft-Gault [C-G] formula 
[Cockcroft 1976]) or measured creatinine clearance of <30 mL/min. 
14. Have amylase or lipase >2.0 × ULN. 
15. Have abnormal calcium or phosphorus: 
a. Inorganic phosphorus higher than 1.02 × ULN of the testing laboratory. 
b. Total serum calcium (can be corrected) higher than 1.02 × ULN of the testing laboratory. 
16. Have clinically significant cardiac disease including any of the following: 
a. New York Heart Association (NYHA) Class ≥2B; subjects with known history or current 
symptoms of cardiac disease, or history of treatment with cardiotoxic agents, should have 
a clinical risk assessment of cardiac function using the NYHA classification. 
b. Uncontrolled hypertension (refer to European Society of Cardiology and European 
Society of Hypertension guidelines [Williams 2018]). 
c. Presence of CTCAE v5.0 Grade ≥2 ventricular arrhythmias, atrial fibrillation, 
bradycardia, or conduction abnormality. 
d. Unstable angina pectoris or acute myocardial infarction ≤3 months before the first dose 
of study drug. 
e. Average QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the 
first ECG, a total of 3 ECGs separated by ≥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. 
f. History of congenital long QT syndrome. 
17. Have had a recent (≤3 months before the first dose of study drug) transient ischemic attack or 
stroke. 
18. If female, are 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. 
19. Have a known allergy/hypersensitivity reaction to any components of the study drug. 
20. Have any other concurrent disease or condition that, in the view of the investigator, would 
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7 TREATMENTS 
7.1 
Treatments Administered 
Subjects will receive hard gelatin capsules of infigratinib (or matching placebo) for oral use at a 
dose of 125 mg QD (administered as one 100-mg capsule and one 25-mg capsule) QD using a 
3 weeks on (Days 1-21)/1 week off (Days 22-28) schedule for each 28-day treatment cycle. 
Treatment with study drug will continue for a maximum of 52 weeks (13 cycles; Cycle 1 [C1] 
through Cycle 13 [C13]), or until local/regional or contralateral invasive or metastatic recurrence 
(whichever occurs first) is confirmed by BICR, or until other criteria specified in Section 8.1.1 
are met, whichever occurs first. Subjects with mild/moderate renal or hepatic impairment should 
have their dose adjusted; see Section 7.2.1 for dosing recommendations. Study drug may be 
dispensed at study visits on Day 1 of C1, C2, C4, C7, C10, and C13 and/or monthly at study 
visits per local standard practice. 
7.2 
Information on Dosing with Study Drug 
7.2.1 
Subject Instructions for 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 weeks 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 should be instructed to take the daily dose of study drug in the morning, at 
approximately the same time each day (24±4-hour interval). Subjects will take their first dose of 
study drug at the study center on Cycle 1 Day 1 (C1D1). On the days of PK sampling, subjects 
should not take their study drug dose at home; subjects should bring their study drug with them 
to the study center where dosing of study drug will be supervised and administration time 
recorded. Administration may fall outside of the ±4-hour interval on the days of PK sampling. 
On PK sampling days after C1D1, the time of the last study drug dose (ie, time of study drug 
administration on the previous day) before the predose PK sample will be recorded in the eCRF. 
Study drug 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 study drug 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 study drug, 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 


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4 hours postdosing, this event is to be noted on the Dose Administration page of the 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 (PD) effect and should be replaced with H2-antagonists or antacids. Study 
drug 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 study drug doses by 2 hours. 
Subjects must avoid the consumption of grapefruits, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges or juice within 7 days before the first dose of 
study drug and throughout the treatment period. This is due to a potential CYP3A4 interaction 
with study medication. Non-Seville oranges and their juice are allowed. 
If a subject is not taking study medication (eg, study treatment is on hold for an AE), then no PK 
sample will be collected. PK sampling will resume once the subject is back on study medication. 
If study drug is on hold for ≤14 days, and the criteria for restarting treatment are met, study 
treatment can be restarted on any day of the cycle between D1 to D21. Study drug should not be 
restarted on D22 through D28 of a cycle; if criteria for treatment restart fall on a day between 
D22 and D28, treatment restart must wait until D1 of the next cycle. 
7.2.2 
Description of Test Article 
Study drug (test article) will be supplied as hard gelatin capsules for oral use at dose strengths of 
25 and 100 mg or matching placebo. Excipients will include microcrystalline cellulose, lactose 
monohydrate, hypromellose 2910, crospovidone, colloidal silicon dioxide, magnesium stearate, 
and hard gelatin capsule. Infigratinib and the matching placebo will be manufactured under Good 
Manufacturing Practice (GMP) for investigational use. 
The study center 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 study center personnel only. 
7.2.3 
Packaging and Labeling 
Study drug capsules will be packaged in high-density polyethylene (HDPE) bottles with intact 
induction seal child-resistant closures. Medication 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 
Study drug 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 


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designated study center personnel have access. Upon receipt, study drug should 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 
study drug in a drug accountability log. Subjects will be asked to return all used and unused 
bottles of study drug 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 study drug, packaging, drug labels, and a copy of 
the completed drug accountability log to the field monitor. 
At study close-out, study drug 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 Study Drug 
Subject management and treatment decisions 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 the study treatment. 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 6 (AEs considered 
possibly related to study drug) and Table 7 (skin toxicity). In addition, per investigator’s medical 
judgment, dose modification (hold) can be applied for subject’s safety (eg, perioperatively); the 
medical monitor must be consulted for dose modifications that are not related to tolerability 
issues. Dosage changes must be recorded on the Dose Administration page of the eCRF. 
The following guidelines should be applied. 
• Each subject may be allowed up to 3 study drug dose reductions according to 
protocol-specified dose modifications for AEs. Prospective sponsor medical monitor 
approval is required for the third dose reduction (Table 5). Note: the minimum daily dose 
allowed in the study is 50 mg. 
• Treatment-related toxicity will be managed as detailed in Table 6, and additional guidelines 
in the protocol, or following institutional guidelines. Management of related toxicity, 
including during a period of study treatment hold, will continue until the toxicity is stable at 
Grade ≤1, returns to baseline, or in accordance with the assessment of the treating physician. 
• If treatment is resumed at the same dose of study drug, and the same toxicity recurs with the 
same or worse severity regardless of duration, dose must be reduced to the next lower dose 


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level. If treatment is resumed at the lower dose of study drug, and the same toxicity recurs 
with the same or worse severity, the subject should have a second dose reduction.  
• Subjects who permanently discontinue the study drug for a study-related AE or an abnormal 
laboratory value must be followed up as described in Section 7.2.5.2. 
• Study drug must be permanently discontinued for a delay of >14 days due to a treatment-
related toxicity and may only be restarted with written permission of the medical monitor if 
(1) the delay is not due to an AE that requires permanent study drug discontinuation as 
provided in Table 6, and (2) the subject has not met other criteria requiring study drug 
discontinuation as provided in Section 8, and (3) 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 study drug discontinuation (see Table 6), with prospective 
sponsor medical monitor approval, the delay may be extended to a maximum of 28 days 
before permanent treatment discontinuation is required.  
• If study drug is on hold for ≤14 days, and the criteria for restarting treatment are met, study 
treatment can be restarted on any day from D1 to D21 of a cycle. Study drug should not be 
restarted on D22 to D28 of a cycle; in such cases, treatment restart must wait until D1 of the 
next cycle. 
Table 5: 
Dose Reduction Scheme  
Dose Reduction  
Starting Dose Level 0 
Dose Level -1 
Dose Level -2 
Dose Level -3 a 
Study drug 
125 mg  
or matching placebo 
100 mg  
or matching placebo 
75 mg  
or matching placebo 
50 mg  
or matching placebo 
a  Dose reduction to 50 mg requires prospective sponsor medical monitor approval. Details are provided in the text 
above.  
NOTE: The minimum daily dose of study drug allowed in the study is 50 mg. 
 


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Table 6: 
Criteria for Interruption and Re-initiation of Study Drug for Adverse Events Considered to be Possibly Related 
to Study Drug 
Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
CARDIAC DISORDERS 
Cardiac – Prolonged QTcF Interval 
Grade 2:  
Average QTc 481 - 500 msec  
Maintain dose level of study drug. 
Two additional ECGs separated by ≥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 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 study drug. 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, hypomagnesemia and 
decreased blood oxygenation. 
• 
Subjects should receive appropriate electrolyte replacement and should not receive further 
study drug until electrolytes are documented to be within normal limits.  
 
Once the QTcF prolongation has resolved to <481 msec, subjects may be re-treated at 1 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 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. 


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Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
• 
Subjects who experience recurrent QTcF ≥501 msec after 1 dose reduction will be 
discontinued from study treatment. 
Grade 4: 
Torsade de pointes or polymorphic ventricular tachycardia 
or signs/symptoms of serious arrhythmia 
Discontinue study drug.  
INVESTIGATIONS-HEMATOLOGY 
Neutrophil Count Decreased (Neutropenia) 
Grade 3 
(ANC <1000 - 500/mm3 [<1.0 - 0.5 × 109/L]) 
Hold dose of study drug until resolved to CTCAE Grade ≤1 or baseline, then  
• 
If resolved within ≤7 days, maintain dose level of study drug.  
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of study drug. 
• 
If not resolved within ≤14 days, discontinue study drug. 
Grade 4  
(ANC <500/mm3 [<0.5 × 109/L]) 
Hold dose of study drug until resolved to CTCAE Grade ≤1, then ↓ 1 dose level of study drug. 
If not resolved within ≤14 days, discontinue study drug. 
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 study drug until resolved to CTCAE Grade ≤ 1, then  
• 
If resolved within ≤14 days, ↓ 1 dose level of study drug. 
• 
If not resolved within 14 days, discontinue study drug 
Grade 4 
Discontinue study drug. 
Anemia 
Grade 3  
(hemoglobin <8.0 g/dL [<4.9 mmol/L; <80 g/L]; transfusion 
indicated) 
Hold dose of study drug until resolved or corrected to CTCAE Grade ≤1 or baseline, then maintain 
dose level. 
Grade 4 
Hold dose of study drug until resolved or corrected to CTCAE Grade ≤1 or baseline, then ↓ 1dose 
level. 
Platelet Count Decreased (Thrombocytopenia) 
Grade 3  
(platelet <50,000 - 25,000/mm3 [<50 - 25 × 109/L])  
Hold dose of study drug until resolved to CTCAE Grade ≤1 or baseline, then  
• 
If resolved within ≤7 days, maintain dose level of study drug. 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of study drug. 
• 
If not resolved within ≤14 days, discontinue study drug. 
 


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Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Grade 4  
(platelet <25,000/mm3 [<25 × 109/L]) 
Hold dose of study drug until resolved to CTCAE Grade ≤1 or baseline, then ↓ 1 dose level. 
• 
If not resolved within ≤14 days, discontinue study drug. 
INVESTIGATIONS – RENAL 
Serum Creatinine  
Creatinine clearance <30 mL/min (calculated or measured) 
Hold dose of study drug 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 study drug until resolved to Grade ≤1 or baseline, then: 
• 
If resolved within ≤7 days, maintain dose level of study drug. 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level of study drug 
• 
If not resolved within ≤14 days, discontinue study drug. 
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 >3.0 × baseline) 
Discontinue study drug. 
INVESTIGATIONS – HEPATIC 
Blood Bilirubin Increased (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 study drug until resolved to CTCAE Grade ≤1, then: 
• 
If resolved within ≤7 days, maintain dose level of study drug. 
• 
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 study drug. 
Note: If CTCAE Grade 3 or 4 hyperbilirubinemia is due to hemolysis, then ↓ 1 dose level of study 
drug and continue treatment at the discretion of the investigator. 
AST or ALT Increased 
 
Grade 3  
(>5.0 – 20.0 × ULN if baseline was normal;  
>5.0 – 20.0 × baseline if baseline was abnormal) 
Hold dose of study drug until resolved to CTCAE Grade ≤1 or baseline, then: 
• 
If resolved within ≤7 days, ↓ 1 dose level of study drug. 
• 
If not resolved within ≤7 days, discontinue study drug. 
Grade 4  
(>20.0 × ULN if baseline was normal; 
>20.0 × baseline if baseline was abnormal) 
Discontinue study drug. 


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Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
AST or ALT and Bilirubin Increased 
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 study drug until both transaminases and bilirubin resolved to CTCAE Grade ≤1 or 
baseline, then: 
• 
If resolved within ≤7 days, ↓ 1 dose level of study drug.  
• 
If not resolved within ≤7 days, discontinue study drug. 
AST or ALT >5.0 × ULN and total bilirubin >2.0 × ULN 
Discontinue study drug 
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 study drug until resolved to CTCAE Grade ≤2, then:  
• 
↓ 1 dose level of study drug.  
• 
If not resolved within ≤14 days, discontinue study drug. 
For recurrent Grade 3 asymptomatic lipase or amylase elevation despite dose reduction, study 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, study 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 study drug; 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 study drug until resolved to >2.0 mg/dL (>0.6 mmol/L), then: 
• 
↓ 1 dose level of study drug. 
• 
If not resolved within ≤14 days, discontinue study drug.  
Serum phosphate <1.0 mg/dL (<0.3 mmol/L)  
(life threatening consequences) 
Discontinue study drug. 
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 study drug and optimize phosphate-lowering therapy as clinically indicated. 


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Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Serum phosphate >7.5 mg/dL for >7 days despite maximal 
phosphate-lowering therapy  
 
• 
Hold dose of study drug until resolved to serum phosphate ≤5.5 mg/dL. 
• 
Restart study drug 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 
• 
↓ 1 dose level of study drug 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 study drug with maximal phosphate binder dosing.  
It is recommended that phosphate binder dosing continues during study drug 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 of study drug each cycle (Days 
22-28) unless serum phosphate is not normalized and during study drug dose interruptions for 
non-hyperphosphatemia AEs. 
Serum phosphate with life-threatening consequences;  
urgent intervention indicated (eg, dialysis) 
Discontinue study drug. 
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 study drug until resolved to Grade 1 or baseline, then: 
• 
If resolved within ≤7 days after suspending study drug, maintain dose level. 
• 
If resolved between >7 days and 14 days, ↓ 1 dose level. 
• 
If not resolved within ≤14 days, discontinue study drug. 
Serum calcium Grade ≥3 
Corrected serum calcium (>12.5 - 13.5 mg/dL  
[>3.1 - 3.4 mmol/L]) 
Ionized calcium (>1.6 - 1.8 mmol/L), hospitalization 
indicated 
Discontinue study drug. 
GASTROINTESTINAL SYSTEM DISORDERS 
Pancreatitis 
Grade 2 (asymptomatic enzyme elevation with radiologic 
findings only) 
 Hold dose of study drug until resolved to CTCAE Grade <2, then: 
• 
↓ 1 dose level of study drug.  
• 
If not resolved within ≤14 days, discontinue study drug. 
For recurrent Grade 2 asymptomatic radiologic pancreatitis despite dose reduction, discontinue 
study drug. 
Grade 3 or Grade 4 
Discontinue study drug. 
Diarrhea 
General Comment:  
Antidiarrheal medication is recommended at the first sign of abdominal cramping, loose stools, or 
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Worst Toxicity CTCAEa (version 5.0) Grade (Unless 
Otherwise Specified) 
Dose Modifications any Time During a Cycle of Therapy 
Grade 1 (increase of <4 stools/day over baseline; mild 
increase in ostomy output compared to baseline) 
Maintain dose level of study drug, initiate antidiarrheal 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 study drug until resolved to CTCAE Grade ≤1. 
• 
Optimize antidiarrheal treatment.  
• 
For reoccurrence of diarrhea CTCAE Grade 2, hold dose of study drug until resolved to 
CTCAE Grade ≤1, then ↓ study drug 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 study drug until resolved to CTCAE Grade ≤1. 
• 
Optimize antidiarrheal treatment. 
• 
↓ study drug by 1 dose level. 
• 
For reoccurrence of diarrhea CTCAE Grade 3, despite optimal antidiarrheal treatment, 
discontinue study drug. 
Grade 4 
Discontinue study drug. 
Vomiting 
 
Grade 2 (outpatient IV hydration; medical intervention 
indicated) not controlled by optimal anti-emetic therapy 
Hold dose of study drug until Grade ≤1, then ↓ 1 dose level. 
• 
If not resolved within ≤14 days, discontinue study drug. 
Grade 3 (tube feeding, TPN, or hospitalization indicated) not 
controlled by optimal anti-emetic therapy or Grade 4 
Discontinue study drug.  
EYE DISORDERS (CONFIRMED BY OPHTHALMOLOGIC EXAMINATION) 
Retinal Disorders 
Grade 2 or 3 central serous retinopathy and central serous 
retinopathy-like events 
Hold dose of study drug until resolved to Grade ≤1 and continue ophthalmic evaluations.  
• 
If resolved within ≤14 days, ↓ study drug by 1 dose level. 
• 
If not resolved within ≤14 days, discontinue study drug. 
Grade ≥1 retinal vein occlusion,  
Grade 4 central serous retinopathy and central serous 
retinopathy-like events  
Discontinue study drug. 
Other Ocular/Visual Toxicity 
Grade ≥3 
Hold dose of study drug until resolution to Grade ≤1. 
• 
If resolution within ≤14 days, ↓ 1 dose level. 
• 
If not resolved within ≤14 days, discontinue study drug. 
OTHER CLINICALLY SIGNIFICANT AEs 
Grade 3 
Hold dose of study drug until resolved to CTCAE Grade ≤1, then ↓ 1 dose level of study drug. 
• 
If not resolved within ≤14 days, discontinue study drug. 
Grade 4 
Discontinue study drug. 
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; IV=intravenous; 


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LLN=lower limit of normal; 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 the 
sponsor medical monitor. 


