Clinical trial NCT04172675
Conditions: Urinary Bladder Neoplasms
Keywords: Non muscle invasive bladder cancer (NMIBC) Bacillus calmette- guerin (BCG) failure BCG unresponsive
Sponsor: Janssen Research & Development, LLC
Start date: 2020-02-28; Completion date: 2025-02-27
Enrollment: 107 participants; Allocation: RANDOMIZED; Intervention model: PARALLEL

Brief summary:
The purpose of this study is to evaluate recurrence-free survival (RFS) in participants treated with erdafitinib vs Investigator's Choice, for participants with high-risk non-muscle-invasive bladder cancer (NMIBC) who harbor fibroblast growth factor receptor (FGFR) mutations or fusions, and who recurred after bacillus calmette-guerin (BCG) therapy.

Detailed description:
This study enrolls participants with high risk NMIBC and FGFR mutations or fusions. Erdafitinib is an oral pan-fibroblast growth factor receptor (FGFR) 1-4 inhibitor with demonstrated clinical activity in participants with solid tumors, including urothelial carcinoma, with alterations in the FGFR pathway. In Cohort 1, participants will be randomized to erdafitinib or to Investigators Choice (intravesical gemcitabine or intravesical mitomycin C \[MMC\] or hyperthermic MMC). The study consists of screening period, treatment phase, follow-up phase, and long-term extension phase.

Arms: arm 1: Participants with high-risk non-muscle-invasive bladder cancer (NMIBC) presenting as papillary tumor only (carcinoma in situ \[CIS\], absent), with disease recurrence after bacillus Calmette- Guerin (BCG) therapy will receive treatment with erdafitinib. arm 2: Participants with high-risk NMIBC presenting as papillary tumor only (CIS, absent), with disease recurrence after BCG therapy will receive the investigator's choice of either intravesical gemcitabine or intravesical mitomycin C (MMC) or hyperthermic MMC. Participants who are randomized to gemcitabine or MMC or hyperthermic MMC in Cohort 1 and demonstrate a recurrence via investigator disease assessment will have the opportunity to cross over to treatment with erdafitinib. arm 3: Participants with high-risk, BCG- unresponsive NMIBC presenting as CIS with or without concurrent papillary tumor will receive treatment with erdafitinib. arm 4: Marker lesion study in intermediate-risk NMIBC presenting as papillary disease only. All enrolled participants will receive treatment with erdafitinib.
Interventions: intervention 1: Erdafitinib intervention 2: Investigator Choice (Gemcitabine) intervention 3: Investigator Choice (Mitomycin C)
Intervention descriptions: intervention 1: Participants will receive erdafitinib orally beginning on Cycle 1 Day 1 until 2 years of treatment have been completed, disease recurrence, intolerable toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or study termination, whichever occurs first. Each cycle is of 28 days. intervention 2: Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months. intervention 3: Investigator's Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly maintenance for at least 6 months.

Protocol documents:
Prot_000.pdf: 
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
1
Status: Approved, Date: 13 July 2023
Janssen Research & Development *
Clinical Protocol
A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical
Chemotherapy in Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred
With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) and FGFR Mutations or
Fusions
Protocol 42756493BLC2003; Phase 2
Amendment 6
JNJ-42756493  (erdafitinib)
*Janssen Research & Development is a global organization that operates through different legal entities in
various countries/territories. Therefore, the legal entity acting as the sponsor for Janssen Research &
Development studies may vary, such as, but not limited to Janssen Biotech, Inc.; Janssen Products, LP;
Janssen Biologics, BV; Janssen-Cilag International NV; Janssen, Inc; Janssen Pharmaceutica NV; Janssen
Sciences Ireland UC; Janssen Biopharma Inc.; or Janssen Research & Development, LLC. The term
“sponsor” is used throughout the protocol to represent these various legal entities; the sponsor is
identified on the Contact Information page that accompanies the protocol.
United States (US)sites of this study will be conducted under US Food & Drug Administration
Investigational New Drug (IND) regulations (21 CFR Part 312).
Regulatory Agency Identifier Number(s):
IND: 117490
EudraCT NUMBER: 2019-002449-39
Status: 
Approved
Date: 
13 July 2023
Prepared by: Janssen Research & Development, LLC
EDMS number: 
EDMS-ERI-181257523, 8.0
GCP Compliance: This study will be conducted in compliance with Good Clinical Practice, and applicable regulatory
requirements.
Confidentiality Statement
The information provided herein contains Company trade secrets, commercial or financial information that the Company
customarily holds close and treats as confidential.  The information is being provided under the assurance that the recipient
will maintain the confidentiality of the information under applicable statutes, regulations, rules, protective orders or
otherwise.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
2
Status: Approved, Date: 13 July 2023
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE
DOCUMENT HISTORY
Document 
Date
Amendment 6 
13 July 2023
Amendment 5 
24-Sep-2021
Amendment 4 
08-Feb-2021
Amendment 3 
26-Oct-2020
Amendment 2 
26-Mar-2020
Amendment 1 
06-Nov-2019
Original Protocol 
24-Sep-2019
A Protocol Amendment Summary of Changes Table for the current amendment is provided below.
Protocol Amendment Summary of Changes Tables for previous amendments are provided in
Section 10.15 (Appendix 15).
Amendment 6 (13 July 2023)
Overall Rationale for the Amendment: to add the Long-term Extension (LTE) Phase, which
requires modification of the Study Completion, End of Study, and Subject Completion definitions.
The LTE Phase will allow continued access to study drug for subjects who continue to derive
benefit from treatment, as determined by their investigator. As an alternative to entering the LTE
Phase, subjects receiving erdafitinib may exit the study and continue to receive treatment on any
other post-trial access program, when permitted by local regulations. Otherkeychanges made with
this amendment include:
 
to update statistical language within the protocol to reflect early enrollment termination and
change in study's regulatory intent from registrational to non-registrational;
 
to state that no additional subjects will be allowed to crossover from Investigator’s Choice to
erdafitinib;
 
to clarify visit windows for the End-of-Treatment (EOT) visit and for Disease Assessment
Follow-up visits in the Follow-up Phase;
 
to remove requirement for urine collection for assay development at the time of high-risk
disease recurrence; and
 
to state that it is no longer required to send redacted images of Optical Coherence Tomography
(OCT)scans, photographs, and fluorescein angiograms to the sponsor-selected central vendor.
Section Number 
and Name
Description of Change 
Brief Rationale
1.1, Synopsis
(Objectives and
Endpoints, Overall
Design, Statistical
Methods);
1.2, Schema;
1.3, Schedule of
Activities;
2.3, Benefit-Risk
Assessment;
3, Objectives and
Statistical language has been updated throughout the
protocol. Changes include:
 Secondary endpoints for Cohort 1 limited to
time to progression (TTP), overall survival
(OS), and recurrence-free survival (RFS) rate
at 6 months and 12 months
 Exploratory efficacy endpoints for Cohort 2
modified to complete response (CR)rate at
8 weeks, CR rate at 32 weeks, and duration of
response (DOR)
To 
reflect 
early 
enrollment
termination and change in study’s
regulatory intent from registrational
to non-registrational.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
3
Status: Approved, Date: 13 July 2023
Section Number 
and Name
Description of Change 
Brief Rationale
Endpoints; 
4.1, Overall Design; 
4.2, Scientific 
Rationale for Study 
Design; 
8, Study 
Assessments and 
Procedures; 
8.1.1.3, Full-study 
Screening Phase; 
8.2.2, Patient- 
Reported Outcomes; 
8.3, Safety 
Assessments; 
8.10, Medical 
Resource Utilization 
and Health 
Economics; 
9.1, Statistical 
Hypothesis;
9.2, Sample Size
Determination;
9.3, Populations for
Analyses;
9.4.1, General
Considerations;
9.4.2, Primary
Endpoint
(Cohort 1);
9.4.3, Secondary
Efficacy Endpoints
(Cohort 1);
9.4.4,
Tertiary/Exploratory
Endpoints;
9.4.5, Safety
Analyses;
9.4.6.1,
Pharmacokinetic
Analyses;
9.4.6.3, Medical
Resource Utilization
Analyses
(removed);
9.5, Interim
Analysis;
9.6, Independent
Data Monitoring
Committee;
10.2, Appendix 2:
Regulatory, Ethical,
and Study Oversight
Considerations
(Committees
Structure)
 Exploratory efficacy endpoints for Cohort 3
modified to CR rate, best overall response
(BOR), and DOR
 Evaluation of health-related quality of life
(HRQoL) removed as secondary objective for
all cohorts, therefore, patient-reported outcome
(PRO) assessment/data collection is no longer
required for all subjects in all phases.
 Stated that due to early enrollment termination
and change in study’s regulatory intent for
Cohort 1 from registrational to
non-registrational, no formal hypothesis
testing will be performed for any of the
cohorts.
 Actual numbers of subjects enrolled to each
cohort are shown along with planned sample
sizes
 Removed all analyses other than descriptive
reporting
 Revised to show that interim analyses are no
longer planned
 Streamlined planned summaries for clinical
laboratory tests and electrocardiograms
 Streamlined planned pharmacokinetic (PK)
analyses

Removed planned medical resource utilization
(MRU)analyses, therefore, MRU data
collection is no longer required for all subjects
in all phases.
 Cessation of Independent Data Monitoring
Committee (IDMC) oversight
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
4
Status: Approved, Date: 13 July 2023
Section Number 
and Name
Description of Change 
Brief Rationale
1.1, Synopsis 
(Overall Design, 
Treatment Groups 
and Duration); 
4.1, Overall Design; 
6.1.2, Investigator’s 
Choice of Treatment
–Cohort 1 Only;
6.1.3, Continuation
of Treatment After
Disease Recurrence;
6.1.4, Erdafitinib
Crossover;
10.10, Appendix 10:
Erdafitinib
Crossover
The following text has been added to the listed 
sections of the protocol: 
‘Note: 
no 
additional 
crossover 
from 
Investigator’s Choice to erdafitinib will be 
permitted.’ 
Due to early termination of study
enrollment, the risk-benefit of
erdafitinib has not been established
for this indication, therefore new
cross-overs to erdafitinib will not be
permitted.
1.1, Synopsis 
(Overall Design); 
1.2, Schema; 
1.3, Schedule of 
Activities; 
4.1, Overall Design; 
4.4, Study 
Completion, End of 
Study, and Subject 
Completion
Definitions; 
6.7, Access to Study 
Drug in the 
Long-term 
Extension Phase;
8, Study
Assessments and
Procedures;
8.1.2, Treatment
Phase;
8.1.3.2, Long-term
Follow-up;
8.1.3.2.1, Disease
Assessment
Follow-up;
8.1.3.2.2, Survival
Follow-up;
8.1.5, Long-term
Extension Phase
(new section);
8.3, Safety
Assessments;
8.4, Adverse Events
and Serious Adverse
Events;
10.14, Appendix 14:
Long-term
Extension Phase
(new appendix)
The LTE Phase was added to the protocol with 
Section 10.14, Appendix 14, which includes a 
Schedule of Activities. The LTE Phase is also 
reflected as appropriate in the synopsis and body of 
the protocol. As an alternative to entering the LTE 
Phase, subjects receiving erdafitinib may exit the
study and continue to receive treatment on any other
post-trial access program, when permitted by local
regulations.
Within Section 4.4, to align with incorporation of
the LTE Phase, definitions for Study Completion,
End of Study, and Subject Completion have been
modified.
The LTE Phase will allow continued
access to study drug for subjects
who continue to derive benefit from
treatment, as determined by their
investigator.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
5
Status: Approved, Date: 13 July 2023
Section Number
and Name
Description of Change 
Brief Rationale
1.3, Schedule of
Activities
Window for the EOT visit has been modified as 
follows (deleted text in strikethrough, new text in 
bold): 
+7 days after last dose permanent treatment
discontinuation
For consistency 
with existing
language 
in 
Section 
8.1.2,
Treatment Phase.
1.3, Schedule of 
Activities 
Within the Follow-up Phase, the visit window for
Disease Assessment Follow-up visits now reads as
follows (text in bold has been added):
‘Every 24 weeks (±2 weeks) from the last
disease assessment visit in the Treatment
Phase’
Clarification.
1.3, Schedule of 
Activities
(Cystoscopy row) 
The following text has been added (in bold):
Cohort 1 and Cohort 2: C3D1 then every
12 weeks (±1 week) until C26D1, end of
treatment, or until disease recurrence or
progression, whichever occurs first.
Cohort 3 only: C2D1, C3D1, C4D1 (±1 week) or
until CR (if earlier). After CR, every 12 weeks
(±1 week) until C26D1, end of treatment, or until
disease recurrence or progression, whichever
occurs first. If PR, see Section 8.2.1.5.
Clarification.
1.3, Schedule of 
Activities; 
4.1, Overall Design; 
8.9, Biomarkers 
The pre-transurethral resection of bladder tumor
(TURBT) voided urine sample that was to be
collected for assay development at the time of
high-risk disease recurrence has been marked as ‘no
longer required’ in  the Schedule of Activities.
Corresponding changes have been made in the
protocol body.
This sample is not needed due to
early enrollment termination.
5.4, Screen Failures 
The following text has been added: ‘This study will
use IWRS. The investigator will generate screening
and enrollment logs directly from IWRS.’
To align with protocol template.
7.1, Discontinuation 
of Study Drug 
The following criterion has been added to the list of
reasons for which a subject’s study drug must be
discontinued:
 Subject reaches the maximum treatment
duration as defined in Section 6.1.
Internal consistency.
8.1.2, Treatment 
Phase
The following text has been added (in bold):
With the exception of hyperphosphatemia
(see Table 3), adverse event information will be
graded using the National Cancer Institute
Common Terminology Criteria for Adverse
Events (NCI-CTCAE), Version 5.0.
Clarification.
8.3.5, 
Ophthalmologic 
Examination  
Added text stating that it is no longer required to
send redacted images of OCT  scans, photographs,
and fluorescein angiograms to the sponsor-selected
central vendor.
This review is not needed due to
change in study’s regulatory intent
from registrational to
non-registrational.
8.4.1, Time Period 
and Frequency for 
Collecting Adverse
Text in strikethrough has been removed, and text in
bold has been added to this sentence:
To align with protocol template.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
6
Status: Approved, Date: 13 July 2023
Section Number
and Name
Description of Change 
Brief Rationale
Event and Serious
Adverse Event
Information
‘All serious adverse events occurring during the
study must be reported to the appropriate
sponsor contact person by study-site personnel
within immediately but no later than 24 hours
of their knowledge of the event.’
10.2, Appendix 2:
Regulatory, Ethical,
and Study Oversight
Considerations
(Informed Consent
Process)
The screening period now reflects 35 days 
(previously 30 days). Also, added that subjects 
undergoing molecular screening do not need to 
re-sign a new Molecular Eligibility ICF to submit 
historical samples to the central laboratory.
Aligned screening period with body
of protocol and added clarification
regarding 
molecular 
eligibility
consent.
Throughout the
protocol
Minor grammatical, formatting, or spelling changes
were made. Country revised to country/territory
throughout.
To correct minor errors and to align
with current protocol template.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
7
Status: Approved, Date: 13 July 2023
TABLE OF CONTENTS
PROTOCOL AMENDMENT SUMMARY OF CHANGES TABLE ............................................................... 2
TABLE OF CONTENTS ............................................................................................................................... 7
LIST OF IN-TEXT TABLES AND FIGURES.............................................................................................. 11
1. 
PROTOCOL SUMMARY................................................................................................................... 12
1.1. 
Synopsis......................................................................................................................................... 12
1.2. 
Schema.......................................................................................................................................... 15
1.3. 
Schedule of Activities..................................................................................................................... 16
2. 
INTRODUCTION................................................................................................................................ 29
2.1. 
Study Rationale.............................................................................................................................. 29
2.2. 
Background .................................................................................................................................... 30
2.2.1. 
Fibroblast Growth Factor Receptors........................................................................................... 30
2.2.2. 
Erdafitinib.................................................................................................................................... 31
2.2.3. 
Comparator Drugs ...................................................................................................................... 33
2.2.3.1. 
Gemcitabine............................................................................................................................. 33
2.2.3.2. 
Mitomycin C............................................................................................................................. 34
2.3. 
Benefit-Risk Assessment............................................................................................................... 34
3. 
OBJECTIVES AND ENDPOINTS ..................................................................................................... 36
4. 
STUDY DESIGN ................................................................................................................................ 37
4.1. 
Overall Design................................................................................................................................ 37
4.2. 
Scientific Rationale for Study Design............................................................................................. 40
4.2.1. 
Study-Specific Ethical Design Considerations ........................................................................... 42
4.2.2. 
Participant Input Into Design ...................................................................................................... 43
4.3. 
Justification for Dose...................................................................................................................... 43
4.3.1. 
Erdafitinib Dose Selection........................................................................................................... 43
4.3.2. 
Gemcitabine Dose Selection ...................................................................................................... 43
4.3.3. 
Mitomycin C Dose Selection....................................................................................................... 44
4.4. 
Study Completion, End of Study, and Subject Completion Definitions.......................................... 44
5. 
STUDY POPULATION ...................................................................................................................... 44
5.1. 
Inclusion Criteria............................................................................................................................ 45
5.2. 
Exclusion Criteria........................................................................................................................... 49
5.3. 
Lifestyle Considerations................................................................................................................. 50
5.4. 
Screen Failures.............................................................................................................................. 51
6. 
STUDY DRUG ................................................................................................................................... 51
6.1. 
Study Drug Administered ............................................................................................................... 52
6.1.1. 
Erdafitinib.................................................................................................................................... 52
6.1.2. 
Investigator’s Choice of Treatment –Cohort 1 Only .................................................................. 53
6.1.2.1. 
Gemcitabine Administration..................................................................................................... 54
6.1.2.2. 
Mitomycin C Administration..................................................................................................... 54
6.1.3. 
Continuation of Treatment After Disease Recurrence................................................................ 54
6.1.4. 
Erdafitinib Crossover .................................................................................................................. 54
6.2. 
Preparation/Handling/Storage/Accountability ................................................................................ 55
6.3. 
Measures to Minimize Bias: Randomization and Blinding............................................................. 55
6.4. 
Study Drug Compliance ................................................................................................................. 56
6.5. 
Concomitant Therapy..................................................................................................................... 56
6.5.1. 
Permitted Medications ................................................................................................................ 56
6.5.2. 
Prohibited Medications ............................................................................................................... 57
6.5.3. 
Precautions for Concomitant Medications.................................................................................. 57
6.6. 
Dose Modification........................................................................................................................... 58
6.6.1. 
Erdafitinib Up-titration Guidelines............................................................................................... 58
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
8
Status: Approved, Date: 13 July 2023
6.6.2. 
Erdafitinib Dose Interruptions ..................................................................................................... 58
6.6.2.1. 
Guidance for Specific Erdafitinib Toxicities ............................................................................. 59
6.6.2.1.1. 
Guidelines for the Management of Elevated Phosphate Levels.......................................... 59
6.6.2.1.2. 
Guidelines for the Management of Dry Mouth and Mucositis.............................................. 61
6.6.2.1.3. 
Guidelines for the Management of Dry Skin and Skin Toxicity............................................ 62
6.6.2.1.4. 
Guidelines for Management of Nail Toxicity (Onycholysis, Onychodystrophy, and
Paronychia).......................................................................................................................... 63
6.6.2.1.5. 
Guidelines for the Management of Eye Toxicity Associated With Vision Changes............. 66
6.6.2.1.6. 
Guidelines for the Management of Dry Eye......................................................................... 68
6.6.3. 
Investigator’s Choice Dose Modification..................................................................................... 68
6.7. 
Access to Study Drug in the Long-term Extension Phase............................................................. 68
7. 
DISCONTINUATION OF STUDY DRUG/SUBJECT
DISCONTINUATION/WITHDRAWAL/STUDY CLOSURE............................................................... 69
7.1. 
Discontinuation of Study Drug ....................................................................................................... 69
7.2. 
Subject Discontinuation/Withdrawal From the Study..................................................................... 69
7.2.1. 
Withdrawal From the Future Use of Research Samples............................................................ 70
7.3. 
Lost to Follow-up............................................................................................................................ 70
8. 
STUDY ASSESSMENTS AND PROCEDURES ............................................................................... 70
8.1. 
Study Procedures........................................................................................................................... 71
8.1.1. 
Screening.................................................................................................................................... 71
8.1.1.1. 
Molecular Eligibility Screening Phase (Cohort 1 and Cohort 2).............................................. 71
8.1.1.2. 
Cohort 3 Molecular Eligibility................................................................................................... 75
8.1.1.3. 
Full-study Screening Phase..................................................................................................... 75
8.1.2. 
Treatment Phase ........................................................................................................................ 76
8.1.3. 
Follow-up Phase......................................................................................................................... 78
8.1.3.1. 
Safety Follow-up...................................................................................................................... 78
8.1.3.2. 
Long-term Follow-up................................................................................................................ 78
8.1.3.2.1. 
Disease Assessment Follow-up........................................................................................... 78
8.1.3.2.2. 
Survival Follow-up................................................................................................................ 78
8.1.4. 
Unscheduled Visits ..................................................................................................................... 79
8.1.5. 
Long-term Extension Phase ....................................................................................................... 79
8.2. 
Efficacy Assessments .................................................................................................................... 79
8.2.1. 
Disease Assessments ................................................................................................................ 79
8.2.1.1. 
Cohort 1 ................................................................................................................................... 79
8.2.1.2. 
Cohort 2................................................................................................................................... 79
8.2.1.3. 
Cohort 3................................................................................................................................... 79
8.2.1.4. 
Histopathologic Assessment and FGFR (All Cohorts)............................................................ 80
8.2.1.5. 
Cystoscopy, Urine Cytology, Bladder Mapping, and CT/MRI Urogram .................................. 80
8.2.2. 
Patient-Reported Outcomes....................................................................................................... 82
8.3. 
Safety Assessments....................................................................................................................... 83
8.3.1. 
Physical Examinations................................................................................................................ 83
8.3.2. 
Vital Signs................................................................................................................................... 83
8.3.3. 
Electrocardiograms..................................................................................................................... 83
8.3.4. 
Clinical Safety Laboratory Assessments .................................................................................... 84
8.3.5. 
Ophthalmologic Examination...................................................................................................... 84
8.3.6. 
Pregnancy Testing: Urine or Serum β-hCG ............................................................................... 85
8.3.7. 
ECOG Performance Status ........................................................................................................ 85
8.4. 
Adverse Events and Serious Adverse Events ............................................................................... 85
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious Adverse Event
Information.................................................................................................................................. 86
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse....................................................... 86
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events ....................................................... 86
8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events and Anticipated
Events......................................................................................................................................... 87
8.4.5. 
Pregnancy................................................................................................................................... 87
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
9
Status: Approved, Date: 13 July 2023
8.4.6. 
Disease-Related Events and Disease-Related Outcomes Not Qualifying as Adverse
Events or Serious Adverse Events............................................................................................. 88
8.4.7. 
Adverse Events of Special Interest............................................................................................. 88
8.5. 
Treatment of Overdose .................................................................................................................. 88
8.6. 
Pharmacokinetics........................................................................................................................... 88
8.6.1. 
Evaluations ................................................................................................................................. 88
8.6.2. 
Analytical Procedures................................................................................................................. 89
8.6.3. 
Pharmacokinetic Parameters and Evaluations........................................................................... 89
8.7. 
Pharmacodynamics........................................................................................................................ 90
8.8. 
Genetics......................................................................................................................................... 90
8.9. 
Biomarkers..................................................................................................................................... 90
8.10. 
Medical Resource Utilization and Health Economics .................................................................... 93
9. 
STATISTICAL CONSIDERATIONS.................................................................................................. 93
9.1. 
Statistical Hypothesis..................................................................................................................... 93
9.2. 
Sample Size Determination ........................................................................................................... 93
9.3. 
Populations for Analyses................................................................................................................ 94
9.4. 
Statistical Analyses ........................................................................................................................ 94
9.4.1. 
General Considerations.............................................................................................................. 95
9.4.2. 
Primary Endpoint (Cohort 1)....................................................................................................... 95
9.4.3. 
Secondary Efficacy Endpoints (Cohort 1)................................................................................... 95
9.4.4. 
Tertiary/Exploratory Endpoints ................................................................................................... 96
9.4.5. 
Safety Analyses.......................................................................................................................... 96
9.4.6. 
Other Analyses ........................................................................................................................... 97
9.4.6.1. 
Pharmacokinetic Analyses ...................................................................................................... 97
9.4.6.2. 
Biomarkers Analyses............................................................................................................... 98
9.5. 
Interim Analysis.............................................................................................................................. 98
9.6. 
Independent Data Monitoring Committee ...................................................................................... 98
10. SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ............................ 99
10.1. 
Appendix 1: Abbreviations ............................................................................................................. 99
10.2. 
Appendix 2: Regulatory, Ethical, and Study Oversight Considerations....................................... 101
REGULATORY AND ETHICAL CONSIDERATIONS ........................................................................ 101
FINANCIAL DISCLOSURE ................................................................................................................ 104
INFORMED CONSENT PROCESS ................................................................................................... 104
DATA PROTECTION ......................................................................................................................... 105
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH.................... 106
COMMITTEES STRUCTURE ............................................................................................................ 106
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA......................................... 107
DATA QUALITY ASSURANCE .......................................................................................................... 108
CASE REPORT FORM COMPLETION ............................................................................................. 108
SOURCE DOCUMENTS .................................................................................................................... 109
MONITORING .................................................................................................................................... 110
ON-SITE AUDITS............................................................................................................................... 111
RECORD RETENTION ...................................................................................................................... 111
STUDY AND SITE START AND CLOSURE...................................................................................... 111
10.3. 
Appendix 3: Adverse Events: Definitions and Procedures for Recording, Evaluating,
Follow-up, and Reporting............................................................................................................. 113
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS............................................................ 113
SEVERITY CRITERIA........................................................................................................................ 114
SPECIAL REPORTING SITUATIONS ............................................................................................... 115
PROCEDURES .................................................................................................................................. 115
CONTACTING SPONSOR REGARDING SAFETY........................................................................... 117
PRODUCT QUALITY COMPLAINT HANDLING................................................................................ 117
10.4. 
Appendix 4: Contraceptive and Barrier Guidance and Collection of Pregnancy Information...... 118
10.5. 
Appendix 5: ECOG Performance Status Scale ........................................................................... 121
10.6. 
Appendix 6: Estimated Creatinine Clearance .............................................................................. 122
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
10
Status: Approved, Date: 13 July 2023
10.7. 
Appendix 7: The Stages of Heart Failure –New York Heart Association (NYHA)
Classification ................................................................................................................................ 123
10.8. 
Appendix 8: Amsler Grid .............................................................................................................. 124
10.9. 
Appendix 9: Drugs Classified as Strong In Vivo Inhibitors of CYP3A4/2C9 or as Moderate
to Strong Inducers of CYP3A4/2C9Enzymes ............................................................................. 125
10.10. Appendix 10: Erdafitinib Crossover.............................................................................................. 126
10.11. Appendix 11: Bladder Map........................................................................................................... 135
10.12. Appendix 12: Guidance for 6 mg Daily Dose with Up-titration..................................................... 136
10.13. Appendix 13: Guidance on Study Conduct During a National Disaster for Enrolled
Subjects ....................................................................................................................................... 138
10.14. Appendix 14: Long-term Extension Phase................................................................................... 140
10.15. Appendix 15: Protocol Amendment History................................................................................. 144
11. REFERENCES................................................................................................................................. 171
INVESTIGATOR AGREEMENT............................................................................................................... 174
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
11
Status: Approved, Date: 13 July 2023
LIST OF IN-TEXT TABLES AND FIGURES
TABLES
Table 1: 
Erdafitinib Dose Modification Rules Based on Toxicity Severity .............................................. 58
Table 2: 
Erdafitinib Dose Reduction Levels............................................................................................ 59
Table 3: 
Grading of Hyperphosphatemia Adverse Events ..................................................................... 59
Table 4: 
Guidelines for Management of Serum Phosphate Elevation.................................................... 60
Table 5: 
Guidelines for Management of Dry Mouth (Xerostomia).......................................................... 61
Table 6: 
Guidelines for the Management of Oral Mucositis.................................................................... 62
Table 7: 
Guidelines for Management of Dry Skin................................................................................... 63
Table 8: 
Grading of Nails Adverse Events.............................................................................................. 64
Table 9: 
Guidelines for Management of Nail Toxicity (Onycholysis/Onychodystrophy)......................... 65
Table 10: Guidelines for Management of Paronychia.............................................................................. 66
Table 11: Guidelines for Management of Eye Toxicity............................................................................. 67
Table 12: Hazard Ratio Confidence Intervals........................................................................................... 94
FIGURES
Figure 1: Schematic Overview of the Study............................................................................................. 15
Figure 2: Study 42756493BLC2003 (THOR2) Tissue Testing Paradigm................................................ 74
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
12
Status: Approved, Date: 13 July 2023
1. 
PROTOCOL SUMMARY
1.1. 
Synopsis
A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical Chemotherapy in
Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred With High Risk Non-Muscle-
Invasive Bladder Cancer (NMIBC) and FGFR Mutations or Fusions
Erdafitinib (JNJ-42756493) is an oral pan-fibroblast growth factor receptor (FGFR) 1-4 inhibitor with
demonstrated clinical activity in subjects with solid tumors, including urothelial carcinoma, with alterations
in the FGFR pathway.
OBJECTIVES AND ENDPOINTS
Cohort 1 (papillary disease only)
Primary Objective: To evaluate recurrence-free survival (RFS) in  subjects treated with erdafitinib vs
Investigator’s Choice, for subjects with high-risk NMIBC who harbor FGFR mutations or fusions, and who
recurred after BCG therapy.
Secondary Objective and Endpoints: To evaluate other measures of efficacy. Endpoints include time to
progression, overall survival (OS), and RFS rate at 6 months and 12 months.
Cohort 2 (carcinoma in situ [CIS] with or without papillary disease)
Exploratory Objective: To evaluate the efficacy of erdafitinib in terms of the complete response (CR) rate
at 8 weeks, CR rate at 32 weeks, and duration of response (DOR) in subjects with high-risk,
BCG-unresponsive NMIBC and FGFR mutations or fusions.
Cohort 3 (intermediate-risk marker lesion) at select study sites
Exploratory Objective: To evaluate the efficacy of erdafitinib in terms of the CR rate, best overall response
(BOR), and DOR in subjects with intermediate-risk NMIBC and FGFR mutations or fusions.
Other secondary objectives for all cohorts
Secondary objectives for all cohorts include the following:
 
To evaluate erdafitinib pharmacokinetics
 
To evaluate safety and tolerability of erdafitinib
Hypothesis
For Cohort 1, erdafitinib treatment will delay the onset of tumor recurrence for subjects with papillary
disease only, who recurred after BCG therapy, with FGFR mutations or fusions, and with all lesions
removed.
For Cohort 2, erdafitinib treatment will lead to CR for subjects with CIS with or without papillary disease
and FGFR mutations or fusions.
For Cohort 3, erdafitinib treatment will lead to CR in the marker lesion for subjects with a papillary marker
lesion and FGFR mutations or fusions.
Due to early enrollment termination and change in study’s regulatory intent for Cohort 1 from registrational
to non-registrational, no formal hypothesis testing will be performed for any of the cohorts.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
13
Status: Approved, Date: 13 July 2023
OVERALL DESIGN
This is an open-label, global, multicenter, randomized, Phase 2 study of the safety and efficacy of erdafitinib
in subjects with NMIBC and FGFR mutations or fusions (see Section 5.1).
Cohort 1 (n=240 planned) will include subjects with high-risk NMIBC presenting as papillary tumor only,
with disease recurrence after BCG therapy, and who either refuse or are not eligible for cystectomy. The
reason for not being eligible for cystectomy or for refusing cystectomy will be entered into the electronic
case report form (eCRF). Subjects will be assigned randomly 2:1 to treatment with erdafitinib or the
investigator’s choice of either intravesical gemcitabine or intravesical mitomycin C (MMC)/hyperthermic
MMC, respectively. Randomization will be stratified by tumor stage (Ta vs T1) and type of prior BCG
therapy (BCG-unresponsive vs BCG-experienced). BCG strain administered will also be documented in
the eCRF. Subjects in the BCG-experienced strata will be capped at approximately 50% of the total study
population (See Section 6.3). Investigators must choose between intravesical gemcitabine or intravesical
MMC/hyperthermic MMC for each subject at screening, and the choice of the agent must take prior
exposure into consideration. Subjects in Cohort 1 with locally confirmed high-risk recurrence on
Investigator’s Choice may cross over to treatment with erdafitinib. Note: no additional crossover from
Investigator’s Choice to erdafitinib will be permitted. Molecular screening must start within 12 weeks after
the last transurethral resection of bladder tumor (TURBT) done for high risk recurrence if molecular testing
is being done on post-BCG specimen. Peri-operative intravesical chemotherapy prior to study entry per
local standard of care and prior immunotherapy (eg, PD1 inhibitor etc) are allowed.
Cohort 2 and Cohort 3 are exploratory.
Cohort 2 (n=20 planned) will include subjects with high-risk, BCG-unresponsive NMIBC presenting as
CIS with or without concurrent papillary tumor, and who either refuse or are not eligible for cystectomy.
The reason for not being eligible for cystectomy or for refusing cystectomy will be entered into the eCRF.
All subjects enrolled in Cohort 2 will receive treatment with erdafitinib. Peri-operative intravesical
chemotherapy prior to study entry per local standard of care and prior immunotherapy (eg, PD1 inhibitor
etc) are allowed. Additionally, subjects in this cohort may receive chemotherapy as bridging therapy after
adequate BCG therapy while being considered for trial.
Cohort 3 (n=20 planned) will be enrolled at select study sites and will include subjects with intermediate-
risk NMIBC presenting as papillary disease only. All previous tumors for these subjects must be low grade
(G1-G2), Ta, or T1, with no previous CIS. Furthermore, subjects must have a risk of progression less than
5% for 2 years, and the risk of recurrence must be greater than 50% as calculated using the European
Organisation for Research and Treatment of Cancer (EORTC) risk calculator.19 There are no predefined
BCG or intravesical chemotherapy requirements for subjects enrolled in Cohort 3. All tumors must be
removed except for a single, untouched 5 to 10 mm lesion. All subjects enrolled in Cohort 3 will receive
treatment with erdafitinib.
Molecular eligibility will be determined before screening for remaining eligibility criteria. The Treatment
Phase will begin on Day 1 for subjects meeting all eligibility criteria. The Follow-up Phase includes a
30-day Safety Follow-up Visit, disease assessment follow-up, and survival follow-up. An Independent Data
Monitoring Committee (IDMC) will be commissioned for the study. Due to the company decision to
terminate study enrollment and considering the recent IDMC review (6 July 2022) found the safety of
erdafitinib in this study to be consistent with the known safety profile of erdafitinib, no further monitoring
by the IDMC will be conducted.
The Long-term Extension (LTE) Phase will allow continued access to study drug for subjects who continue
to derive benefit from treatment, as determined by their investigator. Subjects may enter the LTE Phase
following implementation  of Amendment 6, provided they meet the criteria for entry specified in the
protocol. No data will be collected in the eCRF during the LTE Phase, and only serious adverse events
(SAEs) will be reported to the company safety repository. As an alternative to entering the LTE Phase,
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
14
Status: Approved, Date: 13 July 2023
subjects receiving erdafitinib may exit the study and continue to receive treatment on any other post-trial
access program, when permitted by local regulations.
TREATMENT GROUPS AND DURATION
Subjects receiving erdafitinib will take erdafitinib tablets orally, at a starting dose of 6 mg, once daily for
28 days in a 28-day cycle. After review of safety and tolerability data from approximately 5 to 10 additional
subjects dosed with the 6-mg daily regimen (without up-titration), the IDMC may recommend a
modification of the dosing regimen to include up-titration to 8 mg daily. The details of the IDMC
recommendation will be communicated in writing to the investigative sites and, per local regulation, to
health authorities. With the exceptions noted below for Cohort 2 and Cohort 3, treatment may continue for
a maximum of 2 years or until the subject has disease recurrence or progression, intolerable toxicity,
withdraws consent, there is a decision by the investigator to discontinue treatment, or the study is closed,
whichever occurs first.
 