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7.2.5.2 
Follow-up for Toxicities 
Subjects whose study drug 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, dermatologist, should be 
consulted as deemed necessary. Further guidelines and dose modifications for the management 
of specific study drug-induced toxicities (hyperphosphatemia, diarrhea) are provided in Table 6. 
All subjects must be followed up for AEs and SAEs for 30 days following last dose of study 
drug. 
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 study drug-induced AEs (eg, hyperphosphatemia, renal toxicities) are provided 
in Table 6 and Section 7.5. For more information, refer to the nonclinical toxicity and/or clinical 
data presented in the infigratinib Investigator’s Brochure. 
Treatment of AEs or lab abnormalities should follow the protocol where specified, otherwise 
local institutional guidelines with regard to safety management should apply. 
7.3 
Randomization and Blinding 
Subjects will be randomly assigned in a 1:1 ratio to 1 of the 2 treatment arms. Subjects must be 
randomly assigned to study treatment within 120 days of completing surgery and start treatment 
within 1 week of randomization. (Note: only under certain unforeseen circumstances that are not 
caused by noncompliance or inappropriate planning [eg, adverse weather], randomization may 
occur after day 120 from definitive surgery but window for randomization and dosing should be 
127 days total (120 days +7 days). Randomization will be stratified by lymph node involvement 
(yes vs no), prior neoadjuvant cisplatin chemotherapy (yes vs no), Stage (pT2 vs >pT2), and 
disease type (UTUC vs UBC). The number of subjects refusing cisplatin-based perioperative 
therapy will be capped at approximately 10% of the total population (approximately 22 subjects), 
no more than 15% of the population will be enrolled with UBC, and ≤25% of UTUC subjects 
will have Stage pT2 UTUC (limit will be based on stratification). Documented medical monitor 
approval is required before randomization. Interactive Response Technology (IRT) will be used 
to assign subjects to treatment based on the 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 a double-blind study. Subjects, Investigators, study monitors, and the study team will be 
blinded to the treatment administered, except for a designated QED Clinical Supply 
representative. Staff associated with tracking, assaying, and analyzing PK samples may have 
access to the PK-related information only, and the contract research organization (CRO) 
analyzing PK samples for concentration will be unblinded to study treatment.  


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Treatment assignment may be unblinded by the sponsor/designee to satisfy expedited safety 
reporting requirements of regulatory authorities. If an SAE report meets expedited safety 
reporting criteria, the sponsor’s safety representative or designee will unblind the study treatment 
for the respective patient for regulatory reporting purposes.  
Emergency unblinding: Treatment unblinding by the investigator should be conducted in an 
emergency only when knowledge of the treatment assignment will affect the management of a 
subject who experiences a treatment-emergent AE. The investigator will have the ability to 
perform emergency unblinding. The knowledge of the actual treatment the unblinded subject 
received should be concealed from any site-level (including any party involved in subject 
assessment, for example, ophthalmologist) or sponsor (and their representative) personnel 
involved in managing subject’s data, in order to protect ongoing data acquisition and 
interpretation.  
The sponsor recognizes, however, that unblinding for nonemergency situations will be of 
increasing concern to many sites as additional treatment options become available for subjects 
who have recurrence of their urothelial carcinoma by BICR. For such subjects, single-subject 
unblinding in nonemergency situations may be performed by the study team only with medical 
monitor approval for the purpose of facilitating subsequent treatment decisions, including 
assessment of eligibility for other clinical trials.  
The process of unblinding in these circumstances will require written request submitted to 
medical monitor (sponsor or representative) with reason for the unblinding request. The 
nonemergency unbinding may occur only with written approval by the medical monitor.  
Including for these cases of nonemergency unblinding, the knowledge of the actual treatment the 
unblinded subject received should be concealed from any site-level (including any party involved 
in subject assessment, for example, ophthalmologist) or sponsor (and their representative) 
personnel who continue to manage patient’s data in order to protect ongoing data acquisition and 
interpretation 
The investigator must notify the medical monitor or designee after determining it is necessary to 
unblind a subject’s treatment assignment. The investigator must also indicate in source 
documents and in the eCRF that the blind was broken and provide the date and reason for 
breaking the blind. Any AE or SAE associated with breaking the blind must be recorded and 
reported as specified in this protocol. 
In order to limit the number of individuals with access to the unblinded information, 
Investigators or dedicated study personnel should handle this information with highest 
confidentiality. Any documentation regarding the treatment assignment should be kept in an 
envelope, securely stored, and not attached to the subject’s files in order to allow for 
unbiased/blinded continuation of subject’s evaluation, and the information should not be 
communicated or distributed to any personnel other than those who need to know for subject 
management. 
Unblinding of study treatment should not result in withdrawal of the subject from the 
study, and these subjects will continue to be followed per the protocol.  


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The investigator can unblind treatment via the IRT system. The investigator should document all 
occurrences of unblinding in the study file and the reason for unblinding should be documented.  
If the investigator would like to discuss the subject’s treatment assignment (once known) with 
the sponsor, the site may liaise with the unblinded Global Study Manager (GSM). The 
investigator is to communicate directly with the unblinded GSM via email at: 
proof302unblinded@prahs.com. The unblinded GSM will then convey any discussions to the 
medical monitor in a “blinded” fashion for any case that requires medical input. If there is an 
urgent question pertaining to subject management, the site should call the medical monitor but 
not disclose treatment assignment or unblinding status unless specifically requested. 
7.4 
Compliance 
The investigator or responsible site personnel should instruct the subject to take study drug 
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 dosing non-
compliance should be conducted and documented, as needed. 
Subjects will be instructed to return all used and unused bottles of study drug to the study center 
at the end of each cycle and at the end of the study or at the time of discontinuation of study 
drug. Compliance will be assessed by the investigator and/or study personnel, and compliance 
information will be captured in the Drug Accountability Form. This information must be 
captured in the source document at each subject visit. 
7.5 
Supportive Care Guidelines 
Any supportive care for disease related symptoms, including any medication or therapy for a 
concurrent medical condition are permitted, except if specifically prohibited below. 
7.5.1 
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 according to the label of these agents or as dictated by local 
practice or guidelines established by the American Society of Clinical Oncology (ASCO), 
European Society of Medical Oncology (ESMO), or other appropriate regional societies. 
7.5.2 
Management of Hyperphosphatemia 
Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of the 
FGFR pathway. While on study drug, 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. Phosphorus will be checked at screening and starting on Cycle 1 Day 4. 
Subjects who experienced hyperphosphatemia should take a phosphate binder such as sevelamer, 
sacroferric oxyhydroxide, lanthanum carbonate, ferric citrate, etc. within 30 minutes of a meal on 
the day while taking study drug. Once the subject has had hyperphosphatemia, the subject should 


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remain on a low phosphate diet, if possible, and take phosphate binder on the days study drug is 
taken even, if the serum phosphorus is normalized. Unless otherwise specified by the local 
prescribing information or institutional practice, the following regimen should be used to manage 
hyperphosphatemia: 
• For serum phosphorus >5.5 – ≤7.5 mg/dL 
○ Start sevelamer 800 mg 3-times per day with meals  
○ Increase the dose of sevelamer up to 1200 mg every 8 hours 
• For serum phosphorus >7.5 mg/dL 
○ Increase the dose of sevelamer up to 1600 mg (2 tablets per meal) every 8 hours 
○ Consider adding acetazolamide, 2 to 3 tablets (250 mg) per day 
During the study drug cycle, subjects do not need to be on a low phosphate diet or take a 
phosphate binder during their 1 week off study treatment period (Days 22-28 of cycle) unless 
serum phosphate is not normalized. Other dose modifications for hyperphosphatemia are 
provided in Table 6, but should be modified as per country or institutional practice. 
7.5.3 
Management of Diarrhea 
Study drug dose modification recommendations are provided in Table 6. 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/antimotility 
agents is recommended at the first sign of diarrhea as initial management. Some subjects may 
require concomitant treatment with >1 antidiarrheal agent. When therapy with antidiarrheal 
agents does not control the diarrhea to tolerable levels, study treatment should be temporarily 
interrupted or dose reduced (Table 5). 
7.5.4 
Management of Alopecia, Palmar-Plantar Erythrodysesthesia Syndrome, 
Paronychia, and Stomatitis 
Recommendations for management (not required per protocol) of stomatitis (adapted from Rugo 
2017), PPES, paronychia (adapted from Segaert 2005), and alopecia are provided in Table 7. 
These recommendations and the additional information provided below, which includes 
management of dry skin and dry mouth/xerostomia (adapted from Lacouture 2020), are 
guidelines only and institutional guidelines should be followed where applicable.  
In addition, as a general guideline, if toxicity is tolerable and treated, study treatment may be 
continued for Grade 1 and Grade 2 AEs and interrupted for Grade 3 AEs; rechallenge at a 
reduced dose may be initiated when dermatologic events improve to Grade ≤1 or baseline or for 
a well-tolerable Grade 2 toxicity. 


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Table 7: 
Management of Skin Toxicity 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
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 0/1 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) 
• 
Topical povidone iodine 2%–10% applied BID  
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) 
• 
Topical povidone iodine 2%–10% applied BID 
• 
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/mL swish and spit 1 teaspoon (5 mL) 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 
Abbreviations: BID=2 times daily; OTC=over-the-counter; TID=3 times daily; TMP/SMX DS=sulfamethoxazole 
and trimethoprim. 
Additional guidelines for specific skin toxicities: 
• Alopecia: hair camouflaging methods (such as TOPPIK™) may be considered. Alopecia 
typically reverses when treatment is discontinued. 
• PPES: Prevention strategies for PPES include prophylactic removal of hyperkeratotic areas, 
application of moisturizing cream containing urea ≥10%, pedicures, and cushioning of 
callused areas. Other preventive tactics include avoiding activities that cause force or rubbing 
on the hands and feet during the first 6 weeks of treatment and limiting contact with harsh 
chemicals and sources of heat (eg, saunas, sun exposure). 


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• Stomatitis: Preventive strategies may include dental work to eliminate existing tooth and gum 
disease before starting treatment and education regarding the importance of thorough and 
frequent cleaning of the oral cavity. Avoiding salty, spicy, or citrus-based foods, and hot 
beverages may help prevent stomatitis. 
• Dry skin: Subjects should be advised to moisturize skin and avoid excessive exposure to 
detergents and soaps containing fragrances. Urea preparations have been shown to prevent 
transepidermal water loss, and salicylic acid preparations are helpful due to their keratolytic, 
bacteriostatic, and fungicidal properties. Exfoliation of scaly areas of xerosis is 
recommended. More severe grade 3 xerosis, which can result in asteatotic dermatitis, can be 
treated with low-potency topical steroids (eg, hydrocortisone 2.5% cream or ointment, 
triamcinolone 0.1% cream). 
• Dry mouth/xerostomia: The importance of good oral hygiene, regular dentist visits, and other 
strategies for preventing oral disease should be stressed. Toothpaste with high fluoride 
content is recommended to prevent cavities. Treatment may include systemic and topical 
salivary stimulants (eg, cevimeline and pilocarpine, and intraoral topical agents, such as 
chewing gums and saliva stimulants and substitutes). 
7.5.5 
Management of Dry Eye and Blurred Vision 
For management of dry eyes and/or blurred vision, the following supportive measures can be 
implemented singly or in combination and as advised in consultation with an ophthalmologist: 
1) Artificial tears, 4 times per day. 
2) Artificial tears without preservative, 6 times per day. 
3) Ointments (any over-the-counter or Vaseline®). 
4) Steroid drops (prescription; may help with corneal haze). 
5) Punctal plugs (requires ophthalmologist management).  
7.6 
Prior and Concomitant Medications 
At Screening, subjects are to be asked about their history of prior medication (including prior 
antineoplastic therapy); Investigators are to check for use of any disallowed prior medications, as 
outlined in the Exclusion Criteria for the study (Section 6.2).  
For each subject enrolled in the study, all anticancer therapies ever taken for urothelial 
carcinoma 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. 


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Cancer medications taken by the subject after last dose of study drug are to be recorded on the 
appropriate page of the eCRF. Non-medication cancer therapies and surgeries are to be recorded 
on the appropriate page of the eCRF. 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as well as 
estrogen replacement hormone treatment. 
7.6.1 
Permitted Concomitant Therapy Requiring Caution and/or Action 
Details for specific medications that require action and/or caution while on study in subjects 
potentially 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 antacids. Study drug 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 study drug doses by 2 hours. 
Infigratinib 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) 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 and frequency of monitoring increased. Refer to 
Section 7.6.2 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 (TdP), 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. 
Preliminary data have shown that infigratinib has no effect on cardiac conduction or ECG 
intervals (see current version of the infigratinib Investigator’s Brochure). Medications that have 
the possible, conditional, or established risk of QTc prolongation or causing TdP are allowed but 


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should be used with caution while on study. 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. 
Subjects with newly detected NMIBC or low-grade/noninvasive UTUC can be treated with 
non-systemic standard therapy, such as BCG instillation, intravesical treatment, and mitomycin 
gel. 
7.6.2 
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. 
Other investigational therapies must not be used while the subject is on the study. Other than 
study drug, anticancer therapy (eg, chemotherapy, biologic or radiation therapy, surgery) must 
not be given to subjects while the subject is on the study drug. If such agents are required, then 
the subject must be discontinued from study drug but will continue in the study with all 
described study-related assessments, including assessment for recurrence (conducted until 
metastatic recurrence [see Section 9.8]) as well as use of other anticancer therapy and survival. 
Exceptions are nonsystemic treatments for low-grade/noninvasive UTUC or NMIBC, such as 
intravesical treatment, mitomycin gel, or BCG instillation.  
Proton pump inhibitors are prohibited; see Section 7.6.1 for rationale. 
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 7.6.1.  
Strong and moderate 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 must also avoid the consumption of grapefruits, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges or juice within 7 days before the first dose of 
study drug and throughout the treatment period due to a potential CYP3A4 interaction with study 
drug. 
Medications that increase the serum levels of phosphorus and/or calcium are prohibited. Chinese 
herbal medicines and Chinese patent medicines for the treatment of cancer are not allowed 
during the treatment period. 