For Cohort 2, erdafitinib must be discontinued if CR is not observed within 3 months.
 
For Cohort 3, after 3 months of study treatment: 1) Subjects with stable disease or progression of the
marker lesion must discontinue erdafitinib and a TURBT of the marker lesion must be performed. 2)
Subjects with CR may continue erdafitinib. 3) Subjects with partial response (PR) may, at the
investigator’s discretion, either continue treatment with erdafitinib or discontinue erdafitinib and
undergo TURBT of the marker lesion.
Subjects in Cohort 1 assigned to Investigator’s Choice will receive intravesical gemcitabine or intravesical
MMC/hyperthermic MMC as described in Section 6.1.2. All dose modifications or omissions will be
managed by the treating physician per local standard of care after discussion with the sponsor. Investigator’s
Choice treatment will be given once weekly for at least 4 doses of induction followed by monthly
maintenance for at least 6 months. Additional doses of induction or maintenance are allowed per local
standard of care. This treatment may continue until it is completed, disease recurrence, intolerable toxicity,
withdrawal of consent, a decision by the investigator to discontinue treatment, or the study is closed,
whichever occurs first.
Subjects in Cohort 1 with locally confirmed high-risk recurrence on Investigator’s Choice may cross over
to treatment with erdafitinib (Section 10.10). Note: no additional crossover from Investigator’s Choice to
erdafitinib will be permitted.
EVALUATIONS
The timing of all study evaluations is provided in the Schedule of Activities (Section 1.3). Disease
assessments include regularly scheduled cystoscopy, bladder mapping, local assessment of urine cytology,
and contrast-enhanced computed tomography (CT) or magnetic resonance imaging (MRI) urograms.
Central histopathologic review of biopsied tumor tissue will be performed for Cohort 1. Biomarker
assessments include molecular screening to determine eligibility for the study and exploratory DNA, RNA,
and protein analyses using archival or fresh biopsy tissue, urine, and blood. Erdafitinib concentration will
be measured in blood and biopsied tissue for pharmacokinetic analysis. Safety assessments will include
adverse event reports, physical examinations, 12-lead electrocardiograms (ECGs), clinical laboratory tests,
vital sign measurements, β-human chorionic gonadotropin (β-hCG) pregnancy tests, and ophthalmologic
examinations.
STATISTICAL METHODS
The cohorts will be analyzed separately. Descriptive statistics and subject listings will be used to summarize
the data. For continuous variables, number of observations, means, standard deviations, medians,
interquartiles (IQs), and ranges will be used. For discrete variables, frequency will be summarized. The
comparisons between the 2 treatment groups in Cohort 1 will be performed using descriptive statistics.
NCT04172675


NCT04172675


NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
17
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
for screening or baseline purposes
provided the procedure meets the protocol-
defined criteria and has been performed
within 35 days prior to dosing.
Inclusion/excl
usion criteria
See Section 5.1 and Section 5.2. Confirm
inclusion/exclusion criteria C1D1
X
X
C1D1
predose
Medical
history
including
smoking
history
Record histological documentation of
specific tumor type, prior anticancer
therapy, demographic information.
X
Tumor tissue
for molecular
eligibility,
histopatholog
y staging, and
biomarker
testing
During the Molecular Eligibility Phase, send
biopsy sample to the central laboratory for
FGFR testing (all cohorts). After a FGFR
status is confirmed, send central
histopathologic sample for a blinded
independent central review (BICR) (Cohort
1 only). Biomarker evaluation (all cohorts)
will be analyzed from the tissue sent for
FGFR analysis.b See Section 8.6.1 and the
Laboratory Manual for instruction on
sample handling. Also see Section 5.1
(Inclusion Criterion no. 3), Section 8.1.1.1,
Section 8.1.1.2, Section 8.2.1 and
Section 8.9(tissue biomarkers).
X
NCT04172675


NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
19
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
from approximately 5 to 10 additional
subjects dosed with the 6-mg daily
regimen, the IDMC may recommend a
modification of the dosing regimen to allow
up-titration to the 8-mg daily regimen
based on phosphate levels measured on
Cycle 2 Day 1. See Section 10.12,
Appendix 12.) (see Section 4.3.1 and
guidelines in Section 6.6.1). See
Section 6.1.1 for guidelines on treatment
discontinuation for subjects in Cohort 2 and
Cohort 3 with limited response after 3
months of treatment.
completed, disease
recurrence or progression
(Cohort 1, Cohort 2, and
Cohort 3), intolerable toxicity,
withdrawal of consent, a
decision by the investigator
to discontinue treatment, or
study termination, whichever
occurs first
Investigator’s
Choice
Cohort 1 only. Intravesical gemcitabine or
intravesical MMC/hyperthermic MMC as
Investigator’s Choice. See Section 6.1.2for
additional information. Other assessments
required for
Day 14 in the Schedule of Activities will be
performed on Day 15 for Investigator’s
Choice subjects. On C1D8 and C1D22,
AEs and any new concomitant therapies
will be recorded in the eCRF.
Investigator’s Choice
treatment will be given once
weekly for at least 4 doses of
induction on C1D1, C1D8,
C1D15, C1D22 (±2 days)
followed by monthly
maintenance on C2D1,
C3D1, C4D1, C5D1, C6D1,
C7D1 (±2 days). Additional
doses of induction or
maintenance are allowed per
local standard of care.
If >4 induction doses are
given and the start of the
monthly maintenance dose
falls either on Day 8,
NCT04172675


NCT04172675


NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
22
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
Comprehensi
ve metabolic
panel
All Subjects. If screening sample is drawn
within 3 days before C1D1, C1D1
measurement does not have to be
repeated. For exact assessment see
Section 8.3.4. After Cycle 6 Visit, perform
every 3 cycles until end of treatment, eg,
Cycle 6, Cycle 9, Cycle 12.
X 
X 
X 
X 
X 
X
Phosphate
All subjects during screening. Before
dosing on C1D1.
Only erdafitinib-treated subjects from
C1D1. See Section 8.3.4
X 
X 
X 
X
1,25-
dihydroxyvita
min D
All subjects 
X
X
All subjects: C13D1
(±1 week)
X
Parathyroid
hormone
All subjects during screening. Only
erdafitinib-treated subjects from C1D1.
After Cycle 6 Visit, perform every 3 cycles
until end of treatment, eg, Cycle 6, Cycle 9,
Cycle 12 (see Section 8.3.4).
X
X
C2, C3
only
X
C1 only
X
NCT04172675


NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
24
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
Bladder
mapping
Cohort 1: For subjects in Cohort 1, bladder
mapping at screening will be only done if
there is prior history of CIS. During
treatment or follow-up phase will only be
done if urine cytology is positive for
malignant cells and cystoscopy is negative.
Cohort 2: All subjects in Cohort 2 will have
bladder mapping at screening and at Cycle
12.
Cohort 3: No bladder mapping will be done
for subjects in Cohort 3. See Section
8.2.1.5
Cohorts 1 and 2: In addition, tissue from
any positive biopsy (any grade of
recurrence) from bladder mapping should
be sent for exploratory biomarker analysis
to central laboratory.
X
Cohort 2
only
C12D1
(±1
week)
Urine cytology
Cohort 1 and Cohort 2 only: Urine sample
may be collected either from bladder
washing during cystoscopy or from a
voided urine specimen (bladder wash
specimen is preferred). Analysis will be
done locally (see Section 8.2.1).
Cohort 3: will perform a urine cytology
during bladder washing at time of CR only.
X
Cohort 1 and Cohort 2: C3D1
then every 12 weeks (±1
week) until C26D1, end of
treatment, or until disease
recurrence or progression.
Cohort 3 will perform a urine
cytology during bladder
washing at time of CR only.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
25
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
MRU Data
Collection
Cohort 1 and Cohort 2 only. See
Section 8.10. Note: MRU data collection is
no longer required for all subjects in all
phases.
X
Cohort 1 and Cohort 2 only:
C3D1 then every 12 weeks
(±1 week) until C26D1, end 
of treatment, or until disease
recurrence or progression.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
CT/MRI
Urogram
If a subject cannot tolerate intravenous
contrast, a retrograde pyelogram is
acceptable (see Section 8.2.1).
X
Starting from Cycle 6, every 24 weeks (±2 weeks)
until recurrence/progression.
PGIC
PRO measures to be completed before any
other study procedures. See Section 8.2.2.
Note: PRO assessment/data collection is
no longer required for all subjects in all
phases.
X
C2D1
only
X
PGIS
EORTC QLQ-
C30
EORTC QLQ-
NMIBC24
EQ-5D-5L
PRO assessments will be completed
before any other study procedures at the
corresponding visit. See Section 8.2.2for
additional detail. Note: PRO assessment/
data collection is no longer required for all
subjects in all phases.
X
X
Day 1 of each cycle while on
treatment
X
Voided urine
sample for
assay
development
A voided urine sample will be collected
after disease recurrence and before
TURBT (except for patients being
considered for study after TURBT).
Samples for subjects who are found to
have low or intermediate risk disease
X
X
(pre
TURBT)
No longer
required
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
26
Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
recurrence must be discarded (except for
eligible Cohort 3 subjects).
Urine for
(ie, for
biomarker
research)
Samples for urine biomarker research will
not interfere with urine cytology and will be
taken from excess bladder washing
sample/ urine/cells remaining after urine
cytology sample amount is aliquoted for
testing or from independent sampling, as
appropriate.
X
All Cohorts: C3D1 then every
12 weeks (±1 week) until
C26D1, end of treatment, or
until disease recurrence or
progression.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
Blood
(plasma) for
ctDNA
See Section 8.9.
All Cohorts: C1D1 (predose),
C3D1, then every 12 weeks
(±1 week) until C26D1, end
of treatment, or until disease
recurrence or progression.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
PK: blood
sample for
erdafitinib
Subjects receiving erdafitinib only. Record
dosing and PK collection times. If indicated
by the emerging safety findings or if the
scheduled PK samples are not collected
due to treatment interruption, C2D1 blood
samples may be collected at a later site
visit (C2D14, C3D1, or C3D14). See
Section 8.6.1.
X
C1D14: predose
X
C2D1:  predose
and 3h (±1 h)
postdose
CCI
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Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
PK: blood
sample for
erdafitinib at
time of tissue
specimen
collection
Subjects receiving erdafitinib only. See
Section 8.6.1
Plasma PK sample collected at the same
time as the tissue specimen collection during
the Treatment Phase
PK: tissue
specimen for
erdafitinib
Subjects receiving erdafitinib only. See
Section 8.6.1 and Laboratory Manual for
instruction on tissue sample handling
Tissue specimens from any biopsy during
the Treatment Phase including bladder
mapping biopsies (Cohort 1 and Cohort 2)
Protein
binding blood
sample
Subjects receiving erdafitinib only. See
Section 8.6.1 and the Laboratory Manual
for description of the assessment and
sample processing.
X
C2D1
3h (±1 h)
postdose
Blood sample
for CYP2C9
genotyping
Subjects receiving erdafitinib only. See
Section 8.8.
X
C1D14 anytime (or later time point)
24-hour PK
urine sample
First approximately 20 subjects receiving
erdafitinib (from any cohort):
24-hour urine collection: subjects will need
to return the 24-hour urine collection on
C1D15.
X
C1
Survival
status and
subsequent
anticancer
therapy
May be assessed via telephone call, email,
or visit to the study site. Survival status,
start of alternate anticancer therapy, and
results of standard-of-care cystoscopy will
be monitored at least every 12 weeks (±2
weeks) until death, withdrawal of consent,
X
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Clinical Protocol 42756493BLC2003 –Amendment 6
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Status: Approved, Date: 13 July 2023
NOTES
Urine Sample
for Assay
Development
Molecular
Eligibility
Phase
Screening
Phase
Treatment Phasea (28 days Cycle) 
Follow-up Phasea
Cycles 1, 2, 3
Cycle 
4+ 
EoT  
Visit 
30-day
Safety 
Follow-up 
Visit 
Disease
Assessment
Follow-up
Survival
Follow-
up
Day 1 
Day 14  
Day1 
Visit window
After disease
recurrence
and before
TURBT  
N/A
- 35
day
s
- 14
days
C1:0 
days 
C2, C3: 
±2 days 
±2 
days 
±2 
days 
+7 days 
after 
permanent 
treatment 
discontinu 
ation  
30 (+7) 
days after 
last dose 
Every
24 weeks
(±2 weeks)
from the
last disease
assessment
visitin the
Treatment
Phase
Every
12 ±2
weeks
or end of study, whichever occurs first. See
Section 8.1.3.2.2.
β-hCG= beta-human chorionic gonadotropin; BCG= bacillus Calmette-Guérin; C=cycle; CR=complete response; CIS=carcinoma in situ; CT=computed tomography; ctDNA=circulating
tumor DNA; CXDX=Cycle X Day X; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; EORTC QLQ-C30=European Organisation for Research and
Treatment of Cancer Quality-of-life Questionnaire Core 30; ePRO=electronic patient-reported outcome; EQ-5D-5L=European Quality of Life –5 Dimensions-5 Levels; EoT=End of
Treatment; FGFR=fibroblast growth factor receptor; ICF=informed consent form; IDMC=Independent Data Monitoring Committee; MMC=mitomycin C; MRI=magnetic resonance
imaging; MRU=medical resource utilization; NMIBC=non-muscle-invasive bladder cancer; PGIC=Patient’s Global Impression of Change (of cancer); PGIS=Patient’s Global
Impression of Severity (of cancer); PK=pharmacokinetic; PR=partial response; SoA=Schedule of Activities; TURBT=transurethral resection of bladder tumor
a 
Guidance for study conduct for ongoing subjects in the event of a national disaster is provided in Section 10.13 (Appendix 13).
b 
Subjects enrolling in the study based on Molecular eligibility from pre-BCG tissue specimen and post-BCG local NGS/PCR testing must also submit the post-BCG tissue specimen
tissue for central confirmation of Molecular eligibility status.
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Status: Approved, Date: 13 July 2023
2. 
INTRODUCTION
Erdafitinib (JNJ-42756493) is an oral pan-FGFR 1-4 inhibitor with demonstrated clinical activity
in subjects with solid tumors, including urothelial carcinoma, identified to have alterations in the
FGFR pathway. In the United States, erdafitinib (BALVERSATM) was approved on 12 April 2019
for the treatment of adult patients with locally advanced or metastatic urothelial carcinoma that
has susceptible FGFR3 or FGFR2 genetic alterations and has progressed during or following at
least 1 line of prior platinum-containing chemotherapy, including within 12 months of neoadjuvant
or adjuvant platinum-containing chemotherapy. This Phase 2 study will evaluate the safety and
efficacy of erdafitinib in subjects with high-risk NMIBC and FGFR mutations or fusions, who
received BCG therapy and recurred.
For the most comprehensive nonclinical and clinical information regarding erdafitinib, refer to the
latest version of the Investigator's Brochure (IB) and Addenda for erdafitinib.
The term "sponsor" used throughout this document refers to the entities listed in the Contact
Information page(s), which will be provided as a separate document.
2.1. 
Study Rationale
Bladder cancer is the tenth most common malignancy worldwide, with an estimated 549,000 new
cases and 200,000 deaths reported in 2018.7 Seventy percent of these patients are diagnosed with
an early stage NMIBC.26 Approximately 25% of NMIBC patients with poorly differentiated, low-
stage tumors are considered to have ‘high risk non-muscle-invasive bladder cancer’ (high-risk
NMIBC; including high-grade pTa, pTis, and pT1).24 The natural history of high-risk NMIBC is
unpredictable; rates of recurrence vary from 15 to 78%, and rates of progression to muscle invasion
and metastasis vary from <1 to 45%,42 and long-term outcomes suggest that around 20 to 25% of
these patients die from bladder cancer.43
The mainstay of treatment for high-risk NMIBC is TURBT (biopsy only for patients with CIS)
followed by intravesical treatment with BCG. Primary radical cystectomy is an option for some
patients. Approximately 30 to 40% of patients will experience recurrence after BCG therapy.6
Valrubicin is the only US Food and Drug Administration (FDA)-approved intravesical treatment
for BCG-refractory CIS in patients who are unfit or unwilling to undergo cystectomy. Valrubicin
is not approved for treatment of papillary disease. The CR rate after valrubicin treatment is 18%,
and 4% of patients are disease-free 2 years following therapy.15 Once the disease progresses to
muscle-invasive bladder cancer, prognosis is poor, even with combined-modality therapy, with a
10-year OS of 36%. Hence, radical cystectomy is considered the standard of care for any patient
with BCG-unresponsive high-grade NMIBC.5,29
Radical cystectomy entails high morbidity (up to 60%) and negatively affects HRQoL. These
comorbidities occur even in high-volume centers of excellence and regardless of open versus
robotic approaches.34 The procedure itself has a mortality rate of 3%.40 Hence, some patients refuse
surgery. Additionally, some patients are medically unfit for surgery due to such factors as age,
functional status, American Society of Anesthesiologists class, comorbidities, body mass
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Status: Approved, Date: 13 July 2023
index, etc. Therefore, there is a need for new therapies to prevent invasive bladder cancer in the
intact bladder.
Fibroblast growth factor receptors FGFR1 to FGFR4 are tyrosine kinases that are present in many
types of endothelial and tumor cells and are shown to play an important role in tumor cell growth,
survival, and migration as well as in maintaining tumor angiogenesis.25 There are varied
mechanisms for FGFR-related oncogenesis, including gene amplification, mutations, and
fusions.13  FGFR3 genetic alterations are found in 60 to 70% of early stage NMIBC.28 The observed
frequency of FGFR alterations in bladder cancer changes with tumor stage and grade. For example,
in one study, TaG1 (158/257) and TaG2 (139/239) tumors displayed similar mutation frequencies
of 61.5% and 58.1%, respectively. The mutation frequency was lower among TaG3 (30/88;
34.1%), T1G2 (7/26; 26.9%), and T1G3 tumors (20/119; 17%).23 Hernandez et al, in a prospective
cohort of 772 patients with NMIBC, showed that FGFR3 mutations are prevalent in low-grade Ta
and that these mutations are independent predictors of recurrence in patients with low-grade Ta
tumors.23,26
Erdafitinib is a pan-FGFR tyrosine kinase inhibitor. In Study 42756493BLC2001
(NCT02365597), erdafitinib demonstrated clinical activity in subjects with metastatic urothelial
cancer and prespecified FGFR  mutations and fusions.36 The presence of 
 in
NMIBC and the 
 provide a 
 in
patients with NMIBC who recurred following BCG treatment. Erdafitinib differs in 3 aspects from
existing therapies: 1) the treatment is a targeted therapy for a subset of patients with an activating
FGFR genetic aberration in the tumor; 2) selected patients may benefit by avoiding or delaying
cystectomy; and 3) erdafitinib is systemic therapy with proven efficacy in advanced disease and,
therefore, may safeguard against risk of developing invasive/metastatic disease.
2.2. 
Background
2.2.1. 
Fibroblast Growth Factor Receptors
Fibroblast growth factor receptors FGFR1 to FGFR4 are tyrosine kinases that are present in many
types of normal and tumor cells and are shown to play an important role in tumor cell growth,
survival, and migration as well as in maintaining tumor angiogenesis.25 Upon binding to their
natural ligand, FGF family members, FGFRs dimerize and autophosphorylate the tyrosine residue
in the kinase domain activation loop to become fully activated. Activated FGFR further
phosphorylate multiple signaling proteins bound to their intracellular portion, resulting in
activation of Ras/mitogen-activated protein kinase (MAPK) and PI3-kinase/Akt signaling
pathways. Other downstream signaling components of FGFRs include Src and Rsk. The result is
FGFR stimulation of cell growth, survival, migration, and differentiation, depending on the cell
type.
Overexpression of FGFRs, or aberrant regulation of their activity, has been implicated in many
forms of human malignancies including urothelial carcinoma. There are varied mechanisms for
FGFR-related oncogenesis including gene amplification, mutations, and fusions. Therefore,
targeting FGFRs with a small molecule kinase inhibitor is an attractive strategy for the
development of a novel cancer treatment.
CCI
CCI
CCI
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Status: Approved, Date: 13 July 2023
FGFR Alterations in High-risk NMIBC
FGFR3 genetic alterations are found in 60 to 70% of early stage NMIBC.28 The timing and
sequence of FGFR3 (and other mutations) may correlate with bladder cancer stage and grade. The
observed frequency of FGFR alterations in bladder cancer changes with tumor stage and grade.
For example, in one study, TaG1 (158/ 257) and TaG2 (139/239) tumors displayed similar
mutation frequencies of 61.5% and 58.1%, respectively. The mutation frequency is lower among
TaG3 (30/88; 34.1%), T1G2 (7/26; 26.9%), and T1G3 tumors (20/119; 17%).23 Hernandez et al,
in a prospective cohort of 772 patients with NMIBC, showed that FGFR3 mutations are prevalent
in low-grade Ta and that these mutations are independent predictors of recurrence in patients with
low-grade Ta tumors.23,26 In a more recent study with  pooled dataset of matched clinical and
genomic data for 263 patients with stage pT1 showed that FGFR alterations were frequent in high-
risk pts (39% mutations, 6% fusions, not mutually exclusive). Additionally, this study distinct from
previous reports, showed that prognosis for patients with FGFR alterations was not different from
those without FGFR alterations.8
2.2.2. 
Erdafitinib
Nonclinical Studies
Erdafitinib has been shown to have high affinity and low nanomolar inhibitory activity for all
FGFR family members, FGFR 1, 2, 3 and 4. It has demonstrated activity in FGFR
pathway-activated cancer cell lines including squamous non-small cell lung cancer, gastric, breast,
hepatocellular cancer, endometrial, bladder, multiple myeloma, and acute myeloid leukemia.
Target inhibition and pathway modulation have been demonstrated in cellular models at active
cellular concentrations. Brief exposure to erdafitinib has been demonstrated to result in long-term
target inhibition. Erdafitinib has been shown to have in vivo antitumor activity in mouse xenograft
models of FGFR-driven gastric, bladder, and squamous non-small-cell lung carcinoma (NSCLC)
tumor models, and in patient-derived xenografts from squamous NSCLC, gastric, breast, and
hepatocellular tumors.
An in vitro metabolism study in human liver microsomes and hepatocytes showed major
involvement of cytochrome 450 (CYP) enzymes CYP2C9 and CYP3A4. Long terminal phase half-
life of erdafitinib (>50 hours) in plasma was observed resulting in approximately 3-fold
accumulation of Cmax and area under the curve (AUC)following multiple daily dosing.
Clinical Studies
In humans, erdafitinib exhibited dose-related increase in the maximum concentration (Cmax) and
AUC and time-independent PK within the dose range of 0.5 mg to 12 mg, both after single and
multiple daily dosing. Median time to maximum concentration (tmax) observed ranged from 2 to 4
hours (erdafitinib as capsule). Relative bioavailability was comparable under fed and fasted
conditions. Erdafitinib is highly bound to plasma proteins such as α1-acid glycoprotein (α1-AGP).
Free fractions of erdafitinib in human plasma were small (average ~0.36%). Erdafitinib is a
P-glycoprotein (P-gp)substrate.
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Status: Approved, Date: 13 July 2023
In a Phase 1 study (Study 42756493EDI1001, n=187), the antitumor effect of erdafitinib was
observed in subjects with urothelial cancer with selected FGFR aberrations, as well as other solid
tumors. For all subjects with relapsed/refractory urothelial cancer, the overall response rate (ORR)
across dose levels was 40.0% (12/30 subjects). At the 9 mg dose level, ORR was
70.0% (7/10 subjects) for response-evaluable subjects with urothelial cancer who harbored
selected FGFR aberrations. The most frequently reported adverse events were hyperphosphatemia
(65%), dry mouth (46%), asthenia (45%), stomatitis (39%), constipation (37%), and decreased
appetite (34%).
In the global Phase 2 study (Study 42756493BLC2001, n=210), the antitumor effect of erdafitinib
was further demonstrated in subjects with relapsed/refractory advanced urothelial cancer with
defined FGFR mutations and gene fusions. In this study, multiple dosing regimens were evaluated
including the 6-mg and 8 mg-daily regimens with up-titration. Subjects enrolled in the erdafitinib
6-mg daily regimen (78 subjects) received the 6-mg daily starting dose with up-titration to 8 mg
daily or remained at the 6-mg daily dose based on the phosphate level measured at Cycle 2 Day 1.
Subjects enrolled in 8-mg daily regimen (99 subjects) received the 8-mg daily starting dose with
up-titration to 9 mg daily or remained at the 8-mg daily dose based on the phosphate level
measured on Cycle 1 Day 14. Selected efficacy and safety data from the BLC2001a study for the
6-mg and 8-mg daily regimens are shown below:
BLC2001 Efficacy  
6-mg Daily  
Dosing Regimen  
8-mg Daily
Dosing Regimen
Overall Response Rate (ORR) 
       and Confidence interval 
34.6%  
(24.1%, 45.2%) 
40.4%
(30.7%, 50.1%)
Disease Control Rate (DCR) 
       and Confidence interval 
73.1% 
(63.2%, 82.9%) 
79.8%
(71.9%, 87.7%)
BLC2001 Drug-related
Treatment-emergent Adverse Events (TEAEs)
   Drug-related TEAEs 
88.5% 
97.0%
   Drug-related Grade 3-4 TEAEs 
28.2%  
45.5%
   Drug-related TEAEs leading to dose interruption  
46.2%  
61.6%
   Drug-related TEAEs leading to treatment 
        discontinuations
7.7% 
12.1%
a 
The analysis is based on the BLC2001 Primary Analysis.
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Status: Approved, Date: 13 July 2023
Selected efficacy and safety data from an analysis of the BLC2001a 6-mg daily dosing regimens
(with and without up-titration) are shown below:
BLC2001 Efficacy  
6-mg 
Daily Dosing Regimen  
(Not Up-titrated) 
6-mg
Daily Dosing Regimen
(Up-titrated)
Overall Response Rate (ORR) 
       and Confidence interval 
34.0%  
(20.5%, 47.6%) 
35.5%
(18.6%, 52.3%)
Disease Control Rate (DCR) 
       and Confidence interval 
68.1% 
(54.8%, 81.4%) 
80.6%
(66.7%, 94.6%)
BLC2001 Drug-related
Treatment-emergent Adverse Events (TEAEs)
   Drug-related TEAEs  
83.0% 
96.8%
   Drug-related Grade 3-4 TEAEs 
29.8%  
25.8%
   Drug-related TEAEs leading to dose interruption  
48.9%  
41.9%
   Drug-related TEAEs leading to treatment 
        discontinuations
10.6%  
3.2%
Furthermore, subjects received a starting dose of erdafitinib 8 mg once daily with a dose increase
to 9 mg once daily for subjects whose serum phosphate levels were below the target of 5.5 mg/dL
between days 14 and 17; a dose increase occurred in 41% of subjects. The ORR (CR + PR) was
32.2% as assessed by a blinded independent review committee, and duration of response (DoR)
was 5.4 months. The most frequently reported adverse events were hyperphosphatemia (76%),
stomatitis (56%), diarrhea (47%), and dry mouth (45%).
For the most comprehensive nonclinical and clinical information regarding erdafitinib, refer to the
latest version of the Investigator’s Brochure.
2.2.3. 
Comparator Drugs
Subjects in Cohort 1 who are assigned to receive treatment with Investigator’s Choice will receive
either intravesical gemcitabine or intravesical MMC/hyperthermic MMC. The subject’s treating
physician will determine during screening based on clinical judgment, which comparator,
gemcitabine or MMC/hyperthermic MMC, is appropriate for the individual subject.
2.2.3.1. 
Gemcitabine
Gemcitabine is a pyrimidine antimetabolite that inhibits DNA synthesis by inhibition of DNA
polymerase and ribonucleotide reductase. It is cell cycle-specific for the S-phase of the cycle.
Gemcitabine has been extensively studied as a salvage intravesical chemotherapeutic option with
many different regimens. Intravesicular gemcitabine may have similar efficacy and lower
incidence of dysuria and hematuria compared with BCG.45 For patients with high-risk NMIBC
who are unresponsive to BCG and who are unsuitable for radical cystectomy, bladder sparing
strategies are warranted, indicatingthatthe use of intravesical use of gemcitabine and MMC should
be considered.18 In a multicenter Phase 2 study of 58 patients who had undergone 2 or more prior
BCG courses, gemcitabine demonstrated a 12-month disease-free rate of 28%.38 Although a
a 
The analysis is based on the BLC2001 Primary Analysis.
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Status: Approved, Date: 13 July 2023
second induction of BCG may be an option for patients who recur or persist after a single course
of induction intravesical BCG, a Phase 2 randomized trial demonstrated that intravesical
gemcitabine was associated with a superior 2-year RFS compared to BCG (19% versus 3%;
p<0.008) among patients with high-risk non-muscle-invasive recurrence after a single course of
BCG, albeit with no significant difference in progression.14
An intravesical regimen of 2 g gemcitabine weekly for 6 weeks and then monthly to 12 months
was used in the SWOG S0353 study.38 Intravesical administration of gemcitabine can lead to local
irritation of bladder, which can lead to a sense of urination, burning during urination, infection,
abdominal pain, fever, and rarely ulcers in bladder. Refer to current product labeling for additional
information.
2.2.3.2. 
Mitomycin C
Mitomycin C is the only approved chemotherapeutic among the class of mitomycin therapies and
is often referred to as mitomycin. Mitomycin alkylates DNA to produce DNA cross-linking
(primarily with guanine and cytosine pairs) and inhibits DNA and RNA synthesis. Mitomycin is
not cell cycle-specific but has its maximum effect against cells in late G and early S phases.
Multiple studies have evaluated MMC for the treatment of bladder cancer. Intravesicular MMC
has also been evaluated extensively and widely used in patients who are unresponsive to BCG and
who are unsuitable for radical cystectomy. Mitomycin C was evaluated by Addeo et al. in 120
previously treated patients. After a median follow-up of 36 months, MMC demonstrated a
recurrence-free rate of 61%, and therapy was generally well tolerated.1 Di Stasi et al used a regimen
of 6 weekly treatments, a further 6 weekly treatments for nonresponders, and 10 monthly follow-
up treatments for responders.16 Intravesical administration of MMC can lead to local irritation of
bladder, which can lead to a sense of urination, burning during urination, infection, abdominal
pain, fever, and rarely ulcers in bladder. Refer to current product labeling for additional
information.
2.3. 
Benefit-Risk Assessment
Patients with high-risk NMIBC who recurred after BCG treatment are at high risk for adverse
outcomes with an 11.4% probability of progression at 1 year and a disease-specific death rate of
4.8% at 1 year.9 Hence, both the American Urological Association  (AUA) and European
Association of Urology (EAU) guidelines recommend radical cystectomy as the only standard
therapy for these patients. There is an ongoing shortage of BCG necessitating development of
strategies to prioritize use of intravesical BCG (alternate schedule and reduced dose approaches)
and identify alternate treatment approaches, such as use of intravesical chemotherapies.
Consequently, many patients are either not receiving the full prescribed dose of BCG, or not
receiving BCG treatment at all, and are being treated with intravesical chemotherapeutic agents.
Additionally, a proportion of patients do not tolerate the full dose or course of BCG treatment.
Data presented by Richards et al of US Surveillance, Epidemiology and End Results
(SEER)-Medicare database evaluating 39,532 NMIBC patients demonstrated that only 30% of
intermediate-risk and 29% of high-risk patients received adequate BCG.33
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The superiority of BCG compared with intravesical chemotherapy to prevent recurrence of
high-risk NMIBC is proven. However, the optimal number of induction instillations and the
optimal frequency and duration of maintenance instillations is not fully known. A full dose of BCG
must comprise 1 full vial with a minimum of 1 x 108 colony forming units (CFU). The largest
individual study of 1,355 patients (EORTC 30962) compared different BCG strengths (full dose
vs 1/3 dose) and different BCG maintenance schedules (1 year vs 3 years) and found no difference
in RFS between 1/3 dose and full dose administered for either 1 year or 3 years.31  Although a
subset of high-risk patients treated with a 3-year full dose schedule had an improved RFS with no
difference in progression or survival, the study was not formally powered to test this hypothesis.
Many patients are medically unfit to undergo surgery and some refuse due to the high morbidity
(up to 60%) the procedure entails and negative effects on quality of life. These comorbidities occur
even in high-volume centers of excellence and regardless of open versus robotic approaches.34 The
procedure itself has a mortality rate of 3%.40 Hence, some patients refuse surgery. Additionally,
some patients are medically unfit for surgery due to such factors as age, functional status,
American Society of Anesthesiologists class, comorbidities, body mass index, etc. Valrubicin is
the only FDA-approved intravesical treatment for BCG-refractory CIS in patients who are unfit or
unwilling to undergo cystectomy. The CR rate after valrubicin treatment is 18%; 4% of patients
are disease-free at 2 years following therapy.15 Other salvage therapies such as intravesical
gemcitabine have shown activity.12
The FGFR pathway has a central role in the pathogenesis of NMIBC. Thirty percent of patients
progressing to high-risk NMIBC harbor FGFR3 mutations. Furthermore, the molecular luminal
subtype of bladder cancer, which is enriched with the FGFR3 mutation, has an immunoquiescent
immune signature suggesting that they may not benefit from immunotherapy.11  In clinical studies
in the advanced bladder cancer disease setting, erdafitinib treatment resulted in durable antitumor
response. Corresponding DoR, progression-free survival (PFS), and OS endpoints suggest clinical
benefit for patients with  locally advanced or metastatic urothelial cancer who have FGFR
alterations and have relapsed after platinum-based chemotherapy. FGFR mutation is an early
molecular event in bladder cancer and appears to be one of the main drivers of bladder
carcinogenesis. Study BLC2001 demonstrated clinically meaningful efficacy in heavily pretreated
metastatic bladder cancer patients. Metastatic bladder cancer is well known to have clonal
evolution and higher genomic instability compared with earlier stages of disease, such as NMIBC.
Therefore, it was hypothesized that testing erdafitinib in early-stage bladder cancer might offer
clinically meaningful benefit for patients with FGFR mutations.
The potential risks of erdafitinib to adults, include central serous retinopathy and
hyperphosphatemia. The benefit-risk  of erdafitinib was acceptable in the urothelial cancer
population; the profile was characterized by mostly mild to moderate eye, skin, and nail disorders.
The events in the urothelial population were manageable with available medical measures,
temporary treatment interruption, or eventual dose reduction.
Taking into account the measures utilized to minimize risk to subjects in this study (guidance for
specific erdafitinib toxicities in Section 6.6.2, prohibited medications in Section 6.5.2, precautions
for concomitant medications in Section 6.5.3, and monitoring of results of safety assessments in
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Section 8.3), the potential risks identified in association with erdafitinib are justified by the
anticipated benefits that may be afforded to patients with high-risk NMIBC and FGFR gene
alterations, 
 More detailed information about the known and expected
benefits and risks of erdafitinib may be found in the Investigator’s Brochure.
3. 
OBJECTIVES AND ENDPOINTS
Cohort 1 Efficacy Objectives 
Cohort 1 Efficacy Endpoints
Primary
To evaluate RFS in subjects treated with
erdafitinib vs Investigator’s Choice, for
subjects with high-risk NMIBC who harbor
FGFR mutations or fusions, and who
recurred after BCG therapy
 