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7.6.3 
COVID-19 Vaccinations 
The effect of coronavirus disease 2019 (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).  
There is no detailed or conclusive information on studies conducted with the COVID-19 
vaccines in subjects 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 
All applicable guidelines should be followed, and vaccinations should adhere to the 
manufacturer’s guidelines for eligibility and contraindications to receive the vaccine (Garassino 
2020; ASCO 2021; 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. 
7.7 
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 Concomitant Therapy 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) (in Appendix 2 
[Section 17.2]). 
8 SUBJECT DISCONTINUATION AND STUDY TERMINATION 
8.1 
Subject Discontinuation 
8.1.1 
Discontinuation of Study Drug 
Discontinuation of study treatment does not represent withdrawal from the trial. 
If study treatment is permanently discontinued for reasons other than subject’s withdrawal of 
consent, the subject will remain in the study to be evaluated for all study prespecified 
assessments (such as safety follow-up, efficacy, etc.) See Section 2 for data to be collected at the 
time of discontinuation of study treatment and follow-up. 
Subjects must be discontinued from study drug for:  


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• Local/regional or contralateral invasive or metastatic recurrence (whichever occurs first) by 
BICR:  
○ Subjects should remain on study treatment until local/regional or contralateral invasive or 
metastatic recurrence is confirmed by BICR. 
○  All subjects’ imaging (CT/magnetic resonance imaging [MRI] scans) will be read locally 
and submitted for BICR read, together with any supporting report (including pathology 
and cytology reports) if a biopsy was conducted (for example, if recurrence was 
suspected). A central read should be requested at the time of investigator-assessed disease 
recurrence for confirmation by BICR.  
○ If BICR confirms recurrence (local/regional or contralateral invasive or metastatic 
recurrence, whichever occurs first), the subject must be permanently discontinued from 
study treatment. 
○ If locally diagnosed local/regional or contralateral invasive or metastatic recurrence is not 
confirmed by BICR, treatment continuation is allowed at Investigator's decision.  
○ BICR diagnosis of a local/regional or contralateral invasive or metastatic recurrence, 
independently from and undiagnosed by local team, will not be communicated to the 
clinical site.  
• Pregnancy. 
• 52-week treatment phase completed. 
• AE that leads to substantial changes in individual risk-benefit considerations. 
• Delay of study drug administration of >14 days (exclusive of scheduled dose interruption, 
with exceptions noted in Section 7.2.5.1). 
• Death. 
In addition, subjects may be discontinued from study drug for any of the following reasons:  
• New medical condition that does not allow continuation of study drug compliance. 
• Protocol deviation, including non-compliance with dosing regimen and retroactive failure to 
fulfill study entry criteria. 
• 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; if a subject withdraws consent from study treatment, it is required to 
document if the subject agrees or not 1) with continuation with study assessments; 2) to be 
followed for long-term follow-up and initiation of new anticancer therapies.  
• Investigator request 
• Use of other investigational therapies. 


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• Use of anticancer therapy (eg, chemotherapy, biologic or radiation therapy, surgery) other 
than the study drug. Exceptions are non-systemic treatments for low-grade or noninvasive 
UTUC or NMIBC, such as intravesical treatment, mitomycin gel, or BCG instillation. 
The investigator must notify the sponsor/representatives if a subject is discontinued prematurely 
from study drug for any reasons, including reasons other than radiological or pathologic 
local/regional or contralateral invasive or metastatic recurrence. Subject’s withdrawal from 
treatment must be documented and must also capture subject’s permission or not to be followed 
for long-term follow up and anticancer therapy initiation. At the time of discontinuation of study 
drug, subjects are to complete the EOT visit (no later than 5 days after treatment 
discontinuation), the 30-day Follow-up visit (according to Table 2 and Section 9.7), and 
subsequent follow-up visits and assessments, according to Table 2, Section 9.8, and Section 9.9. 
The reason for treatment discontinuation is to be documented in the eCRF including identifying 
one reason as the primary reason for treatment discontinuation. 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 discontinued from treatment due to protocol 
deviation or Investigator’s request, specifics are to be recorded in the eCRF. 
8.1.2 
Discontinuation from Study 
Subjects have the right to withdraw from the study at any time without prejudice. Pending the 
criteria for which the subject withdraws consent, as listed below, those specified assessments 
must be discontinued and no further assessments conducted. Further attempts to contact the 
subject are not allowed unless safety findings require communication or follow-up. 
Subjects may be discontinued from the study for the following reasons:  
• Subject’s formal withdrawal of informed consent. If a subject withdraws consent from study 
participation, the level of withdrawal must be documented. Below are the possible levels of 
subject’s withdrawals: 
○ Full withdrawal: withdrawal from all study treatments, procedures, assessments, and any 
type of follow-up (survival, new anticancer therapy, etc.) 
○ Withdrawal from all study assessments or procedures; survival follow-up is permitted, 
together with collection of data related to initiation of new anticancer therapy. 
○ Withdrawal from survival follow-up (subject or family cannot be contacted; public record 
data can be reviewed).  
○ 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. 


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•
Protocol deviation.
•
Study complete.
•
Death.
•
Other.
The reason for discontinuation from the study is to be documented in the eCRF, including the 
exact level of subject’s withdrawal from the study. 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 violation 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 QED Therapeutics, Inc. (QED). 
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, 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 to ensure 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 Schedule of Assessments (Table 2 and Table 3). 
9.1 
Molecular Prescreening 
Written documentation of the FGFR3 alteration by FoundationOne CDx (F1CDx) through 
Foundation Medicine USA (FoundationOne CDx 2020). is required for study eligibility.  
The sponsor must review all cases for which written documentation of the FGFR3 alteration by 
F1CDx was obtained as part of routine clinical care for adherence to the study protocol. If 
F1CDx testing is not performed as part of routine clinical care, molecular prescreening is 
required to confirm the presence of FGFR3 alteration from tissue (subjects must provide written 
consent before the molecular prescreening). Molecular prescreening by F1CDx should be 
performed using the tumor sample from the definitive surgical resection (cystectomy, 
nephroureterectomy, or distal ureterectomy) because this tumor provides the most current 
readout of FGFR3 status (see Appendix 5 [Section 17.5] for instructions for optimal tumor 
specimens). If the surgical specimen is not available, an archival biopsy sample can be used 
when: 
•
Biopsy sample is also confirmed invasive urothelial carcinoma (≥pT2).


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• Subject did not receive systemic anticancer therapy after the biopsy was obtained. 
• The biopsy is collected ≤4 months before the definitive surgery.  
• The most recent biopsy is submitted (if >1 biopsy procedure was performed).  
The sponsor must review all cases where an archival biopsy sample that is not from the definitive 
surgical resection is used to assess FGFR3 alterations by F1CDx (including when a biopsy 
sample is used to determine the FGFR3 alteration by F1CDx that was obtained as part of routine 
clinical care). Sites must consult with QED if the pre-surgical biopsy sample is the only sample 
available to submit to the central laboratory for molecular prescreening to ensure adherence with 
the above criteria. 
Tumor samples for molecular prescreening will be sent to Foundation Medicine USA (with a 
corresponding pathology report) Results of the analysis will be communicated to each respective 
study center. The results of molecular prescreening will be used to validate F1CDx as a 
companion diagnostic for the identification of patients with invasive urothelial carcinoma who 
may benefit from treatment with infigratinib following the detection of FGFR3 alterations. 
If written documentation by F1CDx of the FGFR3 alteration from the tumor sample obtained 
from the definitive surgical resection is not available before obtaining prescreening consent, 
molecular prescreening is required and the subjects must provide written informed consent for 
molecular prescreening (Section 13.3). Molecular prescreening assessments and confirmation 
can be done any time before dosing.  
For all subjects who undergo molecular prescreening, data collected as part of the assessment for 
FGFR3 alterations, including the following, will be collected and used for analysis of the 
exploratory objectives: (1) genetic alterations identified on the F1CDx gene panel as well as 
tumor mutational burden (TMB), and microsatellite instability (MSI); (2) pathologic disease 
stage of the sample tested; (3) sample type: biopsy (specify type such as core needle biopsy, 
excision biopsy, fine needle aspiration, cytology cell block) or resection from definitive surgery 
(specify type of surgery) and date of sample collection; (4) anatomic site of tumor collection; 
(5) UTUC or UBC; (6) prior neoadjuvant treatment (with date and name).  
9.2 
Main Study Informed Consent 
Upon confirmation that a subject’s tumor contains the required FGFR3 alteration (Section 10.3) 
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) 
 All baseline/screening assessments, including screening cystoscopy (for subjects with a bladder) 
and imaging assessments must be conducted within 28 days before randomization. 
After the main ICF is signed, screening activities will include the following:  


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• Cystoscopy (for subjects with a bladder) and CT or MRI scan (chest, abdomen, and pelvis), 
unless available within 28 days before randomization. Baseline CT/MRI scans must be 
submitted for BICR to confirm absence of residual or metastatic disease prior to 
randomization. Images should be submitted in time to allow for return of the results before 
120 days post-surgery. Refer to the Study Manual for details regarding image collection and 
transfer or shipment. 
• Collection of written documentation of F1CDx determined FGFR3 alteration processed at 
Foundation Medicine USA.  
• Inclusion/exclusion assessment (If the subject did not receive platinum-based chemotherapy 
in the perioperative setting [see inclusion criterion #4, Section 6.1], the reason must be 
documented in the case report form [CRF]). 
• Demography. 
• ECOG performance status. 
• Relevant medical history/current medical conditions. 
• Diagnosis and extent of cancer. 
• Prior medication and antineoplastic therapy. 
• Ophthalmic assessment (performed by an ophthalmologist). 
• Full physical examination. 
• Height and weight (body mass index [BMI] determination). 
• Vital signs. 
• 12-lead ECG. 
• Blood draw for hematology, clinical chemistry, and coagulation assessments. 
• Urine collection (urinalysis [micro- and macroscopic; for subjects with a bladder], and 
cytology [all subjects]). 
• Pregnancy test (serum or urine pregnancy test at screening) for women of childbearing 
potential within 7 days before the first dose of study drug. 
• Protocol-mandated procedure-related SAEs; see Section 10.5.1.3. 
• Randomization after subject deemed eligible (including documented medical monitor 
approval) and treatment starts within 1 week of randomization.  
In the event that subjects have a baseline/screening laboratory assessment that excludes them 
from the study, that assessment can be repeated to re-check their eligibility, if conducted within 
the 120 days from the definitive surgery. 
9.4 
Study Drug Dosing During Treatment Period (Days 1-28, Cycles 1-13) 
Daily dosing of study drug using a 3 weeks on (Days 1-21)/1 week off (Days 22-28) schedule for 
each 28-day treatment cycle. 


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Study drug may be dispensed at study visits on Day 1 of C1, C2, C4, C7, C10, and C13 and/or 
monthly at study visits per local standard practice. 
9.5 
Study Visits During Treatment Period (Cycle 1 Day 1 to Cycle 13 Day 21) 
The following assessments are to be performed during the Treatment Period as indicated below 
and as detailed in Table 2 and Table 3. Screening assessments conducted within 3 days before 
the first treatment can be used to satisfy the C1D1 requirement. 
Throughout the treatment period, subjects will be monitored for AEs and concomitant 
medication use. Other safety assessments, including full or abbreviated/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 3. Laboratory tests 
will be collected and analyzed on the scheduled day, even if study drug is withheld. 
The following assessments will be performed on C1D1, C2D1, C4D1, C7D1, C10D1, and 
C13D1, unless otherwise indicated: 
• Quality of Life (QOL) assessments (before study drug administration). 
• ECOG performance status. 
• Ophthalmic assessment (C2D1, C4D1, C7D1, C10D1, C13D1, and if clinically indicated). 
Retinal optical coherence tomography (OCT) scan images will be read locally and images 
will be sent to the OCT imaging vendor. Refer to the Study Manual for details regarding 
image collection and transfer or shipment. 
• Physical examination (full physical examination at C1D1, abbreviated or symptom-directed 
physical examination thereafter). 
• Weight (and BMI determination). 
• Vital signs. 
• 12-lead ECG (predose on C1D1 and C2D1). 
• If local programmed death-ligand 1 (PD-L1) testing is already known, record it (C1D1). If 
PD-L1 results are not known, and tissue was sent for testing, record the PD-L1 results as 
soon as available. While the PD-L1 results are not required for assessment of eligibility, 
testing for PD-L1 is required (it is not optional) (see Section 10.3 for additional details). 
• Blood draw:  
○ Hematology will be assessed at the following timepoints:. 
 Cycle 1 (Day 1). 
 Cycles 2, 4, 7, 10, and 13 (Day 21). 
○ Clinical chemistry will be assessed at the following timepoints: Every attempt should be 
made to collect clinical chemistry sample at the same time as the PK sample taken at 4 
hours post study drug administration. 


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 Cycle 1 (Day 1, Day 4, Day 7, Day 14, and Day 21).  
 Cycles 2-13 (Day 21).  
○ Coagulation as clinically indicated. 
○ cfDNA will be assessed at the following timepoints (see Table 3 for details): 
 Cycle 1 Day 1 predose. 
 Cycle 1 Day 21 predose.  
 Cycle 3 and every other cycle thereafter (C5, C7, etc.) on Day 21 predose.  
In addition, attempts should be made to collect a blood sample from any subject who 
discontinues study drug due to an AE at the time of discontinuation, if the sample can be 
collected within 24 hours of last dose. 
If a subject is not on study medication, then no cfDNA will be collected. cfDNA 
sampling will resume once the subject is back on study medication. 
○ PK will be assessed at the following timepoints (see Table 3 for details): 
 Cycle 1 Day 1 predose and 4 hours (±30 min) postdose. 
 Cycle 1 Day 21 predose and 4 hours (±30 min) postdose.  
 Cycle 2 and all subsequent cycles on Day 21 predose and 4 hours (±30 min) postdose.  
In addition, attempts should be made to collect a blood sample from any subject who 
discontinues study drug due to an AE at the time of discontinuation, if the sample can be 
collected within 24 hours of last dose.  
If a subject is not on study medication, then no PK will be collected. PK sampling will 
resume once the subject is back on study medication. 
• Urine collection: 
○ Urinalysis (micro- and macroscopic), if clinically indicated. 
○ Urine cytology on C4D1, C7D1, C10D1, and C13D1. 
○ cfDNA will be assessed at the following timepoints (see Table 3 for details): 
▪ 
Cycle 1 Day 1 predose. 
▪ 
Cycle 1 Day 21 predose.  
▪ 
Cycle 3 and every other cycle thereafter (C5, C7, etc.) on Day 21 predose.  
• Pregnancy test (blood or urine) for women of childbearing potential; monthly on Day 21 of 
C1 to C13. 
• CT or MRI (chest, abdomen, and pelvis) scan on C4D1, C7D1, C10D1, and C13D1. All 
CT/MRI scans must be submitted for BICR. Refer to the Study Manual for details regarding 
image collection and transfer or shipment. 
• Cystoscopy (for subjects with a bladder) on C4D1, C7D1, C10D1, and C13D1. 


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• Study drug may be dispensed at study visits on D1 of C1, C2, C4, C7, C10, and C13 and/or 
monthly at study visits per local standard practice; study drug administration will be as 
detailed in Section 9.4. 
• All AEs (see Section 10.5.1.3) on D1 of C1, C2, C4, C7, C10, and C13 and on D21 of every 
cycle. 
• Concomitant medication use on D1 of C1, C2, C4, C7, C10, and C13 and on D21 of every 
cycle. 
• Newly obtained tumor sample (if medically feasible) upon any recurrence. Biopsy reports, 
including pathology and cytology, must be submitted for BICR, as well as imaging (CT/MRI 
scans) assessments. Refer to the Study Manual for details regarding report collection and 
transfer or shipment. With subject consent, tumor samples collected upon local/regional or 
contralateral invasive or metastatic recurrence as part of standard of care may be provided to 
the sponsor for exploratory objectives related to biomarkers of urothelial carcinoma biology 
and the potential association of biomarkers with efficacy, disease recurrence, and resistance 
to study medications. 
Subjects will be dispensed study drug and instructed on daily dosing using a 3 weeks on 
(Days 1-21)/1 week off (Days 22-28) schedule for each 28-day treatment cycle (see Section 7.1). 
9.6 
Cycle 13 Day 28 or EOT Visit (±5 Days) 
At Cycle 13 Day 28 or when the decision is made to discontinue treatment, subjects will 
complete an EOT visit, no later than 5 days after treatment discontinuation.  
Assessments to be performed on C13D28 or EOT are as detailed in Table 2 and Table 3 and will 
include the following: 
• QOL assessments (not needed if completed within the previous 7 days at a regularly 
scheduled visit). 
• ECOG performance status. 
• Ophthalmic assessment, unless performed within previous 4 weeks. 
• Full physical examination. 
• Weight (and BMI determination). 
• Vital signs. 
• 12-lead ECG. 
• Blood draw for: 
○ Hematology and clinical chemistry (every attempt should be made to collect clinical 
chemistry sample at the same time as the PK sample taken at 4-hours post study drug 
administration). 
○ Coagulation (if indicated). 


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○ PK (if sample can be collected within 24 hours of last dose). 
○ cfDNA (unless performed within 28 days); at the time of local/regional or contralateral 
invasive or metastatic recurrence, a blood sample will be collected for analysis of 
cfDNA. 
• Urine collection:  
○ Urinalysis, if clinically indicated. 
○ Cytology (unless performed within 4 weeks). 
○ cfDNA (unless performed within 28 days); at the time of local/regional or contralateral 
invasive or metastatic recurrence, a urine sample will be collected for analysis of cfDNA. 
• Pregnancy test (blood or urine) for women of childbearing potential. 
• CT or MRI (chest, abdomen, and pelvis) scan, unless performed within previous 4 weeks or 
subject prematurely discontinued treatment due to local/regional or contralateral invasive or 
metastatic recurrence. CT/MRI scans must be submitted for BICR. Refer to the Study 
Manual for details regarding image collection and transfer or shipment. 
• Cystoscopy (for subjects with a bladder), unless performed within previous 4 weeks. 
• All AEs. 
• Concomitant medication use. 
• Newly obtained tumor sample (if medically feasible) upon any recurrence. Biopsy reports, 
including pathology and cytology, must be submitted for BICR, as well as imaging (CT/MRI 
scans) assessments. Refer to the Study Manual for details regarding report collection and 
transfer or shipment. With subject consent, tumor samples collected upon local/regional or 
contralateral invasive or metastatic recurrence as part of standard of care may be provided to 
the sponsor for exploratory objectives related to biomarkers of urothelial carcinoma biology 
and the potential association of biomarkers with efficacy, disease recurrence, and resistance 
to study medications. 
9.7 
30-day Post-treatment Follow-up (±5 Days)  
All subjects must complete safety follow-up assessments 30 days after the last dose of the study 
drug, as outlined in Table 2.  
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.  
9.8 
Follow-up Every 6 Months (±7 Days) after EOT and at EOS  
Subjects who prematurely discontinue treatment for reasons other than local/regional or 
contralateral invasive or metastatic recurrence (eg, for reasons detailed in Section 8.1.1) will be 
followed up until BICR-confirmed local/regional or contralateral invasive or metastatic 
recurrence and for 1 year after the final DFS event goal is reached (EOS). Note that all efficacy 


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assessments specified in Table 2 for the first year since start of treatment should continue 
according to the schedule if the subject prematurely discontinues treatment before 
BICR-confirmed local/regional or contralateral invasive or metastatic recurrence, ie, CT or MRI, 
cystoscopy (for subjects with a bladder), and urine cytology and cfDNA at C4D1, C7D1, C10D1, 
and C13D1. For subjects started on a non-study related anticancer therapy after discontinuing 
from study treatment, imaging assessment of disease status should continue, until metastatic 
recurrence by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred.  
After a subject completes 12 months of study treatment, the following assessments are to be 
conducted every 6 months (with the exception of CT or MRI scans; schedule for this assessment 
is noted below). 
• QOL assessments until 18 months after start of treatment. 
• Abbreviated or symptom-directed physical examination. 
• Weight (and BMI determination). 
• Vital signs. 
• Blood draw for cfDNA. 
• Urine cytology and cfDNA (every 6 months after EOT for an additional 12 months [24 
months in total since start of treatment] and then annually until local/regional or contralateral 
invasive or metastatic recurrence). 
• CT or MRI (chest, abdomen, and pelvis) scan every 3 months up to 24 months in total since 
start of treatment, then annually until metastatic recurrence confirmed by BICR or metastatic 
recurrence by investigator assessment if local/regional or contralateral invasive recurrence by 
BICR has already occurred (subjects who complete 52 weeks of treatment without metastatic 
recurrence will continue to have radiographic assessments according to the schedule 
described until metastatic recurrence by BICR or metastatic recurrence by investigator 
assessment if local/regional or contralateral invasive recurrence by BICR has already 
occurred). All CT/MRI scans must be read locally and submitted for BICR as well as any 
supporting report (including pathology and cytology reports) if a biopsy was conducted at the 
time of recurrence. A patient discontinued from study treatment and started on a new 
anticancer therapy will continue to be assessed by imaging until metastatic recurrence is 
confirmed by BICR or metastatic recurrence by investigator assessment if local/regional or 
contralateral invasive recurrence by BICR has already occurred. Refer to the Study Manual 
for details regarding image collection and transfer or shipment. 
• Cystoscopy (for subjects with a bladder; every 6 months after EOT up to 24 months in total 
since start of treatment and then annually until local/regional or contralateral invasive or 
metastatic recurrence). 
• Antineoplastic therapies since discontinuation of study treatment: to inquire at every study 
visit.  


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• Newly obtained tumor sample (if medically feasible) upon any recurrence. Biopsy reports, 
including pathology and cytology, must be submitted for BICR as well as imaging (CT/MRI 
scans) assessments. Refer to the Study Manual for details regarding report collection and 
transfer or shipment. With subject consent, tumor samples collected upon local/regional or 
contralateral invasive or metastatic recurrence as part of standard of care may be provided to 
the sponsor for exploratory objectives related to biomarkers of urothelial carcinoma biology 
and the potential association of biomarkers with efficacy, disease recurrence, and resistance 
to study medications. 
• Survival follow up. 
At the time of local/regional or contralateral invasive or metastatic recurrence, blood (2 tubes, 
16-20 mL) and urine sample will be collected for analysis of cfDNA. 
9.9 
Survival Follow-up and New Antineoplastic Therapies  
After either BICR-confirmed metastatic recurrence, or investigator-confirmed metastatic 
recurrence if BICR-confirmed local/regional or contralateral recurrence has already occurred, 
subjects will be followed up for survival status every 6 months for 1 year, then annually 
thereafter (via telephone or office visit) for 1 year (±14 days) after the final DFS event goal is 
reached (ie, EOS).  
Antineoplastic therapies since discontinuation of study treatment should also be collected for 
1 year (±14 days) after the final DFS event goal is reached (ie, EOS). Use of anticancer therapy 
will be collected for all subjects, including from the time of study treatment discontinuation, 
regardless of reason for discontinuation. For subjects started on a non-study related anticancer 
therapy after discontinuing from study treatment, imaging assessment of disease status should 
continue until metastatic recurrence by BICR or metastatic recurrence by investigator assessment 
if local/regional or contralateral invasive recurrence by BICR has already occurred.  
If a subject requests withdrawal of consent specifically from survival follow-up, this request 
must be documented in the subject's medical record. In such cases, the site staff may use public 
information source (such as county records) to obtain information about survival status and only 
as appropriate per local regulations. 
After the EOS (1 year after the DFS primary analysis), subjects will continue to be followed for 
OS (under a separate protocol) for approximately 14 years, or all of the subjects die or drop from 
this follow up, whichever is earlier, referred to as long-term OS follow up. The data for the 
long-term OS will be reported in a separate study report. 
9.10 
End of Treatment and End of Study 
End of treatment: Subjects will stay on study drug until they complete 52 weeks of treatment or 
experience local/regional or contralateral invasive or metastatic recurrence (whichever occurs 
first), if no other reasons requiring permanent discontinuation of treatment are met (see 
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End of Study: EOS is defined as 1 year after the time at which the final DFS event goal is 
reached. At the EOS, the investigator is to document the primary reason for EOS for each 
subject, as defined in Section 8.1.2. 
See Section 9.9 for details on long-term OS follow-up after EOS. 
10 STUDY ASSESSMENTS 
10.1 
Efficacy Assessments 
Efficacy will be assessed by disease recurrence and OS. To assess disease recurrence, CT/MRI 
scans, cystoscopy (for subjects with a bladder), and urine cytology will be performed. 
Assessments are scheduled based on first dosing day of the dosing cycle and do not change due 
to dose interruptions and will be conducted as detailed in Table 2 and Table 3.  
Chest, abdomen, and pelvic CT scans are required for all subjects at screening, unless available 
within 28 days before 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. (Note that for individual 
subjects, the same modality [CT or MRI] should be used for radiographic assessments 
throughout the study). Details are provided in the Subject Scanning Guide. Scans must be sent 
for BICR to confirm absence of residual or metastatic disease prior to randomization. All 
postbaseline radiological assessments, including imaging obtained at unscheduled time points to 
determine disease recurrence, as well as imaging obtained for other reasons but captures 
radiologic recurrence, will be sent for BICR. Subject’s imaging will be read locally and 
submitted for BICR as well as any supporting report (including pathology and cytology reports) 
if a biopsy was conducted at the time when recurrence was suspected. At the time of 
investigator-determined disease recurrence, a confirmatory BICR assessment should be 
requested. Refer to the Study Manual for details regarding image collection and transfer or 
shipment. 
Subjects should remain on study treatment until local/regional or contralateral invasive or 
metastatic recurrence is confirmed by BICR. If BICR confirms recurrence (local/regional or 
contralateral invasive or metastatic recurrence, whichever occurs first), the subject must be 
permanently discontinued from study treatment. If locally diagnosed local/regional or 
contralateral invasive or metastatic recurrence is not confirmed by BICR, treatment continuation 
is allowed at Investigator's decision. BICR diagnosis of a local/regional or contralateral invasive 
or metastatic recurrence, independently from and undiagnosed by local team, will not be 
communicated to the clinical site (see Section 8.1.1). 
If a subject discontinues treatment prematurely for reasons other than local/regional or 
contralateral invasive or metastatic recurrence, CT/MRI scans (chest, abdomen, and pelvis), 
cystoscopy (for subjects with a bladder), and urine cytology should continue to be taken at the 
intervals outlined in Table 2. For subjects started on a non-study related anticancer therapy after 
discontinuing from study treatment, imaging assessment of disease status should continue until 
metastatic recurrence by BICR or metastatic recurrence by investigator assessment if 
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For this study, definitions of recurrence are as follows: 
• Local/regional or contralateral invasive recurrence: recurrence of the original diagnosis of 
invasive urothelial carcinoma (within the urinary tract, renal or ureter bed, urinary soft tissue 
or locoregional lymph nodes). This does not include local/regional recurrence of 
noninvasive, or low-grade, or high grade UTUC or NMIBC. 
• Metastatic recurrence: Recurrence at any site or lymph node other than the urinary tract or 
local region of primary tumor.  
• Intraluminal low-risk recurrence: Any local/regional or contralateral recurrence of 
noninvasive, low-grade, or high-grade UTUC or NMIBC. 
These determinations will be recorded in the eCRF. 
Acceptable criteria for the diagnosis of recurrence are listed in Table 8 under “Unequivocal 
Recurrence”. For some recurrence sites, both histologic/cytologic and radiologic criteria for 
unequivocal recurrence are described. Histologic/cytologic confirmation is the preferred criteria 
to determine unequivocal recurrence, and new lesions should be biopsied to confirm recurrence 
when safe and feasible. Radiologic assessments completed to evaluate for disease recurrence 
must be submitted for BICR. Refer to the Study Manual for details regarding image collection 
and submission. New lesions meeting criteria for radiologic unequivocal recurrence, as well as 
highly suspicious lesions, should be biopsied to confirm recurrence when appropriate. Biopsy 
reports, including pathology and cytology reports, must be submitted for BICR (as well as 
radiological imaging as described above). Refer to the Study Manual for details regarding report 
collection and submission. For highly suspicious lesions or indeterminate lesions that are not 
amenable to biopsy, interval imaging surveillance should be performed as clinically indicated 
until disease recurrence is confirmed by biopsy or the subject has radiographic evidence of 
unequivocal recurrence according to Table 8. The frequency of surveillance imaging should be 
determined by the rate of tumor growth. For indeterminate or highly suspicious lesions that are 
followed using interval imaging surveillance, if recurrence is confirmed, the date of recurrence 
will be the date of first recognition of the findings. When both imaging and biopsy dates are 
available, the earlier date should be used as the date of recurrence.  
Table 8: 
Definitions of Recurrence by Site  
Site of 
Recurrence 
Unequivocal Recurrence 
Highly Suspicious 
Lesions 
Indeterminate 
Lesions 
Renal bed 
Pathologic confirmation of disease (cytology 
or histology)  
OR  
Radiologic evidence of new focal defects on 
CT or MRI imaging that is consistent with 
recurrence or new tumor per RECIST v1.1, 
ie, its longest diameter is ≥1 cm. 
 
Ureteric bed 
Pathologic confirmation of disease (cytology 
or histology) 
OR  


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Site of 
Recurrence 
Unequivocal Recurrence 
Highly Suspicious 
Lesions 
Indeterminate 
Lesions 
Radiologic evidence of new focal defects on 
CT or MRI imaging consistent with 
recurrence or new tumor per RECIST v1.1. 
Invasive 
Urinary Bladder 
Cancer (UBC): 
Cystoscopic and TUR/biopsy confirmation 
of new lesions, stage T2, T3, or T4. 
Nonmuscle 
Invasive 
Bladder Cancer 
(NMIBC) 
Cystoscopic and TUR/biopsy confirmation 
of new lesions, stage Ta, Tis, or T1. 
Upper Tract 
Urothelial 
Carcinoma 
(UTUC) 
Histologically/cytologically confirmed high 
grade, invasive UTUC defined as pT1, T2, 
T3, and T4  
OR 
Histologically/cytologically confirmed high 
grade noninvasive or low-grade noninvasive 
UTUC defined as pTa and pTis 
Lung and 
pleura 
Pathologic confirmation of disease (cytology 
or histology) 
OR 
>3 non-calcified pulmonary nodules, all 
>1 cm or new innumerable nodules of any 
size; for solitary pulmonary nodules, >2 cm. 
Proof of neoplastic pleural effusion must be 
established by cytology or pleural biopsy. 
Any number of 
nodules associated 
with thoracic 
adenopathy or not 
present at baseline 
Any pulmonary 
nodules not meeting 
criteria for 
unequivocal 
recurrence or highly 
suspicious lesion 
Liver  
Pathologic confirmation of disease (cytology 
or histology) 
OR 
Abdominal CT or MRI demonstrating lesion 
≥1 cm with confirmation of growth ≥5 mm or 
appearance of ≥1 new lesions on subsequent 
scans ≥4 weeks later. 
Proof of neoplastic abdominal ascites must 
be established by cytology or histology. 
Nodules <10 mm in 
size that do not 
appear compatible 
with benign 
processes; lesions of 
any size not present 
on prior imaging 
Any mass not 
meeting criteria for 
other 2 categories or 
that characteristically 
enhances compatible 
with benign 
processes 
Central nervous 
system 
Positive cerebral spinal fluid (CSF) cytology 
or biopsy 
OR 
Positive brain CT imaging or MRI imaging 
consistent with metastatic disease. 
 