Recurrence-free survival (RFS)
Secondary
To evaluate other measures of efficacy  
 
Time to progression
 
OS
 
RFS rate at 6 months and 12 months
Cohort 2 Efficacy Objective 
Cohort 2 Exploratory Efficacy Endpoints
Exploratory
To evaluate the efficacy of erdafitinib in
subjects with high-risk, BCG-unresponsive
NMIBC and FGFR mutations or fusions
 
CR rate at 8 weeks
 
CR rate at 32 weeks
 
Duration of response (DOR)
Cohort 3 Efficacy Objective 
Cohort 3 Exploratory Efficacy Endpoints
Exploratory
To evaluate the efficacy of erdafitinib in 
subjects with intermediate-risk NMIBC and
FGFR mutations or fusions
 
CR rate
 
Best overall response (BOR)
 
DOR
Other Secondary Objectives – 
All Cohorts 
Other Secondary Endpoints –
All Cohorts
To evaluate erdafitinib PK  
 
PK concentration and PK parameters derived using the existing
population PK model
To evaluate safety and tolerability of 
erdafitinib
 
Incidence and severity of adverse events
Refer to Section 8, Study Assessments and Procedures, for evaluations related to endpoints.
HYPOTHESIS
For Cohort 1, erdafitinib treatment will delay the onset of tumor recurrence for subjects with
papillary disease only, who recurred after BCG treatment, with FGFR mutations or fusions, and
with all lesions removed.
For Cohort 2, erdafitinib treatment will lead to CR for subjects with CIS with or without papillary
disease and FGFR mutations or fusions.
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For Cohort 3, erdafitinib treatment will lead to CRin the marker lesion for subjects with a papillary
marker lesion and FGFR mutations or fusions.
Due to early enrollment termination and change in study’s regulatory intent for Cohort 1 from
registrational to non-registrational, no formal hypothesis testing will be performed for any of the
cohorts.
4. 
STUDY DESIGN
4.1. 
Overall Design
This is an open-label, global, multicenter, randomized, Phase 2 study of the safety and efficacy of
erdafitinib in subjects with NMIBC and FGFR mutations or fusions (see Section 5.1).
Cohort 1 (n=240 planned) will include subjects with  high-risk NMIBC  presenting as papillary
tumor only, with disease recurrence after BCG therapy, and who either refuse or are not eligible
for cystectomy. It is essential that the subject’s refusal to receive or medical ineligibility for
cystectomy be documented clearly in source documents at screening (see Section 10.2, Source
Documents). The reason for not being eligible for cystectomy or for refusing cystectomy will be
entered into the eCRF. These subjects will be assigned randomly 2:1 to treatment with either
erdafitinib or the investigator’s choice of either intravesical gemcitabine or intravesical
MMC/hyperthermic MMC (Investigator’s Choice), respectively. Randomization will be stratified
by tumor stage (Ta vs T1) and type of prior BCG therapy (BCG-unresponsive vs BCG-
experienced). BCG strain administered will also be documented in the eCRF. Investigators must
choose between intravesical gemcitabine or intravesical MMC/hyperthermic MMC  for each
subject at screening, and the choice of agent must take prior exposure into consideration. Peri-
operative intravesical chemotherapy prior to study entry per local standard of care and prior
immunotherapy (eg, PD1 inhibitor etc)are allowed.
Cohort 2 and Cohort 3 are exploratory.
Cohort 2 (n=20 planned) will include subjects with high-risk, BCG-unresponsive NMIBC
presenting as CIS with or without concurrent papillary tumor, who either refuse or are not eligible
for cystectomy. The reason for not being eligible for cystectomy or for refusing cystectomy will
be entered into the eCRF. All subjects enrolled into Cohort 2 will receive treatment with
erdafitinib. Peri-operative intravesical chemotherapy prior to study entry per local standard of care
and prior immunotherapy (eg, PD1 inhibitor etc) are allowed. Additionally, subjects in this cohort
may receive chemotherapy as bridging therapy after adequate BCG therapy while being considered
for trial.
Cohort 3 (n=20 planned) will be enrolled at select study sites and will include subjects with
intermediate-risk NMIBC presenting as papillary disease only. All previous tumors for these
subjects must be low grade (G1-G2), Ta or T1, with no previous CIS. Furthermore, subjects must
have a risk of progression less than 5% for 2 years, and the risk of recurrence must be greater than
50% as calculated using the EORTC risk calculator.19 There are no predefined BCG or intravesical
chemotherapy requirements for subjects enrolled in Cohort 3. All tumors must be removed except
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for a single, untouched 5 to 10 mm lesion. All subjects enrolled in Cohort 3 will receive treatment
with erdafitinib.
The first approximately 20 subjects participating who receive erdafitinib (from any cohort) will
provide a 24-hour urine collection for assessment of erdafitinib pharmacokinetics.
The primary endpoint for Cohort 1 is RFS. Exploratory endpoints for Cohort 2 are CR rate at
8 weeks, CR rate at 32 weeks, and DOR. Exploratory endpoints for Cohort 3 are CR rate, best
overall response (BOR), and DOR. A diagram of the study design is provided in Section 1.2,
Schema.
The study comprises molecular eligibility, screening, treatment, follow-up, and LTE phases. For
Cohort 1 and Cohort 2, molecular eligibility will be established for each potential subject before
screening for other eligibility criteria. This assessment may be performed by either the central
laboratory  or by  sponsor review of existing local laboratory reports generated by a Clinical
Laboratory Improvement Amendments (CLIA)-certified10 or equivalent laboratory. Molecular-
eligible subjects may then be screened for remaining eligibility criteria. For Cohort 3, see
Section 8.1.1.2 for guidelines to establish molecular eligibility. Subjects being considered for the
study before the TURBT, will provide a voided urine sample after disease recurrence and before
TURBT. These subjects must sign the Informed Consent Form (ICF) for Urine Sample for Assay
Development. Subjects being considered for study after TURBT will not provide this urine sample.
Subjects with T1 disease will undergo TURBT of the base of the lesion (the biopsy should contain
muscle fibers) before study entry to ensure the absence of muscle-invasive disease. If there are no
muscle fibers in the biopsy, the subject must undergo re-TURBT before randomization or
enrollment and must have evidence of uninvolved muscularis propria in the pathologic specimen
from either the first or the second TURBT.
The Treatment Phase will begin on Day 1 for subjects meeting all eligibility criteria, at which time
subjects will receive their study drug. Subjects receiving erdafitinib will take erdafitinib tablets
orally, 6 mg once daily for 28 days in a 28-day cycle. After review of safety and tolerability data
from approximately 5 to 10 additional subjects dosed with the 6-mg daily regimen (without up-
titration), the Independent Data Monitoring Committee (IDMC) may recommend a modification
of the dosing regimen to allow up-titration to the 8-mg daily regimen. The details of the IDMC
recommendation will be communicated in writing to the investigative sites and, per local
regulation, to health authorities. With the exceptions noted below for Cohort 2 and Cohort 3,
treatment may continue until the subject has high risk disease recurrence or progression,
intolerable toxicity, withdraws consent, there is a decision by the investigator to discontinue
treatment, or the study is closed, whichever occurs first. Treatment with erdafitinib may continue
for a maximum of 2 years.
 
For Cohort 2, erdafitinib must be discontinued if CR is not observed within 3 months.
 
For Cohort 3, after 3 months of study treatment: 1) Subjects with stable disease or progression
of the marker lesion must discontinue erdafitinib and a TURBT of the marker lesion must be
performed. 2) Subjects with CR may continue erdafitinib. 3) Subjects with PR may, at the
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investigator’s discretion, either continue treatment with erdafitinib or discontinue erdafitinib
and undergo TURBT of the marker lesion.
For subjects in Cohort 1 who have locally confirmed high-risk recurrence on Investigator’s Choice,
the subject may cross over to erdafitinib (Section 10.10). Note: no additional crossover from
Investigator’s Choice to erdafitinib will be permitted.
The Follow-up Phase includes a 30-day Safety Follow-up Visit, disease assessment follow-up, and
survival follow-up.
The LTE Phase will allow continued access to study drug for subjects who continue to derive
benefit from treatment, as determined by their investigator. Subjects may enter the LTE Phase
following implementation of Amendment 6, provided they meet the criteria for entry specified in
LTE Figure 1. Limits for continuation of study drug in this phase are described in Section 6.7. No
data will be collected in the eCRF during the LTE Phase, and only SAEs will be reported to the
company safety repository. As an alternative to entering the LTE Phase, subjects receiving
erdafitinib may exit the study and continue to receive treatment on any  other post-trial access
program, when permitted by local regulations. Detail regarding the LTE Phase (including a
Schedule of Activities)is provided in Section 10.14, Appendix 14.
Subjects will be assessed for disease response by cystoscopy and bladder mapping for detection of
new lesions, local assessment of urine cytology, and CT/MRI urograms. Tissue slides/blocks from
subjects in Cohort 1 with any locally confirmed recurrence or progression will be sent for central
histopathologic review. Health-related quality-of-life assessments will use the following PRO
measures: PGIS, PGIC, EORTC QLQ-C30, EORTC QLQ-NMIBC24, and EQ-5D-5L. Note: PRO
assessment/data collection is no longer required for all subjects in all phases. Refer to Section 8.2,
Efficacy Assessments, for additional information. Safety assessments will include medical review
of adverse events, ophthalmologic assessment, targeted physical examinations, vital sign
measurements, 12-lead ECG assessments, clinical laboratory tests, and pregnancy testing (see
Section 8.3, Safety Assessments).
An IDMC will be commissioned to review safety and efficacy data during the study, primarily for
Cohort 1 (refer to Committees Structure in Section 10.2, Regulatory, Ethical, and Study Oversight
Considerations for details). Due to the company decision to terminate study enrollment and
considering the recent IDMC review (6 July 2022) found the safety of erdafitinib in this study to
be consistent with the known safety profile of erdafitinib, no further monitoring by the IDMC will
be conducted. The originally planned interim analyses will not be conducted.
Subjects who receive erdafitinib during the main study will have plasma erdafitinib concentration
measurements during the Treatment Phase for pharmacokinetic assessment.
Biomarker assessments will be performed for all subjects. Biomarker assessments include
molecular screening to determine eligibility for the study and exploratory DNA, RNA, and protein
analyses using archival or fresh biopsy tissue and blood (ctDNA), as well as urine samples, for
exploratory biomarker research (see Section 8.9). An additional urine sample will be collected for
assay development (see Section 8.9).
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4.2. 
Scientific Rationale for Study Design
Choice of Comparator for Cohort 1
While the primary treatment for high-risk NMIBC is transurethral resection (biopsy only for
patients with  CIS) followed by intravesical treatment with BCG, approximately 30 to 40% of
patients will experience recurrence after BCG therapy. For patients with , papillary NMIBC who
have high-risk NMIBC, the only recommended treatment option following progression or
recurrence after BCG therapy is radical cystectomy. However, many patients either are medically
unfit to undergo surgery or refuse it. In this setting, there are few effective treatment options
available.
There are very limited treatment options to treat BCG-unresponsive, high-risk papillary NMIBC.
In a multicenter Phase 2 study of 58 patients who had undergone 2 or more prior BCG courses,
gemcitabine demonstrated a 12-month disease-free rate of 28%.38 Furthermore, National
Comprehensive Cancer Care guidelines acknowledge gemcitabine as an option for treatment of
these patients.30 While a second induction of BCG may be an option for patients who recur or
persist after a single course of induction intravesical BCG, a Phase 2 randomized trial
demonstrated that intravesical gemcitabine was associated with a superior 2-year RFS compared
to BCG (19% versus 3%; p<0.008) among patients with high-risk non-muscle-invasive recurrence
after a single course of BCG, albeit with no significant difference in progression.14 Mitomycin C
has also been evaluated and widely used in this setting, and in one study where BCG-refractory
NMIBC patients were followed up over a 15-month-period, 31% remained recurrence-free.39
Valrubicin is approved in the United States only for treatment of CIS; however, subjects in Cohort
1 are limited to those with papillarydisease only, and efficacy in the approved indication is limited
(see Section 2.1).
Thus, the choice of gemcitabine and MMC/hyperthermic MMC as comparators to erdafitinib is
supported by current treatment practice and clinical data.2
Three-cohort Design
Urothelial bladder cancer is a heterogenous disease with 2 distinct pathways leading to bladder
carcinogenesis.28 The two-pathway’ model proposes that papillary NMIBC develops via epithelial
hyperplasia and recruitment of a branching vasculature; whereas, CIS is proposed to develop via
flat dysplasia. These 2 subtypes pose distinct challenges for clinical management and appear to be
directed by 2 separate molecular drivers.
Papillary bladder cancers, which constitute 80% of bladder cancer at diagnosis, have a more
insidious course compared with CIS. Despite its high recurrence rate (40-80%), papillary NMIBC
generally shows a favorable prognosis. However, progression to muscle-invasive and/or metastatic
disease occurs in approximately 15% of patients, and once patients develop progression, their
prognoses are generally unfavorable.20 Papillary cancers are characterized by very high
frequencies of activating mutations in FGFR3 (>70% in early stages). Conversely, CIS patients
make up ~20% of bladder cancer patients at diagnosis but have a high risk for progression to
muscle-invasive and metastatic disease. Patients with CIS commonly test positive for classical
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tumor suppressor genes, most notably TP53 and RB1.28 Pietzak showed FGFR mutations in 5/22
(23%) of NMIBC samples with concurrent papillary and CIS. FGFR positivity in a pure CIS
population has not been reported.32 Hence, Cohort 2 was originally planned to be a 20-subject
exploratory cohort.
Papillary disease and CIS are distinct entities at a molecular level and have different clinical
outcomes. However, aside from the option to resect papillary disease (but not CIS), they are
currently treated uniformly with intravesical BCG, which is a tuberculosis-like mycobacterium
that produces a local immune response that mediates tumor regression. Even though most patients
initially respond to BCG, approximately 30 to 40% of patients will become unresponsive and
experience recurrence after BCG. These tumors are at high risk for progression, with a 1-year rate
for TiG3 of 11.4%, and patients are faced with the option of removal of the bladder.9 For patients
who are either unfit or refuse cystectomy there are very few treatment options available. Treatment
has not advanced for several decades, and new approaches to systemic therapy are needed.
It is prudent to differentiate across 2 separate cohorts, because papillary NMIBC and CIS are
different molecularly and prognostically. In Cohort 1 (papillary disease) without active disease at
study entry, a randomized controlled study design using a time-to-event endpoint such as RFS is
acceptable. In Cohort 2 (CIS), in absence of pharmacologic intervention or cystectomy, disease
will progress; and, therefore, a single-arm study  with CR  rate as the primary endpoint is
appropriate (FDA BCG-unresponsive NMIBC: Developing Drugs and Biologics for Treatment;
Guidance for Industry).
All current available treatments are applied as adjuvant therapy in patients with papillary NMIBC.
This precludes on-target efficacy assessment, as studies are done without measurable disease.
Hence, it is logical to test newer therapies on measurable cancer, such as a marker lesion, which
offers the prospect of avoiding treatment of patients with ineffective agents. A review of 23 well
documented marker lesion studies involving more than 1,200 patients suggest that marker lesion
studies are safe to perform without risk of progression in patients who have multiple recurrent,
non-muscle-invasive bladder tumors with all previous tumors being low grade (G1-G2) Ta or T1,
no previous CIS, and negative urinary cytology. Subjects must have a risk of progression less than
5% for 2 years, and the risk of recurrence must be greater than 50% as calculated using EORTC
risk calculator.19,22 Hence, it is prudent to evaluate the marker lesion study as a separate cohort
(Cohort 3), given that it will enroll a different risk group (intermediate risk) compared with
Cohort 1 and Cohort 2 (high risk).
Blinding, Control, Study Phase/Periods, Treatment Groups
An active control will be used in Cohort 1 to determine the sensitivity of the clinical endpoints in
this study. Randomization stratified by tumor stage (Ta vs T1) and type of prior BCG therapy
(BCG-unresponsive vs BCG-experienced) will be used to minimize bias in the assignment of
subjects to treatment groups, to increase the likelihood that known and unknown subject attributes
(eg, demographic and baseline characteristics) are evenly balanced across treatment groups, and
to enhance the validity of statistical comparisons across treatment groups. Neither the sponsor,
investigators, nor subjects will be blinded to treatment assignment in Cohort 1. Using a placebo
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control is not practical and would place an enormous burden on subjects, as erdafitinib is an oral
regimen and the comparators require intravesical administration.
Biomarker Collection
The goal of the biomarker analyses is to further understand the
. Biomarker samples may be used to help address
emerging issues and to enable the development of safer, more effective, and ultimately
.
Patient-reported Outcomes Research
Patient-reported outcome data complement data collected by other methods to support the clinical
data and cost-effectiveness modeling as well as contributing to enhanced communication of value
to patients, clinicians, regulators, and payers. The PRO endpoints of interest include domain scales
from the EORTC QLQ-C30, EORTC NMIBC24, and EQ-5D-5L. These PRO measures will be
administered to test the hypothesis that treatment with erdafitinib maintains HRQoL as measured
by time to symptom and functional deterioration by a prespecified meaningful change threshold.
PRO data will be collected as outlined in the Schedule of Activities (Section 1.3) to understand
how the endpoints change over time, with treatment and with the clinical state of the subject. Note:
PRO assessment/data collection is no longer required for all subjects in all phases.
Medical Resource Utilization Data Collection
Treatment of NMIBC with erdafitinib versus Investigator’s Choice may result in lower utilization
ofhealthcare resources.
4.2.1. 
Study-Specific Ethical Design Considerations
Potential subjects will be fully informed of the risks and requirements of the study and, during the
study, subjects will be given any new information that may affect their decision to continue
participation. They will be told that their consent to participate in the study is voluntary and may be
withdrawn at any time with no reason given and without penalty or loss of benefits to which they
would otherwise be entitled. Only subjects who are fully able to understand the risks, benefits, and
potential adverse events of the study, and provide their consent voluntarily will be enrolled.
The intermediate-risk population selected for the marker lesion cohort (Cohort 3) has a low risk of
disease progression(less than 5% for 2 years). Furthermore, the subjects are a molecularly selected
subgroup being treated with a targeted therapy given systemically that has shown clinical
efficiencyin metastatic bladder cancer. This mayfurther reduce any risk of progression. The safety
of subjects in this cohort will be closely monitored, as outlined in the Schedule of Activities.
Guidance has been provided in the protocol to limit the possibility that an ineligible subject is
enrolled into Cohort 3 (see Section 8.1.1.2). This is expected to minimize the risk that subjects
with non-qualifying marker lesions will need to undergo additional cystoscopy and resection.
The total blood volume (approximately 682 mL) that will be collected is considered within the
normal range allowed for this subject population over this time frame. An additional 682 mL may
be collected from subjects who participate in the Erdafitinib Crossover (see Section 10.10). For
CCI
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adult subjects, the amount of blood collected is less than the American Red Cross standard blood
donation of 500 mL over 60 days3 and is aligned with World Health Organization blood donation
guidelines.44
4.2.2. 
Participant Input Into Design
The results of the study may be made available to all participants through a plain language
summary; a technical summary of results on registries such as clinicaltrials.gov,
clinicaltrialsregister.eu or other national registries at the conclusion of the study according to local
standards/restrictions.
4.3. 
Justification for Dose
4.3.1. 
Erdafitinib Dose Selection
The starting dose of erdafitinib will be 6 mg daily. Erdafitinib will be provided as tablets for oral
administration. Subjects will be instructed to take a 6-mg daily dose on a continuous dosing
schedule. A cycle is defined as 28 days.
Clinical efficacy and safety data considered for dose selection are summarized in Section 2.2.2.
The erdafitinib dosing regimen of 6 mg daily (with and without up-titration) has demonstrated
clinical activity with lower rates of Grades 3 to 4 drug-related TEAEs, drug-related TEAEs leading
to dose interruption, and drug-related TEAEs leading to discontinuation relative to the 8-mg daily
regimen (with up-titration)in subjects with advanced or metastatic urothelial carcinoma.
The BLC2003 IDMC  reviewed safety data for the first 4 subjects treated with erdafitinib and
recommended the change in dosing to 6 mg daily. The lower dose of 6 mg daily (without up-
titration)
 this regimen with a lower dose of 6 mg
daily may be better suited, with respect to the overall risk-benefit profile, for the NMIBC patient
population without advanced, imminently life-threatening disease.
4.3.2. 
Gemcitabine Dose Selection
The dose of intravesical gemcitabine is 2,000 mg. Gemcitabine will be provided by the sponsor.
It will be administered at the site once weekly for at least 4 weeks of induction and then monthly
for at least 6 months. Additional doses of induction or maintenance are allowed per local standard
of care. Please refer to the gemcitabine Investigational Product Preparation Instructions (IPPI)for
additional information on the preparation, handling, and administration of gemcitabine.
It is the expert opinion in the AUA and EAU Guidelines that indicate if a high-risk NMIBC patient
is unwilling or unfit for cystectomy following BCG, a clinical trial or intravesical chemotherapy
is appropriate.4,17,18 Therefore, receiving intravesical gemcitabine in a clinical trial is a reasonable
option for patients who refuse or are unfit for cystectomy.
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4.3.3. 
Mitomycin C Dose Selection
The dose of intravesical mitomycin C is 40 mg. Mitomycin C will be provided by the sponsor. It
will be administered at the site once weekly for at least 4 weeks of induction and then monthly for
at least 6 months. Additional doses of induction or maintenance are allowed per local standard of
care. Mitomycin C may also be given as hyperthermic MMC.2 Please refer to the MMC IPPI for
additional information on the preparation, handling, and administration of MMC.
Mitomycin C is indicated for intravesical infusion at the dose of 40 mg/40mL and the European
Urological Association Guidelines recommend 20 to 40 mg as the standard dose of MMC for
patients for whom BCG has failed in NMIBC.18,41
4.4. 
Study Completion, End of Study, and Subject Completion Definitions
Study Completion Definition
The study is considered completed when the last subject on the study transitions to the LTE Phase
or discontinues from the study. At the time of study completion, there will be no further data
collection in the study database.
End of Study Definition
The end of study is defined as when the last subject receives the last dose of study drug on the
study, including administration in the LTE Phase (see Section 10.14, Appendix 14).
Subject Completion Definitions
A subject will be considered as having completed treatment if he or she has completed 2 years of
erdafitinib or has completed a maximum duration  of Investigator’s Choice therapy  per local
standard of care (including any treatment received in the LTE Phase).
A subject's participation in the main  study (not including the LTE Phase) will be considered
completed when one of the following criteria is met, whichever occurs first:
 
18 months have elapsed since the first dose of study treatment (ie, Cycle 1 Day 1)
 
Subject experiences confirmed high-risk disease recurrence/progression at any point during
the study.
 
Subject death.
5. 
STUDY POPULATION
This study will enroll subjects with NMIBC and FGFR mutations or fusions. Potential subjects
intended for enrollment in Cohort 1 or Cohort 2 who meet molecular eligibility criteria (see
Inclusion Criterion no. 3) may be screened for the additional inclusion and exclusion criteria
described in the following sections during the 35-day period before the first dose of study drug.
Subjects intended for enrollment in Cohort 3 will have molecular eligibility and screening for other
eligibility criteria performed as described in  Section 8.1.1.2. Screening procedures
(Section 8.1.1.3) should be completed according to the timing provided in the Schedule of
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Activities (Section 1.3). Refer to Section 5.4, Screen Failures, for conditions under which the
repeat of any screening procedure is allowed.
The inclusion and exclusion criteria for enrolling subjects in this study are described below. If
there is a question about these criteria, the investigator must consult with the appropriate sponsor
representative and resolve any issues before enrolling a subject in the study. Waivers are not
allowed.
For a discussion of the statistical considerations of subject selection, refer to Section 9.2, Sample
Size Determination.
5.1. 
Inclusion Criteria
Each potential subject must satisfy all of the following criteria to be enrolled in the study:
1. 
≥18 years of age (or the legal age of consent in the jurisdiction in which the study is taking
place).
2. 
Histologically confirmed, recurrent, non-muscle-invasive urothelial carcinoma of the
bladder.
a. Histopathology: any urothelial cell carcinoma (UCC)variant (ie, UCC with
squamous and/or glandular differentiation, micropapillary, nested,
plasmacytoid, neuroendocrine, sarcomatoid) are allowed. Presence of any
lymphovascular invasion (LVI) will be considered as evidence ofhigh risk.
b. Papillary disease (Cohort 1) must be high-risk disease, defined as high-grade
Ta/T1 lesion. Additionally, subjects must have all visible tumor resected
completely prior to randomization and documented at baseline cystoscopy.
Negative cytology for high-grade urothelial carcinoma is required before
randomization.
c. CIS (Cohort 2) is not expected to be completely excised, but concurrent
papillary disease must be completely excised before enrollment and
documented at baseline cystoscopy. Urine cytology is not expected to be
negative for malignant cells.
d. Marker Lesion (Cohort 3) must have recurrent intermediate-risk disease with all
previous tumors being low grade (G1-G2), Ta or T1, and no previous CIS.
Additionally, subjects must have a risk of progression less than 5% in the next 2
years and a risk of recurrence greater than 50%, calculated using the EORTC
risk calculator.19 All tumors must be removed except for a single untouched 5 to
10 mm lesion (Marker Lesion).
3. 
Criterion modified per Amendment 2
3.1 Criterion modified per Amendment 3
3.2 At least 1 of the following tumor FGFR mutations or fusions as determined by local*
or central testing:
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FGFR3 Mutations 
FGFR2 and FGFR3 Gene Fusions
 
R248C
 
S249C
 
G370C
 
Y373C
 
FGFR2-BICC1
 
FGFR2-CASP7
 
FGFR3-TACC3
 
FGFR3-BAIAP2L1
*Local tissue-based results (if already existing) from next-generation sequencing
(NGS) or polymerase chain reaction (PCR) tests performed in CLIA-certified or
equivalent laboratories, or results from commercially available NGS tests. Subjects
enrolling based on local testing must submit tissue for central confirmation of FGFR
status. Subjects enrolling as referrals from ANNAR study do not need to submit tissue
for central FGFR confirmation.  If archival tissue is not available, contact the sponsor
for further guidance.
4. 
Criterion modified per Amendment 1.
4.1.
4a. BCG-unresponsive.
BCG-unresponsive subjects must meet at least one of the following:
i.  Persistent or recurrent CIS alone or with recurrent Ta/T1 (noninvasive papillary
disease/tumor invades the subepithelial connective tissue) disease within
12 months of completion of adequate BCG therapy (Cohort 2 only).
ii.  Recurrent high-grade Ta/T1 disease within 6 months of completion of adequate
BCG therapy.
iii. T1 high-grade at the first disease assessment following an induction BCG course.
Adequate BCG (Minimum Treatment Requirements)
1) At least 5 of 6 full doses of an initial induction course plus at least 1 maintenance
(2 of 3 full weekly full doses) in a 6-month period. (See Section 2.3 for a
description of “full dose”.)
         OR
2) At least 5 of 6 full doses of an initial induction course plus at least 2 of 6 full
doses of a second induction course.
4b BCG Experienced.
BCG experienced subjects must meet the following:
i. Recurrent high-grade Ta/T1 disease within 12 months of completion ofBCG
therapy (as defined below).
Prior BCG (Minimum Treatment Requirements)
1) At least 5 of 6 full doses of an initial induction course.
OR
2) At least 5 of 6 full doses of an initial induction course plus at least 1
maintenance (2 of 3 weekly doses) in a 6-month period. One-halfdose or one-
third dose is allowed during maintenance.
*Note: Cohort 1: may be BCG-unresponsive as defined in 4a or BCG experienced as
defined in 4b.
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Cohort 2: must be BCG-unresponsive as defined in 4a.
Cohort 3: has no predefined prior BCG or intravesical chemotherapy requirement.
5. 
Refuses or is not eligible for cystectomy (Cohort 1 and Cohort 2 only)
6. 
Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1
(Section 10.5)
7. 
Criterion modified per Amendment 2
7.1 Criterion modified per Amendment 4
7.2 Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating
agent in preceding 2 weeks):
i.  Absolute neutrophil count (ANC) ≥1,000/mm3
ii.  Platelet count ≥75,000/mm3
iii. Hemoglobin ≥8.0 g/dL
b. Liver function:
i.  Total bilirubin ≤1.5 x institutional ULN OR direct bilirubin ≤ULN for subjects
with total bilirubin levels >1.5xULN
ii.  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x
institutional ULN
c. Renal function:
Creatinine clearance >30 mL/min calculated using the Cockcroft-Gault formula
(Section 10.6).
d. Phosphate:
<ULN within 14 days before the first dose of study drug on Cycle 1 Day 1
(medical management allowed)
8. 
Must sign an informed consent form (ICF) (or their legally acceptable representative
must sign) indicating that he or she understands the purpose of, and procedures required
for, the study and is willing to participate in the study.
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9. 
A woman of childbearing potential must have a negative pregnancy test (β-hCG) (urine
or serum) within 7 days before randomization (Cohort 1) or the first dose of study drug
(Cohort 2 and Cohort 3).
10. 
Criterion modified per Amendment 2
10.1 Contraceptive use by men or women should be consistent with local regulations
regarding the use of contraceptive methods for subjects participating in clinical studies.
a.  For women of childbearing potential (defined as: fertile, following menarche and until
becoming postmenopausal unless permanently sterile):
 
Highly effective method of contraception (failure rate of <1% per year when used
consistently and correctly).
 
Permanent sterilization methods (for the purposes of this study) include
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy.
 
Examples of highly effective contraceptives include:
 
user-independent 
methods: 
implantable 
progestogen-only 
hormone
contraception associated with inhibition of ovulation; intrauterine device;
intrauterine hormone-releasing system; vasectomized partner; sexual
abstinence: true abstinence when this is in line with the preferred and usual
lifestyle of the subject (Note: periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods], declaration of abstinence for the
duration of exposure to study drug, and withdrawal are not acceptable methods
of contraception.)
 
user-dependent methods: combined (estrogen- and progestogen-containing)
hormonal contraception associated with inhibition of ovulation: oral,
intravaginal, and transdermal; progestogen-only hormone contraception
associated with inhibition of ovulation: oral and injectable
 
agrees to remain on a highly effective method of contraception during the study and
for at least 6 months after the last dose of study drug
 
agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
during the study and for at least 6 months after the last dose of study drug
 
not breastfeeding and not planning to become pregnant during the study and for at
least 6 months after the last dose of study drug
b. For men who are sexually active with women of childbearing potential:
 
agrees to use a condom with spermicidal foam/gel/film/cream/suppository
 
agrees to not donate sperm during the study and for at least 6 months after the last
dose of study drug
 
not planning to father a child during the study or within 6 months after the last dose
of study drug
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5.2. 
Exclusion Criteria
Any potential subject who meets any of the following criteria will be excluded from participating
in the study:
1. 
Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of
the bladder
2. 
Histopathology demonstrating any small cell component, pure adenocarcinoma, pure
squamous cell carcinoma, or pure squamous CIS of the bladder
3. 
Prior treatment with an FGFR inhibitor
4. 
Active malignancies (ie, progressing or requiring treatment change in the last
24 months) other than the disease being treated under study. The only allowed
exceptions are:
a. skin cancer treated within the last 24 months that is considered completely cured
b. adequately treated lobular carcinoma in situ (LCIS) and ductal CIS
c. history of localized breast cancer and receiving antihormonal agents, or history
of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
5. 
Current central serous retinopathy or retinal pigment epithelial detachment of any grade
6. 
History of uncontrolled cardiovascular disease including:
a. any of the following in the preceding 3 months: unstable angina, myocardial
infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known
congestive New York Heart Association Class III-IV  heart failure
(Section 10.7), cerebrovascular accident, or transient ischemic attack.
b. QTc prolongation as confirmed by ECG assessment at screening (Fridericia;
QTc >480 milliseconds).
c. Pulmonary embolism or other venous thromboembolism within the preceding 2
months.
7. 
Criterion modified per Amendment 1.
7.1. Known human immunodeficiency virus (HIV) infection, unless the subject has
been on a stable anti-retroviral therapy regimen for the last 6 months or more and has
had no opportunistic infections and a CD4 count >350 in the last 6 months.
8. 
Criterion modified per Amendment 1.
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8.1. Evidence of active hepatitis B or C infection (for example, subjects with history of
hepatitis C infection but normal hepatitis C virus polymerase chain reaction test and
subjects with hepatitis B with positive HBsAg antibody are allowed).
9. 
Not recovered from toxicity of prior anticancer therapy (except toxicities which are not
clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss)
10. 
Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers,
known gastric ulcers, or unhealed incisions
11. 
Major surgery within 4 weeks before Cycle 1 Day 1 (TURBT is not considered major
surgery)
12. 
Criterion modified per Amendment 2
12.1 Severe hypocalcemia (corrected serum calcium of <7 mg/dl), acute and unhealed
bone fractures, known underlying bone disease, or at an increased risk of bone fracture.
In addition, any condition for which, in the opinion of the investigator, participation
would not be in the best interest of the subjects (eg, compromise the well-being) or that
could prevent, limit, or confound the protocol-specified assessments. Examples include
ongoing active infection requiring systemic therapy and uncontrolled ongoing medical
conditions.
13. 
Criterion deleted per Amendment 3
14. 
Criterion added per Amendment 2
As determined by the investigator, contraindications to the use of gemcitabine or
MMC/hyperthermic MMC (Cohort 1)per local prescribing information
15. 
Criterion added per Amendment 3
Treatment with any other investigational agent within 30 days prior to randomization.
NOTE: Investigators should ensure that all study enrollment criteria have been met at screening.
If a subject's clinical status changes (including any available laboratory results or receipt of
additional medical records) after screening but before the first dose of study treatment, such that
he or she no longer meets all eligibility criteria, then the subject should be excluded from
participation in the study. Section 5.4, Screen Failures, describes options for retesting. The
required source documentation to support meeting the enrollment criteriaare noted inSection 10.2,
Regulatory, Ethical, and Study Oversight Considerations.
5.3. 
Lifestyle Considerations
Potential subjects must be willing and able to adhere to the following lifestyle restrictions during
the study to be eligible for participation:
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1. 
Refer to Section 6.5, Concomitant Therapy, for details regarding prohibited and
restricted therapy during the study.
2. 
Subjects should avoid consuming grapefruit or Seville oranges (or products containing
grapefruit or Seville oranges)due to CYP 3A4/5 inhibition.
3. 
Agree to follow all requirements that must be met during the study as noted in the
Inclusion and Exclusion Criteria (eg, contraceptive requirements; see Section 10.4)
4. 
Male and female subjects should be advised on sperm banking and egg preservation,
respectively, prior to entering the study, if appropriate.
Subjects should check with the study sites before taking over-the-counter medication known to
increase serum levels of phosphate, such as potassium phosphate supplements (oral or IV), vitamin
D supplements, antacids, and phosphate-containing enemas and laxatives (oral/rectal) thought to
increase serum phosphate level (Section 6.5.3).
5.4. 
Screen Failures
Subject Identification, Enrollment, and Screening Logs
The investigator agrees to complete a subject identification and enrollment log to permit easy
identification of each subject during and after the study. This document will be reviewed by the
sponsor study-site contact for completeness. This study will use IWRS. The investigator will
generate screening and enrollment logs directly from IWRS.
The subject identification and enrollment log will be treated as confidential and will be filed by
the investigator in the study file. To ensure subject confidentiality, no copy will be made. All
reports and communications relating to the study will identify subjects by subject identification
and age at initial informed consent. In cases where the subject is not randomized (Cohort 1) or
enrolled (Cohort 2 and Cohort 3) into the study, the date seen and age at initial informed consent
will be used.
If insufficient tissue is available at the first molecular eligibility assessment, another tissue sample
may be submitted (this is not considered rescreening). Subjects will be allowed to be rescreened
once for main study eligibility  after consultation with  the sponsor’s medical monitor, if the
investigator has a valid reason to rescreen (eg, resolution of conditions previously meeting the
exclusion criteria).
6. 
STUDY DRUG
For this study, study drug refers to erdafitinib (administered during the main study or Erdafitinib
Crossover; Section 10.10)and Investigator’s Choice provided by the sponsor. Study drugs used as
part ofthe main study are described in the following sections.
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6.1. 
Study Drug Administered
6.1.1. 
Erdafitinib
Erdafitinib will be provided as tablets for oral administration. Subjects will be instructed to take a
6-mg daily dose (without up-titration) beginning on Cycle 1 Day 1, with continuous dosing on a
28 day schedule. With the exceptions noted below for Cohort 2 and Cohort 3, treatment with
erdafitinib may continue for a maximum of 2 years or until the subject has high risk  disease
recurrence or progression, intolerable toxicity, withdraws consent, there is a decision by the
investigator to discontinue treatment, or the study is closed, whichever occurs first.
 
For Cohort 2, erdafitinib must be discontinued if CR is not observed within 3 months.
 
For Cohort 3, after 3 months of study treatment: 1) Subjects with stable disease or progression
of the marker lesion must discontinue erdafitinib and a TURBT of the marker lesion must be
performed. 2) Subjects with CR may continue erdafitinib. 3) Subjects with PR may, at the
investigator’s discretion, either continue treatment with erdafitinib or discontinue erdafitinib
and undergo TURBT of the marker lesion.
The erdafitinib dose may be modified with guidance to up-titrate to the 8-mg daily regimen, after
IDMC review of safety and tolerability data from approximately 5 to 10 additional subjects who
received the 6-mg daily regimen. Details of any such recommendation will be communicated
separately. Should the dosing regimen be modified to include up-titration, please follow the
instruction in Section 10.12 Appendix 12.
Each dose should be taken at approximately the same time each day, with or without food.
Erdafitinib is to be taken with approximately 240 mL (8 ounces) of water. The tablets should be
swallowed intact. Subjects should avoid consuming food or drinks containing grapefruit or Seville
oranges due to CYP 3A4/5 inhibition. Refer to the pharmacy manual/study site investigational
product manual for additional guidance on study drug preparation, handling, and storage.
If a dose of erdafitinib is missed, subjects should take the missed dose as soon as possible up to
6 hours after the normal schedule of that day. If it has been more than 6 hours since the missed
dose, then that dose should be skipped, and resume the regular daily dose schedule for erdafitinib
the next day. Extra tablets should not be taken to make up for the missed dose. If vomiting occurred
with drug administration, no replacement dose will be taken. If the subject vomits up to 4 hours
after the study drug administration, document the study drug as administered on the dose form in
the eCRF, with a comment noting that the subject vomited and at how many hours after the study
drug administration.
On days when pharmacokinetic sampling is performed, erdafitinib dosing and predose
pharmacokinetic sample collection must be coordinated so that at least 4 hours have elapsed
between the last dose of erdafitinib and collection of the predose pharmacokinetic sample. This
may require that subjects receive their daily dose of erdafitinib at the study site after collection of
the predose pharmacokinetic samples.
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Erdafitinib will be dispensed at the first visit of each cycle. All study drug doses dispensed must
be captured in the source documents. Unused study drug in the issued bottles and empty bottles
must be returned to the site at each study visit. Study drug must be returned to the site when a
subject discontinues study treatment. Returned tablets may not be reissued in this study or outside
the study (follow study drug accountability guidelines in the study Investigational Product
Procedures Manual [IPPM]). Erdafitinib administration must be captured in the source documents
and the eCRF.
Erdafitinib will be manufactured and provided under the responsibility of the sponsor. Refer to the
IB for a list of excipients.
The exposure of erdafitinib is predicted to increase by 50% in subjects with the CYP2C9 *3/*3
genotype, estimated to be 0.4% to 3% of the population among various ethnic groups. Therefore,
monitor for increased adverse reactions in subjects who are known or suspected to have
CYP2C9*3/*3 genotype. Dose titration is guided by serum phosphate levels in all subjects
irrespective of genotype; therefore, the implications of higher exposures of erdafitinib including
safety may be addressed.
6.1.2. 
Investigator’s Choice of Treatment –Cohort 1 Only
Subjects in Cohort 1 assigned to receive Investigator’s Choice will receive either intravesical
gemcitabine or intravesical MMC/hyperthermic MMC. Investigator’s choice treatment will be
given once weekly for at least 4 doses of induction followed by monthly maintenance for at least
6 months. Additional doses of induction or maintenance are allowed per local standard of care.
If more than 4 induction doses are given and the start of the monthly maintenance dose falls on
Day 8, Day 15, or Day 22 of subsequent cycles, all corresponding pre-dose assessments should be
done on the same day (±2 days) as the maintenance dose is administered as highlighted in the
example below:
 If subject starts monthly maintenance at C2D8, the following visits will occur at C3D8;
C4D8; C5D8; C6D8; C7D8; C8D8.
 If subject starts monthly maintenance at C2D15, following visits will occur at C3D15;
C4D15; C5D15; C6D15; C7D15; C8D15.
 If subject starts monthly maintenance at C2D22, following visits will occur at C3D22;
C4D22; C5D22; C6D22; C7D22; and C8D22.
Treatment may continue until treatment is completed, high  risk disease recurrence, intolerable
toxicity, withdrawal of consent, a decision by the investigator to discontinue treatment, or the study
is closed, whichever occurs first. As all subjects in Cohort 1 would have recurred within 12 months
of last dose of BCG, they are considered not to be candidates for re-treatment with BCG.21
Dose modifications or omissions will be managed by the treating physician per local standard of
care after discussion with the sponsor. Investigators must indicate their Investigator’s Choice
selection for each subject in the interactive web response system (IWRS) at screening, and the
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choice of the agent must take prior exposure into consideration. Subjects may not be switched to
the alternate Investigator’s Choice agent after randomization has occurred.
For subjects in Cohort 1 who have locally confirmed high-risk recurrence on Investigator’s Choice,
the subject may cross over to erdafitinib (see Section 10.10). Note: no additional crossover from
Investigator’s Choice to erdafitinib will be permitted.
6.1.2.1. 
Gemcitabine Administration
Gemcitabine will be administered as an intravesical instillation with 2,000 mg dose once weekly
for at least 4 induction doses followed by monthly maintenance for at least 6 months. Additional
doses of induction or maintenance are allowed per local standard of care.
Gemcitabine instillation must be captured in the source documents and the eCRF.
Refer to the IPPI provided separately for additional information on the preparation, handling, and
administration of gemcitabine.
6.1.2.2. 
Mitomycin C Administration
Mitomycin C or hyperthermic MMC will be administered as an intravesical instillationwith 40 mg
dose once weekly for at least 4 induction  doses followed by monthly maintenance for at least
6 months. Additional doses of maintenance are allowed per local standard ofcare.
Mitomycin C or hyperthermic MMC instillation must be captured in the source documents and the
eCRF.
Refer to the IPPI provided separately for additional information on the preparation, handling, and
administration of MMC/hyperthermic MMC.
6.1.3. 
Continuation of Treatment After Disease Recurrence
Subjects will not continue erdafitinib treatment after high risk disease recurrence or progression.
For subjects in Cohort 1 who have locally confirmed high-risk recurrence on Investigator’s Choice,
the subject may cross over to erdafitinib, if bythe assessment of investigator, this is best treatment
option for subject (Section 10.10). Subjects will have an End-of-Treatment (EoT) Visit for the
comparator and begin the crossover with erdafitinib beginning at C1D1. Note: no additional
crossover from Investigator’s Choice to erdafitinib will be permitted.
In Cohort 2 or Cohort 3, erdafitinib must be discontinued at the time of progression or recurrence
as described in Section 6.1.1.
6.1.4. 
Erdafitinib Crossover
Subjects who are randomized to gemcitabine or MMC/hyperthermic MMC in Cohort 1 and
demonstrate locally confirmed high-risk  recurrence while receiving study drug will have the
opportunity to cross over to treatment with erdafitinib. There must be an agreement to do so by the
investigator, subject, and the sponsor’s medical monitor. Documentation of high-risk disease
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recurrence will be reviewed by the sponsor’s medical monitor before crossover occurs and must
be entered onto the eCRF. Please refer to Section 10.10 for the schedule of assessments. Note: no
additional crossover from Investigator’s Choice to erdafitinib will be permitted.
6.2. 
Preparation/Handling/Storage/Accountability
Preparation/Handling/Storage
Refer to the study pharmacy manual (Investigational Product Binder) /study IPPI and IPPM for
additional guidance on study drug preparation, handling, and storage.
Accountability
The investigator is responsible for ensuring that all study drug received at the site is inventoried
and accounted for throughout the study. The dispensing of study drug to the subject, and the return
of study drug from the subject (if applicable), must be documented on the drug accountability
form. Subjects, or their legally acceptable representatives where applicable, must be instructed to
return all original containers, whether empty or containing study drug. All study drugwill be stored
and disposed of according to the sponsor's instructions. Study-site personnel must not combine
contents of the study drug containers.
Study drug must be handled in strict accordance with the protocol and the container label and must
be stored at the study site in a limited-access area or in a locked cabinet under appropriate
environmental conditions. Unused study drug, and study drug returned by the subject, must be
available for verification by the sponsor's study site monitor during on-site monitoring visits. The
return to the sponsor of unused study drug, or used returned study drug for destruction, will be
documented on the drug return form. When the study site is an authorized destruction unit and
study drug supplies are destroyed on-site, this must also be documented on the drug return form.
Study drug should be dispensed under the supervision of the investigator or a qualified member of
the study-site personnel, or by a hospital/clinic pharmacist. Study drug will be supplied only to
subjects participating in the study. Returned study drug must not be dispensed again, even to the
same subject. Whenever a subject brings his or her study drug to the study site for pill count, this
is not seen as a return of supplies. Study drug may not be relabeled or reassigned for use by other
subjects. The investigator agrees neither to dispense the study drug from, nor store it at, any site
other than the study sites agreed upon with the sponsor. Further guidance and information for the
final disposition of unused study drugs are provided in the study IPPI and IPPM.
6.3. 
Measures to Minimize Bias: Randomization and Blinding
This is an open-label study; neither the sponsor, investigators, nor subjects will be blinded to
assigned treatment. Central randomization will be implemented in this study. In Cohort 1, subjects
will be randomly assigned to 1 of 2 treatment groups in a 2:1 randomization ratio (erdafitinib:
Investigator’s Choice)based on a computer-generated randomization schedule prepared before the
study by or under the supervision of the sponsor. The randomization will be balanced by using
randomly permuted blocks and will be stratified by the type of resected papillary disease (Ta vs
T1) and type of prior BCG therapy (BCG-unresponsive vs BCG experienced). Subjects in the
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BCG-experienced strata will be capped at approximately 50% of the total study population. The
IWRS will assign a unique code, which will dictate the study drug assignment and matching study
drug kit for the subject. The requestor must use his or her own user identification and personal
identification number when contacting the IWRS and will then give the relevant subject details to
uniquely identify the subject. Investigators must indicate their Investigator’s Choice selection for
each subject during screening. All tissue samples with a local investigator assessment of any
recurrence will be sent to central lab for an independent pathologic assessment regardless of risk
category in order to decrease bias.
All subjects in Cohort 2 and Cohort 3 will be assigned to treatment with erdafitinib.
6.4. 
Study Drug Compliance
The investigator or designated study personnel will maintain a log of the amount of study drug
dispensed and returned, if applicable. Drug supplies will be inventoried and accounted for
throughout the study.
Subjects will receive instructions on erdafitinib compliance at their Cycle 1 Day 1 visit. The time
of erdafitinib intake will be recorded on days when PK sampling occurs. On days when the subject
visits the study site for dose administration or PK sampling, the investigator or designee will
supervise administration of the study drug and the exact time of administration will be recorded in
the eCRF. During the study, the investigator or designated study research staff will be responsible
for providing additional instruction to reeducate any subject who is not compliant with the study
drug schedule.
6.5. 
Concomitant Therapy
Concomitant therapies must be recorded at the time of study screening(concomitant therapy within
the 35 days before Cycle 1 Day 1), during the Treatment Phase, and up to 30 days after the last
dose of study drug (30-day Safety Follow-up Visit). All therapies (prescription or over-the-counter
medications) continued at the start of the study or started during the study and different from the
study drug must be recorded in the eCRF.
The sponsor must be notified in advance (or as soon as possible thereafter) of any instances in
which prohibited therapies are administered.
In addition to concomitant therapy, all prior anticancer therapy will be recorded in the eCRF.
6.5.1. 
Permitted Medications
Permitted medications are to be recorded at the time of screening (within 35 days prior to the first
dose of study drug), throughout the study, and up to 30 days after the last dose of study drug in the
appropriate section of the eCRF.
 
Symptomatic treatment: Supportive care, such as antibiotics, analgesics, transfusions, etc.,
and concomitant medications for the symptomatic treatment of related toxicities (Grade 1 to
4) may be administered according to the standard of care at the site, and the treating
physician’s discretion, as clinically indicated.
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 
Prophylactic medication: Appropriate prophylactic antiemetic regimens may be provided if
required, in accordance with local institutional guidelines or practice guidelines.
 
Chronic supportive therapies are permitted as medically necessary.
 
COVID-19 vaccination: Note: Administration of non-live vaccines approved or authorized
for emergency use (eg, COVID-19) by local health authorities are allowed before or during
this study.
6.5.2. 
Prohibited Medications
The following concomitant medications are prohibited during the study. The sponsor must be
notified in advance, or as soon as possible thereafter, of any instances in which prohibited therapies
were administered.
 
Concurrent investigational agents during the Treatment Phase
 
Concurrent antineoplastic agents or hormonal anticancer therapy during the Treatment Phase,
except as allowed by Exclusion Criterion no. 4 (see Section 5.2)
6.5.3. 
Precautions for Concomitant Medications
The following precautions are advised:
 
Based on in vitro data, erdafitinib is metabolized by cytochrome CYP2C9 and CYP3A4. A
clinical DDI study showed that on average, erdafitinib exposure (Cmax  and AUC) was
increased by 5% to 34%, respectively, when co-administered with itraconazole (a strong
inhibitor of CYP3A4) and 21% to 48%, respectively, when co-administered with fluconazole
(a moderate inhibitor of CYP2C9). For this reason, strong CYP3A4 and moderate CYP2C9
inhibitors should be used with caution (See Section 10.9). Consider alternative therapies with
no or minimal CYP2C9 or CYP3A4 inhibition potential during treatment with erdafitinib. If
co-administration  of a moderate inhibitor of CYP2C9 or strong inhibitor of CYP3A4  is
unavoidable, monitor the subject closely for adverse reactions and consider dose
modifications accordingly. If the strong inhibitor is discontinued, the erdafitinib dose may be
increased in the absence of drug-related toxicity.
 
The impact of moderate CYP2C9 inducers and strong CYP3A inducers (such as rifampin) on
erdafitinib was not clinically studied. Co-administration of erdafitinib with these agents may
significantly decrease erdafitinib exposure. Therefore, the concomitant use of these agents
with erdafitinib should be avoided (see Section 10.9). Co-administration of erdafitinib with
moderate CYP3A inducers may decrease erdafitinib exposure. Caution should be exercised
for concomitant administration of erdafitinib and moderate inducers of CYP3A4
(see Section 10.9).
 
Until further data become available, concomitant use of erdafitinib with CYP3A4 substrates
with narrow therapeutic indices should be avoided.
 
Erdafitinib was shown to inhibit, via in  vitro experiments, human P-gp at concentrations
achieved at therapeutic doses in humans. If the compound is administered with drugs that are
substrates of P-gp, there is the potential for observing increased concentrations of the substrate
drug. Caution should be exercised for co-administered drugs that are P-gp substrates; separate
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erdafitinib administration by at least 6 hours before or after administration of P-gp substrates
with narrow therapeutic index.
 
Erdafitinib was shown to be an OCT2 inhibitor in vitro. PBPK simulations with metformin,
an OCT2 substrate, predicted a lack of clinically relevant interaction with erdafitinib.
However, until further data are available, consider reducing the dose of OCT2 substrates or
consider alternative agents based on tolerability.
 
For subjects taking erdafitinib, medications known or thought to increase serum levels of
phosphate including potassium phosphate supplements (oral or IV), vitamin D supplements,
antacids, and phosphate-containing enemas and laxatives (oral/rectal) should be used with
caution in case of strong medical need and when the benefit outweighs the risk. Check
phosphate levels more regularly during treatment.
6.6. 
Dose Modification
Any dose/dosage adjustment should be overseen by medically-qualified study-site personnel
(principal or subinvestigator unless an immediate safety risk appears to be present).
6.6.1. 
Erdafitinib Up-titration Guidelines
The erdaftinib dose is modified to the 6-mg daily regimen (without up-titration). After review of
safety and tolerability data from approximately 5 to 10 additional subjects who received the 6-mg
daily regimen, the IDMC may recommend that the erdafitinib dose be modified to allow
up-titration to the 8-mg daily regimen. Details of any such recommendation will be communicated
separately. Should the dosing regimen be modified to include up-titration, please follow the
instruction in Section 10.12, Appendix 12.
6.6.2. 
Erdafitinib Dose Interruptions
Treatment with erdafitinib should be discontinued or modified based on toxicities as described in
Table 1. For eye, skin/nail, dry mouth/mucositis, and phosphate toxicity, specific
recommendations in the management guidelines are provided in Section 6.6.2.1.
Table 1: 
Erdafitinib Dose Modification Rules Based on Toxicity Severity
Toxicity 
Grade
Action 
Dose modification after resolution of adverse eventa
1 
None 
Continue same dose.
2 
None, or consider interruption if 
the 
toxicity 
is 
considered 
clinically significant 
If interrupted, restart at same dose if toxicity is completely
resolved to baseline or consider restarting at 1 dose lowerb if not
completely resolved to baseline (but resolved to Grade 1).
3 
Interrupt drug 
Restart at 1 dose lowerb if recovered to baseline (to ≤Grade 1 or
back to baseline for non-hematologic toxicity) within 28 days;
restart at 2 doses lowerb if not completely resolved to baseline
(but resolved to Grade 1) within 28 days. Discontinue drug if
unresolved for >28 days.
4 
Interrupt drug 
Discontinue.
a
For eye, skin/nail, dry mouth/mucositis, and phosphate toxicity please follow specific recommendations in the
management guidelines (Section 6.6.2.1).
b
Please refer to Table 2.
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 
Subjects with any grade of toxicity (Grade 1 to 4) should be provided symptomatic treatment
where applicable.
 
If erdafitinib is interrupted consecutively for 1 week or longer due to drug-related toxicity, the
study drug may be reintroduced at either the same dose level or the first reduced dose level
following recovery from the toxicity (see dose reduction levels in Table 2). A second dose
reduction may be implemented following a second occurrence of drug-related toxicity.
 
If erdafitinib must be withheld for more than 28 days for a drug-related adverse event that
fails to resolve to an acceptable level (eg, ≤Grade 1 non-hematologic toxicity or back to
baseline), treatment with erdafitinib should be discontinued except when the subject has been
deriving benefit from treatment, and the investigator believes, based on his or her clinical
judgment, that continued treatment with erdafitinib is in the best interest of the subject.
Erdafitinib may be restarted at the same or a lower dose (Table 2) if the sponsor’s medical
monitor concurs with the assessment.
 
If the erdafitinib dose was reduced and the adverse event that was the reason for this dose
reduction has completely resolved, the dose may be re-escalated to the next higher dose if the
subject was deriving benefit from treatment, and the investigator believes, based on his or her
clinical judgment, that dose re-escalation of erdafitinib is in the best interest of the subject and
the sponsor’s medical monitor concurs with the assessment.
 
In all cases of clinically significant impaired wound healing or imminent surgery or potential
bleeding complications, it is recommended that dose administration be interrupted,
appropriate clinical laboratory data (eg, coagulation parameters) be carefully monitored, and
supportive therapy administered, where applicable. Dose administration may be restarted
when it is considered safe and at an appropriate dose, according to the investigator’s
assessment.
Table 2: 
Erdafitinib Dose Reduction Levels
Category 
Dose
Starting dose 
6 mg
1st dose reduction 
5 mg
2nd dose reduction  
4 mg
3rd dose reduction 
STOP
Note that the erdafitinib dose reduction levels table for the 6-mg daily regimen with up-titration to
the 8-mg daily regimen is provided in Section 10.12, Appendix 12.
6.6.2.1. 
Guidance for Specific Erdafitinib Toxicities
6.6.2.1.1. 
Guidelines for the Management of Elevated Phosphate Levels
Hyperphosphatemia will be graded as outlined in Table 3. Guidelines for the clinical management of elevated
serum phosphate levels are presented in
Table 4.
Table 3: 
Grading of Hyperphosphatemia Adverse Events
Adverse Event 
Grade 0 
Grade 1 
Grade 2 
Grade 3 
Grade 4
Hyperphosphatemia 
<5.50 mg/dL 
<1.75 mmol/L
5.50-6.99 
mg/dL 
7.00-8.99 
mg/dL 
9.00-10.00 
mg/dL (2.91-3.20 
mmol/L), or 
>10.00 mg/dL
(>3.20 mmol/L),
or symptomatic
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1.75-2.24
mmol/L
2.25-2.90 
mmol/L 
asymptomatic 
soft-tissue 
calcification with 
any phosphate 
level
soft-tissue
calcification with
any phosphate
level
Table 4: 
Guidelines for Management of Serum Phosphate Elevation
Serum Phosphate
Level 
Study Drug Management 
Symptom Management
<5.50 mg/dL 
(<1.75 mmol/L)
(Grade 0)
Continue erdafitinib treatment. 
None.
5.50-6.99 mg/dL 
(1.75-2.24 
mmol/L)
(Grade 1)
Continue erdafitinib treatment. 
Restriction of phosphate intake to
600 –800 mg/day.
7.00-8.99 mg/dL 
(2.25-2.90 
mmol/L) 
(Grade 2) 
Continue erdafitinib treatment. 
A dose reduction will be implemented for persistenta
hyperphosphatemia (defined as serum phosphate 
≥7 mg/dL for a period of 2 months) or if clinically 
necessary (eg, in the presence of additional adverse 
events linked to hyperphosphatemia or electrolyte
disturbances)
Restriction of phosphate intake to
600 –800 mg/day.
Start sevelamer 800 to 1,600 mg
TID with food until phosphate
level is <7.0 mg/dL.
9.00-10.00 mg/dL 
(>2.91-3.20 
mmol/L) 
(Grade 3) 
Withholdb erdafitinib treatment until serum phosphate 
level returns to <7.0 mg/dL (weekly testing 
recommended).
Restart treatment at the same dose level. 
A dose reduction will be implemented for persistent a
hyperphosphatemia (defined as serum phosphate
≥9 mg/dL for a period of 1 month) or if clinically
necessary (eg, in the presence of additional adverse
events linked to hyperphosphatemia or electrolyte
disturbances)
Restriction of phosphate intake to
600 –800 mg/day.
Sevelamer up to 1,600 mg TID
with food until serum phosphate
level is <7.0 mg/dL.
>10.00 mg/dL 
(>3.20 mmol/L) 
(Grade 4) 
Withholdb erdafitinib treatment until serum phosphate 
level returns to <7.0 mg/dL (weekly testing 
recommended).
Restart treatment at the first reduced dose level.
If persistenta hyperphosphatemia (≥10.00 mg/dL) for
>2 weeks, erdafitinib must be discontinued permanently.
Medical management as clinically
appropriate.
Significant 
alteration in 
baseline renal 
function or Grade 3 
hypocalcemia 
Erdafitinib must be discontinued permanently. (In 
situations where the subject is having clinical benefit and 
the investigator and the sponsor’s medical monitor agree
that continuation of treatment is in the best interest of the
subject, the drug may be restarted at
2 dose levels lower if appropriate. Follow other
recommendations described above, Section 6.6.2.)
Medical management as clinically
appropriate.
Note: These are general guidelines that are based on emerging data and consensus experience of participating investigators or the
experts in the field. The treating physicians must use clinical judgment and local standard of care to decide the best way to
manage phosphate elevation. If sevelamer hydrochloride (Renagel®) is not available, use of other phosphate binders (non-
calcium containing) based on the local standard is recommended, including sevelamer carbonate (Renvela) or lanthanum
carbonate (Fosrenol®). These guidelines will be updated based on emerging data. Additional information on phosphorous in
foods by class of food can also be found at www.permanente.net/homepage/kaiser/pdf/42025.pdf. Additional information for
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phosphate management and diet can be found at the National Kidney Foundation website
(http://www.kidney.org/atoz/content/phosphorus.cfm)
a. Persistent hyperphosphatemia is considered to be more than 1 sequential phosphate value above the cut-off.
b. Study drug interruptions for hyperphosphatemia suggested to be 7 days in duration.
6.6.2.1.2. 
Guidelines for the Management of Dry Mouth and Mucositis
Guidelines for the clinical management of dry mouth (xerostomia) and mucositis are provided in
Table 5 and Table 6, respectively.
 
General Prophylaxis for dry mouth and oral mucositis:
 
Good oral hygiene
 
Use a soft toothbrush
 
Avoidance of spicy, acidic, hard, and hot food and beverages
 
Use of mild-flavored toothpastes
 
Use of salt and baking soda mouthwashes 3 or 4 times per day
 
Water soluble lubrication agents like artificial saliva (for xerostomia or dry mouth)
Table 5: 
Guidelines for Management of Dry Mouth (Xerostomia)
Grade and Definition 
Study Drug (Erdafitinib) Management 
Symptom Management
Grade 1: symptomatic (eg, dry or 
thick saliva) without significant 
dietary alteration; unstimulated
saliva flow >0.2 mL/min
Continue erdafitinib at current dose. 
Sorbitol lozenges as
needed
Grade 2: moderate symptoms; oral 
intake alterations (eg, copious 
water, other lubricants, diet limited 
to purees or soft, moist foods); 
unstimulated saliva 0.1 to
0.2 mL/min
Continue erdafitinib at current dose. 
Sorbitol lozenges as
needed and Cevimeline 30
mg TID or Pilocarpine 5
mg TID, orally
Grade 3: inability to adequately 
aliment orally; tube feeding or TPN 
indicated; unstimulated saliva less 
than 0.1 mL/min  
Hold erdafitinib (for up to 28 days), with 
weekly reassessments of clinical 
condition. 
When resolved to ≤Grade 1 or baseline, 
restart at 1 dose level below in
consultation with the medical monitor.
Sorbitol lozenges as
needed and Cevimeline 30
mg TID or Pilocarpine 5
mg TID, orally
Grade 4: life-threatening 
consequences, urgent intervention 
indicated
Discontinue erdafitinib. 
Evaluation and therapy as
clinically indicated
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Table 6: 
Guidelines for the Management of Oral Mucositis
Grade 
Study Drug (Erdafitinib) Management 
Symptom Management
Grade 1 
Continue erdafitinib at current dose. 
 
Continue general prophylaxis
recommendations.
 
Dexamethasone solution
(0.5 mg/5 mL solution) swish
and spit QID or similar solution
that is available in your
country/territory and lidocaine 2-
5% jelly or solution.
 
Consider clotrimazole/nystatin if
subjects are at risk of developing
oral candidiasis.
Grade 2 
 
Consider holding erdafitinib if the 
subject has other study drug-related 
concomitant Grade 2 AEs. 
 
Hold erdafitinib if the subject was 
already on symptom management 
(dexamethasone solution swish and 
spit and lidocaine 2%-5% jelly or 
solution) for more than a week. 
 
If the erdafitinib is withheld, reassess 
in 1-2 weeks. 
 
If this is the first occurrence of 
toxicity and resolves to ≤ Grade 1 or
baseline within 2 weeks, restart at
same dose.
 
If recurrent event or takes > 2 weeks
to resolve to ≤ Grade 1 or baseline,
then restart at 1 dose level below.
 
Dexamethasone solution
(0.5 mg/5 mL solution) swish
and spit QID or similar solution
that is available in your
country/territory and lidocaine 2-
5% jelly or solution.
 
Consider concomitant etiologies
such as oral candidiasis, oral
herpes and recommend
appropriate anti-fungal or
anti-viral agents.
Grade 3 
Hold erdafitinib, with reassessments of 
clinical condition in 1-2 weeks. 
When resolves to ≤Grade 1 or baseline, 
restart at 1 dose level below in 
consultation with the medical monitor. 
Dexamethasone solution
(0.5 mg/5 mL solution) swish and
spit QID or similar solution that is
available in your country/territory
and lidocaine 2%-5% jelly or
solution.
Consider pain management
strategies.
Consider IV hydration.
Grade 4 
Discontinue erdafitinib. 
Evaluation and therapy as clinically
indicated.
6.6.2.1.3. 
Guidelines for the Management of Dry Skin and Skin Toxicity
Guidelines for the management of dry skin are provided in
Table 7.
 
General prophylaxis for dry skin and skin toxicity:
 
Avoid unnecessary exposure to sunlight and excessive use of soap.
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 
Avoid bathing in excess; use tepid rather than hot water.
 
Use moisturizers regularly; apply thick, alcohol-free and oil-in-water based emollient
cream on exposed and dry areas of the body.
 
Avoid perfumed products, bubble bath, perfumed soaps, and take breaks from shaving.
 
Use broad spectrum sunscreen with a skin protection factor (SPF) ≥15.
 
Wear cotton clothes next to skin rather than wool, synthetic fibers, or rough clothing.
 
Use occlusive alcohol-free emollient creams (jar or tub) for treatment of mild/moderate
xerosis.
 
For scaly areas, use exfoliants (ammonium lactate 12% or lactic acid cream 12%).
Table 7: 
Guidelines for Management of Dry Skin
Grade and Definition 
Study Drug (Erdafitinib) Management Symptom Management
Grade 1: Dry skin covering 
less than 10% body surface 
area (BSA) and no associated 
erythema or pruritus 
Continue erdafitinib at current dose. 
Use fragrance free moisturizing
cream or ointment BID over entire
body.
Use ammonium lactate 12% cream
or salicylic acid 6% cream BID
over dry/scaly/hyperkeratotic areas
such as palms and soles.
Grade 2: Dry skin covering 
10% to 30% BSA and 
associated with erythema or 
pruritis with limited 
instrumental activities of daily 
living (IADL) 
Continue erdafitinib at current dose. 
Use fragrance free moisturizing
cream or ointment BID over entire
body.
Use ammonium lactate 12% cream
or salicylic acid 6% cream BID
over dry/scaly/hyperkeratotic areas
such as palms and soles.
Use zinc oxide 13%-40% at night
for areas with fissures.
Grade 3: Dry skin covering 
>30% BSA and associated 
with pruritis; limiting self-care 
activities of daily living 
(ADL) 
Hold erdafitinib (for up to 28 days), with 
weekly reassessments of clinical 
condition. 
When resolves to ≤Grade 1 or baseline, 
restart at 1 dose level below in
consultation with the medical monitor.
Use topical corticosteroid ointment
or cream* BID and zinc oxide 13%
-40% at night for areas with
fissures.
Grade 4: Dry skin with life- 
threatening consequences, 
urgent intervention indicated
Discontinue erdafitinib. 
Evaluation and therapy as clinically
indicated
*Topical Corticosteroid Ointments: Clobetasol 0.05%, Betamethasone 0.05%, Fluocinonide 0.05%
BID=twice a day
6.6.2.1.4. 
Guidelines for Management of Nail Toxicity (Onycholysis,
Onychodystrophy, and Paronychia)
Adverse events related to nails will be graded as outlined in Table 8. Guidelines for the
management of nail discoloration/loss/ridging (onycholysis/onychodystrophy) are provided in
Table 9. Guidelines for the management of paronychia are provided in Table 10.
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Table 8: 
Grading of Nails Adverse Events
Adverse Event 
Grade 1 
Grade 2 
Grade 3 
Grade 4
Nail Changes 
(onychodystrophy) 
Nail discoloration, 
asymptomatic 
separation of the 
nail bed from the 
nail plate or nail 
loss 
Nail/finger tips 
pain, symptomatic 
separation of the 
nail bed from the 
nail plate or nail 
loss; limiting 
instrumental ADL 
Severe nail finger 
tips pain, 
symptomatic 
separation of the 
nail bed from the
nail plate or nail
loss; significantly
limiting
instrumental ADL
Life-threatening
consequences,
urgent intervention
indicated
ADL= activities of daily living
 
General Prophylaxis for nail toxicity:
 
Good hygienic practices; keep fingers and toes clean
 
Keep nails trimmed but avoid aggressive manicuring
 
Use gloves for housecleaning and gardening to minimize damage and prevent infection
 
Nail polish and imitation fingernails should not be worn until the nails have grown out
and returned to normal
 
Wear comfortable shoes (wide sized shoes with room for the toes)
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Table 9: 
Guidelines for Management of Nail Toxicity (Onycholysis/Onychodystrophy)
Grade 
Study Drug (Erdafitinib) Management 
Symptom Management
Grade 1 
Continue erdafitinib at current dose. 
 
Continue general prophylaxis
recommendations.
 
Over-the-counter nail strengthener OR
poly-urea urethane nail lacquer
(Nuvail™) OR diethylene glycol
monoethylether nail lacquer daily
(Genadur)daily.
 