Lymph Node  
Pathologic confirmation of disease (cytology 
or histology) 
OR 
Lymph nodes ≥1.5 cm short axis, with 
confirmation of growth ≥5 mm or appearance 
of new lesions on subsequent scans ≥4 weeks 
later 
Lymph nodes <1.5 
cm short axis that 
increase in size on 
subsequent imaging 
but remain less than 
1.5 cm 
Lymph nodes that are 
stable ≥1 cm and 
<1.5 cm short axis 


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Site of 
Recurrence 
Unequivocal Recurrence 
Highly Suspicious 
Lesions 
Indeterminate 
Lesions 
Bone 
Pathologic confirmation of disease (cytology 
or histology) 
OR 
≥2 lesions of the bone on bone scan 
confirmed on CT or MRI. 
For solitary lesions, subsequent scan required 
to demonstrate growth or ≥ 1 new lesion 
≥4 weeks apart 
≥1 bone lesion with 
characteristic 
findings on imaging 
Any bone lesion 
without characteristic 
findings or not 
meeting criteria for 
unequivocal 
recurrence or highly 
suspicious lesion 
Other organs 
Pathologic confirmation of disease (cytology 
or histology) 
OR 
CT or MRI demonstrating lesion that is 
≥1 cm with confirmation of growth ≥ 5 mm 
or appearance of ≥1 new lesions on 
subsequent scans ≥ 4 weeks later 
Nodules <10 mm in 
size that do not 
appear compatible 
with benign 
processes; lesions of 
any size not present 
on prior imaging 
Any mass not 
meeting criteria for 
other 2 categories or 
that characteristically 
enhances compatible 
with benign 
processes 
Abbreviations: CT=computed tomography; MRI=magnetic resonance imaging; RECIST=Response Evaluation 
Criteria in Solid Tumors; TUR=transurethral resection.  
All organ locations for recurrence up to 28 days from the first metastatic recurrence event will be 
reported on the eCRF and, for the purpose of analysis, will be considered part of the first 
recurrence. 
10.2 
Pharmacokinetic Assessments 
Blood samples will be collected at the time points specified in Table 3. 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 be excluded from 
PK analysis for that day and should not have blood samples collected for PK analysis. If a 
subject is not on study medication, then no PK will be collected. PK sampling will resume once 
the subject is back on study medication. 
Complete dosing information, including the date and time of actual blood draw and time of the 
last study drug dose before 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 (BHS697, BQR917, and 
CQM157) will be measured by a central laboratory using a validated liquid chromatography-
tandem mass spectrometry (LC-MS/MS) 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.  


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PK parameters listed in Table 9 will be estimated for infigratinib and its active metabolites. 
Concentrations of metabolites will be reported and summary statistics (eg, mean, standard 
deviation, %CV) calculated, as appropriate. 
Table 9: 
Pharmacokinetic Parameters 
Term  
Definition 
Ctrough 
Trough observed plasma concentration (before drug administration) 
Cmax 
Maximum observed plasma concentration after drug administration (defined as 
the 4-hour postdose concentration) 
 
10.3 
Assessment of Biomarkers and Eligible FGFR3 Alterations 
Biomarker assessments will be performed to confirm subject eligibility and potentially aid in 
understanding the effects of infigratinib treatment on biomarkers of urothelial carcinoma and 
FGFR pathway regulation as related to clinical outcome. 
Subjects must have written documentation of the FGFR3 alteration by F1CDx testing (through 
Foundation Medicine USA). The sponsor must review all written documentation of the FGFR3 
alteration by F1CDx that was obtained as part of routine clinical care for adherence to the study 
protocol.  
If F1CDx testing is not performed as part of routine clinical care, molecular prescreening is 
required to confirm the presence of FGFR3 alteration from tissue (subjects must provide written 
informed consent for the molecular prescreening). See Appendix 5 (Section 17.5) for details on 
the specimen requirements for F1CDx testing. F1CDx should be performed using the tumor 
sample from the definitive surgical resection (cystectomy, nephroureterectomy, or distal 
ureterectomy) because this tumor provides the most current readout of FGFR3 status. If the 
surgical specimen is not available, an archival biopsy sample can be used when prespecified 
criteria are met (see Section 9.1). The sponsor must review all cases where an archival biopsy 
sample is used to assess FGFR3 alterations (either locally as part of routine clinical care or 
centrally through molecular prescreening) for adherence to the study protocol. Molecular 
prescreening results (and any leftover tumor material) will be used to validate F1CDx as a 
companion diagnostic for the identification of patients with urothelial carcinoma who may 
benefit from treatment with infigratinib following the detection of FGFR3 alterations. The 
companion diagnostic validation may require a bridging study that will use leftover tumor 
samples from enrolled subjects collected during prescreening.  
Subjects with an FGFR3 alteration identified as described below (in addition to all other 
inclusion/exclusion criteria) will be eligible for enrollment in the study. Subjects with susceptible 
FGFR alteration(s) other than the ones described below will be enrolled in the study only 
following discussion between the investigator and the medical monitor.  
• FGFR3 mutation is confirmed if: 
○ FGFR3 gene is mutated in Exon 7 (R248C, S249C), Exon 10 (G370C, A391E, Y373C), 
or Exon 15 (K650M/T, K650E/Q). 


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• FGFR3 gene fusion/rearrangement is confirmed based on the following criteria: 
○ Any fusion/rearrangement with a literature-derived known partner gene regardless of 
strand or frame.  
○ Fusion/rearrangements in the same strand that are in frame with a novel partner gene.  
○ Fusion/rearrangements with one breakpoint in the intron 17 - exon 18 hotspot region and 
the other breakpoint in an intergenic region or another gene. This rule excludes 3′ 
duplications comprising only exon 18. 
• The amino acid numbers for the FGFR3 mutations refer to the functional FGFR3 isoform 1 
(NP_000133.1) that is the NCBI Refseq ID used to report genetic alterations in FGFR3 by 
the F1CDx test.  
Assessment of the PD-L1 status is not an eligibility criterion, subjects are allowed to participate 
in the study regardless of the PD-L1 status results. Nevertheless, PD-L1 results are required and 
will be recorded in the eCRF. If PD-L1 status is not already known, the assessment will be 
initiated on subject’s tumor sample from the definitive surgery or a biopsy (following the same 
rules for biopsy sample as described for the FGFR3 testing requirements in Section 9.1; refer to 
the Laboratory Manual for additional information). If PD-L1 status was not available at 
screening, the PD-L1 testing can be initiated at C1D1 or at any time after the subject is deemed 
eligible.  
If PD-L1 status is not already known at the time of screening, tumor tissue collected prior to 
treatment with study drug will be assessed for PD-L1 protein expression using a Food and Drug 
Administration (FDA)-approved immunohistochemistry (IHC) assay (PD-L1 IHC 22C3 
pharmDx) to support the exploratory objectives. If not already known, the PD-L1 IHC should be 
performed using the tumor sample from the definitive surgical resection (cystectomy, 
nephroureterectomy, or distal ureterectomy). If the surgical specimen is not available, a biopsy 
sample can be used instead. Refer to the Laboratory Manual for additional details regarding PD-
L1 biomarker assessments. If tumor tissues or biopsy sample are not available, PD-L1 testing 
will not be expected.  
Blood and urine samples for assessment of cfDNA will be collected as outlined in Table 2 and 
Table 3 to support exploratory objectives. These samples will be used for analysis of DNA to 
explore whether genetic alterations or other biomarkers found in tumor samples may also be 
observed in blood or urine, and if any biomarkers are prognostic or predictive of efficacy, 
disease recurrence, and/or resistance to study medications. 
With subject consent, tumor samples collected upon local/regional or contralateral invasive or 
metastatic recurrence as part of standard of care may be provided to the sponsor for exploratory 
objectives related to biomarkers of urothelial carcinoma biology and the potential association of 
biomarkers with efficacy, disease recurrence, and resistance to study medications. Additional 
archival tumor samples (including leftover DNA from subjects who underwent molecular 
prescreening) may also be collected for biomarker assessments to support the exploratory 
objectives. Biomarker assessments using tumor tissue left over from FGFR3 prescreening and 
cfDNA derived from blood or urine may include (but are not limited to): (1) genetic analysis 


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including transcriptomic, whole genome sequencing, whole exome sequencing, or targeted gene 
sequencing; (2) protein analysis including proteome analysis and IHC.  
QED designated laboratories(s) will be used for processing of all tumor, blood samples, and 
urine samples collected. The central laboratory will provide kits to collect and ship these samples 
to QED designated lab(s) for analysis. Refer to the Study Manual for additional instructions on 
the handling, storage and shipment of samples. Sample collection must be captured on the 
appropriate eCRF and requisition page(s). 
If the subject consents to long-term storage, samples collected during molecular prescreening or 
as part of the main study may be stored for up to 15 years for additional future research related to 
infigratinib, cancer, or other study treatments. This may also include research to help develop 
ways to detect, monitor, or treat cancer. A decision to perform additional research studies would 
be based on outcome data or from new scientific findings related to the drug class or disease, as 
well as reagent and assay availability. 
10.4 
Quality of Life 
Subject QOL will be evaluated using the EuroQOL 5 dimensions, 5 levels questionnaire (EQ-
5D-5L), which measures 5 dimensions of health, including mobility, self-care, usual activities, 
pain/discomfort, anxiety, and general health and the European Organization for Research and 
Treatment of Cancer (EORTC) Quality of Life Questionnaire Core 30 (QLQ-C30), which are 
reliable and valid measures of QOL in cancer subjects. QOL will be evaluated at the times 
outlined in Table 2. At each time point, the EQ-5D-5L is to be completed first, followed by the 
EORTC QLQ-C30. 
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.  
If a subject cannot complete the QOL instrument (questionnaire) 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-5L 
The EQ-5D-5L 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 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 


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influence the subject’s assessments. Every effort should be made to maintain an unbiased 
assessment.  
At each scheduled assessment, the EQ-5D-5L should be administered before 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). 
EORTC QLQ-C30 
The EORTC QLQ-C30 was developed to assess the QOL of cancer subjects (Aaronson 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, 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). 
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 1 of the outcomes listed above. 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
○ 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. 


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○ 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). 
Recurrence or progression of underlying malignancy is not considered as an AE if it is clearly 
consistent with the suspected recurrence or progression of the underlying cancer as defined by 
RECIST criteria v1.1, or other criteria as determined by protocol. Hospitalization due solely to 
the recurrence or progression of underlying malignancy should NOT be reported as an SAE. 
Clinical symptoms of recurrence or progression may be reported as AEs if the symptom cannot 
be determined as exclusively due to the recurrence or progression of the underlying malignancy, 
or does not fit the expected pattern of recurrence or progression for the disease under study. 
Symptomatic deterioration may occur in some subjects. In this situation, recurrence or 
progression is evident in the subject’s clinical symptoms, but is not supported by the tumor 
measurements. Or, the disease recurrence or progression is so evident that the investigator may 
elect not to perform further disease assessments. In such cases, the determination of clinical 
recurrence or progression is based on symptomatic deterioration. These determinations should be 
a rare exception as every effort should be made to document the objective recurrence or 
progression of underlying malignancy. 
Overdose of study drug is to be reported as an AE when drug is administered or taken at a daily 
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 recurrence or progression of the disease 
under study, it should be reported as an AE or SAE. 
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 randomly assigned to study treatment, 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.  


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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 
version 5.0, Grade 1-5); duration (start and end date); relationship to study drug; 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 immediately and under no 
circumstances later than 24 hours of learning of its occurrence via email: 
SAEintake@covance.com; or fax (please refer Study Manual for country-specific fax numbers).  
After randomization, every SAE, regardless of suspected causality, occurring after the subject 
has been randomly assigned to study treatment through 30 days after the subject has taken 
his/her last dose of study drug must be reported on the SAE eCRF immediately and under no 
circumstances later than 24 hours of learning of its occurrence. If there are any issues with 
electronic data capture (EDC), please send a completed paper SAE report form to Covance 
Safety via email: SAEintake@covance.com or fax (please refer to the Study Manual for country-
specific fax numbers). Any SAEs experienced after this 30-day period should only 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 
progression of the initial SAE must be reported as follow-up to the original episode within 
24 hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event. 
Follow-up information is submitted in the same way as the initial SAE. 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 


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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 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 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 × ULN (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 with accompanying ischemic AEs. 
• Overdose, defined as a daily dose ≥200 mg of study drug, and that is associated with an AE 
that is potentially related to study drug. 
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 AE eCRF. 
Once an AE is detected, it should be followed up 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 up according to standard of care until resolution or stability. 
Also see Section 7.2.5.2 for follow up information on toxicities. 


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10.5.2 
Pregnancies 
All women of childbearing potential are to undergo pregnancy testing (blood or urine) at the 
times specified in Table 2 and Table 3. Female subjects must be discontinued from study drug in 
the event of pregnancy. 
To ensure subject safety, each pregnancy in 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 Drug Safety (email: SAEintake@covance.com; fax: please refer 
to the Study Reference Manual for country-specific fax numbers). 
Any SAE experienced by a subject during pregnancy must be reported on the applicable SAE 
Report Form and be reported 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 and Table 3. 
Parameters included in the panel are listed in Table 10. 
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. 


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Table 10: 
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, BUN (or urea), potassium, sodium, magnesium, phosphorus 
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 
PT or INR, PTT 
Abbreviations: ALT=alanine aminotransferase; AST=aspartate aminotransferase; BUN=blood urea nitrogen; 
INR=international normalized ratio; PT=prothrombin time; PTT=partial thromboplastin time; RBC=red blood 
cell; SGOT=serum glutamic-oxaloacetic transaminase; SGPT=serum glutamic-pyruvic 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. 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, C1D1, and C13D28/EOT visits; at all other times indicated in Table 2, abbreviated, 
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, 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 before 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.  
Clinically significant ECG findings must be discussed with the medical monitor prior to 
enrolling the subject. Clinically significant ECG abnormalities present before 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. 