Use non-alcohol- containing
moisturizing creams.
Grade 2 
Consider holding erdafitinib with 
reassessment in 1-2 weeks. 
If first occurrence and it resolves to 
≤Grade 1 or baseline within 2 weeks,
restart at same dose.
If recurrent event or takes >2 weeks to
resolve to ≤Grade 1 or baseline, then
restart at 1 dose level below in
consultation with the medical monitor.
 
Manage as per Grade 1.
 
For signs of infection (periungual
edema/erythema/ tenderness or
discharge), obtain bacterial cultures,
and then start the following:
o 
treatment with oral antibiotic for
2 weeks (cefadroxil 500 mg BID,
ciprofloxacin 500 mg BID, or
sulfamethoxazole/ trimethoprim
BID)
AND
o topical antifungal lacquer daily
for 6+ weeks (ciclopirox olamine
8% OR efinaconazole 10% OR
amorolfine 5% weekly OR
bifonazole/urea ointment daily)
 
Silver nitrate application weekly AND
topical antibiotics AND vinegar
soaksa.
Grade 3 
Hold erdafitinib, with reassessment in 1-2 
weeks. 
When resolves to ≤Grade 1 or baseline, 
restart at 1 dose level below in 
consultation with the medical monitor. 
Silver nitrate application weekly AND
topical antibiotics AND vinegar soaks.a
For signs of infection (periungal
edema/erythema/ tenderness or discharge),
obtain bacterial cultures, and then start the
following: treatment with oral antibiotic
for 2 weeks (cefadroxil 500 mg BID,
ciprofloxacin 500 mg BID, or
sulfamethoxazole/trimethoprim BID).
For cases of severe/refractory infection
consider intravenous antibiotics.
Consider dermatological or surgical
evaluation.
Grade 4 
Discontinue erdafitinib 
Evaluation and therapy as clinically
indicated
a 
Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes
every day. Examples of topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B
BID= bis in die (two times each day)
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Table 10: 
Guidelines for Management of Paronychia
Grade 
Study Drug (Erdafitinib) 
Management
Symptom Management
Grade 1 
Continue erdafitinib at current dose. 
Topical antibiotics AND vinegar
soaksa
Grade 2 
Continue erdafitinib at current dose. 
Consider erdafitinib holding if no 
improvement in 1 to 2 weeks. 
When resolves to ≤Grade 1 or baseline, 
restart at same or 1 dose level below in 
consultation with the medical monitor 
Topical antibiotics AND vinegar
soaksa AND topical antifungal lacquer
daily for 6+ weeks (ciclopirox olamine
8% OR efinaconazole 10% OR
amorolfine 5% weekly OR
bifonazole/urea ointment daily)
For signs of infection (periungal
edema/erythema/tenderness or
discharge), obtain bacterial cultures,
and then start the following: treatment
with oral antibiotic for 2 weeks
(cefadroxil 500 mg BID, ciprofloxacin
500 mg BID, or sulfamethoxazole/
trimethoprim [Bactrim™] DS BID).
Grade 3 
Hold erdafitinib (for up to 28 days), 
with weekly reassessments of clinical 
condition. 
When resolves to ≤Grade 1 or base
line, restart at one dose level below in
consultation with the medical monitor.
Vinegar soaksa AND consider nail
avulsion
For signs of infection (periungal
edema/erythema/tenderness or
discharge), obtain bacterial cultures,
and then start the following: treatment
with oral antibiotic for 2 weeks
(cefadroxil 500 mg BID, ciprofloxacin
500 mg BID, or sulfamethoxazole/
trimethoprim [Bactrim] DS BID).
For cases of severe/refractory infection
consider intravenous antibiotics.
Consider dermatological or surgical
evaluation.
a 
Vinegar soaks consist of soaking fingers or toes in a solution of white vinegar in water 1:1 for 15 minutes
every day. Examples of topical antibiotic ointments: Mupirocin 2%, gentamycin, bacitracin zinc/polymixin B
6.6.2.1.5. 
Guidelines for the Management of Eye Toxicity Associated With
Vision Changes
Any new or worsening visual symptoms, for example, blurred vision, partial or complete loss of
vision, double vision, floaters or color spots or halos around light, change in color or night vision,
photophobia, ocular pain or stinging sensation, or foreign body sensation should be further
evaluated and managed per the guidelines in Table 11.
Amsler grid (illustrated in Section 10.8): For any positive Amsler grid test, the subject should be
referred for a full ophthalmologic examination within 7 days. However, if the subject has an
abnormal Amsler grid test and otherwise normal ophthalmologic examination at baseline (during
screening), a repeat ophthalmologic examination would be recommended only if, in the opinion
of the investigator, there is a likelihood of significant change from the subject’s baseline Amsler
grid test at screening, or the subject has developed new clinical symptoms.
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Table 11: 
Guidelines for Management of Eye Toxicity
Grade and Definition 
Study Drug (Erdafitinib) Management 
Symptom Management
Grade 1: Asymptomatic or
mild symptoms; clinical or
diagnostic observations only
Or abnormal Amsler grid test
Refer for an ophthalmologic examination. If an
ophthalmologic examination cannot be performed within 7
days, withhold treatment with erdafitinib until an
examination can be performed.
If there is no evidence of eye toxicity on ophthalmologic
examination, continue erdafitinib at the same dose level.
If diagnosis from ophthalmologic examination is keratitis or
retinal abnormality such as central serous retinopathy (CSR)/
retinal pigment epithelial detachments (RPED), withhold
erdafitinib until signs and symptoms have resolved.
If toxicity is reversible (complete resolution or stabilization
and asymptomatic) in 4 weeks according to ophthalmologic
examination, resume erdafitinib at the next lower dose level
after consultation with the sponsor’s medical monitor.
Retinal pigment epithelial detachment, if observed, should be
monitored at approximately 2-3-week intervals until
resolution.
Monitor for recurrence every 1 to 2 weeks for a month and as
clinically appropriate thereafter. If there is no recurrence,
then re-escalation can be considered in consultation with the
medical monitor.
Refer the subject for an
ophthalmologic examination.
For retinal pathology perform
OCT as appropriate and
consider referral to a retinal
specialist for further evaluation.
Follow specific treatment per
the ophthalmologist’s
recommendation.
Grade 2: Moderate; minimal,
local
or noninvasive intervention
indicated; limiting age
appropriate instrumental ADL
Immediately withhold erdafitinib.
If there is no evidence of drug-related corneal or retinal
pathology on ophthalmologic examination, withhold
erdafitinib until signs and symptoms have resolved. Resume
erdafitinib therapy at the next lower dose level.
If diagnosis from ophthalmologic examination is keratitis or
retinal abnormality such as CSR/RPED, withhold erdafitinib
until signs and symptoms have resolved, stabilized, or subject
is lost to follow-up or withdraws consent (which ever
happens first).
If toxicity is reversible (complete resolution or stabilization
and asymptomatic) within 4 weeks according to
ophthalmologic examination, resume erdafitinib at the next
lower dose level after consultation with the sponsor’s medical
monitor.
Retinal pigment epithelial detachment, if observed, should be
monitored at approximately 2-3-week intervals until
resolution.
Monitor for recurrence every 1 to 2 weeks for a month and as
clinically appropriate thereafter. If there is no recurrence,
then re-escalation can be considered in consultation with the
medical monitor.
Refer subject to an
ophthalmologist for evaluation
with an ophthalmologic
examination.
For retinal pathology, perform
OCT as appropriate and
consider referral to a retinal
specialist for further evaluation.
Follow specific treatment per
the ophthalmologist’s
recommendation.
Grade 3: Severe or medically
significant but not immediate
sight-threatening;
hospitalization or prolongation
of existing hospitalization
indicated; disabling; limiting
self-care ADL
If the toxicity is Grade 3, report as a serious adverse event
and withhold erdafitinib. If the toxicity is Grade 3 and
reversible (complete resolution or stabilization and
asymptomatic) within 4 weeks and the subject is having
clinical benefit, and the investigator and the sponsor’s
medical monitor agree that continuation of treatment is in the
best interest of the subject, then erdafitinib may be resumed
at 2 dose levels lower if appropriate.
Retinal pigment epithelial detachment, if observed, should be
monitored at approximately 2-3-week intervals until
resolution.
Monitor for recurrence using appropriate investigations every
Refer subject to an
ophthalmologist for evaluation
with an ophthalmologic
examination.
For retinal pathology, perform
OCT as appropriate and
consider referral to a retinal
specialist for further evaluation.
Follow specific treatment per
the ophthalmologist’s
recommendation.
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Table 11: 
Guidelines for Management of Eye Toxicity
Grade and Definition 
Study Drug (Erdafitinib) Management 
Symptom Management
1 to 2 weeks for a month and as clinically appropriate
thereafter. For cases of recurrence, consider permanent
discontinuation.
Grade 4: Sight-threatening
consequences; urgent
intervention indicated;
blindness (20/200 or worse) in
the affected eye
Permanently discontinue treatment with erdafitinib.
Report as a serious adverse event and monitor resolution of
the event until complete resolution, stabilization or the
subject is lost to follow-up or withdraws consent (which ever
happens first).
Promptly refer subject to an
ophthalmologist for evaluation
with an ophthalmologic
examination.
Follow specific treatment per
the ophthalmologist’s
recommendation.
ADL=Activities of Daily Living, OCT= Optical Coherence Tomography
6.6.2.1.6. 
Guidelines for the Management of Dry Eye
 
General considerations: Avoid unnecessary exposure to sunlight, use sunglasses in bright
light.
 
Prophylactic management: Frequent use of artificial tear substitutes and ocular demulcents
is strongly recommended, ie, every 2 hours during time awake.
 
Reactive management:
 
Withhold erdafitinib for Grade 3 toxicity
 
Artificial tear substitutes if not started, every 2 hours during time awake
 
Ocular demulcents
 
Severe treatment-related dry eye should be evaluated by an ophthalmologist
6.6.3. 
Investigator’s Choice Dose Modification
Changes to intravesical gemcitabine or intravesical MMC/hyperthermic MMC  dose or regimen
for subjects in Cohort 1 assigned to receive Investigator’s Choice (ie, additional doses of induction
or maintenance) will be directed by local standard of care at the study site (see Section 6.1.2).
6.7. 
Access to Study Drug in the Long-term Extension Phase
The LTE Phase will allow continued access to study drug for subjects who continue to derive
benefit from treatment, as determined by their investigator. Subjects may enter the LTE Phase
following implementation of Amendment 6, provided they meet the criteria for entry specified in
LTE Figure 1.
The continuation of study drug in the LTE Phase is limited as follows:
 
Erdafitinib (Cohort 1, Cohort 2, Cohort 3): Provision of erdafitinib may continue for a
maximum of 2 years in total (inclusive of administration in the Treatment Phase, Erdafitinib
Crossover, and the LTE Phase, as applicable) or until the investigator decides it is in the best
interest of the subject that erdafitinib be discontinued, whichever comes first.
 
Investigator’s choice of either intravesical gemcitabine or intravesical MMC/hyperthermic
MMC (Cohort 1): provision of intravesical gemcitabine or intravesical MMC/hyperthermic
MMC may continue per local standard of care.
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No data will be collected in the eCRF during the LTE Phase, and only SAEs will be reported to
the company safety repository. As an alternative to entering the LTE Phase, subjects receiving
erdafitinib may exit the study and continue to receive treatment on any other post-trial access
program, when permitted by local regulations. Detail regarding the LTE Phase (including a
Schedule of Activities) is provided in Section 10.14, Appendix 14.
7. 
DISCONTINUATION OF STUDY DRUG/SUBJECT
DISCONTINUATION/WITHDRAWAL/STUDY CLOSURE
7.1. 
Discontinuation of Study Drug
A subject's study drug must be discontinued if:
 
The subject withdraws consent to receive study drug.
 
The investigator believes that for safety reasons or tolerability reasons (eg, adverse event) it
is in the best interest of the subject to discontinue study drug.
 
The subject becomes pregnant; discontinuation of study drug in this instance should be
discussed with the sponsor’s medical monitor.
 
High-risk recurrence (Cohort 1) or progression of disease (Cohort 1, Cohort 2 and Cohort 3)
is assessed, except as described in Section 6.1.3.
 
Subject reaches the maximum treatment duration as defined in Section 6.1.
 
The sponsor closes the study.
 
The sponsor reserves the right to close the study or close the study site at any time for
any reason at the sole discretion of the sponsor, e.g. in case of unacceptable risk,
intolerable toxicity, or change in the risk/benefit profile; this might include recurrence of
adverse events of which character, severity, or frequency is new in comparison to the
existing risk profile. Also, data derived from other clinical trials or toxicology studies
which negatively influence the risk/benefit assessment might cause discontinuation or
termination of the study.
Ifa subject discontinues study drug for any reason before the end of the Treatment Phase, an EoT
Visit should be performed. The primary reason for drug discontinuation will be clearly
documented in the subject’s medical record and recorded in the eCRF. Study drug assigned to the
subject who discontinued study drug may not be assigned to another subject.
7.2. 
Subject Discontinuation/Withdrawal From the Study
A subject will be withdrawn from the study for any of the following reasons:
 
Lost to follow-up
 
Withdrawal of consent
 
Death
When a subject withdraws before studycompletion, the reason for withdrawal is to be documented
in the eCRF and in the source document. If the reason for withdrawal from the study is withdrawal
ofconsent, then no additional assessments are allowed.
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Withdrawal of Consent
A subject declining to return for scheduled visits does not necessarily constitute withdrawal of
consent. Alternate follow-up mechanisms that the subject agreed to when signing the consent form
apply as local regulations permit.
7.2.1. 
Withdrawal From the Future Use of Research Samples
The subject may withdraw consent for use of samples for future research. In such a case, samples
will be destroyed after they are no longer needed for the clinical study. Details of the sample
retention for research are presented in the ICF.
7.3. 
Lost to Follow-up
A subject will be considered lost to follow-up if he or she repeatedly fails to return for scheduled
visits and is unable to be contacted by the study site. A subject cannot be deemed lost to follow-
up until all reasonable efforts made by the study-site personnel to contact the subject are deemed
futile. The following actions must be taken if a subject fails to return to the study site for a required
study visit:
 
The study-site personnel must attempt to contact the subject to reschedule the missed visit as
soon as possible, to counsel the subject on the importance of maintaining the assigned visit
schedule, to ascertain whether the subject wishes to or should continue in the study.
 
Before a subject is deemed lost to follow-up, the investigator or designee must make every
reasonable effort to regain contact with the subject (where possible, 3 telephone calls, e-mails,
fax, and, if necessary, a certified letter to the subject’s last known mailing address, or local
equivalent methods). Locator agencies may also be used as local regulations permit. These
contact attempts should be documented in the subject’s medical records.
 
Should the subject continue to be unreachable, they will be considered to have withdrawn
from the study.
Should a study site close, eg, for operational, financial, or other reasons, and the investigator cannot
reach the subject to inform them, their contact information will be transferred to another study site.
8. 
STUDY ASSESSMENTS AND PROCEDURES
The study comprises molecular eligibility, screening, treatment, follow-up, and LTE phases. The
frequency and timing of assessments and procedures to be performed are outlined in the Schedule
of Activities (Section 1.3) and further discussed within this section.
All PRO assessments should be conducted and completed before any other tests, procedures, or
consultations to prevent influencing subject perceptions. Note: PRO assessment/data collection is
no longer required for all subjects in all phases.
Assessments and procedures should be completed on the day indicated (± window indicated); if
this is not possible because of a weekend, holiday, or emergency, the assessment or procedure
should be completed within 48 hours of the scheduled day.
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The amount of blood drawn from each subject in this study will be approximately 24 mL during
screening; 241 mL from C1D1 through Cycle 6; 288 mL from Cycle 6 through Cycle 24; 37 mL
at the EoT Visit; 12 mL during the safety follow-up; and 80 mL for subjects who have disease
assessments after recurrence/progression during the Follow-up Phase, for a total volume of
682 mL. Repeat or unscheduled samples may be taken for safety reasons. Serum or urine
pregnancy tests should be performed for women of childbearing potential, as determined necessary
by the investigator or required by local regulation to establish the absence of pregnancy at any
time during the subject's participation in the study. The calculated volume of blood is an estimate;
the actual amount may vary depending on local laboratory standard procedures, a subject’s visit
schedule, and childbearing potential.
The actual dates and times of sample collection must be recorded in the source document and
laboratory requisition form. Instructions for the collection, handling, storage, and shipment of
samples are found in the Laboratory Manual that will be provided. Collection, handling, storage,
and shipment of samples mustbe under the specified, and where applicable, controlled temperature
conditions as indicated in the Laboratory Manual.
8.1. 
Study Procedures
8.1.1. 
Screening
Screening will consist of a Molecular Eligibility Screening Phase and a Full-study Screening
Phase. Also, subjects being considered for the study before the TURBT, will provide a voided
urine sample after disease recurrence and before TURBT. These subjects must sign the ICF for
Assay Development prior to collection of this urine sample.
8.1.1.1. 
Molecular Eligibility Screening Phase (Cohort 1 and Cohort 2)
Molecular eligibility can be established either by central laboratory testing or local testing. Consent
for molecular eligibility screening (but not full-study screening) may be performed remotely
including consent by telephone or video consultation, unless not permitted according to local
guidance.
The molecular eligibility informed consent process may occur in 1 of 3 ways:
 
If archived tissue is available, the Molecular Eligibility ICF is signed.
 
If a new tissue biopsy is required, the Main-study ICF is signed.
 
If a historical report (local testing) is available indicating the subject is molecularly eligible
for the study, the Molecular Eligibility Requirement is determined complete and the subject
will sign the Main-study ICF.
If tissue is insufficient at the first molecular eligibility assessment, another tissue sample may
be submitted to the central laboratory (this is not considered rescreening).
 
During the Molecular Eligibility Screening Phase, tissue from 2 different times points may be
used to determine eligibility for this study, ie, pre-BCG Tissue specimen  (tumor tissue
collected before subject receives BCG treatment for NMIBC) or post-BCG Tissue specimen
(tumor tissue collected from recurrence after BCG treatment)(see Figure 2):
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Pre-BCG Tissue Molecular Screening
1) Archival tissue sample will be sent to the central laboratory for testing if the subjects meet both
of the following criteria:
a) Have had prior history of high or intermediate risk NMIBC
b) Have completed a minimum of initial BCG induction (at least 5 of 6 full doses of an initial
induction).
The central laboratory will evaluate subjects for molecular eligibility by analyzing specimens
for the presence of FGFR mutations and gene fusions. The sponsor or central
laboratory/designee will communicate results of the molecular eligibility testing to the site. If
the subject is deemed molecularly eligible for the study, the subject will be followed at the site
with routine standard of care. If the subject has a recurrent high risk NMIBC within 12 months
of last dose of BCG, then the subject maysign the Main-study ICF. If the subject does not have
a recurrent high risk NMIBC at less than 12 months of last dose of BCG, then the subject is
molecularly ineligible for the study and is considered a molecular screen failure.
2) Subject with a historical report (local testing) indicating the subject is molecularly eligible for
the study will be determined to have completed Molecular Eligibility Requirement. If the
subject has a recurrent high risk NMIBC within 12 months of last dose of BCG, then subjects
may sign the Main-study ICF.
Post-BCG Tissue Molecular Screening
1) Subjects with archival post-BCG tissue specimen with recurrent high risk NMIBC within
12 months of last dose of BCG will have a specimen sent to the central laboratory for testing.
The central laboratory will evaluate molecular eligibility by analyzing specimens for the
presence of FGFR mutations and gene fusions. The sponsor or central laboratory/designee will
communicate results of the molecular eligibility testing to the site. If a subject is deemed
molecularly eligible for the study, then the subject may sign the Main-study ICF.
2) Subjects with recurrent high risk NMIBC within12 months of last dose of BCG and ahistorical
report (local testing) indicating the subject is molecularly eligible for the study will be
determined to have completed Molecular Eligibility Requirement. These subjects may sign the
Main-study ICF.
For subjects with both pre-BCG and post-BCG tissue specimen available, the site pathologist
will determine best tissue for molecular testing. Additional tissue may be requested if a
specimen is not adequate for testing. If FGFR status is known from a locally tested NGS/PCR
assay, a subject will need to sign the Main-study ICF in order for tissue to be submitted to the
central laboratory for retrospective molecular eligibility confirmation.
Eligibility must be determined before randomization (Cohort 1) or the first dose of study drug
(Cohort 2 and Cohort 3). See Section 5.1, inclusion criteria for requirements regarding FGFR
mutations or fusions. For subjects in Cohort 2 with concurrent papillary  disease, molecular
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eligibility  can  be determined from either the CIS specimen or the papillary lesion. Figure 2
provides an overview of testing for molecular eligibility.
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Subjects enrolling in the study based on Molecular eligibility from pre-BCG tissue specimen and
post-BCG  local NGS/PCR testing must also submit the post-BCG tissue specimen  tissue for
central confirmation of Molecular eligibility  status. The results of this retrospective central
confirmation do not affect the subject’s eligibility for the study. Results of retrospective testing
will not be communicated to the site. Please refer to the Laboratory Manual for instructions.
In countries/territories where the ANNAR protocol pre-screening has received approval to be
implemented, as required by health authorities or ethics, subjects may be identified for this study
by participation in the ANNAR pre-screening protocol (Study 42756493BLC0002), during which
subjects with urothelial carcinoma undergo molecular eligibility testing. Those subjects who test
positive for the select FGFR mutations or fusions required for this study, will sign the Main-study
ICF and proceed to the Screening Phase. Tissue for central confirmation of FGFR status is not
submitted for these subjects as this step was completed as part of the ANNAR pre-screening
protocol.
8.1.1.2. 
Cohort 3 Molecular Eligibility
Additional provisions have been put in place to limit the possibility that subjects will be enrolled
into Cohort 3 without meeting molecular eligibility criteria.
1) It is anticipated that investigators will identify subjects with low-grade /intermediate-risk,
multi-focal papillary-only disease for possible enrollment into Cohort 3.
2) Identified subjects will sign the Molecular Eligibility ICF to determine FGFR status from
archived tissue sample, if available.
3) Subjects whose archived tissue sample meets the Molecular Eligibility Requirement will sign
the Main-study ICF before the next planned TURBT and before any study-specific procedures
take place once routine surveillance cystoscopy shows multi-focal papillary only recurrence
(see Section 1.3). Eligibility criteria will be assessed prior to the TURBT, so that a marker
lesion can be left behind after resection of other papillary lesions as appropriate. Submit tissue
from on-study TURBT for central confirmation of FGFR status. The results of this
retrospective central confirmation do not affect the subject’s eligibility for the study. Also,
results of retrospective confirmation studies will not be communicated to the site.
4) Subjects identified by the investigator but without archived tissue samples available for
molecular eligibility testing will sign the Main Study ICF before any study-specific procedure
takes place once routine surveillance cystoscopy shows multi-focal papillary-only recurrence
(see Section 1.3). Before the TURBT is performed, the site will assess that the subject will
meet the other inclusion and exclusion criteria prior to leaving behind a marker lesion.
Molecular eligibility testing will be performed on recurrent papillary disease tissue collected
during the on-study TURBT. Subjects who fail the Molecular Eligibility Requirement at the
time of recurrence, will have the marker lesion resected.
8.1.1.3. 
Full-study Screening Phase
During the Full-study Screening Phase all subjects who have qualifying FGFR mutations or
fusions, as determined during the Molecular Eligibility Phase, will consent to the main study by
signing the Main-study ICF. The Full-study Screening Phase includes the interval between signing
the Main-study ICF and the day the subject is randomized (Cohort 1) or receives the first dose of
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study drug (Cohort 2 and Cohort 3). The Full-study Screening Phase should not exceed 35 days.
Assessments that are required to demonstrate eligibility may be performed over the course of 1 or
more days during the screening process. Molecular screening must start within 12 weeks after the
last TURBT done for high risk  recurrence if molecular testing is being done on post-BCG
specimen.
The first HRQoL assessments will occur during the Screening Phase using the following PRO
measures: PGIS, EORTC QLQ-C30, EORTC  QLQ-NMIBC24, and EQ-5D-5L. Assessment of
PGIC will only occur during the Treatment Phase. The PRO measures will be electronically
(ePRO) collected, according to the Schedule of Activities (Section 1.3), to understand change over
time (all cohorts) and difference between treatment groups (Cohort 1). Patient-reported outcome
questionnaires should be completed before any other assessments at each clinic visit. Subjects
should be provided a private, quiet area to complete the questionnaires. The study site staff should
instruct the subject to carefully read the instructions and questions of the PRO instrument before
marking responses, that there are no right or wrong answers, and that their responses to the
questionnaire will not be used to determine their study eligibility. If a subject cannot read for any
reason, it is acceptable for the subject to have the questions read and responses marked on the
ePRO by an independent witness. Note: PRO assessment/data collection is no longer required for
all subjects in all phases.
Procedures conducted, before signing the Main-study ICF, as part of the subject’s routine clinical
management (eg, blood count, disease assessment) may be used for screening orbaseline purposes
provided the procedure meets the protocol-defined criteria and has been performed within 35 days
prior to dosing (see Section 1.3). All information associated with eligibility requirements must be
entered onto the appropriate eCRF. Requirements for biopsy specimens for histologic assessment
at screening are provided in Section 8.2.1. The subject’s previous anticancer therapies and TURBT
details, the dose and timing of administrations, and the subject’s responses to each therapy will be
collected and recorded in source documents and the eCRF.
Results from the screening evaluations will be reviewed to confirm subject eligibility before
enrollment. Tests with results that fail eligibility requirements may be repeated once during
screening if the investigator believes that the results suspected to be due to test error or that the
underlying issue has been resolved. For screening assessments that are repeated, the most recent
available results before initiation of study drug will be used to determine subject eligibility.
8.1.2. 
Treatment Phase
The Treatment Phase will begin on Cycle 1 Day 1 following randomization or enrollment into the
study. Subjects may be randomized up to 1 day before C1D1 but no later than C1D1 predose. With
the exceptions noted below for Cohort 2 and Cohort 3, treatment may continue until the subject
has high risk disease recurrence or progression, intolerable toxicity, withdraws consent, there is a
decision by the investigator to discontinue treatment, or the study is closed, whichever occurs first.
For subjects receiving erdafitinib, treatment may continue for a maximum of 2 years.
 
For Cohort 2, erdafitinib must be discontinued if CR is not observed within 3 months.
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 
For Cohort 3, after 3 months of study treatment: 1) Subjects with stable disease or progression
of the marker lesion must discontinue erdafitinib and a TURBT of the marker lesion must be
performed. 2) Subjects with CR may continue erdafitinib. 3) Subjects with PR may, at the
investigator’s discretion, either continue treatment with erdafitinib or discontinue erdafitinib
and undergo TURBT of the marker lesion.
For Cohort 1 and Cohort 2, during the Treatment Phase, subjects who demonstrate a positive urine
cytology with a negative cystoscopy will remain on study drug until the next disease assessment.
If both the urine cytology and cystoscopy are positive for high-risk recurrence (high-grade Ta, T1
or CIS) or progression at the next disease assessment, the subject will discontinue study drug.
For subjects randomized to Investigator’s Choice, refer to Section 6.1.2 for study drug
administration.
Adverse events occurring any time after the subject signs the Main-study ICF until 30 days after
the last dose of study drug in the Treatment Phase are to be recorded for all subjects. With the
exception of hyperphosphatemia (see Table 3), adverse event information will be graded using the
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE),
Version 5.0. See Section 10.3 for complete details on adverse event reporting. Concomitant
medications will also be recorded following the discontinuation of treatment until 30 days after
last dose of study drug in the Treatment Phase.
Throughout the Treatment Phase, the investigator will assess response to study drug using findings
from cystoscopy, bladder mapping, urine cytology, and CT/MRI urogram. Biopsy of visible
lesions will be performed during cystoscopy or TURBT. Tissue slides/blocks from subjects in
Cohort 1 with any locally confirmed recurrence or progression will be sent for central
histopathologic review. In addition, tissue from any positive biopsy (any grade of recurrence or
bladder mapping) should be sent to central laboratory  for exploratory biomarker analysis (all
cohorts). For subjects receiving erdafitinib only, tissue from all biopsies performed (normal and
abnormal) will be sent to central laboratory for determination of erdafitinib level. On Cycle 1
Day 14, the first approximately  20 subjects receiving erdafitinib (from any cohort) will have
24-hour urine PK samples collected. Efficacy assessments are described further in Section 8.2. For
subjects who discontinue study drug without documented disease recurrence or progression, every
effort should be made to continue monitoring their disease status according to the disease
assessment schedule, until (1) the start of new anticancer treatment, (2) high risk disease recurrence
or progression, (3) withdrawal of consent, (4) death, or (5) 18 months have elapsed since the first
dose of study treatment (ie, Cycle 1 Day 1), whichever occurs first.
End-of-Treatment Visit
An EoT Visit will be performed within 7 days after a subject’s permanent discontinuation of
erdafitinib or Investigator’s Choice, either at the end of the Treatment Phase or for any otherreason
before then. If the EoT Visit coincides with a regular study visit, the EoT evaluations will be
conducted in lieu of the regular visit assessments, and the data will be entered into the EoT Visit
in the eCRF. The subject should be encouraged to return for the Safety Follow-up Visit.
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Subjects who have an EoT Visit following treatment with Investigators Choice and then cross over
to treatment with erdafitinib will have an EoT Visit performed when erdafitinib is stopped (See
Section 10.10).
8.1.3. 
Follow-up Phase
8.1.3.1. 
Safety Follow-up
The safety follow-up period is the interval between the EoT Visit and 30 days (+7 days) after the
last dose of study drug. Reasonable efforts should be made to have the subject return for the Safety
Follow-up Visit, to be scheduled 30 to 37 days after the EoT Visit (or after the last dose of
treatment if the EoT Visit was not performed), and to report any adverse events and new
concomitant medications that occur during that time. Adverse events and serious adverse events
must be reported up until at least 30 days (+7 days) after the last dose of study drug, the date of
the Safety Follow-up Visit, or until toxicities resolve, return to baseline, or are deemed irreversible,
whichever is longer. If a subject begins new anticancer therapy, the adverse event reporting period
for non-serious adverse events ends at the time the new treatment started.
8.1.3.2. 
Long-term Follow-up
Required follow-up for subjects in Disease Assessment Follow-up and Survival Follow-up at the
time of Amendment 6 implementation is described in Section 10.14 (Appendix 14).
8.1.3.2.1. 
Disease Assessment Follow-up
For subjects who discontinue study drug without documented disease recurrence or progression,
every effort should be made to continue monitoring their disease status according to the disease
assessment schedule and continue to perform other assessments during this period (see
Section 1.3) until (1) the start of new anticancer treatment, (2) high risk disease recurrence or
progression, (3) withdrawal of consent, (4) death, or (5) 18 months have elapsed since the first
dose of study treatment (ie, Cycle 1 Day 1), whichever occurs first. The results of the disease
assessments will be documented in the eCRF. At the time of recurrence or progression, tissue
sampling will be sent to the central laboratory for blinded independent central review (BICR).
8.1.3.2.2. 
Survival Follow-up
Once a subject has confirmed disease recurrence or progression or starts a new anticancer therapy,
he or she will begin the follow-up for survival status for a maximum of 2 years. New anticancer
therapy will be collected in the eCRF. The subject will be contacted by telephone or email, or the
subject will visit the study site, at least every 12 weeks (±2 weeks) from the confirmed date of
disease recurrence or progression or start of new anticancer therapy to assess for survival status
until death, withdrawal of consent, or study discontinuation following Amendment 6
implementation, whichever occurs first. The results ofstandard-of-care follow-up cystoscopy will
also be collected during this period.
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8.1.4. 
Unscheduled Visits
Clinic visits or diagnostic laboratory visits not prescribed in the protocol may be performed at any
time as clinically indicated. Results of assessments performed at these visits will be entered as
“unscheduled” visit in the eCRF. The sponsor may also request that an additional visit be
performed, if needed, based on emerging safety data.
8.1.5. 
Long-term Extension Phase
The LTE Phase will allow continued access to study drug for subjects who continue to derive
benefit from treatment, as determined by their investigator. Subjects may enter the LTE Phase
following implementation of Amendment 6, provided they meet the criteria for entry specified in
LTE Figure 1. Limits for continuation of study drug in this phase are described in Section 6.7. No
data will be collected in the eCRF during the LTE Phase, and only SAEs will be reported to the
company safety repository. As an alternative to entering the LTE Phase, subjects receiving
erdafitinib may exit the study and continue to receive treatment on any other post-trial access
program, when permitted by local regulations. Detail regarding the LTE Phase (including a
Schedule of Activities) is provided in Section 10.14, Appendix 14.
8.2. 
Efficacy Assessments
8.2.1. 
Disease Assessments
8.2.1.1. 
Cohort 1
Cohort 1, papillary tumors only, subjects with T1 disease must undergo TURBT of the base of the
lesion (the biopsy should contain muscle fibers) before study entry (baseline) to ensure the absence
of muscle-invasive disease and to determine histopathology staging at the time the subject was
deemed to have recurred after BCG therapy. If there are no muscle fibers in the biopsy, subjects
must undergo re-TURBT before randomization.
8.2.1.2. 
Cohort 2
Cohort 2, CIS, is not expected to be completely excised at baseline, but concurrent papillary
disease must be completely excised before enrollment and documented at baseline cystoscopy.
Urine cytology is not expected to be negative for malignant cells.
8.2.1.3. 
Cohort 3
Cohort 3, marker lesion, must have recurrent intermediate-risk disease with all previous tumors
being low grade (G1-G2) Ta or T1 and no previous CIS at baseline. Additionally, subjects must
have a risk of progression less than 5% in the next 2 years and a risk of recurrence greater than
50%, calculated using the EORTC risk calculator.19 All tumors must be removed except for a
single untouched 5 to 10 mm lesion (marker lesion).
Cohort 3 will perform a urine cytology during bladder washing or from a voided urine specimen
(bladder wash specimen is preferred) at time of CR only. Subjects in Cohort 3 with PR or CR
within 3 months after start of treatment may continue erdafitinib for up to 2 years until progression,
intolerable toxicity, withdrawal of consent, there is a decision by the investigator to discontinue
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treatment, or the study is closed, whichever occurs first. Subjects with stable disease or disease
progression must undergo TURBT of the marker lesion and discontinue erdafitinib. Subjects with
PR may, at the investigator’s discretion, either continue treatment with erdafitinib, or discontinue
erdafitinib and undergo TURBT of the marker lesion.
8.2.1.4. 
Histopathologic Assessment and FGFR (All Cohorts)
For all cohorts, the histopathology assessment will be performed per local standard practice, and
subjects may be enrolled based on local histopathology results If a subject has a positive local
result of FGFR status either by NGS or by PCR, the subject may be enrolled in the Main Study
based on those results. Otherwise, a subject must wait for central FGFR results from the central
laboratory to meet molecular eligibility criteria. For subjects in Cohort 1, after a positive FGFR
status is known, tissue slides/blocks from the post-BCG specimen may be submitted to the central
laboratory for central histopathologic review. A detailed outline for collection, handling, and
evaluation of bladder tissue and interpretation of biopsy specimens will be provided in the
Laboratory Manual. Blinded independent central histopathological review (BICR) will not have
any bearing on enrollment status of the subject. If the central histopathological assessment reveals
T2 or higher disease, the results will be communicated by the medical monitor to the principal
investigator.
During the Treatment Phase and Follow-up Phase, tissue slides/blocks from subjects in Cohort 1
with any locally confirmed recurrence or progression will be sent for BICR.
8.2.1.5. 
Cystoscopy, Urine Cytology, Bladder Mapping, and CT/MRI Urogram
Cystoscopy (Cohort 1 and Cohort 2) will be performed as indicated in the Schedule of Activities
to assess disease response. Whenever possible, the same individual should perform cystoscopy
throughout the study for a given subject. For subjects in Cohort 1 and Cohort 2, cystoscopy will
be done at screening, at C3D1, then every 12 weeks (±1 week) for up to 2 years of treatment or
until high risk disease recurrence or progression. After treatment has stopped, cystoscopies will be
performed every 24 weeks (every 6 months) (±2 weeks) for an additional 2 years or until high risk
disease recurrence /progression. Note that if a TURBT was done within 6 weeks before
randomization, then the findings of the complete resection from TURBT can be used instead of a
screening cystoscopy.
Cystoscopy (Cohort 3) will be done at screening, and then at C2D1, C3D1, and C4D1 (±1 week)
or until CR, whichever occurs first. After a subject experiences CR, cystoscopy will be performed
every 12 weeks (±1 week) for up to 2 years oftreatment or until disease recurrence or progression.
After treatment has stopped, cystoscopies will be performed every 24 weeks (every 6 months) (±2
weeks) for an additional 2 years or until disease recurrence/progression. If the subject experiences
stable disease or progression of the marker lesion, study drug will be discontinued, an EoT Visit
will be conducted, and the subject will undergo TURBT of the marker lesion. Subjects with PR
after 3 months of treatment may, at the investigator’s discretion, either continue treatment with
erdafitinib or discontinue erdafitinib and undergo TURBT of the marker lesion. Subjects with PR
who continue treatment with erdafitinib will have cystoscopy and other study assessments
performed, as specified in the Schedule of Activities (Section 1.3).
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Urine for cytology will be collected from bladder washing or from a voided urine specimen
(bladder wash specimen is preferred)during cystoscopyfor local assessment for subjects in Cohort
1 and Cohort 2. Urine cytology results for subjects being screened for Cohort 1 must be negative
for high-grade urothelial carcinoma before randomization; for Cohort 2, urine cytology does not
have to be negative at screening. Urine for cytology will be collected from bladder washing or
from a voided urine specimen (bladder wash specimen is preferred) for local assessment for
Cohort 3 at the time of CR only.
Bladder mapping will include biopsies of any suspicious mucosal area (if noted); otherwise,
biopsies should be taken from normal looking mucosa. Samples must be taken from each of the
following regions: 1)dome, 2) anterior wall, 3) right lateral wall, 4) left lateral wall, 5) posterior
wall, and 6) bladder neck/trigone (See Section 10.11). For Cohort 1 subjects bladder mapping at
screening will be only done if there is prior history of CIS. Furthermore, during treatment or
follow-up phase repeat bladder mapping will only be done if urine cytology is positive for
malignant cells and cystoscopy is negative. In Cohort 2, all subjects will have bladder mapping at
screening and at Cycle 12. No bladder mapping will be done for subjects in Cohort 3. Biopsy
samples collected during bladder mapping will be evaluated by the local histopathology laboratory.
Computed tomography/MRI urograms (contrast enhanced) or retrograde pyelograms (if
applicable) will be performed to evaluate subjects for the presence of locally advanced disease to
the upper urinary tract or prostatic urethra. If a subject cannot tolerate intravenous contrast, a
retrograde pyelogram is acceptable. All scheduled CT/MRI urograms will be performed as
indicated in the Schedule of Activities (Section 1.3). CT/MRI urograms should be evaluated by
the same individual throughout the study to limit inter-reviewer variability.
Additionally, unscheduled cystoscopy or CT/MRI urograms may be performed if clinically
indicated. Other diagnostic modalities should not be used exclusively to assess disease status in
the absence of cystoscopy or CT/MRI urogram confirmation. Identical methodology should be
used for disease assessment at baseline and throughout the course of the study.
Local histopathologic findings will be used for the following assessments of recurrence,
progression, and disease response.
Recurrence is defined as follows:
 
Histologicallyproven first appearance of high-grade Ta or T1 lesion bladder cancer in patients
with papillary disease only.
Complete response for Cohort 2 is defined as at least one of the following:
 
Negative cystoscopy and negative (including atypical) urine cytology
 
Positive cystoscopy with biopsy-proven benign or low-grade NMIBC and negative cytology
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Complete response for Cohort 3 is defined as the following:
 
Complete disappearance of the marker lesion without any new lesions; and if any remnant of
the marker lesion, no viable tumor seen on histopathological examination.
 
Negative urine cytology
Partial response for Cohort 3 is defined as the following:
 
Marker Lesion reduction by 50% 35
For subjects in Cohort 1 and Cohort 2, a new low-risk/low-grade papillary lesion may be resected
by TURBT if deemed appropriate by investigator. A new low-risk/low-grade papillary lesion does
not constitute recurrence. Subjects with a positive urine cytology (not atypical cells) but with
negative cystoscopy will continue treatment until next scheduled evaluation in 12 weeks. Tissue
slides/blocks from subjects in Cohort 1 with any locally confirmed recurrence or progression will
be sent for central histopathologic review.
However, tissue from any positive biopsy (any grade of recurrence) should be sent to the central
laboratory for exploratory biomarker analysis (all cohorts) and determination of erdafitinib level
(subjects receiving erdafitinib only). Refer to the Laboratory Manual for instruction on sample
handling.
8.2.2. 
Patient-Reported Outcomes
Note: PRO assessment/data collection is no longer required for all subjects in all phases.
The PGIS and PGIC are single-item questionnaires to evaluate a patient’s global impression of
severity and global impression of change of cancer, respectively.
The EORTC QLQ-C30 is a core questionnaire for evaluating the HRQoL of patients participating
in cancer clinical studies. It is a 30-item questionnaire with 9 multi-item subscales and 6 single
items. It incorporates 5 functional scales (physical, role, cognitive, emotional, and social
functioning), 3 symptom scales (fatigue, pain, and nausea or vomiting), and a global health status
or HRQoL scale. The single items assess dyspnea, appetite loss, sleep disturbance, constipation,
diarrhea, and perceived financial impact of disease and treatment. Ratings for each item range from
1 (not at all) to 4 (very much). The QLQ-C30 is designed to be used across cancer populations and
takes about 11 minutes to complete.
The EORTC QLQ-NMIBC24 is a 24-item questionnaire for evaluating the HRQoL of patients
with superficial (non-muscle-invasive) bladder cancer. The questionnaire is designed to
supplement the QLQ-C30 and incorporates 6 multi-item scales and 5 single items. Ratings for each
item range from 1 (not at all) to 4 (very much). The scales cover urinary symptoms, malaise,
worries about the future, bloating and flatulence, sexual function, and male sexual problems. The
single items assess intravesical treatment issues, sexual intimacy, sexual enjoyment, risk of
contaminating partner, and female sexual problems. The EORTC QLQ-NMIBC24 takes about 8
minutes to complete.
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EQ-5D-5L is a standardized measure of health status developed by the EuroQol Group to provide
a simple, generic measure of health for clinical and economic appraisal. The EQ-5D-5L descriptive
system comprises the following 5 dimensions: mobility, selfcare, usual activities, pain/discomfort,
and anxiety/depression, as well as the EQ Visual Analogue Scale (EQ VAS). The EQ-5D-5L can
be completed in under 5 minutes.
8.3. 
Safety Assessments
Safety assessments will be based on medical review of adverse event reports and the results of
vital sign measurements, 12-lead ECG, physical examinations, clinical laboratory tests,
ophthalmologic examinations, and other safety evaluations at specified time points as described in
the Schedule of Activities.
Any clinically significant abnormalities or toxicities persisting at the time of study discontinuation
or transition to the LTE Phase will be followed by the investigator until resolution or until reaching
a clinically stable endpoint. For adverse events such as skin/nail and mucosal toxicity, upon subject
consent, photographs may be taken for assessment and monitoring of the toxicity.
Details regarding the IDMC are provided in Committees Structure in Section 10.2, Regulatory,
Ethical, and Study Oversight Considerations. Due to the company decision to terminate study
enrollment and considering the recent IDMC review (6 July 2022) found the safety of erdafitinib
in this study to be consistent with the known safety profile of erdafitinib, no further monitoring by
the IDMC will be conducted.
8.3.1. 
Physical Examinations
A full physical examination, including height and weight, will be performed at screening. Subjects
should have a repeated physical examination at Cycle 1 Day 1 before dosing if the previous
physical examination during screening occurred more than 14 days previously. Targeted physical
examinations, including involved organs of the disease state, will be performed at subsequent visits
as listed in the Schedule of Activities (Section 1.3). Height and weight measurements are not
required after screening. The investigator must review physical examination results and record any
clinically relevant changes occurring during the study in the adverse event section of the eCRF.
8.3.2. 
Vital Signs
Vital signs will be assessed per the Schedule of Activities (Section 1.3). Blood pressure (systolic
and diastolic), heart rate, and temperature will be assessed. The investigator mustreviewvital signs
results and record any clinically relevant changes occurring during the study in the adverse event
section of the eCRF.
8.3.3. 
Electrocardiograms
12-lead electrocardiograms will be performed as specified in the Schedule of Activities
(Section 1.3). Additional ECGs may be performed as clinically indicated. During the Treatment
Phase, ECGs should be performed before study drug is taken for the day. The subject should rest
in a supine position for at least 5 minutes before ECG recording and should refrain from talking
or moving arms or legs. The 12-lead ECG recorder device used should have been recently serviced
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and calibrated. The following intervals should be measured: PR, QRS, QT, QTcF (Fridericia), RR.
QTcF (Fridericia) will be used for assessment of QTc interval. It is recommended that all ECGs
be performed at approximately the same time each day to minimize circadian variation in QT
interval. The investigator will comment on the clinical relevance and document this in the eCRF
(along with details of clinically significant findings).
8.3.4. 
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected for all subjects as indicated
in the Schedule of Activities (Section 1.3). Subjects receiving erdafitinib will have additional
assessments of phosphate and parathyroid hormone as described separately in the Schedule of
Activities. More frequent clinical laboratory tests may be performed, as indicated by the overall
clinical condition of the subject and for abnormalities that warrant more frequent monitoring. The
investigator must review the laboratory results, document this review, and record any clinically
relevant changes occurring during the study in the adverse event section ofthe eCRF.
Laboratory test results completed on Cycle 1 Day 1 (except parathyroid hormone and
1,25-dihydroxyvitamin D) should be reviewed prior to dosing, and subjects should continue to
meet eligibility requirements per the inclusion/exclusion criteria.
The following tests will be performed by the local laboratory:
Hematology Panel (All subjects)
-hemoglobin  
-white blood cell count
-platelet count 
-absolute neutrophil count
Comprehensive Metabolic Panel (All subjects)
-alanine aminotransferase (ALT) 
-calcium
-aspartate aminotransferase (AST) 
- potassium
-total bilirubin  
- albumin
-creatinine 
-sodium  
-magnesium
- bicarbonate (if feasible)
- alkaline phosphatase
1,25-dihydroxyvitamin D (All subjects)
Parathyroid Hormone: All subjects at screening and only subjects receiving erdafitinib from
C1D1.
Phosphate: All subjects at screening and only subjects receiving erdafitinib from C1D1.
8.3.5. 
Ophthalmologic Examination
All subjects must have an ophthalmologic examination performed regardless of symptoms during
the Screening Phase and during the Treatment Phase as specified in the Schedule of Activities
(Section 1.3). Ophthalmologic assessment must include visual acuity, fundoscopy (examination of
both central and peripheral zones should be performed), slit lamp biomicroscopy, and Optical
Coherence Tomography (OCT). The Amsler grid test will also be administered by the treating
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study physician or nurse at screening and other timepoints, as indicated in the Schedule of
Activities (Section 1.3). Any additional follow-up examination may  be performed by the
ophthalmologist as clinically necessary based on the findings of the Amsler grid tests and clinical
assessment. A repeat OCT scan may be done in case of quality issue.
When central serous retinopathy (CSR)/retinal pigment epithelial detachment is suspected, or
fundoscopic retinal abnormalities are observed, as well as each time ocular adverse events lead to
the subject being referred to an ophthalmologist, an OCT should be performed. Fluorescein
angiography could be considered appropriate in conditions such as suspected retinal vein
occlusion. In subjects with suspected retinal pathology such as CSR or retinal vein occlusion, a
consultation with a retina specialist should be considered.
Data from all fluorescein angiograms, retinal photographs, and all OCT scans should be added to
the subject’s case report form. All images of the OCT scan, photographs, and/or fluorescein
angiograms must be stored in the subject’s records and a redacted copy sent to the sponsor-selected
central vendor for possible future independent assessment. Additionally, when OCT is abnormal,
any retinal imaging or angiographic studies conducted must also be stored in the subject’s records
and a redacted copy sent to the sponsor-selected central vendor for possible future independent
assessment. Note: sending redacted copies to the sponsor-selected central vendor is no longer
required.
Amsler Grid Testing
Amsler grid (Section 10.8) testing will be administered to all subjects according to the Schedule
of Activities (Section 1.3). Additional assessments should be performed as clinically indicated.
Observation of wavy, broken or distorted lines, or a blurred/missing area of vision is equivalent to
a positive Amsler grid test. For any positive Amsler grid test, subject should be referred for full
ophthalmologic examination within 7 days.
8.3.6. 
Pregnancy Testing: Urine or Serum β-hCG
Urine or serum samples will be obtained for β-hCG pregnancy testing in female subjects of child
bearing potential at time points indicated in the Schedule of Activities (Section 1.3). Pregnancy
tests will be performed to establish the absence of pregnancy at any time during the subject's
participation in the study.
8.3.7. 
ECOG Performance Status
Eastern Cooperative Oncology Group performance status grade will be determined as part of
screening evaluations. The scoring information is provided in Section 10.5.
8.4. 
Adverse Events and Serious Adverse Events
Timely, accurate, and complete reporting and analysis of safety information from clinical studies
are crucial for the protection of subjects, investigators, and the sponsor, and are mandated by
regulatory agencies worldwide. The sponsor has established Standard Operating Procedures in
conformity with regulatory requirements worldwide to ensure appropriate reporting of safety
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information; all clinical studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Adverse events will be reported by the subject (or, when appropriate, by a caregiver, surrogate, or
the subject's legally acceptable representative) for the duration of the study. During the LTE Phase,
only SAEs will be reported to the company safety repository (see Section 10.14, Appendix 14).
For further details on adverse events and serious adverse events (Definitions and Classifications;
Attribution Definitions; Severity Criteria; Special Reporting Situations; Procedures) as well as
product quality complaints, refer to Section 10.3, Adverse Events: Definitions and Procedures for
Recording, Evaluating, Follow-Up, and Reporting.
8.4.1. 
Time Period and Frequency for Collecting Adverse Event and Serious
Adverse Event Information
All Adverse Events
All adverse events and special reporting situations, whether serious or non-serious, will be reported
from the time a signed and dated Main-study ICF is obtained until 30 days after the subject's last
dose of study drug or before the start of subsequent anticancer therapy, whichever is longer.
Serious adverse events, including those spontaneously reported to the investigator within 30 days
after the last dose of study drug, must be reported using the Serious Adverse Event Form. The
sponsor will evaluate any safety information that is spontaneously reported by an investigator
beyond the time frame specified in the protocol.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor
contact person by study-site personnel immediately but no later than 24 hours of their knowledge
of the event.
Information regarding serious adverse events will be transmitted to the sponsor using the Serious
Adverse Event Form and Safety Report Form of the case report form (CRF), which must be
completed and reviewed by a physician from the study site and transmitted to the sponsor within
24 hours. The initial and follow-up reports of a serious adverse event should be transmitted
electronically or by facsimile (fax).
8.4.2. 
Method of Detecting Adverse Events and Serious Adverse
Care will be taken not to introduce bias when detecting adverse events or serious adverse events.
Open-ended and nonleading verbal questioning of the subject is the preferred method to inquire
about adverse event occurrence.
8.4.3. 
Follow-up of Adverse Events and Serious Adverse Events
Adverse events, including pregnancy, will be followed by the investigator as specified in
Section 10.3, Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
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8.4.4. 
Regulatory Reporting Requirements for Serious Adverse Events and
Anticipated Events
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory
authorities. The sponsor will also report to the investigator (and the head of the investigational
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The
investigator (or sponsor where required) must report SUSARs to the appropriate Independent
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless
otherwise required and documented by the IEC/IRB.
An anticipated event is an adverse event that commonly occurs in the study population independent
of exposure to the drug under investigation. For the purposes of this study the following serious
adverse events will be considered anticipated events:
 
hematuria
 
dysuria
 
nocturia
 
bladder perforation
 
ureteric stenosis
 
urinary incontinence
 
urinary hesitation
 
stranguria
 
ureteric obstruction
 
urine flow decreased
 
urinary retention
 
urinary tract obstruction
 
urinary tract pain
 
urinary tract infection
 
urosepsis
Reporting of Anticipated Events
These anticipated events will be periodically analyzed in aggregate by the sponsor during study
conduct.  The sponsor will prepare a safety report in narrative format if the aggregate analysis
indicates that the anticipated event occurs more frequently in the treatment group than in the
control group and the sponsor concludes there is a reasonable possibility that the drug under
investigation caused the anticipated event.
The plan for monitoring and analyzing the anticipated events is specified in a separate Anticipated
Events Safety Monitoring Plan. The assessment of causality will be made by the sponsor’s
unblinded safety assessment committee.
The sponsor assumes responsibility for appropriate reporting of the listed anticipated events
according to the requirements of the countries/territories in which the studies are conducted.
8.4.5. 
Pregnancy
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious
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adverse events and must be reported using the Serious Adverse Event Form. If a subject becomes
pregnant during the study, the investigator should discuss discontinuation of study drug for the
subject with the sponsor’s medical monitor. Follow-up information regarding the outcome of the
pregnancy and any postnatal sequelae in the infant will be required. Male subjects receiving
gemcitabine or mitomycin C will refrain from sperm donation or fathering a child until 6 months
after the last dose of study drug.
8.4.6. 
Disease-Related Events and Disease-Related Outcomes Not
Qualifying as Adverse Events or Serious Adverse Events
All events that meet the definition of a serious adverse event (SAE) will be reported as SAEs,
regardless of whether they are protocol-specific assessments.
Progression of disease should not be considered nor should be reported as an AE (or SAE).
However, signs and symptoms of disease progression or of clinical sequelae resulting from disease
progression/lack of efficacy that are determined by the investigator to be of clinical significance
should be reported per the usual reporting requirements (Section 8.4 and Section 10.3).
8.4.7. 
Adverse Events of Special Interest
Central serous retinopathy (CSR) is considered an adverse event of special interest. Instructions
for assessing vision abnormalities during the study are provided in Section 8.3.5.
8.5. 
Treatment of Overdose
There is no information on overdosage with erdafitinib. There is no known specific antidote for
erdafitinib overdose. In the event of an overdose, stop erdafitinib and undertake general supportive
measures until clinical toxicity has diminished or resolved. See Section 10.3 (Special Reporting
Situations) for additional information.
8.6. 
Pharmacokinetics
8.6.1. 
Evaluations
Subjects who receive erdafitinib will have biological specimens collected for measurement of
erdafitinib concentration as follows:
 
Scheduled collection of venous blood during Cycle 1 and Cycle 2
 
Tissue specimens from newly detected or progressing lesions during the Treatment Phase
 
Matching venous blood samples collected at the time tissue specimens are collected from new
or progressing lesions
 
A 24-hour urine collection, first approximately 20 subjects who receive erdafitinib (from any
cohort).
Erdafitinib Pharmacokinetic Assessment in Blood
Venous blood samples (2 mL per visit) will be collected for the determination of plasma
concentrations of erdafitinib at the time points specified on the Schedule of Activities (Section 1.3)
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for all subjects who receive erdafitinib. The Laboratory Manual provides detailed information on
the handling and shipment of blood/plasma samples.
 
Predose PK sample: On Cycle 1 Day 14 and Cycle 2 Day 1, erdafitinib should be taken in the
clinic after the predose PK sample. The time of dosing, and the collection time of the PK
sample must be recorded accurately.
 
Postdose PK sample: On Cycle 2 Day 1, a 4-mL venous blood sample will be taken together
with a 3-hour (±1 hour) postdose blood sample for the determination of erdafitinib plasma
protein binding (ie, alpha-1-acid glycoproteins, total protein, and fraction unbound) (see
Schedule of Activities, Section 1.3). The time of dosing, and the time of the protein binding
sample must ±be recorded accurately.
 
If indicated by the emerging safety findings or if the scheduled PK samples are not collected
due to treatment interruption, blood samples may be collected at a later site visit (on Cycle 2
Day 14, Cycle 3 Day 1, or Cycle 3 Day 14). The total number of samples and blood volume
will not be substantially increased without approval of the IEC or IRB.
Erdafitinib Pharmacokinetic Assessment in Urine
A 24-hour urine sample will be collected from the first approximately 20 subjects who received
erdafitinib enrolled (from any cohort) at specified time point in the schedule of assessments.
8.6.2. 
Analytical Procedures
Analytical procedures to determine erdafitinib concentration in blood and tissue are provided in
this section.
Erdafitinib Pharmacokinetic Blood Samples
Blood samples will be processed to obtain plasma for measurement of erdafitinib concentration by
a validated analytical method under the direction of the sponsor. Plasma protein binding, if needed,
will be determined by equilibrium dialysis. After dialysis, the buffer and plasma samples will be
analyzed for erdafitinib content using a qualified liquid chromatography/mass spectrometry
method by the sponsor's Bioanalytical Laboratory. Alpha-1 acid glycoprotein (α1-AGP) will also
be measured in the plasma.
Pharmacokinetic Tissue Samples
Biopsy tissue concentrations of erdafitinib will be determined with a qualified liquid
chromatography/mass spectrometry method by the sponsor's Bioanalytical Laboratory. Refer to
the Laboratory Manual for details on sample handling.
8.6.3. 
Pharmacokinetic Parameters and Evaluations
Erdafitinib pharmacokinetic data in different metrices (plasma and tissue) will be listed for all
subjects with available plasma erdafitinib concentrations. Subjects will be excluded from the
pharmacokinetic analysis if their data do not allow for accurate assessment (eg, missing dosing
and sampling time information; concentration data are not sufficient for pharmacokinetic
parameter calculation). All concentrations below the lowest quantifiable concentration or missing
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data will be labeled as such in the concentration database. All subjects and samples excluded from
the analysis will be clearly documented in the study report.
Population pharmacokinetic analysis of plasma concentration-time data of erdafitinib may be
performed using nonlinear mixed-effect modeling. Previously developed pharmacokinetic models
may be used and updated as considered appropriate. Relationships between plasma concentrations
or metrics of systemic exposure and CYP2C9 polymorphism, markers of pharmacological
activities (serum phosphate), efficacy, or treatment-emergent adverse events may also be explored
as data allow using population approaches. Results of the analyses will be provided in a separate
report.
8.7. 
Pharmacodynamics
Predictive and pharmacodynamic biomarker analyses are described in Section 9.4.6.1.
8.8. 
Genetics
Germline DNA will be collected for subjects receiving erdafitinib (see Section 1.3) from a blood
sample for CYP2C9 genotyping. This will be used to explore the effect of CYP2C9 polymorphism
on the pharmacokinetics of erdafitinib.
8.9. 
Biomarkers
Biomarker investigations in this study include, but are not limited to, assessment ofthe following:
 
Assessment of
 in archival tissue and paired tumor biopsies where available
 
Assessment of
 in pretreatment and longitudinal voided urine samples
 
Circulating tumor DNA from plasma to determine the
 at screening, to assess changes in the levels or types of 
 observed
over time, and to monitor for the
 
Next-generation sequencing for genetic alterations in pretreatment/archival samples and
association of genetic alterations with
 
Serum phosphate levels as a marker of 
Tissue Biomarkers
Tumor tissue collected on study will be used to assess the
 status and identify the
 of the subjects’ tumors, as well as to identify
to treatment with erdafitinib or Investigator’s Choice. Tumor tissue from any positive biopsy (any
grade of recurrence) should be sent for exploratory biomarker analysis to the central laboratory.
Refer to the Laboratory Manual for instruction on sample handling.
Archival or fresh tumor tissue collected at screening will be used to assess the status of 
, via IHC.
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Urothelial cancer can be classified, via molecular signature, into basal, luminal, and p53-like
subtypes, which may inform patient prognosis and response to treatment in the advanced disease
setting.37 The utility of bladder cancer molecular subtyping in the 
 will be assessed. Gene expression analysis, determined by RNAseq analysis or
alternate method, will be utilized to assess the 
e
 subjects. Changes in 
 upon erdafitinib treatment will also be
evaluated in paired tumor biopsies utilizing tissue from lesions biopsied during cystoscopy, where
available. The correlation of bladder molecular subtype
 will be evaluated.
Urine for
 (ie, for biomarker research)
Urine samples will be collected at multiple time points on study to provide a noninvasive method
for 
 and to 
. This would especially
benefit patients with CIS, where due to tumor architecture, diagnosis is performed from cells
derived from urine cytology rather than tumor biopsy. Voided urine specimen will be assessed to
determine the sensitivity of
 from urine.
Longitudinal urine sample collections will be obtained and analyzed in order to determine the
optimal timepoint(s) for
 in this population.
from urine will be assessed at baseline and longitudinally on all subjects from the study, with the
understanding that subjects with papillary disease may not have enough tumor cells present in
urine for
 Understanding whether
 in
patients with papillary disease who have had all visible tumor resected, and whether and when
 can be detected in these patients in relation to
 is an important
scientific question to be addressed in the context of this study.
A voided urine sample for biomarker research will be obtained from the urine cytology sample.
Circulating Biomarkers
Blood samples for circulating biomarkers should be collected predose at timepoints specified in
the Schedule of Activities (Section 1.3).
Serum phosphate levels will be monitored in subjects treated with erdafitinib locally as a marker
of target engagement. The Phase 1 (42756493EDI1001) and Phase 2 (42756493BLC2001) studies
of erdafitinib demonstrated that phosphate levels are a robust PD biomarker of erdafitinib target
engagement, and that achieving target increases in serum phosphate may be associated with
clinical response to erdafitinib.
Circulating Tumor DNA
Blood for analysis of ctDNA will be collected at multiple time points to assess feasibility of
 in the NMIBC disease setting. The ability to detect
ctDNA increases with tumor stage. The utility of 
 in ctDNA from
subjects with non-muscle-invasive disease will be assessed and compared with FGFR status
determination from tissue and urine.
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Circulating tumor DNA are fragments of DNA shed in the bloodstream during cell turnover. In
cancer, a fraction of the circulating DNA is from DNA shed by tumor cells. This ctDNA often
harbors somatic alterations which are reflective of the original tumor.
Circulating tumor DNA may be used to identify patients for targeted therapies, track response to
treatment and the emergence of resistance by monitoring changes in target ctDNA levels over time.
Samples collected prior to and during treatment will be screened for changes in the levels or types
of 
 observed over time, and to monitor for the 
.
Urine for Assay Development
The ability to detect FGFR mutations or fusions in pretreatment urine samples and concordance of
urine FGFR status with archival tissue-based testing will be performed. The sensitivity and utility
of urine-based FGFR testing compared with tumor-based and blood-based (ctDNA, see above)
analyses will be assessed.
Two voided urine samples will be collected; one sample will be collected before the subject is
selected for this study (after disease recurrence and before the TURBT, except for patients being
considered for study after TURBT) and another sample will be collected at the time of high-risk
disease recurrence (before the TURBT procedure at the End of Treatment Visit). As noted in the
Schedule of Activities (Section 1.3), the collection at the time of high-risk recurrence is no longer
required.
Sample Collection and Analysis
Additional biomarkers (DNA, RNA, and protein) relevant to cancer may also be assessed in blood,
urine, and tumor tissue samples collected during the study to better understand the disease and the
.
Adjustments in the timing of biomarker collections may be made during the study based on
emerging data, and some biomarker collections may be ceased if emerging data show lack of utility
for the associated sample collections.
Biomarker analyses are dependent upon the availability of appropriate biomarker assays and
emerging data. Biomarker analyses may be ceased or deferred if, during or at the end of the study,
it becomes clear that the analysis will have no scientific value, that there are not enough samples,
or that there are not enough responders to allow for adequate biomarker evaluation. In the event
the study is stopped early or shows poor clinical efficacy, completion of biomarker assessments is
based on justification and intended utility of the data.
If it is determined at any time before study completion that additional material is needed from a
formalin-fixed, paraffin-embedded tumor sample for the successful completion of the protocol-
specified analyses, the sponsor may request that additional material be retrieved from existing
samples. Also, based on emerging scientific evidence, the sponsor may request additional material
from previously collected tumor samples during or after study completion for a retrospective
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analysis. In this case, such analyses would be specific to research related to the study drug(s) or
diseases being investigated.
8.10. Medical Resource Utilization and Health Economics
MRU and health economics data collection is no longer required for all subjects in all phases.
Medical Resource Utilization data, associated with medical encounters, will be collected in the
eCRF by the investigator and study-site personnel for subjects in Cohort 1 and Cohort 2 as
specified in the Schedule of Activities (see Section 1.3). Protocol-mandated procedures, tests, and
encounters are excluded. The data collected may be used to conduct exploratory economic
analyses and will include:
 
Number and duration of medical care encounters, including surgeries, and other selected
procedures (inpatient and outpatient)
 
Duration of hospitalization (total days length of stay, including duration by wards;
eg, intensive care unit)
 
Number and character of diagnostic and therapeutic tests and procedures
 
Outpatient medical encounters and treatments (including physician or emergency room visits,
tests and procedures, and medications)
9. 
STATISTICAL CONSIDERATIONS
Statistical analysis will be done by the sponsor or under the authority of the sponsor. A general
description of the statistical methods to be used to analyze the efficacy and safety data is outlined
below. Specific details will be provided in the Statistical Analysis Plan.
9.1. 
Statistical Hypothesis
For Cohort 1, the hypothesis is that erdafitinib treatment will delay the onset of tumor recurrence
for subjects with papillary disease only, who recurred after BCG treatment, with FGFR mutations
or fusions, and with all lesions removed.
Due to early enrollment termination and change in study’s regulatory intent from registrational to
non-registrational, formal hypothesis testing will no longer be performed for Cohort 1. No
hypothesis testing will be performed for Cohort 2 or Cohort 3.
9.2. 
Sample Size Determination
Cohort 1 was originally planned to enroll approximately 240 subjects in a 2:1 randomization ratio
(approximately 160 subjects assigned to the erdafitinib treatment arm; 80 subjects assigned to the
control arm, Investigator’s Choice of treatment). The termination of Cohort 1 enrollment resulted
in a sample size of 73 subjects for the purpose of summarizing the data descriptively. With a total
number of 73 subjects under the 2:1 randomization ratio, the 95% CIs for the possible hazard ratios
assumed to be observed at the end of the study are presented as follows (Table 12):
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Table 12: 
Hazard Ratio Confidence Intervals
Number of Events
20 
30 
40 
50
Hazard Ratio
0.4 
(0.16, 1.01) 
(0.19, 0.85) 
(0.21, 0.77) 
(0.22, 0.72)
0.5 
(0.20, 1.27) 
(0.23, 1.07) 
(0.26, 0.96) 
(0.28, 0.90)
0.6 
(0.24, 1.52) 
(0.28, 1.28) 
(0.31, 1.16) 
(0.33, 1.08)
Cohort 2 was planned to enroll approximately 20 subjects. As suggested by  the International
Bladder Cancer Group,27 a 40% CR rate at 6 months would be clinically  meaningful. With
20 subjects, the cohort will produce a 2-sided 95% CI of (16%, 64%) when the observed CR rate
is 40%. The termination of enrollment resulted in a Cohort 2 sample size of 16.
Cohort 3 was planned to enroll approximately 20 subjects. A CR rate of 30% to 50% has been
reported in most previous marker lesion studies.22 With 20 subjects, the lower bound of the 95%
CIs will exclude 0 if the observed CR rate is at least 30%. The 95% CIs for different observed CR
rates based on 20 subjects are as follows:
Observed rate 
95% CI
30% 
(7%, 53%)
40%  
(16%, 64%)
50%  
(26%, 74%)
60%  
(36%, 84%)
The termination of enrollment resulted in a Cohort 3 sample size of 18.
9.3. 
Populations for Analyses
For purposes of analysis, the following populations are defined:
Population 
Description
Intent-to-treat 
All randomized (Cohort 1) or treated (Cohort 2 and Cohort 3) subjects. Subjects in this
population will be analyzed according to the treatment to which they are assigned.
PK-evaluable 
Subjects in the intent-to-treat (ITT) who received at least 1 dose of erdafitinib and had at least
1 pharmacokinetic sample obtained post-treatment.
Biomarker 
Subjects in the ITT whose biomaterial is available and who have consented to participate in
the study’s biomarker evaluations.
Safety  
Subjects in the ITT who received at least 1 dose of study drug. Safety data will be analyzed
according to the actual treatment received.
The ITT population will be used to summarize the study  population and characteristics, and
efficacy data; the Safety Population will be used to summarize the safety data, unless otherwise
specified.
9.4. 
Statistical Analyses
The Statistical Analysis Plan will be finalized prior to database lock and it will include a more
technical and detailed description of the statistical analyses described in this section. This section
is a summary of the planned statistical analyses of the most important endpoints including primary
and key secondary endpoints.
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9.4.1. 
General Considerations
The cohorts will be analyzed separately. Descriptive statistics and subject listings will be used to
summarize the data. For continuous variables, number of observations, means, standard deviations,
medians, interquartiles (IQs), and ranges will be used. For discrete variables, frequency will be
summarized. The comparisons between the 2 treatment groups in Cohort 1 will be performed using
descriptive statistics.
9.4.2. 
Primary Endpoint (Cohort 1)
For Cohort 1, the primary endpoint is RFS. Recurrence-free survival is defined as the time from
the date of randomization until the date of the reappearance of high-risk disease (high-grade Ta,
T1 or CIS), or death, whichever is reported first. Subjects who are recurrence-free and alive or
have unknown status will be censored at the last tumor assessment.
The primary efficacy analysis will be based on the ITT population. The Kaplan-Meier method will
be used to estimate the distribution of overall RFS for each treatment group.
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined
by the following 4 components:
 
Population: all randomized subjects, with high-risk NMIBC who harbor FGFR mutations or
fusions, and who recurred after BCG therapy.
 
Variable: time to event, RFS.
 
Intercurrent event:
 
Treatment discontinuation. Treatment policy approach is used, where the occurrence of
the intercurrent event is irrelevant: the value of the event is used regardless of treatment
discontinuation occurring.
 
Subsequent anticancer therapy. While on treatment strategy will be used, that is, RFS will
be censored at the start date of anticancer therapy. Note that for subjects randomized to
Investigator’s Choice in Cohort 1, the treatment of erdafitinib after cross over is
considered as use of subsequent therapy and the while on treatment strategy will be used.
 