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10.5.7 
Ophthalmic Assessments 
For each subject, ophthalmic examinations are to be performed by an ophthalmologist at the 
times indicated in Table 2 and with any new onset of visual disturbance. 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 read locally and the scans will be sent to the OCT imaging 
vendor. Refer to the study manual for details regarding image collection and transfer or 
shipment.  
10.5.8 
Eastern Cooperative Oncology Group Performance Status 
ECOG performance status will be assessed as detailed in Table 2. ECOG performance status 
describes a patient’s level of functioning in terms of their ability to perform selfcare, daily 
activity and physical ability using the following scale: 
• Grade 0: Fully active, able to carry on all predisease performance without restriction. 
• Grade 1: Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (eg, light housework, office work). 
• Grade 2: Ambulatory and capable of all self-care but unable to carry out any work activities; 
up and about more than 50% of waking hours. 
• Grade 3: Capable of only limited self-care; confined to bed or chair more than 50% of 
waking hours. 
• Grade 4: Completely disabled; cannot carry on any self-care; totally confined to bed or chair. 
• Grade 5: Death. 
10.5.9 
Early Stopping Guidelines and Data Monitoring Committee 
One formal interim analysis of DFS will be performed when approximately 35 confirmed DFS 
events by BICR (independent of investigator assessment) have occurred across both treatment 
arms in the ITT population.  
At the interim analyses, the study will NOT be stopped for efficacy if the efficacy boundary for 
centrally reviewed DFS is crossed. A Haybittle-Peto (Haybittle 1971) boundary with a fixed one-
sided alpha=0.00005 will be spent at the interim analysis, and the rest of the alpha (one-sided 
alpha=0.025) spent at the primary centrally reviewed DFS analysis. 
The study may be stopped due to futility at the interim DFS analysis when the futility boundary 
for testing DFS is crossed. The futility stopping boundary is non-binding to allow for additional 
considerations. The methods of Lan and DeMets spending function approximating O’Brien and 
Fleming, boundaries will be used for the futility boundaries.  


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If a sample size increase is deemed necessary based on the interim result and the promising zone 
approach, the sample size/event goal will be increased by a maximum of 50% (328/105). The 
details of the sample size adaptation method will be prespecified in a separate adaptation plan. 
An independent DMC will periodically monitor the interim data at regularly scheduled meetings, 
according to a prespecified DMC charter and at the interim analysis. 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 the formal interim trial result when 35 confirmed DFS events by BICR are 
reached, 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, or whether sample 
size will need to be increased according to the prespecified rules in the adaptation plan, and 
regarding steps to ensure both subject safety and ethical and trial integrity of the trial. 
In the event that the study is terminated early based on a DMC recommendation, QED will 
notify the appropriate regulatory authorities.  
The DMC or QED 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.  
Records of all meetings will be archived. The DMC will communicate major safety concerns and 
recommendations regarding study modification or termination to QED.  
Further details will be provided in the DMC charter. 
11 STATISTICAL METHODOLOGY 
11.1 
General Considerations 
Data will be analyzed by QED and/or designated 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 efficacy analyses will be conducted on the ITT population, defined as all subjects randomly 
assigned to study treatment; subjects will be analyzed according to their randomized treatment 
arm assignment. The safety analyses will be performed for all subjects who have received ≥1 
dose of study drug according to the treatment they receive. Detailed definitions of the analysis 
populations will be provided in the SAP.  


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The study uses an adaptive design promising zone approach (Mehta 2011). The study will start 
with 218 subjects with a group sequential design with 1 interim analysis at approximately 50% 
of confirmed DFS events by BICR (35 events; independent of investigator assessment). A 
Haybittle-Peto boundary will be used for the efficacy boundary with a fixed one-sided alpha of 
0.00005 spent at the interim analysis for centrally reviewed DFS, and the rest of the alpha 
(one-sided alpha 0.025) spent at the primary centrally reviewed DFS analysis. A Lan DeMets 
spending function approximating O’Brien-Fleming boundaries will be used for the non-binding 
futility boundary.  
If no sample size adaption is needed at the interim analysis, the study is projected to reach the 
planned number of confirmed DFS events by BICR (70 events; independent of investigator 
assessment) 4 years from the randomization of the first subject. If a sample size increase is 
deemed necessary based on the interim result on centrally reviewed DFS using the promising 
zone approach, the sample size/event goal will be increased by a maximum of 50% (328/105). 
The details of the sample size adaptation method will be prespecified in the adaptation plan.  
For the secondary efficacy endpoints DFS (including intraluminal low-risk [noninvasive, 
low-grade or high-grade] recurrence), MFS, and OS, a fixed sequence testing procedure will be 
followed to control the family-wise type I error at a level of one-sided 0.025. 
DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence will be 
tested first if the test on DFS is significant, followed by the test on MFS if both DFS and DFS 
including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence are 
significant. OS will be tested finally if DFS, DFS including intraluminal low-risk (noninvasive, 
low-grade, or high-grade) recurrence, and MFS are all significant. 
A Haybittle-Peto boundary will be used for the secondary endpoints. A fixed one-sided type I 
error with alpha=0.00005 will be spent at the interim analysis, and the rest of the type I error will 
be spent at the time of the primary analysis. 
For DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence and 
MFS, 1 interim analysis will be conducted at the time of interim analysis for DFS, and the 
primary analysis will be conducted at the primary analysis for DFS when the DFS event goal is 
reached. There will be 2 interim analyses for OS, one at interim DFS analysis and the other one 
at primary DFS analysis. The primary analysis for OS will be conducted at approximately 1 year 
after the DFS event goal is reached. For OS analyses, a fixed one-sided type I error with 
alpha=0.00005 will be spent at each of the interim analysis, and the rest of the type I error will be 
spent at the time of the primary OS analysis. The analysis for long-term OS follow-up data will 
be descriptive. 
The same analysis methodology described for centrally reviewed DFS will be applied for 
statistical analyses for DFS including intraluminal low-risk (noninvasive, low-grade, or high-
grade) recurrence, MFS, and OS with corresponding efficacy boundaries.  
Any deviations in analysis from the protocol or SAP-specified analyses will be identified in the 
clinical study report.  
Details on handling of missing data will be included in the SAP. 


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Sensitivity analyses may be conducted to evaluate the potential effect on efficacy outcomes due 
to enrollment of subjects refusing cisplatin-based chemotherapy (yes vs no) and reasons why a 
subject did not receive cisplatin-based chemotherapy (ineligible or refusal) in the 2 treatment 
arms (active vs placebo), using the Cox regression model with this factor as a covariate. 
If sufficient numbers of subjects are enrolled with a component of variant histology, or with 
microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease, 
sensitivity analysis will also be conducted to account for variations in response. Further details 
are provided in the SAP. 
11.2 
Sample Size Determination 
For the initial group sequential design, assuming disease will recur in 46% of subjects in the first 
2 years and a 5% yearly recurrence rate in the third year and beyond for the placebo group, with 
3-year uniform enrollment, 1-year follow-up, 10% yearly drop-out rate, and a hazard ratio (HR) 
of 0.5, the required sample size with initial group sequential design is approximately 
218 subjects to reach 70 confirmed DFS events by BICR (independent of investigator 
assessment) in 4 years. The initial sample size will provide approximately 80% power to detect a 
difference in DFS assuming an HR of 0.5, based on a log-rank test controlling type I error at one-
sided 0.025.  
The sample size may be increased at the interim analysis based on the interim result on centrally 
reviewed DFS using the promising zone approach (Section 11.3.3). The maximum sample size 
increase would be 328 subjects (164 subjects per group) to reach 105 confirmed DFS events by 
BICR (independent of investigator assessment) at the final DFS analysis.  
11.3 
Statistical Hypothesis, Model, and Method of Analysis 
11.3.1 
Disposition of Subjects 
The number of subjects randomly assigned to study treatment and screen failed subjects will be 
summarized. The number and percentage of subjects entering and completing treatment and 
study will be presented by treatment arm. Reason for discontinuation of treatment and study will 
also be summarized.  
11.3.2 
Demographics, Medical History, Baseline Characteristics, and Concomitant 
Medications 
Demographic data, medical history, baseline characteristics, prior anticancer therapy, 
concomitant medication will be summarized by treatment arm.  
11.3.3 
Efficacy Analyses 
The primary objective of the study is to compare the centrally reviewed DFS of subjects with 
invasive urothelial cancer with susceptible FGFR3 alterations treated with infigratinib vs placebo 
following nephroureterectomy, distal ureterectomy, or cystectomy.  
The primary endpoint is centrally reviewed DFS, from date of randomization to local/regional or 
contralateral invasive or metastatic recurrence (according to central review) or death due to any 


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cause, whichever occurs earlier. Criteria for recurrence are specified in Section 10.1. For subjects 
without a bladder who are alive and without recurrence (local/regional or contralateral invasive 
or metastatic) by BICR, DFS will be censored at the last radiology assessment. For subjects with 
a bladder who are alive and without recurrence, DFS will be censored at the last radiology 
assessment if the previous cystoscopy result within 6 months is negative for muscle invasive 
disease, otherwise DFS will be censored at the last complete recurrence assessment. Subjects 
who have no disease assessments after baseline or no death recorded will be censored on the 
randomization date. 
Investigator-reviewed DFS including intraluminal low-risk (noninvasive, low-grade, or 
high-grade) recurrence is defined as the time from randomization to any recurrence as 
determined by the investigator, or death due to any cause, whichever occurs earlier. For subjects 
without documented recurrence and who are still alive, they will be censored at the last complete 
disease assessment (or, if no complete disease assessments are performed after the baseline visit 
or no death recorded, at the time of randomization day). 
Investigator-reviewed MFS is defined as the time from randomization to any metastatic 
recurrence as determined by the investigator or death due to any cause, whichever occurs earlier. 
For subjects without documented metastatic recurrence and who are still alive, they will be 
censored at the last radiology assessment (or, if no radiology assessments are performed after the 
baseline visit or no death recorded, at the time of randomization day). 
OS is defined as date of randomization to death. For subjects without documented death, they 
will be censored at the last known to be alive date.  
The study uses an adaptive design promising zone approach. The study will start with 
218 subjects using a group sequential design with 1 interim analysis at approximately 
35 confirmed DFS events by BICR (independent of investigator assessment). A Haybittle-Peto 
boundary will be used for the efficacy boundary with a fixed one-sided alpha of 0.00005 spent at 
the interim analysis for centrally reviewed DFS, and the rest of the alpha (one-sided alpha 0.025) 
spent at the primary DFS analysis. A Lan DeMets spending function approximating O’Brien-
Fleming boundaries will be used for the non-binding futility boundary. 
If a sample size increase is deemed necessary based on the interim result and the promising zone 
approach, the sample size/centrally reviewed DFS event goal will be increased by a maximum of 
50% (328/105).  
If no sample size adaptation is needed at the interim analysis, the primary analyses of DFS will 
be performed when approximately 70 confirmed DFS events by BICR (independent of 
investigator assessment) have been reached. If sample size is increased and event goal is 
adjusted, then the subsequent analyses will be adjusted accordingly time-wise when the adjusted 
event goal is reached, and the boundary to test DFS when the adjusted event goal is reached will 
be based on the original boundary from the initial group sequential design.  
The primary efficacy analysis will be conducted on the ITT population, which will include all 
subjects who are randomly assigned to study treatment. Subjects will be analyzed according to 
the treatment arm to which they are randomly assigned.  


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For primary DFS analysis, CHW statistics (Cui 1999) based on stratified log-rank test (using 
randomization stratification factors except disease type [UTUC or UBC]) will be used to control 
type I error in case of a sample size increase at the interim analysis. Conventional stratified log-
rank test will be used for the inference on centrally reviewed DFS if sample size is not adjusted 
at the interim analysis. Repeated confidence interval (Jennison 1989; Lehmacher 1999) will be 
provided for the estimated HR based on stratified Cox proportional hazards regression model. 
The disease type (UTUC or UBC) will be excluded from the stratified statistical analyses as a 
stratification factor due to small sample size in UBC (up to 15%). 
In case of sample size re-estimation, the CHW method (Cui 1999) will be used to combine the 
independent increments of the stratified log rank statistics as shown below: 
Let LR1 denote the stratified log rank statistics calculated with respect to events in the 
infigratinib treatment group at the interim analysis and LR2 is the log rank statistics with respect 
to events in the infigratinib treatment group calculated at the primary analysis using all the data 
available. The final test statistic for the primary analysis is 
 
𝑍𝑍𝐶𝐶𝐶𝐶𝐶𝐶= √𝑤𝑤 𝑍𝑍1 + √1 −𝑤𝑤 𝑍𝑍2 
where 𝑤𝑤= 0.5 and 
𝑍𝑍1 = 𝐿𝐿𝐿𝐿1 
𝑍𝑍2 = ඥ𝐷𝐷2
∗ 𝐿𝐿𝐿𝐿2 −ඥ𝐷𝐷1
∗ 𝐿𝐿𝐿𝐿1
ඥ𝐷𝐷2
∗−𝐷𝐷1
∗
 
 
where 𝐷𝐷2
∗ is the event number at the primary analysis after sample size adjustment and 𝐷𝐷1
∗= 𝐷𝐷1 
which is the number of events at the interim analysis. 
The p-value at the primary analysis is defined by 𝑝𝑝𝐶𝐶𝐶𝐶𝐶𝐶= Φ(𝑍𝑍𝐶𝐶𝐶𝐶𝐶𝐶), where Φ is the cumulative 
probability based on standard normal distribution.  
At the primary analysis, 𝑍𝑍𝐶𝐶𝐶𝐶𝐶𝐶 or 𝑝𝑝𝐶𝐶𝐶𝐶𝐶𝐶 will be compared with the original group sequential 
design boundary to test whether centrally reviewed DFS is significant with the control of the 
family-wise type I error at a level of one-sided 0.025.  
For the secondary efficacy endpoints DFS including intraluminal low-risk (noninvasive, 
low-grade, or high-grade) recurrence, MFS and OS, a fixed sequence testing procedure will be 
followed to control the family-wise type I error at a level of one-sided 0.025. 
DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence will be 
tested first if the test on centrally reviewed DFS is significant, followed by the test on MFS if 
both DFS and DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) 
recurrence are significant. OS will be tested finally if DFS, DFS including intraluminal low-risk 
(noninvasive, low-grade, or high-grade) recurrence, and MFS are all significant. 


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A Haybittle-Peto boundary will be used for the secondary endpoints. A fixed one-sided type I 
error with alpha=0.00005 will be spent at the interim analysis, and the rest of the type I error will 
be spent at the time of the primary analysis. 
For DFS including intraluminal low-risk (noninvasive, low-grade, or high-grade) recurrence and 
MFS, one interim analysis will be conducted at the time of interim analysis for centrally 
reviewed DFS, and the primary analysis will be conducted at the primary analysis for centrally 
reviewed DFS when the DFS event goal is reached. There will be 2 interim analyses for OS, one 
at interim centrally reviewed DFS analysis and the other one at primary centrally reviewed DFS 
analysis. The primary analysis for OS will be conducted at approximately 1 year after DFS event 
goal is reached. For OS analyses, a fixed one-sided type I error with alpha=0.00005 will be spent 
at each of the interim analyses, and the rest of the type I error will be spent at the time of the 
primary OS analysis. After the EOS (1 year after the DFS primary analysis), subjects will 
continue to be followed for long-term OS (under a separate protocol) for approximately 14 years, 
or all of the subjects die or drop from this follow up, whichever is earlier. The data for this 
long-term OS follow-up will be reported in a separate study report. 
The same analysis methodology described for centrally reviewed DFS will be applied for 
statistical analysis for DFS including intraluminal low-risk (noninvasive, low-grade, or high-
grade) recurrence, MFS, and OS with corresponding efficacy boundaries.  
Repeated CI will be provided based on Lehmacher (1999) in case of sample size increase. 
Otherwise it will be provided using Jennison (1989).  
Sensitivity analyses may be conducted to evaluate the potential effect on efficacy outcomes due 
to subjects refusing cisplatin-based chemotherapy (yes vs no) and reasons why a subject did not 
receive cisplatin-based chemotherapy (ineligible or refusal) in the 2 treatment arms (active vs 
placebo), using the Cox regression model with this factor as a covariate; details will be provided 
in the SAP. The number of subjects refusing cisplatin-based perioperative therapy will be capped 
at approximately 10% of the total population (approximately 22 subjects).  
If sufficient numbers of subjects are enrolled with a component of variant histology, or with 
microscopic positive noninvasive margins (eg, carcinoma in situ) without gross residual disease, 
sensitivity analysis will also be conducted to account for variations in response. Further details 
are provided in the SAP. 
11.3.4 
Pharmacokinetic Analyses 
Ctrough and Cmax will be estimated from the PK concentration data collected (Section 10.2). PK 
concentration will be summarized as appropriate. Data may be used for population PK analysis 
and PK/PD analysis and results may be reported separately. 
11.3.5 
Biomarker Analyses 
Summary statistics for genetic alterations among different groups of all prescreened subjects will 
be provided.  