Population-level summary: descriptive statistics.
9.4.3. 
Secondary Efficacy Endpoints (Cohort 1)
Secondary endpoints for Cohort 1 include the following:
 
Time to progression: the time from the date of randomizationuntil the date of first documented
evidence of any of the following:
 
Development of or increase in stage to lamina propria invasion (eg, increase from Ta to
T1)
 
Development of or increase in stage to muscle-invasive disease (stage ≥T2)
 
Development of or increase in stage to lymph node (N+) or distant metastasis (M1)
disease (subject must have previously been diagnosed with N0 and/or M0 disease)
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 
Increase in tumor grade from low to high (including CIS)
 
Death
Subjects who are progression-free and alive or have unknown status will be censored at the
date of the last tumor assessment.
 
Overall survival: the time from the date of randomization to the date of the subject’s death
resulting from any cause. Subjects who are alive or have unknown vital status will be censored
at the date the subject was last known to be alive.
 
RFS rate at 6 months and 12 months.
Descriptive statistics will be used to summarize the secondary efficacy endpoints of time to
progression, OS, and RFS rate at 6 months and 12 months for the ITT population in Cohort 1.
Kaplan-Meier methods will be used to estimate the distribution of these endpoints for each
treatment group.
9.4.4. 
Tertiary/Exploratory Endpoints
For Cohort 2, the exploratory endpoints are CR rate at 8 weeks, CR rate at 32 weeks, and DOR.
Complete response is defined as at least one of the following: 1) negative cystoscopy and negative
(including atypical) urine cytology; or 2) positive cystoscopy with biopsy-proven benign or
low-grade NMIBC and negative cytology. The CR rate at 8 weeks and the CR rate at 32 weeks
will be calculated with their associated 2-sided 95% CIs. Duration of response will be analyzed
for subjects in Cohort 2 with a BOR of CR only and is defined as the interval between the date of
initial documentation of a response and the first documented evidence of PD, recurrence, or death
due to any cause. The Kaplan-Meier method will be used to estimate the median DOR with 95%
CI.
For Cohort 3, the exploratory endpoints are CR rate, BOR, and DOR. Complete response is defined
as the disappearance of the marker lesion without any new lesions; and if any remnant of the
marker lesion, no viable tumor seen on histopathological examination. The CR rate will be
calculated with its associated 2-sided 95% CI. For Cohort 3, the best overall response (BOR) is
defined as the best response documented after start of study treatment. CR for Cohort 3 is defined
above. A partial response (PR) for Cohort 3 is defined as marker lesion reduction by 50%. Stable
disease (SD) for Cohort 3 is defined as marker lesion reduction by less than 50%. Progressive
disease (PD) for Cohort 3 is defined as any marker lesion growth beyond baseline. Duration of
response will be analyzed for subjects in Cohort 3 with a BOR of CR or PR and is defined as the
interval between the date of initial documentation of a response and the first documented evidence
of PD, recurrence, or death due to any cause. The Kaplan-Meier method will be used to estimate
the median DOR with 95% CI.
9.4.5. 
Safety Analyses
All safety analyses will be made on the Safety Population.
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Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events will be coded
using the Medical Dictionary for Regulatory Activities (MedDRA). Treatment-emergent adverse
events are adverse events with onset during the Treatment Phase or that are a consequence of a
pre-existing condition that has worsened since baseline. All reported treatment-emergent adverse
events will be included in the analysis. For each adverse event, the percentage of subjects who
experience at least 1 occurrence of the given event will be summarized by treatment group. In
addition, comparisons between treatment groups will be provided if appropriate.
Summaries, listings, datasets, or subject narratives may be provided, as appropriate, for those
subjects who die, who discontinue treatment due to an adverse event, or who experience a severe
or a serious adverse event.
Clinical Laboratory Tests
Laboratory data will be summarized by type of laboratory test. Reference ranges and markedly
abnormal results (specified in the Statistical Analysis Plan) will be used in the summary of
laboratory data. Frequency tabulations of the abnormalities will be made. A listing of subjects with
any  markedly abnormal laboratory results will also be provided. Parameters with predefined
NCI-CTCAE toxicity grades will be summarized.
Electrocardiograms
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings
will be reported (eg, changes in T wave morphology or the occurrence of U waves). Clinically
relevant ECG abnormalities are defined in the SAP.
ECOG Performance Status
Screening ECOG performance status scores will be summarized for each cohort.
9.4.6. 
Other Analyses
9.4.6.1. 
Pharmacokinetic Analyses
The pharmacokinetic analysis of erdafitinib will be performed on data from the PK-evaluable
Population (see Section 9.3). All concentrations below the lowest quantifiable concentration or
missing data will be labeled as such in the concentration database.
Erdafitinib pharmacokinetic data in different metrices (plasma, urine, and tissue) will be listed for
all subjects with available erdafitinib concentrations. Concentrations values below the lower limit
of quantitation will be displayed in listings as zero with a flag and handled as zero in the
calculations for mean, coefficient of variation (CV) for mean, standard deviation, minimum,
median, maximum, but handled as missing for the calculation of the geometric means and their
CV. Subjects will be excluded from the pharmacokinetic analysis if their data do not allow for
accurate assessment of the pharmacokinetic (eg, incomplete administration of the study drug;
missing information of dosing and sampling times; concentration data not sufficient for
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pharmacokinetic parameter calculation). All subjects and samples excluded from the analysis will
be clearly documented in the study report.
If appropriate, descriptive statistics, including arithmetic and geometric mean, median, standard
deviation, CV, geometric CV, minimum and maximum, will be tabulated for erdafitinib PK
concentrations and protein binding data by time point if provided.
9.4.6.2. 
Biomarkers Analyses
Changes in 
 over time will be summarized by treatment group. Associations between baseline
levels and changes from baseline in select markers and
 will be explored.
Results of exploratory biomarker analyses may be presented in a separate report. Planned
biomarker analyses may be deferred if emerging study data show no likelihood of providing useful
scientific information.
9.5. 
Interim Analysis
Two interim analyses were originally planned for Cohort 1. Due to the change in the conduct of
the study, they will no longer be conducted.
9.6. 
Independent Data Monitoring Committee
An IDMC  will be commissioned for reviewing safety data at various intervals outlined in the
IDMC Charter (Section 10.2). Due to the company decision to terminate study enrollment and
considering the recent IDMC review (6 July 2022) found the safety of erdafitinib in this study to
be consistent with the known safety profile of erdafitinib, no further monitoring by the IDMC will
be conducted.
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10. 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS
10.1. Appendix 1: Abbreviations
ADL 
activities of daily living
ANC  
absolute neutrophil count
AUA  
American Urological Association
AUC  
area under the curve
BCG 
bacillus Calmette-Guérin
β hCG  
β-human chorionic gonadotropin
BICR  
blinded independent central review
BSA 
body surface area
CI 
confidence interval
CIS  
carcinoma in situ
CLIA  
Clinical Laboratory Improvement Amendments
CR  
complete response
CSR  
central serous retinopathy
CT  
computed tomography
ctDNA  
circulating tumor DNA
CV  
coefficient of variation
CYP  
Cytochrome
DCR  
disease control rate
DDI 
drug-drug interaction
DoR  
duration of response
EAU  
European Association of Urology
ECG  
Electrocardiogram
ECOG  
Eastern Cooperative Oncology Group
eCRF  
electronic case report form
eDC  
electronic data capture
EMA  
European Medicines Agency
EoT  
end of treatment
ePRO  
electronic patient-reported outcome
EORTC  
European Organisation for Research and Treatment of Cancer
FGFR  
fibroblast growth factor receptor
FDA  
Food and Drug Administration
GCP  
Good Clinical Practice
HR  
hazard ratio
HRQoL 
health-related quality of life
IB  
Investigator’s Brochure
ICF  
informed consent form
ICH  
International Conference on Harmonisation
IDMC  
Independent Data Monitoring Committee
IEC  
Independent Ethics Committee
IPPI 
Investigational Product Preparation Instructions
IPPM  
Investigational Product Procedures Manual
IRB  
Institutional Review Board
ITT  
intent-to-treat
IWRS  
interactive web response system
LCIS  
lobular carcinoma in situ
LTE  
Long-term Extension
MedDRA  
Medical Dictionary for Regulatory Activities
MMC  
mitomycin C
MRI 
magnetic resonance imaging
MRU  
medical resource utilization
NCI-CTCAE 
National Cancer Institute Common Terminology Criteria for Adverse Events
NGS  
next-generation sequencing
NMIBC  
non-muscle-invasive bladder cancer
ORR  
overall response rate
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OS  
overall survival
PCR  
polymerase chain reaction
PD 
Pharmacodynamic
PFS  
progression-free survival
P-gp 
P-glycoprotein
PGIC  
Patient’s Global Impression of Change (of cancer)
PGIS  
Patient’s Global Impression of Severity (of cancer)
PK 
pharmacokinetic(s)
PR 
partial response
PRO  
patient-reported outcome(s) (paper or electronic as appropriate for this study)
PQC  
product quality complaint
RFS  
recurrence-free survival
RFS2 
recurrence-free survival on subsequent anticancer therapy
SUSAR  
suspected unexpected serious adverse reaction
TURBT  
transurethral resection of bladder tumor
ULN  
upper limit of normal
US  
United States
Definitions of Terms
Duration of Study 
Drug 
Period from first dose of study treatment (erdafitinib or Investigator’s Choice) until the last
dose. The duration of erdafitinib study treatment is a maximum of 2 years.
Electronic source 
system  
Contains data traditionally maintained in a hospital or clinic record to document medical
care or data recorded in an eCRF as determined by the protocol. Data in this system may
be considered source documentation.
Investigator’s Choice 
For Cohort 1, subjects not assigned to receive erdafitinib will receive either intravesical
gemcitabine or intravesical MMC/hyperthermic MMC.
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10.2. Appendix 2: Regulatory, Ethical, and Study Oversight Considerations
REGULATORY AND ETHICAL CONSIDERATIONS
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the
protocol, current ICH guidelines on Good Clinical Practice (GCP), and applicable regulatory and
country/territory-specific requirements.
Good Clinical Practice is an international ethical and scientific quality standard for designing,
conducting, recording, and reporting studies that involve the participation of human subjects.
Compliance with this standard provides public assurance that the rights, safety, and well-being of
study subjects are protected, consistent with the principles that originated in the Declaration of
Helsinki, and that the study data are credible.
Protocol Clarification Communications
If text within a final approved protocol requires clarification (eg, current wording is unclear or
ambiguous) that does not change any aspect of the current study conduct, a protocol clarification
communication (PCC) may be prepared. The PCC Document will be communicated to the
Investigational Site, Site Monitors, Local Trial Managers, Clinical Trial Managers, and/or Contract
Research Organizations who will ensure that the PCC explanations are followed by the
investigators.
The PCC Document may be shared by the sites with IECs/IRBs per local regulations.
The PCC Documents must NOT be used in place of protocol amendments, but the content of the
PCC Document must be included in any future protocol amendments.
Protocol Amendments
Neither the investigator nor the sponsor will modify this protocol without a formal amendment by
the sponsor. All protocol amendments must be issued by the sponsor and signed and dated by the
investigator. Protocol amendments must not be implemented without prior IEC/IRB approval, or
when the relevant competent authority has raised any grounds for non-acceptance, except when
necessary to eliminate immediate hazards to the subjects, in which case the amendment must be
promptly submitted to the IEC/IRB and relevant competent authority. Documentation of
amendment approval by the investigator and IEC/IRB must be provided to the sponsor. When the
change(s) involve only logistic or administrative aspects of the study, the IEC/IRB (where
required) only needs to be notified.
During the study, in situations where a departure from the protocol is unavoidable, the investigator
or other physician in attendance will contact the appropriate sponsor representative listed in the
Contact Information page(s), which will be provided as a separate document. Except in emergency
situations, this contact should be made before implementing any departure from the protocol. In
all cases, contact with the sponsor must be made as soon as possible to discuss the situation and
agree on an appropriate course of action. The data recorded in the CRF and source documents will
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reflect any departure from the protocol, and the source documents will describe this departure and
the circumstances requiring it.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities
in each respective country/territory, if applicable. A study may not be initiated until all local
regulatory requirements are met.
Required Prestudy Documentation
The following documents must be provided to the sponsor before shipment of study drug to the
study site:
 
Protocol and amendment(s), if any, signed and dated by the principal investigator
 
A copy of the dated and signed (or sealed, where appropriate per local regulations), written
IEC/IRB approval of the protocol, amendments, ICF, any recruiting materials, and if
applicable, subject compensation programs. This approval must clearly identify the specific
protocol by title and number and must be signed (or sealed, where appropriate per local
regulations) by the chairman or authorized designee.
 
Name and address of the IEC/IRB, including a current list of the IEC/IRB members and their
function, with a statement that it is organized and operates according to GCP and the
applicable laws and regulations. If accompanied by a letter of explanation, or equivalent, from
the IEC/IRB, a general statement may be substituted for this list. If an investigator or a
member of the study-site personnel is a member of the IEC/IRB, documentation must be
obtained to state that this person did not participate in the deliberations or in the vote/opinion
of the study.
 
Regulatory authority approval or notification, if applicable
 
Signed and dated statement of investigator (eg, Form FDA 1572), if applicable
 
Documentation of investigator qualifications (eg, curriculum vitae)
 
Completed investigator financial disclosure form from the principal investigator, where
required
 
Signed and dated Clinical Trial Agreement, which includes the financial agreement
 
Any other documentation required by local regulations
The following documents must be provided to the sponsor before enrollment of the first subject:
 
Completed investigator financial disclosure forms from all subinvestigators
 
Documentation of subinvestigator qualifications (eg, curriculum vitae)
 
Name and address of any local laboratory conducting tests for the study, and a dated copy of
current laboratory normal ranges for these tests, if applicable (eg, CLIA or equivalent
certification and laboratory director curriculum vitae)
 
Local laboratory documentation demonstrating competence and test reliability
(eg, accreditation/license), if applicable
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Status: Approved, Date: 13 July 2023
Independent Ethics Committee or Institutional Review Board
Before the start of the study, the investigator (or sponsor where required) will provide the IEC/IRB
with current and complete copies of the following documents (as required by local regulations):
 
Final protocol and, if applicable, amendments
 
Sponsor-approved ICF (and any other written materials to be provided to the subjects)
 
IB (or equivalent information) and amendments/addenda
 
Sponsor-approved subject recruiting materials
 
Information on compensation for study-related injuries or payment to subjects for
participation in the study, if applicable
 
Investigator's curriculum vitae or equivalent information (unless not required, as documented
by the IEC/IRB)
 
Information regarding funding, name of the sponsor, institutional affiliations, other potential
conflicts of interest, and incentives for subjects
 
Any other documents that the IEC/IRB requests to fulfill its obligation
This study will be undertaken only after the IEC/IRB has given full approval of the final protocol,
amendments (if any, excluding the ones that are purely administrative, with no consequences for
subjects, data or study conduct, unless required locally), the ICF, applicable recruiting materials,
and subject compensation programs, and the sponsor has received a copy of this approval. This
approval letter must be dated and must clearly identify the IEC/IRB and the documents being
approved.
During the study the investigator (or sponsor where required) will send the following documents
and updates to the IEC/IRB for their review and approval, where appropriate:
 
Protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct)
 
Revision(s) to ICF and any other written materials to be provided to subjects
 
If applicable, new or revised subject recruiting materials approved by the sponsor
 
Revisions to compensation for study-related injuries or payment to subjects for participation
in the study, if applicable
 
New edition(s) of the IB and amendments/addenda
 
Summaries of the status of the study at intervals stipulated in guidelines of the IEC/IRB (at
least annually)
 
Reports of adverse events that are serious, unlisted/unexpected, and associated with the study
drug
 
New information that may adversely affect the safety of the subjects or the conduct of the
study
 
Deviations from or changes to the protocol to eliminate immediate hazards to the subjects
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Status: Approved, Date: 13 July 2023
 
Report of deaths of subjects under the investigator's care
 
Notification if a new investigator is responsible for the study at the site
 
Development Safety Update Report and Line Listings, where applicable
 
Any other requirements of the IEC/IRB
For all protocol amendments (excluding the ones that are purely administrative, with no
consequences for subjects, data or study conduct), the amendment and applicable ICF revisions
must be submitted promptly to the IEC/IRB for review and approval before implementation of the
change(s).
At least once a year, the IEC/IRB will be asked to review and reapprove this study, where required.
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about
the study completion (if applicable, the notification will be submitted through the head of
investigational institution).
Country/Territory Selection
This study will only be conducted in those countries/territories where the intent is to launch or
otherwise help ensure access to the developed product if the need for the product persists, unless
explicitly addressed as a specific ethical consideration in Section 4.2.1, Study-Specific Ethical
Design Considerations.
Other Ethical Considerations
For study-specific ethical design considerations, refer to Section 4.2.1.
FINANCIAL DISCLOSURE
Investigators and subinvestigators will provide the sponsor with sufficient, accurate financial
information in accordance with local regulations to allow the sponsor to submit complete and
accurate financial certification or disclosure statements to the appropriate regulatory authorities.
Investigators are responsible for providing information on financial interests during the study and
for 1 year after completion of the study.
Refer to Required Prestudy Documentation (above) for details on financial disclosure.
INFORMED CONSENT PROCESS
Each subject (or a legally acceptable representative) must give written consent according to local
requirements after the nature of the study has been fully explained. The ICF(s) must be signed
before performance of any study-related activity. The ICF(s) that is/are used must be approved by
both the sponsor and by the reviewing IEC/IRB and be in a language that the subject can read and
understand. The informed consent should be in accordance with principles that originated in the
Declaration of Helsinki, current ICH and GCP guidelines, applicable regulatory requirements, and
sponsor policy.
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Status: Approved, Date: 13 July 2023
Informed consent for molecular eligibility may be obtained remotely unless not allowed by local
regulations. Also, subjects being considered for the study before the TURBT, will provide a voided
urine sample after disease recurrence and before TURBT. These subjects must sign the ICF for
Assay Development prior to collection of this urine sample.
Before enrollment in the study, the investigator or an authorized member of the study-site
personnel must explain to potential subjects or their legally acceptable representatives the aims,
methods, reasonably anticipated benefits, and potential hazards of the study, and any discomfort
participation in the study may entail. Subjects will be informed that their participation is voluntary
and that they may withdraw consent to participate at any time. They will be informed that choosing
not to participate will not affect the care the subject will receive for the treatment of his or her
disease. Subjects will be told that alternative treatments are available if they refuse to take part and
that such refusal will not prejudice future treatment. Finally, they will be told that the investigator
will maintain a subject identification register for the purposes of long-term follow up if needed
and that their records may be accessed by health authorities and authorized sponsor personnel
without violating the confidentiality of the subject, to the extent permitted by the applicable law(s)
or regulations. By signing the ICF the subject or legally acceptable representative is authorizing
such access, which includes permission to obtain information about his or her survival status. It
also denotes that the subject agrees to allow his or her study physician to recontact the subject for
the purpose of obtaining consent for additional safety evaluations, and subsequent disease-related
treatments, if needed.
The subject or legally acceptable representative will be given sufficient time to read the ICF and
the opportunity to ask questions. After this explanation and before entry into the study, consent
should be appropriately recorded by means of either the subject's or his or her legally acceptable
representative's personally dated signature. After having obtained the consent, a copy of the ICF
must be given to the subject.
A subject who is rescreened is not required to sign another Main-study ICF if the rescreening
occurs within 35 days from the previous Main-study ICF signature date. Subjects who fall outside
of the 35 days from the previous Main-study ICF date, will need to sign a new Main-study ICF
and have all eligibility criteria re-assessed. Subjects undergoing molecular screening do not need
to re-sign a new Molecular Eligibility ICF to submit historical samples to the central laboratory.
If the subject or legally acceptable representative is unable to read or write, an impartial witness
should be present for the entire informed consent process (which includes reading and explaining
all written information) and should personally date and sign the ICF after the oral consent of the
subject or legally acceptable representative is obtained.
DATA PROTECTION
Privacy of Personal Data
The collection and processing of personal data from subjects enrolled in this study will be limited
to those data that are necessary to fulfill the objectives of the study.
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These data must be collected and processed with adequate precautions to ensure confidentiality
and compliance with applicable data privacy protection laws and regulations. Appropriate
technical and organizational measures to protect the personal data against unauthorized disclosures
or access, accidental or unlawful destruction, or accidental loss or alteration must be put in place.
Sponsor personnel whose responsibilities require access to personal data agree to keep the identity
of subjects confidential.
The informed consent obtained from the subject or his or her legally acceptable representative
includes explicit consent for the processing of personal data and for the investigator/institution to
allow direct access to his or her original medical records (source data/documents) for study-related
monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the
transfer of the data to other entities and to other countries/territories.
The subject has the right to request through the investigator access to his or her personal data and
the right to request rectification of any data that are not correct or complete. Reasonable steps will
be taken to respond to such a request, taking into consideration the nature of the request, the
conditions of the study, and the applicable laws and regulations.
Exploratory biomarker and pharmacokinetic research is not conducted under standards appropriate
for the return of data to subjects. In addition, the sponsor cannot make decisions as to the
significance of any findings resulting from exploratory research. Therefore, exploratory research
data will not be returned to subjects or investigators, unless required by law or local regulations.
Privacy and confidentiality of data generated in the future on stored samples will be protected by
the same standards applicable to all other clinical data.
LONG-TERM RETENTION OF SAMPLES FOR ADDITIONAL FUTURE RESEARCH
Samples collected in this study may be stored for up to 15 years (or according to local regulations)
for additional research. Samples will only be used to understand erdafitinib, to understand NMIBC,
to understand 
, and to develop 
. The research may begin at any time during the study or the post-study storage period.
Stored samples will be coded throughout the sample storage and analysis process and will not be
labeled with personal identifiers. Subjects may withdraw their consent for their samples to be
stored for additional future research (refer to Section 7.2.1, Withdrawal From the Future Use of
Research Samples).
COMMITTEES STRUCTURE
An IDMC composed of at least 1 medical expert in the relevant therapeutic area and at least
1 statistician will be established to monitor data on an ongoing basis to ensure the safety of the
subjects enrolled in this study. The safety review will focus on deaths, treatment discontinuations,
serious adverse events, Grade ≥3 events, and events of special interest. Based on the results from
these scheduled safety review meetings, the IDMC chair may request additional analyses and more
frequent monitoring. All deaths, treatment discontinuations and serious adverse events will be
reviewed by the sponsor’s medical monitor on an ongoing basis to identify safety concerns, and
CCI
CCI
CCI
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the IDMC will be informed of any new potential signals. The plan for monitoring subject safety
and evaluating efficacy, and the roles and responsibilities of the IDMC, are detailed in the IDMC
Charter. Due to the company decision to terminate study enrollment and considering the recent
IDMC review (6 July 2022) found the safety of erdafitinib in this study to be consistent with the
known safety profile of erdafitinib, no further monitoring by the IDMC will be conducted.
PUBLICATION POLICY/DISSEMINATION OF CLINICAL STUDY DATA
All information, including but not limited to information regarding erdafitinib  or the sponsor's
operations (eg, patent application, formulas, manufacturing processes, basic scientific data, prior
clinical data, formulation information) supplied by the sponsor to the investigator and not
previously published, and any data, including exploratorypharmacokinetic and biomarker research
data, generated as a result of this study, are considered confidential and remain the sole property
of the sponsor. The investigator agrees to maintain this information in confidence and use this
information only to accomplish this study and will not use it for other purposes without the
sponsor's prior written consent.
The investigator understands that the information developed in the study will be used by the
sponsor in connection with the continued development of erdafitinib, and thus may be disclosed
as required to other clinical investigators or regulatory agencies. To permit the information derived
from the clinical studies to be used, the investigator is obligated to provide the sponsor with all
data obtained in the study.
The results of the study will be reported in a Clinical Study Report generated by the sponsor and
will contain data from all study sites that participated in the study as per protocol. Recruitment
performance or specific expertise related to the nature and the key assessment parameters of the
study will be used to determine a coordinating investigator for the study. Results of exploratory
pharmacokinetic or biomarker analyses performed after the Clinical Study Report has been issued
will be reported in a separate report and will not require a revision of the Clinical Study Report.
Study subject identifiers will not be used in publication of results. Any work created in connection
with performance of the study and contained in the data that can benefit from copyright protection
(except any publication by the investigator as provided for below) shall be the property of the
sponsor as author and owner of copyright in such work.
Consistent with Good Publication Practices and International Committee of Medical Journal
Editors (ICMJE) guidelines, the sponsor shall have the right to publish such primary (multicenter)
data and information without approval from the investigator. The investigator has the right to
publish study site-specific data after the primary data are published. If an investigator wishes to
publish information from the study, a copy of the manuscript must be provided to the sponsor for
review at least 60 days before submission for publication or presentation. Expedited reviews will
be arranged for abstracts, poster presentations, or other materials. If requested by the sponsor in
writing, the investigator will withhold such publication for up to an additional 60 days to allow for
filing of a patent application. In the event that issues arise regarding scientific integrity or
regulatory compliance, the sponsor will review these issues with the investigator. The sponsor will
not mandate modifications to scientific content and does not have the right to suppress information.
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Status: Approved, Date: 13 July 2023
For multicenter study designs and substudy approaches, secondary results generally should not be
published before the primary endpoints of a study have been published. Similarly, investigators
will recognize the integrity of a multicenter study by not submitting for publication data derived
from the individual study site until the combined results from the completed study have been
submitted for publication, within 18 months after the study end date, or the sponsor confirms there
will be no multicenter study publication. Authorship of publications resulting from this study will
be based on the guidelines on authorship, such as those described in the ICMJE Recommendations
for the Conduct, Reporting, Editing and Publication of Scholarly Work in Medical Journals, which
state that the named authors must have made a significant contribution to the conception or design
of the work; or the acquisition, analysis, or interpretation of the data for the work; and drafted the
work or revised it critically for important intellectual content; and given final approval of the
version to be published; and agreed to be accountable for all aspects of the work in ensuring that
questions related to the accuracy or integrity of any part of the work are appropriately investigated
and resolved.
Registration of Clinical Studies and Disclosure of Results
The sponsor will register and disclose the existence of and the results of clinical studies as required
by law. The disclosure of the final study results will be performed after the end of study in order
to ensure the statistical analyses are relevant.
DATA QUALITY ASSURANCE
Data Quality Assurance/Quality Control
Steps to be taken to ensure the accuracy and reliability of data include the selection of qualified
investigators and appropriate study sites, review of protocol procedures with the investigator and
study-site personnel before the study, periodic monitoring visits by the sponsor, and direct
transmission of clinical laboratory data from a central laboratory into the sponsor's data base.
Written instructions will be provided for collection, handling, storage, and shipment of samples.
Guidelines for CRF completion will be provided and reviewed with study-site personnel before
the start of the study.
The sponsor will review CRF for accuracy and completeness during on-site monitoring visits and
after transmission to the sponsor; any discrepancies will be resolved with the investigator or
designee, as appropriate. After upload of the data into the study database they will be verified for
accuracy and consistency with the data sources.
CASE REPORT FORM COMPLETION
Case report forms (CRF) are prepared and provided by the sponsor for each subject in electronic
format. All data relating to the study must be recorded in CRF. All CRF entries, corrections, and
alterations must be made by the investigator or authorized study-site personnel. The investigator
must verify that all data entries in the CRF are accurate and correct.
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The study data will be transcribed by study-site personnel from the source documents onto an
electronic CRF, if applicable. Study-specific data will be transmitted in a secure manner to the
sponsor.
Worksheets may be used for the capture of some data to facilitate completion of the CRF. Any such
worksheets will become part of the subject's source documents. Data must be entered into CRF in
English. Data should be entered within 3 to 5 working days of the subject visit; evaluation or
assessment and queries should be answered within 5 working days of query generation, unless
otherwise communicated by the team.
All participative measurements (eg, pain scale information or other questionnaires) will be
completed by the same individual who made the initial baseline determinations whenever possible.
If necessary, queries will be generated in the eDC tool. If corrections to a CRF are needed after the
initial entry into the CRF, this can be done in either of the following ways:
 Investigator and study-site personnel can make corrections in the eDC tool at their own
initiative or as a response to an auto query (generated by the eDC tool).
 Sponsor or sponsor delegate can generate a query for resolution by the investigator and study-
site personnel.
SOURCE DOCUMENTS
At a minimum, source documents consistent in the type and level of detail with that commonly
recorded at the study site as a basis for standard medical care must be available for the following:
subject identification, eligibility, and study identification; study discussion and date of signed
informed consent; dates of visits; results of safety and efficacy parameters as required by the
protocol; record of all adverse events and follow-up of adverse events; concomitant medication;
study drug receipt/dispensing/return records; study drug administration information; and date of
study completion and reason for early discontinuation of study drug or withdrawal from the study,
if applicable.
The author of an entry in the source documents should be identifiable.
Specific details required as source data for the study and source data collection methods will be
reviewed with the investigator before the study and will be described in the monitoring guidelines
(or other equivalent document).
The minimum source documentation requirements for Section 5.1, Inclusion Criteria and
Section 5.2, Exclusion Criteria that specify a need for documented medical history are as follows:
 Referral letter from treating physician or
 Complete history of medical notes at the site
 Discharge summaries
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 Clear documentation of a subject’s refusal to undergo cystectomy or medical ineligibility for
cystectomy at screening must be available, and the reason for not being eligible for cystectomy
or for refusing cystectomy will be entered into the eCRF.
 BCG strain will be documented in the source documents and entered into the eCRF.
Inclusion and exclusion criteria not requiring documented medical history must be verified at a
minimum by subject interview or other protocol-required assessment (eg, physical examination,
laboratory assessment) and documented in the source documents.
An eSource system may be utilized, which contains data traditionally maintained in a hospital or
clinic record to document medical care (eg, electronic source documents) as well as the clinical
study-specific data fields as determined by the protocol. These data are electronically extracted for
use by the sponsor. If eSource is utilized, references made to the CRF in the protocol include the
eSource system but information collected through eSource may not be limited to that found in the
CRF.
MONITORING
The sponsor will use a combination of monitoring techniques (central, remote, or on-site
monitoring)to monitor this study.
The sponsor will perform on-site monitoring visits as frequently as necessary. The monitor will
record dates of the visits in a study site visit log that will be kept at the study site. The first
post-initiation visit will be made as soon as possible after enrollment has begun. At these visits,
the monitor will compare the data entered into the CRF with the source documents
(eg, hospital/clinic/physician’s office medical records). The nature and location of all source
documents will be identified to ensure that all sources of original data required to complete the
CRF are known to the sponsor and study-site personnel and are accessible for verification by the
sponsor study-site contact. If electronic records are maintained at the study site, the method of
verification must be discussed with the study-site personnel.
Direct access to source documents (medical records) must be allowed for the purpose of verifying
that the recorded data are consistent with the original source data. Findings from this review will
be discussed with the study-site personnel. The sponsor expects that, during monitoring visits, the
relevant study-site personnel will be available, the source documents will be accessible, and a
suitable environment will be provided for review of study-related documents. The monitor will
meet with the investigator on a regular basis during the study to provide feedback on the study
conduct.
In addition to on-site monitoring visits, remote contacts can occur. It is expected that during these
remote contacts, study-site personnel will be available to provide an update on the progress of the
study at the site.
Central monitoring will take place for data identified by the sponsor as requiring central review.
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ON-SITE AUDITS
Representatives of the sponsor's clinical quality assurance department may visit the study site at
any time during or after completion of the study to conduct an audit of the study in compliance
with regulatory guidelines and company policy. These audits will require access to all study
records, including source documents, for inspection. Subject privacy must, however, be respected.
The investigator and study-site personnel are responsible for being present and available for
consultation during routinely scheduled study-site audit visits conducted by the sponsor or its
designees.
Similar auditing procedures may also be conducted by agents of any regulatory body, either as part
of a national GCP compliance program or to review the results of this study in support of a
regulatory submission. The investigator should immediately notify the sponsor if he or she has
been contacted by a regulatory agency concerning an upcoming inspection.
RECORD RETENTION
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all CRF and
all source documents that support the data collected from each subject, as well as all study
documents as specified in ICH/GCP Section 8, Essential Documents for the Conduct of a Clinical
Trial, and all study documents as specified by the applicable regulatory requirement(s). The
investigator/institution will take measures to prevent accidental or premature destruction of these
documents.
Essential documents must be retained until at least 2 years after the last approval of a marketing
application in an ICH region and until there are no pending or contemplated marketing applications
in an ICH region or until at least 2 years have elapsed since the formal discontinuation of clinical
development of the investigational product. These documents will be retained for a longer period
if required by the applicable regulatory requirements or by an agreement with the sponsor. It is the
responsibility of the sponsor to inform the investigator/institution as to when these documents no
longer need to be retained.
If the responsible investigator retires, relocates, or for other reasons withdraws from the
responsibility of keeping the study records, custody must be transferred to a person who will accept
the responsibility. The sponsor must be notified in writing of the name and address of the new
custodian. Under no circumstance shall the investigator relocate or dispose of any study documents
before having obtained written approval from the sponsor.
If it becomes necessary for the sponsor or the appropriate regulatory authority to review any
documentation relating to this study, the investigator/institution must permit access to such reports.
STUDY AND SITE START AND CLOSURE
First Act of Recruitment
The first site open is considered the first act of recruitment and it becomes the study start date.
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Study Closure
The sponsor reserves the right to close the study site or close the study at any time for any reason
at the sole discretion of the sponsor, e.g. in case of unacceptable risk, intolerable toxicity, or change
in the risk/benefit profile; this might include recurrence of adverse events of which character,
severity, or frequency is new in comparison to the existing risk profile. Also, data derived from
other clinical trials or toxicology studies which negatively influence the risk/benefit assessment
might cause discontinuation or termination of the study. Study sites will be closed upon study
completion. A study site is considered closed when all required documents and study supplies have
been collected and a study-site closure visit has been performed.
The investigator may initiate study-site closure at any time, provided there is reasonable cause and
sufficient notice is given in advance of the intended termination.
Reasons for the early closure of a study site by the sponsor or investigator may include but are not
limited to:
 Failure of the investigator to comply with the protocol, the requirements of the IEC/IRB or
local health authorities, the sponsor's procedures, or GCP guidelines
 Inadequate recruitment of subjects by the investigator
 Discontinuation of further study drug development
The sponsor may close individual study cohorts if there is inadequate recruitment of subjects
within individual cohorts or within the overall study.
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10.3. Appendix 3: Adverse Events: Definitions and Procedures for Recording,
Evaluating, Follow-up, and Reporting
ADVERSE EVENT DEFINITIONS AND CLASSIFICATIONS
Adverse Event
An adverse event is any untoward medical occurrence in a clinical study subject administered a
medicinal (investigational or non-investigational) product. An adverse event does not necessarily
have a causal relationship with the study drug. An adverse event can therefore be any unfavorable
and unintended sign (including an abnormal finding), symptom, or disease temporally associated
with the use of a medicinal (investigational or non-investigational) product, whether or not related
to that medicinal (investigational or non-investigational) product. (Definition per International
Conference on Harmonisation [ICH])
This includes any occurrence that is new in onset or aggravated in severity or frequency from the
baseline condition, or abnormal results of diagnostic procedures, including laboratory test
abnormalities.
Note: The sponsor collects adverse events starting with the signing of the ICF (refer to All Adverse
Events under Section 8.4.1, Time Period and Frequency for Collecting Adverse Events and Serious
Adverse Events Information, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and EU Guidelines on Pharmacovigilance for Medicinal
Products for Human Use is any untoward medical occurrence that at any dose:
 
Results in death
 
Is life-threatening
(The subject was at risk of death at the time of the event. It does not refer to an event that
hypothetically might have caused death if it were more severe.)
 