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Biomarker analysis will be performed using available tumor samples in order to detect changes 
from baseline in the genetic profiles in tumor samples from treated subjects. The difference in 
biomarker results from samples taken before and during treatment may be explored.  
In addition, correlation between genetic biomarkers, subject demographics, and clinical 
endpoints may also be explored. The SAP will provide more details of such descriptive analyses.  
11.3.6 
Analyses of Quality of Life Assessments 
QOL assessments (EQ-5D-5L and EORTC QLQ-C30) will be analyzed using a random effects 
mixed model controlling for baseline scores and stratification factors to assess the difference in 
treatment arms. Two-sided 95% CI will be calculated for the difference between the 2 treatment 
arms.  
In addition, descriptive summaries on the observed data (including change from baseline) will be 
summarized at each assessed time point. Compliance with QOL assessments will be reported.  
11.3.7 
Interim Analysis  
One formal interim analysis of DFS will be performed when approximately 35 confirmed DFS 
events by BICR (independent of investigator assessment) have occurred. A Haybittle-Peto 
boundary will be used for the efficacy boundary with a fixed one-sided alpha of 0.00005 spent at 
the interim analysis for centrally reviewed DFS, and the rest of the alpha (one-sided alpha 0.025) 
spent at the primary DFS analysis. A Lan DeMets spending function approximating 
O’Brien-Fleming boundaries will be used for the non-binding futility boundary. 
At the interim analyses, the study will not be stopped for efficacy if the efficacy boundary for 
DFS is crossed. 
The study may be stopped due to futility at the interim DFS analysis if the futility boundary for 
testing DFS is crossed. The futility stopping boundary is non-binding to allow for additional 
considerations. 
If a sample size increase is deemed necessary based on the interim result using the promising 
zone approach, the sample size/event goal will be increased by a maximum of 50% (328/105). 
The details of the sample size adaptation method based on interim analysis will be prespecified 
in the adaptation plan. 
11.3.8 
Safety Analyses 
Safety analyses will be performed for all subjects who receive ≥1 dose of study drug according 
to the treatment they received. 
11.3.8.1 
Treatment Exposure 
Duration of treatment will be summarized by treatment arm. In addition, the cumulative dose and 
the relative dose intensity (cumulative actual dose/planned cumulative dose) will be summarized. 
The number of subjects with dose interruptions or dose reductions will be tabulated by treatment 
arm. 


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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. These reviews will include all available data on incidence of AEs, SAEs including deaths, 
and events leading to treatment discontinuation.  
All reported AEs will be assigned to a 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 study drug and within last dose date +30 days. The subject incidence rates of 
treatment-emergent AEs will be tabulated by system organ class, preferred term and severity 
grade for all serious, treatment related, and serious treatment related treatment-emergent 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 also will be provided for treatment-emergent AEs leading to study drug modification 
(discontinuation, hold, or reduction). All “on treatment” deaths (ie, deaths that occur after the 
first administration of study drug and within 30 days after last dose of study drug) will be 
summarized. Listings and/or narratives of “on-treatment” deaths, SAEs, and AEs leading to 
study treatment modification (discontinuation, hold, or reduction), 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). 
11.3.8.3 
Other Safety Findings 
Laboratory parameters for hematology and serum blood chemistry will be summarized at 
baseline, at each visit or selected visits, for the maximum and minimum observed postbaseline 
values, and the last observed value, along with the change from baseline. Tables of shifts in 
severity (by CTCAE version 5.0) from baseline for selected laboratory parameters also may be 
provided. Graphical representations of aggregate data may also be presented for parameters of 
interests. 
Vital signs, physical examination results, ophthalmic assessment, and ECG results will be 
summarized by treatment arm using descriptive statistics (including changes from baseline, if 
appropriate). 
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 


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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, 
IRB/IEC/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. 
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, QED 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the study center regularly to check the 
completeness of subject records, the accuracy of entries on the CRFs, 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 CRFs 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. QED monitoring standards require the presence of 
informed consent, adherence to the inclusion/exclusion criteria, documentation of SAEs, and full 
verification for drug accountability (as described in Section 7.2.4). Additional checks of the 
consistency of the source data with the eCRFs are performed according to the study-specific 
monitoring plan. 


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12.3 
Data Collection 
The designated Investigator staff will enter the data required by the protocol into the eCRF. The 
eCRFs have been built using fully validated secure web-enabled software that conforms to 21 
CFR Part 11 requirements. The Investigator and study center 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 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. 
12.4 
Database Management and Quality Control 
QED 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 
investigational study center via the EDC system. Designated Investigator study center staff are 
required to respond promptly to queries and to make any necessary changes to the data. 
Prior medications, concomitant treatments, and post-treatment anticancer medications entered 
into the database will be coded using the WHO Drug Reference List, which employs the 
Anatomical Therapeutic Chemical classification system. Medical history/current medical 
conditions and AEs will be coded using MedDRA terminology. 
PK and biomarker samples will be processed centrally and the results will be sent electronically 
to QED (or a designated CRO). 
The occurrence of any protocol violations will be evaluated. Once the data has been verified to 
be complete and accurate, the database will be declared locked and made available for data 
analysis. Appropriate QED authorization is required prior to making any database changes to 
locked data. 
After database lock, the investigator will receive an electronic CD-ROM copy of the subject data 
for archiving at the investigational 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 QED-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, 


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clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation checklists, 
pharmacy dispensing records, recorded data from automated instruments, copies or transcriptions 
certified after verification as being accurate and complete, microfiches, photographic negatives, 
microfilm or magnetic media, x-rays, and subject files and records kept at the pharmacy, at the 
laboratories, and medico-technical departments involved in the clinical trial. 
Data collection is the responsibility of the clinical trial staff at the 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. 
QED 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 QED, 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 
IRB/IEC/REB before study start. Before 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 QED monitors, auditors, QED Clinical Quality Assurance 
representatives, designated agents of QED, IRBs/IECs/REBs and regulatory authorities as 
required. 


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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. Special attention will 
be given in the ICF for those subjects who refuse perioperative cisplatin-based chemotherapy in 
presenting what are the treatment alternatives versus participation in this clinical trial. The reason 
a subject did not receive cisplatin-based chemotherapy in the perioperative setting will be clearly 
documented in the eCRF. 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 was 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. 
QED will provide to Investigators, in a separate document, a proposed ICF that is considered 
appropriate for this study and complies with the ICH GCP guideline and regulatory 
requirements. Any changes to this ICF suggested by the investigator must be agreed to by QED 
before submission to the IRB/IEC/REB, and a copy of the approved version must be provided to 
the QED 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 and the requirement to refrain from donating sperm and eggs during the study and 
for 1 month following their last dose of study drug. 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 QED. 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 should be provided by study personnel who are directly involved in the 
treatment or evaluation of subjects at the study center before study start. Other aspects of 
finances (such as budgeting with study centers) and insurance will be provided in separate 
documents. 
15 PUBLICATION POLICY 
QED 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. QED assures that the key design elements of this protocol will be posted 
on the 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.  
QED 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 
QED or through the professional medical writing agency. Author(s) may be requested to present 
poster or oral presentation at scientific congress; however, there will be no honorarium provided 
for such presentations. 
As part of its commitment to full transparency in publications, QED 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 QED before 
publication or presentation. 
 


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Oncology. Retrieved from https://www.nccn.org. Accessed 04 October 2018. 
NCCN Guidelines Version 5.2020 Bladder Cancer. NCCN Clinical Practice Guidelines in 
Oncology.  
Pal SK, Rosenberg JE, Hoffman-Censits JH, Berger R, Quinn DI, Galsky MD, et al. Efficacy of 
BGJ398, a fibroblast growth factor receptor 1–3 inhibitor, in patients with previously treated 
advanced urothelial carcinoma with FGFR3 alterations. Cancer Discov. 2018;8(7):812–821. 
Pergam S, Baden LR, Abel G, Adelson K, Bunnell C, Cinar P, et al. Preliminary 
recommendations of the NCCN COVID-19 vaccination advisory committee. NCCN website. 22 
January 2021. https://www.nccn.org/covid-19/pdf/COVID-19_Vaccination_Guidance_V1.0.pdf. 
Porter MP, Kerrigan MC, Donato BM, Ramsey SD. Patterns of use of systemic chemotherapy 
for Medicare beneficiaries with urothelial bladder cancer. Urol Oncol. 2011;29(3):252–258. 
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med. 
2001;33(5):337–343. 
Raman JD, Messer J, Sielatycki JA, Hollenbeak CS. Incidence and survival of patients with 
carcinoma of the ureter and renal pelvis in the USA, 1973-2005. BJU Int. 2010;107:1059–1064. 
Rehman S, Crane A, Din A, Raza SJ, Shi Y, Wilding G, et al. Understanding avoidance, refusal, 
and abandonment of chemotherapy before and after cystectomy for bladder cancer. Urology. 
2013;82(6):1370-1375. 
Roupret M, Babjuk M, Comperat E, Zigeuner R, Sylvester RJ, Burger M, et al. European 
Association of Urology Guidelines on upper urinary tract urothelial cell carcinoma: 2015 update. 
Eur Urol. 2015;68:868–879. 
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everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative 
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upper tract urothelial carcinoma. Eur Urol. 2015;68(6):970–977.  


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Shariat SF, Favaretto RL, Gupta A, Fritsche HM, Matsumoto K, Kassouf W, et al. Gender 
differences in radical nephroureterectomy for upper tract urothelial carcinoma. World J Urol. 
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Siegel RL, Miller KD, Jemal A. Cancer Statistics, 2018. CA Cancer J Clin. 2018;68:7-30. 
Tomlinson DC, Baldo O, Harnden P, Knowles MA. FGFR3 protein expression and its 
relationship to mutation status and prognostic variables in bladder cancer. J Pathol. 
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University of Washington(a). Drug Interaction Solutions. In vivo inducers of CYP3A4 probes. 
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University of Washington(b). Drug Interaction Solutions. In vivo inhibitors of CYP3A4 probes. 
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Biochem J. 2011;437(2):199–213. 
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Wu YM, Su F, Kalyana-Sundaram S, Khazanov N, Ateeq B, Cao X, et al. Identification of 
targetable FGFR gene fusions in diverse cancers. Cancer Discov. 2013;3(6):636–647.  
 


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17 APPENDICES 
17.1 
Appendix 1: List of Concomitant Medications 
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 lists in Table 11 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 is not an exhaustive list of medications. Investigator should use this list solely as 
a guide. 
Table 11: 
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 tracta,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-sulfa, trimipramine 
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 p450; GI=gastrointestinal; 
TdP=Torsades de Pointes 
a 
Study drug should be dosed ≥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 2020; Flockhart 2007; drugbank.ca. 


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17.2 
Appendix 2: List of Prohibited Medications 
Table 12: 
List of Prohibited Medications and Substancesa While on Study 
Category 
Drug Names 
Moderate inhibitors 
of CYP3A4b 
ACT-17882, 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 CYP3A4b 
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 
CYP3A4b 
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 
CYP3A4b 
apalutamide, avasimibe, carbamazepine, enzalutamide, ivosidenib, lumacaftor, mitotane, 
phenobarbital, phenytoin, rifampin, rifapentine, St. John's wort extract,  
Medications which 
increase serum 
phosphate and/or 
calcium 
calcium, parathyroid hormone, phosphate, vitamin D (including multivitamins containing 
vitamin D) 
Medications which 
alter the pH of the 
GI tract 
proton-pump inhibitors (eg, omeprazole, esomeprazole, lansoprazole, pantoprazole, 
rabeprazole) 
Chinese herbal 
medicine and 
Chinese patent 
medicines for 
cancer treatments  
Chinese herbal medicines and Chinese patent medicines for the treatment of cancer are not 
allowed during the treatment period. 
 
Abbreviations: CYP=cytochrome p450; GI=gastrointestinal. 
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 2020 (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 2020, section 4.3). Sponsor’s note: it is 
recommended that women should have been using the same hormonal contraception stably for a minimum of 
3 months before starting study treatment. 
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 woman of childbearing potential 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. 


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17.4 
Appendix 4: Recommended Standards for Lymph Node Dissection (LND) at the 
Time of Selected Definitive Surgeries for Urothelial Carcinoma 
The following is from FDA Guidance for Industry 2020 (Bladder Cancer: Developing Drugs and 
Biologics for Adjuvant Treatment Guidance for Industry). 
Radical Cystectomy/Cystoprostatectomy: 
• Perform bilateral pelvic lymphadenectomy and include common, internal iliac, external iliac, 
and obturator nodes. 
Nephroureterectomy with Cuff of Bladder or Distal Ureterectomy 
• Regional lymphadenectomy is recommended for patients with high-grade upper 
genitourinary (GU) tract tumors. 
○ Left-sided renal pelvic, upper ureteral, and midureteral tumors: 
▪ 
Perform regional lymphadenectomy including the paraaortic lymph nodes from the 
renal hilum to the aortic bifurcation. 
▪ 
Most midureteral tumors will also include the common iliac, external iliac, obturator, 
and hypogastric lymph nodes. 
• Right sided renal pelvic, upper ureteral, and midureteral tumors: 
○ Perform regional lymphadenectomy including the paracaval lymph nodes from the renal 
hilum to the inferior vena cava (IVC) bifurcation. 
○ Most midureteral tumors will also include the common iliac, external iliac, obturator, and 
hypogastric lymph nodes. 
• Distal ureteral tumors: 
○ Perform regional lymphadenectomy including the common iliac, external iliac, obturator, 
and hypogastric lymph nodes. 


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17.5 
Appendix 5: Instructions for Optimal Tumor Specimens for FGFR3 testing 
Instructions for Archival Tumor Tissue 
The archival tumor tissue from the definitive surgical resection (cystectomy, 
nephroureterectomy, or distal ureterectomy) is the preferred specimen as this provides the most 
current readout of fibroblast growth factor receptor 3 (FGFR3) status.  
If the surgical specimen is not available, an archival biopsy sample can be used when: 
• Biopsy sample is also confirmed invasive urothelial carcinoma (≥pT2). 
• Subject did not receive systemic anticancer therapy after the biopsy was obtained. 
• The biopsy is collected ≤4 months before the definitive surgery.  
• The most recent biopsy is submitted (if >1 biopsy procedure was performed).  
Sites must consult with QED if the biopsy sample is the only sample available to submit to the 
central laboratory for molecular prescreening to ensure adherence with the above criteria. 
Choosing the Best Tumor Block 
1. The selected formalin fixed paraffin-embedded (FFPE) block should be chosen by a 
pathologist to contain the most amount of viable tumor. The specimen may contain non-
tumor tissue; however, the specimen should be free of excessive necrosis, fibrosis, and 
lymphoid aggregates that can interfere with molecular testing.  
2. Based on the H&E slide, estimate the tumor nuclei percentage (%TN), which is the total # of 
tumor cells divided by the total # of cells with nuclei. Tumor purity (based on %TN) is most 
important for detecting FGFR3 genetic alterations. (See Table 13: Recommendations for 
Tumor Nuclei Percentage).  
3. The more viable tumor the better, however samples with ≥30% TN is optimum for most 
specimens. 
4. 20% TN is the minimum tumor content allowed but this lower tumor purity may lead to a 
greater risk of test failures.  
5. Tissue surface area (SA) should be ≥25 mm2 to meet the tissue volume requirements of 
1 mm3 (10 slides x 4-5 µm thickness per slide x 25 mm2 SA=1 mm3 tissue volume). 
6. Smaller specimens may qualify by sending more than 10 slides or the FFPE block to meet 
tissue volume requirements. Additional unstained slides may be needed to extract sufficient 
DNA for testing.  
7. For specimens of adequate tissue size (≥25 mm2), the central lab may perform 
macro-enrichment to eliminate normal tissue to meet the tumor purity requirements.  


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Table 13: 
Recommendations for Tumor Nuclei Percentage 
Tumor nuclei 
percentage (% TN) 
%TN illustration a 
Comments 
≥30% TN  
Optimum 
 
 
More likely to pass Pathology Quality Control. 
Significantly higher pass rate because of higher tumor purity. 
20% TN  
Minimum 
 
Submit >10 slides if possible. 
The laboratory may attempt macro-enrichment to increase tumor 
purity. 
More likely to fail testing due to lower tumor purity. 
a 
Cellularity Guide (www.mdanderson.org/documents/for-physicians/clinical-calculators/calculators-cellularity-
guide.pdf) 
 
Additional details on tumor specimen preparation are provided in the Laboratory Manual.  

SAP_001.pdf: 
I nfi grati ni b 
Q E D T hera p e utics  
Pr ot oc ol Q B GJ 3 9 8 -3 0 2  
C o nfi de ntial  
1 5 N o v 2 0 2 2  
Pa ge 1   
 
   
 
Cli ni c al D e v el o p m e nt  
Q B G J 3 9 8 -3 0 2  
P h a s e 3, M ulti c e nt er, D o u bl e -Bli n d, R a n d o mi z e d, Pl a c e b o -
C o ntr oll e d Tri al of I nfi gr ati ni b  f or t h e A dj u v a nt Tr e at m e nt of 
S u bj e ct s wit h I n v a si v e U p p er Tr a ct Ur ot h eli al C ar ci n o m a 
( U T U C) a n d Ur ot h eli al C ar ci n o m a of t h e Bl a d d er ( U C B) wit h 
F G F R 3 G e n o mi c Alt er ati o n s  
St ati sti c al A n al y si s Pl a n  
A ut h or:  
 
 
  
D oc u me nt T y pe  
Statistical A nal ysis Pla n  
D oc u me nt St at us:  
Versi o n 2 .1  
Rele ase D ate:  
2 4  Fe br uar y  2 0 2 3  
 
 
 
 
 
 
 
 
Pr o pert y of Q E D T hera pe utics  
C o nfi de ntial  
Ma y n ot b e use d, di v ul ge d, p u blis he d, or ot her wise discl ose d wit h o ut t he c o nse nt of Q E D T hera pe utics  
 
 
P P D
P P D
P P D


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REVISION HISTORY 
Version  
Approval Date 
Primary Rationale for Revision 
V 1.0 
30 August 2019 
Not Applicable 
V 2.0 draft 
December 2022 
Update per brief CSR 
V 2.0 final 
February 2023 
Incorporate comments, and finalize the SAP 
 
 
 
 
 
 
 
TABLE OF CONTENTS 
TABLE OF CONTENTS ..............................................................................................................2 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ...............................................4 
1 
INTRODUCTION ..................................................................................................................6 
2 
OBJECTIVES .........................................................................................................................6 
2.1 
Primary Objective ..............................................................................................................6 
2.2 
Secondary Objectives.........................................................................................................6 
2.3 
Exploratory Objectives ......................................................................................................7 
3 
STUDY DESIGN ....................................................................................................................7 
3.1 
Overall Study Design .........................................................................................................7 
3.2 
Stratification Factors .........................................................................................................7 
3.3 
Sample Size Considerations ..............................................................................................8 
4 
STUDY ENDPOINTS AND COVARIATES .......................................................................8 
4.1 
Endpoints ............................................................................................................................8 
5 
HYPOTHESES .......................................................................................................................9 
6 
DEFINITIONS ........................................................................................................................9 
7 
ANALYSIS POPULATION ................................................................................................11 
7.1 
Intent to Treatment Population ......................................................................................11 
7.2 
Safety Population .............................................................................................................11 
7.3 
Subgroup Analyses...........................................................................................................11 
8 
STATISTICAL METHODS OF ANALYSIS ....................................................................11 
8.1 
General Principles ............................................................................................................11 
8.2 
Handling of Missing Data ................................................................................................12 
8.3 
Subject Accountability and Disposition .........................................................................12 
8.4 
Demographic and Baseline Characteristics ...................................................................12 
8.5 
Medical History ................................................................................................................13 
8.6 
Prior Anti-cancer Therapy..............................................................................................13 
8.7 
Protocol Deviations ..........................................................................................................13 
8.8 
Efficacy Analyses .............................................................................................................13 
8.9 
Sensitivity Analyses ..........................................................................................................13 
8.10 
Safety Analyses .................................................................................................................13 
8.10.1 
Adverse Events ...........................................................................................................14 
8.10.2 
Concomitant Medications .........................................................................................15 
8.10.3 
Treatment Exposure ..................................................................................................15 
8.10.4 
Laboratory Data Summary .......................................................................................15 


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8.10.5 
Ophthalmic Assessment.............................................................................................16 
8.10.6 
Left Ventricular Ejection Fraction (LVEF) ............................................................16 
8.10.7 
ECG .............................................................................................................................17 
8.10.8 
Vital Signs and ECOG Performance Status ............................................................18 
9 
REFERENCE LIST..............................................................................................................19 
10 APPENDIX ............................................................................................................................20 
 
 
 
 


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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
Abbreviation 
Term/Definition 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count  
AST 
aspartate aminotransferase 
AUC 
area under the curve 
cfDNA 
cell-free DNA 
CI 
confidence interval 
Cmax 
maximum observed concentration  
Cmin 
minimum observed concentration 
Ctrough (min) 
trough observed plasma concentration (before drug administration) 
Css 
average plasma concentration at steady-state 
CRO 
contract research organization 
CSR 
Clinical Study Report 
CTCAE 
Common Terminology Criteria for Adverse Events 
DFS 
disease-free survival 
DMC 
Data Monitoring Committee 
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 
EQ-5D 
EuroQOL five dimensions questionnaire 
FGFR3 
fibroblast growth factor receptor 3 
HR 
hazard ratio 
ICH 
International Council for Harmonization 
ITT 
intent-to-treat 
K-M 
Kaplan Meier 
LVEF 
left ventricular ejection fraction  
MFS 
metastatis-free survival 
MedDRA 
Medical Dictionary for Regulatory Activities 
MIBC 
muscle invasive bladder cancer 
NMIBC 
non-muscle invasive bladder cancer 
OS 
overall survival  
PD-L1 
programmed death-ligand 1 
PK 
pharmacokinetics 
PR 
partial response 
QLQ 
quality of life questionnaire 
QOL 
quality of life 
QTcF 
QTc corrected by Fridericia’s formula 
Racc 
accumulation ratio calculated as Cmin steady-state/Cmin 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SOC 
system organ class 
UBC 
urothelial carcinoma of the bladder  


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UTUC 
upper tract urothelial carcinoma 
 
 


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Infigratinib 
QED Therapeutics
Protocol QBGJ398-302  
Confidential
15 Nov 2022 
Page 10
 
   
withdraw consent for study participation, including consent to be followed, will be censored on 
the date of withdrawal. 
Metastasis-free Survival Time (MFS) 
The investigator reviewed MFS is defined as the time from randomization to any metastatic 
recurrence as determined by the investigator or death due to any cause, whichever occurs earlier. 
Subjects without documented metastatic recurrence and are still alive, will be censored at the last 
radiology assessment, or at the time of randomization if no radiology disease assessments are 
performed after the baseline visit.  
Disease-free Survival Time (DFS) 
Disease-free survival time is calculated as the number of months from randomization to the date 
of local/regional invasive or metastatic recurrence or death due to any cause (referred as DFS 
event) ((date of DFS event - date of randomization + 1)/ (365.25/12)). Subjects without 
recurrence (local/regional invasive or metastatic) or death will be censored at the last radiology 
assessment if previous cystoscopy result within 6 months is negative for muscle invasive disease, 
otherwise, DFS will be censored at the last complete recurrence assessment. Subjects who have 
no disease assessments after baseline will be censored on the randomization date. The primary 
DFS endpoint will be based on the central review (BICR), while for the secondary endpoint, the 
investigator reviewed DFS will be based on investigator review. 
DFS including intraluminal low risk recurrence 
The investigator reviewed DFS including intraluminal low risk recurrence is defined as the time 
from randomization to any recurrence as determined by investigator, or death due to any cause, 
whichever occurs earlier. For subjects without documented recurrence and are still alive, they 
will be censored at the last complete disease assessment (or, if no disease assessments are 
performed after the baseline visit or no death has been recorded, at the time of randomization).  
Relative dose intensity 
The relative dose intensity is defined as cumulative actual dose a subject have received divided 
by the planned cumulative dose. For example, a subject takes study drug from Day 1 to Day 21 
at 125 mg/day; then from Day 29 to Day 30 at 100 mg/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%. 
Study Day 1 
Study Day 1 is defined as the day of the first administration of study treatment after 
randomization.  
Treatment Duration 
Treatment duration is defined as last dose date – first dose date +1.  


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Infigratinib 
QED Therapeutics
Protocol QBGJ398-302  
Confidential
15 Nov 2022 
Page 12
 
   
In general, categorical variables will be summarized using counts and percent. Percent will be 
displayed to one place after the decimal point, with the exception of 100%, which will be 
displayed without additional decimal places.  
Continuous variables will be summarized using number of subjects, mean, median, standard 
deviation, Q1, Q3, minimum, and maximum.  
Time to event endpoints will be analyzed by Kaplan Meier (K-M) method. No statistical test will 
be conducted. 
SAS statistical software, version 9.4 or later, will be used for all analyses.  
If departures from these general conventions are present in the specific evaluations section of this 
SAP, those conventions will take precedence over these general conventions. 
8.2 
Handling of Missing Data 
Partial dates will be defined as dates that are missing certain elements of the date field. This may 
include missing information for the month, day, or year, or two of these elements, but not all 
three. 
Partial dates for adverse events where the start day is missing will be imputed as the first day of 
the month unless the start month of the adverse event is the same as the month when the 
treatment is initiated. In this case, the start day will be imputed as first dose date. The adverse 
event will be counted as treatment emergent adverse event. If the month, year, both month and 
year, or the entire start date is missing, then no data imputation will be implemented. However, 
these events will be counted with regard to treatment adverse event as long as there is no clear 
evidence to indicate adverse event starts before first dose date or after last dose date +30 days.  
In general, for all other partial missing dates, if day is missing, day 15 will be imputed. No other 
imputation will be done if month or year is missing. 
8.3 
Subject Accountability and Disposition 
The number of subjects randomized into the study (including summaries 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 FGFR3 mutation/fusion 
status, details on the mutation/fusion, lymph node involvement, stage at initial diagnosis, time 
from initial diagnosis to randomization, UTUC vs UBC and histology.   


Infigratinib 
QED Therapeutics
Protocol QBGJ398-302  
Confidential
15 Nov 2022 
Page 13
 
   
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 (SOC) and preferred 
terms (PTs). 
8.6 
Prior Anti-cancer Therapy 
Prior anticancer therapy will be summarized including prior neo-adjuvant chemotherapy (yes vs 
no), neo-adjuvant chemotherapy type, and other prior anticancer medication. 
Prior cancer related surgery and its type will also be summarized, in addition to the time from the 
last prior cancer related surgery to randomization. Prior radiotherapy will be also summarized. 
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 
Principal Section 8.1. The analysis of time to event endpoints such as DFS, MFS and OS is 
specified in Section 8.1. 
 
8.9 
Sensitivity Analyses 
Sensitivity analysis will not be performed for the abbreviated CSR. 
8.10 Safety Analyses 
Analysis of safety will be performed on the safety analysis population. 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 data monitoring committee (DMC) periodically 
throughout the study. These reviews will include all available data on incidence of adverse 
events, serious adverse events including deaths. Study data will be monitored by QED’s Global 
Safety Organization on an ongoing basis throughout the course of the study to identify potential 
safety signals and new events of interest. Any unblinding of serious adverse events (SAEs) by 
Global Safety due to regulatory requirements will be shared with the DMC. 


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Infigratinib 
QED Therapeutics
Protocol QBGJ398-302  
Confidential
15 Nov 2022 
Page 18
 
   
8.10.8 
Vital Signs and ECOG Performance Status 
Eastern Cooperative Oncololgy Group (ECOG) performance status will be summarized at 
baseline, each post-baseline visit (based on the visit schedule defined in the protocol along with a 
window), the worst observed post-baseline values, and the last observed value, along with the 
change from baseline.  
Vital sign assessments are performed to characterize basic body function. The following 
parameters were collected: weight (kg), body temperature (°C), pulse rate (beats per minute), 
systolic and diastolic blood pressure (mmHg). The vital sign summaries will include all 
assessments available no later than 30 days after the last study treatment administration date. The 
vital sign will be summarized at baseline, each post-baseline visit, the maximum and minimum 
observed post-baseline values, and last observed value, along with the change from baseline.  


Infigratinib 
QED Therapeutics
Protocol QBGJ398-302  
Confidential
15 Nov 2022 
Page 19
 
   
9 REFERENCE LIST 
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life instrument for use in international clinical trials in oncology. J Natl Cancer Inst 
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Adaptive Designs for Clinical Trials of Drugs and Biologics, Guidance for Industry. 
FDA, Center for Drug Evaluation and Research (CDER), September 2018. 
Cox, DR, Oakes DO. Analysis of Survival Data. Chapman and Hall, London. 1984. 
Cui L, Hung HM, Wang SJ. Modification of sample size in group sequential clinical 
trials. Biometrics. 1999;55(3):853–857. 
Jennison C, Turnbull BW. Interim analyses: the repeated confidence interval approach. J R Stat 
Soc Series B Stat Methodol. 1989;51(3):305–61. 
Laird, NM, Ware JH. Random-effects models for longitudinal data. Biometrics. 1982;38(4):963–
74. 
Lan, KK, DeMets DL. Discrete sequential boundaries for clinical trials. Biometrika. 
1983;70(3):659–63. 
Lehmacher W, Wassmer G. Adaptive sample size calculations in group sequential trials. 
Biometrics. 1999;55(4):1286–90. 
Mehta CR, Pocock SJ. Adaptive increase in sample size when interim results are promising: a 
practical guide with examples. Stat Med. 2011;30(28):3267–84. 
O’Brien, PC, Fleming TR. A multiple testing procedure for clinical trials. Biometrics. 
1979;35:549–56. 
Osoba D, Rodrigues G, Myles J, Zee B, Pater J. Interpreting the significance of changes in 
health-related quality-of-life scores. J Clin Oncol. 1998;16(1):139-44.  
Rabin R, de Charro F. EQ-5D: a measure of health status from the EuroQol Group. Ann Med 
2001;33(5):337-343. 
 
 


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