Requires inpatient hospitalization or prolongation of existing hospitalization
 
Results in persistent or significant disability/incapacity
 
Is a congenital anomaly/birth defect
 
Is a suspected transmission of any infectious agent via a medicinal product
 
Is Medically Important*
*Medical and scientific judgment should be exercised in deciding whether expedited reporting is
also appropriate in other situations, such as important medical events that may not be immediately
life threatening or result in death or hospitalization but may jeopardize the subject or may require
intervention to prevent one of the other outcomes listed in the definition above. These should
usually be considered serious.
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Unlisted (Unexpected) Adverse Event/Reference Safety Information
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable
product reference safety information. For erdafitinib, the expectedness of an adverse event will be
determined by whether or not it is listed in the IB. For gemcitabine or MMC/hyperthermic MMC,
the expectedness of an adverse event will be determined by whether or not it is listed in the
applicable package insert or summary of product characteristics.
Assessment of Causality
The causal relationship to study treatment is determined by the investigator. The following
selection should be used to assess all adverse events.
Related
There is a reasonable causal relationship between study treatment administration and the adverse
event.
Not related
There is not a reasonable causal relationship between study treatment administration and the
adverse event.
The term "reasonable causal relationship" means there is evidence to support a causal relationship.
SEVERITY CRITERIA
Adverse event severity is a clinical determination of the intensity of an adverse event. The severity
assessment for an adverse event or serious adverse event should be completed using the NCI-
CTCAE, Version 5.0. Any adverse event or serious adverse event not listed in the NCI-CTCAE,
Version 5.0 will be graded according to the investigator clinical judgment by using the standard
grades as follows:
 
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 activities of daily living.
 
Grade 3: Severe or medically significant but not immediately life-threatening;
hospitalization or prolongation of hospitalization indicated; disabling; limiting self-care
activities of daily living.
 
Grade 4: Life-threatening consequences; urgent intervention indicated.
 
Grade 5: Death related to adverse event.
The investigator should use clinical judgment in assessing the severity of events not directly
experienced by the subject (eg, laboratory abnormalities).
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SPECIAL REPORTING SITUATIONS
Safety events of interest on a sponsor study drug in an interventional study  that may require
expedited reporting or safety evaluation include, but are not limited to:
 
Overdose of a sponsor study drug
 
Suspected abuse/misuse of a sponsor study drug
 
Accidental or occupational exposure to a sponsor study drug
 
Medication error involving a sponsor product (with or without subject/patient exposure to the
sponsor study drug, eg, name confusion)
 
Exposure to a sponsor study drug from breastfeeding
Special reporting situations should be recorded in the CRF. Any special reporting situation that
meets the criteria of a serious adverse event should be recorded on the serious adverse event page
of the CRF.
Any Grade 3 or higher treatment-emergent retinal abnormality should be reported as a serious
adverse event. Instructions for assessing vision abnormalities during the study are provided in
Section 6.6.2.1.5.
PROCEDURES
All Adverse Events
All adverse events, regardless of seriousness, severity, or presumed relationship to study drug,
must be recorded using medical terminology in the source document and the CRF. Whenever
possible, diagnoses should be given when signs and symptoms are due to a common etiology
(eg, cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper
respiratory infection"). Investigators must record in the CRF their opinion concerning the
relationship of the adverse event to study therapy. All measures required for adverse event
management must be recorded in the source document and reported according to sponsor
instructions.
For all studies with an outpatient phase, including open-label studies, the subject must be provided
with a "wallet (study) card" and instructed to carry this card with them for the duration of the study
indicating the following:
 
Study number
 
Statement, in the local language(s), that the subject is participating in a clinical study
 
Investigator's name and 24-hour contact telephone number
 
Local sponsor's name and 24-hour contact telephone number (for medical personnel only)
 
Site number
 
Subject number
 
Any other information that is required to do an emergency breaking of the blind
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Serious Adverse Events
All serious adverse events that have not resolved by the end of the study, or that have not resolved
upon discontinuation of the subject's participation in the study, must be followed until any of the
following occurs:
 
The event resolves
 
The event stabilizes
 
The event returns to baseline, if a baseline value/status is available
 
The event can be attributed to agents other than the study drug or to factors unrelated to study
conduct
 
It becomes unlikely that any additional information can be obtained (subject or health care
practitioner refusal to provide additional information, lost to follow-up after demonstration of
due diligence with follow-up efforts)
Suspected transmission of an infectious agent by a medicinal product will be reported as a serious
adverse event. Any event requiring hospitalization (or prolongation of hospitalization) that occurs
during a subject 's participation in a study must be reported as a serious adverse event, except
hospitalizations for the following:
 
Hospitalizations not intended to treat an acute illness or adverse event (eg, social reasons such
as pending placement in long-term care facility).
 
Surgery or procedure planned before entry into the study (must be documented in the CRF).
 
A standard procedure for protocol therapy administration will not be reported as a serious
adverse event. (Hospitalization or prolonged hospitalization for a complication of therapy
administration will be reported as a serious adverse event).
 
Administration of blood or platelet transfusion. (Hospitalization or prolonged hospitalization
for a complication of such transfusion remains a reportable serious adverse event.)
 
Procedure for protocol/disease-related investigations (eg, surgery, scans, endoscopy,
sampling for laboratory tests, bone marrow sampling) (Hospitalization or prolonged
hospitalization for a complication of such procedures remains a reportable serious adverse
event).
 
Prolonged hospitalization for technical, practical, or social reasons, in absence of an adverse
event.
 
Planned procedures (ie, planned prior to starting of treatment on study; must be documented
in the eCRF). (Prolonged hospitalization for a complication considered to be at least possibly
related to the study drug remains a reportable serious adverse event.)
Expected progression of disease should not be considered an adverse event (or serious adverse
event). However, if determined by the investigator to be more likely related to the study treatment
than the underlying disease, the treatment-invoked progression (ie the treatment-invoked
signs/symptoms of such progression) , should be reported per the usual reporting requirements.
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Death that is attributed by the investigator explicitly to progression of disease should not be
considered nor reported as an AE (or SAE). However, if determined by the investigator to be more
likely related to the study treatment than being expected from the underlying disease, the
treatment-invoked death due to progression should be reported per the usual reporting
requirements (refer to Adverse Event Definitions and Classifications: Adverse Events: Definitions
and Procedures for Recording, Evaluating, Follow-up, and Reporting).
Progression of disease and death due to disease progression should be documented on the
appropriate eCRF forms (eg, the Disease Progression form and the Death form).
Signs or symptoms of disease progression that are of clinical significance, such as spinal cord
compression, vena cava superior syndrome, major vessel rupture, efflux obstruction or organ
failure, should be documented on the appropriate eCRF forms (eg, the Clinical Progression form).
CONTACTING SPONSOR REGARDING SAFETY
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding safety issues or questions regarding the study are listed in the Contact Information
page(s), which will be provided as a separate document.
PRODUCT QUALITY COMPLAINT HANDLING
A product quality complaint (PQC) is defined as any suspicion of a product defect related to
manufacturing, labeling, or packaging, ie, any dissatisfaction relative to the identity, quality,
durability, or reliability of a product, including its labeling or package integrity. A PQC may have
an impact on the safety and efficacy of the product. Timely, accurate, and complete reporting and
analysis of PQC information from studies are crucial for the protection of subjects, investigators,
and the sponsor, and are mandated by regulatory agencies worldwide. The sponsor has established
procedures in conformity with regulatory requirements worldwide to ensure appropriate reporting
of PQC information; all studies conducted by the sponsor or its affiliates will be conducted in
accordance with those procedures.
Procedures
All initial PQCs must be reported to the sponsor by the study-site personnel within 24 hours after
being made aware of the event.
If the defect is combined with a serious adverse event, the study-site personnel must report the
PQC to the sponsor according to the serious adverse event reporting timelines (refer to
Section 8.4.1, Time Period and Frequency for Collecting Adverse Event and Serious Adverse
Event Information). A sample of the suspected product should be maintained for further
investigation if requested by the sponsor.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted
regarding product quality issues are listed in the Contact Information page(s), which will be
provided as a separate document.
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10.4. Appendix 4: Contraceptive and Barrier Guidance and Collection of
Pregnancy Information
Subjects must follow contraceptive measures as outlined in Section 5.1, Inclusion Criteria.
Pregnancy information will be collected and reported as noted in Section 8.4.5, Pregnancy and
Section 10.3 Adverse Events: Definitions and Procedures for Recording, Evaluating, Follow-up,
and Reporting.
Definitions
Woman of Childbearing Potential (WOCBP)
A woman is considered fertile following menarche and until becoming postmenopausal unless
permanently sterile (see below).
Woman Not of Childbearing Potential
 
premenarchal
A premenarchal state is one in which menarche has not yet occurred.
 
postmenopausal
A postmenopausal state is defined as no menses for 12 months without an alternative medical
cause. A high follicle stimulating hormone (FSH) level (>40 IU/L or mIU/mL) in the
postmenopausal range may be used to confirm a postmenopausal state in women not using
hormonal contraception or hormonal replacement therapy (HRT), however in the absence of
12 months 
of 
amenorrhea, 
a 
single 
FSH 
measurement 
is 
insufficient.
If there is a question about menopausal status in women on HRT, the woman will be required
to use one of the non-estrogen-containing hormonal highly effective contraceptive methods if
she wishes to continue HRT during the study.
 
permanently sterile
Permanent sterilization methods for the purpose of this study include hysterectomy, bilateral
salpingectomy, and bilateral oophorectomy.
Note: If the childbearing potential changes after start of the study (eg, a premenarchal woman
experiences menarche) or the risk of pregnancy changes (eg, a woman who is not heterosexually
active becomes active), a woman must begin a highly effective method of contraception, as
described throughout the inclusion criteria.
If reproductive status is questionable, additional evaluation should be considered.
Contraceptive (birth control) use by men or women should be consistent with local regulations
regarding the acceptable methods of contraception for those participating in clinical studies.
Typical use failure rates may differ from those when used consistently and correctly. Use should
be consistent with local regulations regarding the use of contraceptive methods for subjects in
clinical studies.
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Examples of Contraceptives
EXAMPLES OF CONTRACEPTIVESa ALLOWED DURING THE STUDYINCLUDE:
USER INDEPENDENT
Highly Effective Methods That Are User Independent Failure rate of <1% per year when used
consistently and correctly.
 Implantable progestogen-only hormone contraception associated with inhibition of ovulationb
 Intrauterine device
 Intrauterine hormone-releasing system
 Bilateral tubal occlusion
 Vasectomized partner
(Vasectomized partner is a highly effective contraceptive method provided that the partner is the
sole sexual partner ofthe woman of childbearing potential and the absence of sperm has been
confirmed. If not, additional highly effective method of contraception should be used.
Spermatogenesis cycle is approximately 74days.)
USER DEPENDENT
Highly Effective Methods That Are User Dependent Failure rate of <1% per year when used
consistently and correctly.
 Combined (estrogen- and progestogen-containing) hormonal contraception associated with
inhibition of ovulationb
oral
intravaginal
transdermal
injectable
 Progestogen-only hormone contraception associated with inhibition of ovulationb
oral
injectable
 Sexual abstinence
(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 drug. The
reliability of sexual abstinence needs to be evaluated in relation to the duration of the study and
the preferred and usual lifestyle of the subject.)
NOT ALLOWED AS SOLE METHOD OF CONTRACEPTION DURING THE STUDY (not
considered to be highly effective - failure rate of 1% per year)
 Progestogen-only oral hormonal contraception where inhibition of ovulation is not the primary
mode of action.
 Male or female condom with or without spermicidec
 Cap, diaphragm, or sponge with spermicide
 A combination of male condom with either cap, diaphragm, or sponge with spermicide (double-
barrier methods)c
 Periodic abstinence (calendar, symptothermal, post-ovulation methods)
 Withdrawal (coitus-interruptus)
 Spermicides alone
 Lactational amenorrhea method (LAM)
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a) Typical use failure rates may differ from those when used consistently and correctly. Use should be
consistent with local regulations regarding the use of contraceptive methods for subjects in clinical
studies.
b) Hormonal contraception may be susceptible to interaction with the study drug, which may reduce
the efficacy of the contraceptive method. In addition, consider if the hormonal contraception may
interact with the study drug.
c) Male condom and female condom should not be used together (due to risk of failure with friction).
Pregnancy During the Study
All initial reports of pregnancy in female subjects or partners of male subjects must be reported to
the sponsor by the study-site personnel within 24 hours of their knowledge of the event using the
appropriate pregnancy notification form. Abnormal pregnancy outcomes (eg, spontaneous
abortion, fetal death, stillbirth, congenital anomalies, ectopic pregnancy) are considered serious
adverse events and must be reported using the Serious Adverse Event Form. If a subject becomes
pregnant during the study, the investigator should discuss discontinuation of study drug for the
subject with the sponsor’s medical monitor.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects
included in the study will be reported as noted above.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the
infant will be requested. Follow-up information may continue to be collected up to 12 months after
the birth of a baby, if a congenital anomaly or significant medical condition is diagnosed at birth.
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10.5. Appendix 5: ECOG Performance Status Scale
Grade 
ECOG Performance Status Grade
0 
Fully active, able to carry on all pre-disease performance without restriction
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work
of a light or sedentary nature, eg, light house work, office work
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities. Up
and about more than 50% of waking hours
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking
hours
4 
Completely disabled. Cannot carry on any selfcare. Totally confined to bed or chair
5 
Dead
Reference: Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern Cooperative
Oncology Group. Am J Clin Oncol. 1982;596:649-655.
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10.6. Appendix 6: Estimated Creatinine Clearance
Cockcroft-Gault Formula
eCR = (140-Age) x Mass (Kilograms) x [0.85 if female]
                      72 x Serum Creatinine (in mg/dLl)
OR
eCcr = (140-Age) x Mass (Kilograms) x Constant
                     Serum Creatinine (in µmol/L)
Where Constant = 1.23 for males and 1.04 for females
Reference: http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/  Accessed 13 June 2019.
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10.7. Appendix 7: The Stages of Heart Failure –New York Heart Association
(NYHA) Classification
Class 
Patient Symptoms
Class I (Mild) 
No limitation of physical activity. Ordinary
physical activity does not cause undue fatigue,
palpitation, or dyspnea (shortness of breath)
.
Class II (Mild)
Slight limitation of physical activity.
Comfortable at rest, but ordinary physical
activity results in fatigue, palpitation, or
dyspnea.
Class III
(Moderate)
Marked limitation of physical activity.
Comfortable at rest, but less than ordinary
activity causes fatigue, palpitation, or dyspnea.
Class IV 
(Severe) 
Unable to carry out any physical activity
without discomfort. Symptoms of cardiac
insufficiency at rest. If any physical activity is
undertaken, discomfort is increased.
Reference: Heart Failure Society of America The Stages of Heart Failure –NYHA Classification. Available at
http://www.abouthf.org/questions_stages.html. Accessed October 6, 2008.
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10.8. Appendix 8: Amsler Grid
Subject No.:
Date:
Examiner:
*Note: Please utilize the Amsler Recording Chart that is provided with your study materials.
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10.9. Appendix 9: Drugs Classified as Strong In Vivo Inhibitors of CYP3A4/2C9
or as Moderate to Strong Inducers of CYP3A4/2C9 Enzymes
Strong CYP3A4 Inhibitors
Boceprevir 
Conivaptan
Clarithromycin  
Indinavir
Lopinavir 
Itraconazole
Mibefradil 
Ketoconazole
Nefazodone 
Ritonavir
Posaconazole 
Nelfinavir
Saquinavir 
Erythromycin
Telaprevir 
Troleandomycin
Telithromycin  
Fluconazole
Voriconazole
Strong Inhibitors: ≥5-fold increase in AUC or ≥80% decrease in CL.
Moderate to Strong CYP3A4 Inducers
Moderate CYP3A4 Inducers
Bosentan  
Efavirenz
Etravirine 
Modafinil
Nafcillin  
Lersivirine
Talviraline 
Tipranavir
Lopinavir
Strong CYP3A Inducers
Avasimibe 
Carbamazepine
Barbiturates eg, phenobarbital 
Phenytoin
Rifabutin  
Rifampin
St. John’s wort 
Mitotane
Enzalutamide 
Apalutamide
Strong Inducers: ≥80% decrease in area under the curve (AUC). Moderate Inducers: 50% to 80% decrease in AUC.
Moderate CYP2C9 Inhibitors
Fluconazole 
Amiodarone
Miconazole 
Piperine
Oxandrolone 
Atacigual
Tienilic acid 
Azapropazone
Bucolome 
Sulfaphenazole
Benzbromarone
Moderate CYP2C9 Inducers
Carbamazepine 
Rifampin
Enzalutamide 
Aprepitant
Reference:  University of Washington’s Drug Interaction Database
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664.htm#4
Note: Both these references may not be exhaustive and up-to-date at any given time. Please consult the product
information of ongoing and new concomitant medications for the most accurate information on potential moderate
to strong inhibitors or inducers of CYP3A4 and CYP2C9.
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10.10. Appendix 10: Erdafitinib Crossover
Note: no additional crossover from Investigator’s Choice to erdafitinib will be permitted.
Subjects who have already crossed over to erdafitinib may continue to receive study
treatment and transition to the LTE Phase (please refer to Section 10.14, Appendix 14).
This appendix is intended as a supplement to the main study protocol to describe the eligibility
criteria, treatment schedule, and assessments to be conducted during the Erdafitinib Crossover for
subjects in Cohort 1 who have locally confirmed high-risk recurrence and who were randomized
to Investigator’s Choice with either intravesical gemcitabine or intravesical MMC/hyperthermic
MMC. The appendix is not intended to be a stand-alone document, and rather than repeating key
sections of the main protocol, cross-references back to the main protocol have been included, as
applicable.
Subjects who were randomized in Cohort 1 to either gemcitabine or MMC/hyperthermic MMC,
who have locally confirmed high-risk recurrence, recommendation by the investigator, and review
by the sponsor’s medical monitor, will be offered the option to cross over to erdafitinib, beginning
with C1D1 and a more limited Schedule of Activities.
Overall Design of the Erdafitinib Crossover
Each cycle is 28 days, and administration of erdafitinib is to occur daily for up to a maximum of
2 years or until high risk disease recurrence or progression, intolerable toxicity, withdrawal of
consent, there is a decision by the investigator to discontinue treatment, or the study is closed,
whichever occurs first. Scheduled assessments to be performed for eligibility and treatment during
the Erdafitinib Crossover are outlined in the Schedule of Activities in CO Table 1.
The amount of blood drawn from each subject during the Erdafitinib Crossover will be
approximately 24 mL during screening; 241 mL through Cycle 6; 288 mL from Cycle 6 through
Cycle 24; 37 mL at the EoT Visit, 12 mL during the safety follow-up, and 80 mL for subjects who
have disease assessments after recurrence/progression during the Follow-up Phase for a total
volume of 682 mL.
Erdafitinib Up-titration Guidelines for Crossover Subjects
The erdafitinib dose is modified to the 6-mg daily regimen (without up-titration). After review of
safety and tolerability data from approximately 5 to 10 additional subjects who received the 6-mg
daily regimen, the IDMC may recommend that the erdafitinib dose be modified to allow
up-titration to the 8-mg daily regimen. Details of any such recommendation will be communicated
separately. Should the dosing regimen be modified to include up-titration, please follow the
instruction in Section 10.12, Appendix 12.
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NOTES
Screening
Phase
(Must begin within 60 days of
recurrence)
Treatment Phase (28 days Cycle) 
Follow-up Phase
Cycles 1, 2, 3 
Cycle 4+ 
EoT  
Visit 
30-day 
Safety 
Follow-up 
Visit 
Disease
Assessmen
t
Follow-up
Survival
Follow-up
Day 1 
Day 14 
Day1 
Visit window  
- 35 days
C1:0 days 
C2, C3: ± 2 
days 
±2
days
±2 days 
+7 days 
after last 
dose 
30 (+7) days 
after last 
dose 
Every 24
weeks
±2 weeks
Every 12 ±2
weeks
cytology is positive for malignant cells
and cystoscopy is negative.
Urine cytology
Urine sample may be collected either
from bladder washing during
cystoscopy or from a voided urine
specimen (bladder wash specimen is
preferred). Analysis will be done locally
(see Section 8.2.1).
X
C3D1 then every 12 weeks (±1 week)
until C26D1 or until disease recurrence
or progression.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
CT/MRI Urogram  
If a subject cannot tolerate intravenous
contrast, a retrograde pyelogram is
acceptable (see Section 8.2.1).
X
Starting from Cycle 6, every 24 weeks (±2weeks) until
recurrence/progression.
Blood (plasma) for ctDNA  
See Section 8.9.
C1D1 (predose), C3D1, then every 12
weeks (±1 week) until C26D1 or until
disease recurrence or progression.
X
X
For 2 years
or until
disease
recurrence/
progression
(see Section
8.1.3.2.1)
Survival status and 
subsequent anticancer 
therapy 
May be assessed via telephone call,
email, or visit to the study site. Survival
status, start of alternate anticancer
therapy, and results of standard-of-
care cystoscopy will be monitored at
least every 12 weeks (±2 weeks) until
death, withdrawal of consent, or end of
study, whichever occurs first. See
Section 8.1.3.2.2.
X
β-hCG= beta-human chorionic gonadotropin; C=cycle; CT=computed tomography; ctDNA=circulating tumor DNA; CXDX=Cycle X Day X; D=day; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology
Group; EoT=End of Treatment; ICF=informed consent form; IDMC= Independent Data Monitoring Committee; MRI=magnetic resonance imaging
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Eligibility Criteria for Erdafitinib Crossover
To be eligible for cross over to treatment with erdafitinib, subjects in Cohort 1 randomized to
Investigator’s Choice with gemcitabine or MMC/hyperthermic MMC  must meet all of the
following inclusion and none of the exclusion criteria.
Inclusion Criteria for Erdafitinib Crossover
Each potential subject must satisfy all of the following inclusion criteria before beginning
Erdafitinib Crossover.
1. 
Eastern Cooperative Oncology Group (ECOG) performance status Grade 0 or 1
(Section 10.5)
2. 
Criterion modified per Amendment 2
2.1  Adequate bone marrow, liver, and renal function:
a. Bone marrow function (without the support of cytokines or erythropoiesis-stimulating
agent in preceding 2 weeks):
i.  Absolute neutrophil count (ANC) ≥1,000/mm3
ii.  Platelet count ≥75,000/mm3
iii.  Hemoglobin ≥8.0 g/dL
b. Liver function:
i.  Total bilirubin ≤1.5 x institutional ULN OR direct bilirubin ≤ULN for subjects
with total bilirubin levels >1.5xULN
ii.  Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5x
institutional ULN
c.Renal function:
Creatinine clearance >30 mL/min calculated using the Cockcroft-Gault formula,
(Section 10.6).
d. Phosphate:
<ULN within 14 days before the first dose of study drug on Cycle 1 Day 1
(medical management allowed)
3. 
Must sign an ICF (or their legally acceptable representative must sign)within 60 days of
recurrence indicating that he or she understands the purpose of, and procedures required
and is willing to participate in the Erdafitinib Crossover.
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4. 
A woman of childbearing potential must have a negative pregnancy test (β-hCG) (urine
or serum) within 7 days before first dose of erdafitinib in the Erdafitinib Crossover.
5. 
Contraceptive use by men or women should be consistent with local regulations regarding
the use of contraceptive methods for subjects participating in clinical studies.
a.  For women of childbearing potential (defined as: fertile, following menarche and until
becoming postmenopausal unless permanently sterile):
 
Highly effective method of contraception (failure rate of <1% per year when used
consistently and correctly).
 
Permanent sterilization methods (for the purposes of this study) include
hysterectomy, bilateral salpingectomy, and bilateral oophorectomy).
 
Examples of highly effective contraceptives include:
 
user-independent 
methods: 
implantable 
progestogen-only 
hormone
contraception associated with inhibition of ovulation; intrauterine device;
intrauterine hormone-releasing system; vasectomized partner; sexual
abstinence: true abstinence when this is in line with the preferred and usual
lifestyle of the subject (Note: periodic abstinence [eg, calendar, ovulation,
symptothermal, post-ovulation methods], declaration of abstinence for the
duration of exposure to study drug, and withdrawal are not acceptable methods
of contraception.)
 
user-dependent methods: combined (estrogen- and progestogen-containing)
hormonal contraception associated with inhibition of ovulation: oral,
intravaginal, and transdermal; progestogen-only hormone contraception
associated with inhibition of ovulation: oral and injectable
 
agrees to remain on a highly effective method of contraception during the study and
for at least 3 months after the last dose of study drug
 
agrees to not donate eggs (ova, oocytes) for the purposes of assisted reproduction
during the study and for at least 3 months after the last dose of study drug
 
not breastfeeding and not planning to become pregnant during the study and for at
least 3 months after the last dose of study drug
b. For men who are sexually active with women of childbearing potential:
 
agrees to use a condom with spermicidal foam/gel/film/cream/suppository
 
agrees to not donate sperm during the study and for at least 3 months after the last
dose ofstudy drug
 
not planning to father a child during the study or within 3 months after the last dose
of study drug
6. 
Criterion added per Amendment 1.
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Status: Approved, Date: 13 July 2023
Locally confirmed high-risk recurrence while receiving Investigator’s Choice, and the
subject has all visible tumor resected completely prior to enrollment and documented at
baseline cystoscopy
Exclusion Criteria for Erdafitinib Crossover
Any individual who meets any of the following criteria will be excluded from participating in the
Erdafitinib Crossover:
1. 
Histologically confirmed, muscle-invasive (T2 or higher stage) urothelial carcinoma of
the bladder
2. 
Histopathology demonstrating a small cell component, pure adenocarcinoma, pure
squamous cell carcinoma, or pure squamous CIS of the bladder
3. 
Active malignancies (ie, progressing or requiring treatment change in the last
24 months) other than the disease being treated under study. The only allowed
exceptions are:
a. skin cancer treated within the last 24 months that is considered completely cured
b. adequately treated LCIS and ductal CIS
c. history of localized breast cancer and receiving antihormonal agents, or history
of localized prostate cancer (N0M0) and receiving androgen deprivation therapy
4. 
Current central serous retinopathy or retinal pigment epithelial detachment of any grade
5. 
History of uncontrolled cardiovascular disease including:
a.any of the following in the preceding 3 months: unstable angina, myocardial
infarction, ventricular fibrillation, Torsades de Pointes, cardiac arrest, or known
congestive New York Heart Association Class III-IV heart failure (Section 10.7),
cerebrovascular accident, or transient ischemic attack.
b.QTc prolongation as confirmed by ECG assessment at screening (Fridericia; QTc
>480 milliseconds).
c.Pulmonary embolism or other venous thromboembolism within the preceding 2
months.
6. 
Criterion modified by Amendment 1.
6.1. Known HIV infection, unless the subject has been on a stable anti-retroviral therapy
regimen for the last 6 months or more and has had no opportunistic infections and a
CD4 count >350 in the last 6 months
7. 
Criterion modified by Amendment 1.
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Status: Approved, Date: 13 July 2023
7.1. Evidence of active hepatitis B or C infection (for example, subjects with history of
hepatitis C infection but normal hepatitis C virus polymerase chain reaction test and
subjects with hepatitis B with positive HBsAg antibody are allowed).
8. 
Not recovered from toxicity of prior anticancer therapy (except toxicities which are not
clinically significant such as alopecia, skin discoloration, neuropathy, hearing loss)
9. 
Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers,
known gastric ulcers, or unhealed incisions
10. 
Major surgery within 4 weeks before Cycle 1 Day 1 of erdafitinib treatment (TURBT
is not considered major surgery)
11. 
Criterion modified per Amendment 2
11.1 Severe hypocalcemia (corrected serum calcium of <7 mg/dl), acute and unhealed
bone fractures, known underlying bone disease, or at an increased risk of bone fracture.
In addition, any condition for which, in the opinion of the investigator, participation
would not be in the best interest of the subjects (eg, compromise the well-being) or that
could prevent, limit, or confound the protocol-specified assessments. Examples include
ongoing active infection requiring systemic therapy and uncontrolled ongoing medical
conditions.
12. 
12.1 Criterion deleted with Amendment 3
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Status: Approved, Date: 13 July 2023
10.12. Appendix 12: Guidance for 6 mg Daily Dose with Up-titration
DO NOT FOLLOW THIS GUIDANCE UNLESS SPECIFICALLY INSTRUCTED TO DO SO
BY THE SPONSOR. After review of safety and tolerability data from approximately 5 to 10
additional subjects who received the 6 mg daily dosing regimen, the IDMC may recommend a
dose modification to up-titrate from 6 mg to 8 mg daily based on phosphate levels at Cycle 2
Day 1. The details of the IDMC recommendation will be communicated in writing to the
investigative sites and, per local regulation, to health authorities. The pharmacodynamic biomarker
(serum phosphate) data considered in selection of the 6-mg daily starting dose (with up-titration
to 8-mg daily) are summarized below.
Data supporting Up-titration to the 8-mg Daily Dosing Regimen
Data from Phase 1 Study 42756493EDI1001 indicate that an increase in the serum phosphate level
of at least 35% over the baseline level may be associated with antitumor response. Therefore, a
pharmacodynamic (PD) objective of a 50% increase in the serum phosphate level over baseline is
considered clinically meaningful. Given the median serum phosphate level of 3.6 mg/dL at
baseline in the Phase 1 study, and the phosphate level of 3.3 mg/dL at baseline in the Phase 2 Study
BLC2001 (BLC2001 Interim Analysis 1 data), an increase of at least 50% for the majority of
subjects would correspond to an absolute serum phosphate level of approximately 5.5 mg/dL
(which is also 35% over the upper limit of normal [ULN] for serum phosphate). Overall, 6 mg is
the lowest sustained dose that achieves, in 77.8% of subjects in the Phase 1 study,
hyperphosphatemia consistent with a biologically significant inhibition of FGFR. Emerging
pharmacokinetic/pharmacodynamic modeling suggests that 
and would potentially benefit from dose up-titration.
Guidelines for Dose Titration of Erdafitinib from 6-mg Daily to 8-mg Daily Regimen
Erdafitinib treatment may be up-titrated or maintained based on the phosphate level measured on
Cycle 2 Day 1 taking into account any toxicity to that day, as described in in the figure below. The
dose reduction schedule is provided in the table on the following page.
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Status: Approved, Date: 13 July 2023
Appendix 12, Figure 1: Dose Titration of Erdafitinib from 6-mg to 8-mg Daily Regimen
Appendix 12, Table 1: Dose Schedule and Dose Reductions - 6 mg Daily Dosing (with Up-titration)
Category 
With Up-titration
Starting dose 
6 mg
Up-titration  
8 mg
1st dose reduction 
6 mg
2nd dose reduction  
5 mg
3rd dose reduction 
4 mg
4th dose reduction 
STOP
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JNJ-42756493 (erdafitinib)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
10.13. Appendix 13: Guidance on Study Conduct During a National Disaster for
Enrolled Subjects
It is recognized that a national disaster, eg, pandemic, may have an impact on the conduct of this
clinical study. In alignment with the recent health authority guidances, the Sponsor is providing
guidance for study-related patient management in the event of disruption to the per-protocol
conduct of the study as outlined throughout the protocol. These measures are to be followed on a
temporary basis. Once the national situation allows, the usual study conduct methods will resume.
This guidance does not supersede any local or government requirements or the clinical judgement
of the Investigator to protect the health and well-being of patients and site staff. If at any time a
subject’s safety is considered to be at risk, study drug will be discontinued, and study follow-up
will be conducted, as outlined in the protocol. (Note: These measures do not apply to subjects who
have not initiated study treatment.)
Scheduled visits for safety monitoring and other protocol-required assessments that cannot be
conducted in-person will be performed remotely/virtually (eg, telephone contact, telemedicine,
remote nursing, remote administration of study drug), where feasible, or delayed until the time at
which access is determined to be appropriate by the Investigator and Sponsor. Study assessments
requiring investigator judgement, should be conducted by the investigator. At each contact,
subjects will be interviewed to collect adverse events data and any changes to concomitant
medications. Subjects will also be questioned regarding general health status to fulfill the physical
examination requirement.
Flexibility for all protocol-required assessments will be provided on a case by case basis, and with
agreement between the Sponsor and Investigator. However, every effort should be made to adhere
to protocol-specified assessments, including follow-up, if it is in the best interest of the subject.
The Sponsor will continue to monitor the conduct and progress of the clinical study and any
changes (eg, delay or discontinuation in recruitment) will be communicated to the sites and health
authorities.
Guidance specific to this protocol:
 
Missed assessments or change to protocol assessments will be documented in the source
documentation and in the case report form. All study conduct performed outside of the
protocol should be documented in the source documentation.
 
If a site visit is not feasible, the Investigator may discuss with the Sponsor other mechanisms
for the subject to receive study drug (eg, direct to patient shipment, obtain from another
Investigative Site participating in the study).  Any change in dispensing study drug must be
documented in the source documentation and eCRF.
 
Safety assessments may be conducted at a local facility after discussion with the Sponsor.
 
Critical laboratory tests, imaging or other diagnostic tests may be done at an
authorized/certified (as legally required nationally) local laboratory or clinical facility. A copy
of the laboratory report must be reviewed by the Investigator and retained, along with the
reference ranges, for the source documentation and provided with the eCRF.
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Clinical Protocol 42756493BLC2003 –Amendment 6
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Status: Approved, Date: 13 July 2023
 
Consenting of subjects for full-study screening and for molecular eligibility screening will be
performed as applicable (including also remote consenting by telephone or video consultation)
according to local guidance for the informed consent.
Note: Administration of non-live vaccines approved or authorized for emergency use (eg, COVID-
19) by local health authorities are allowed before or during this study. For guidance on vaccination,
please refer to National Comprehensive Cancer Network (NCCN). Preliminary recommendations
of the NCCN COVID-19 Vaccination Advisory Committee* Version 1.0 1/22/2021. NCCN
https://www.nccn.org/covid-19/pdf/COVID-19_Vaccination_Guidance_V1.0.pdf 
(2021),
Garassino, M. C. et al. The European Society for Medical Oncology call to action on COVID-19
vaccinations and patients with cancer: Vaccinate. Monitor. Educate. Ann. Oncol.
https://doi.org/10.1016/j.annonc.2021.01.068 (2021), and Desai et al COVID-19 vaccine guidance
for patients with cancer participating in oncology clinical trials Nature Reviews Vol18; 313
https://doi.org/10.1038/s41571-021-00487-z.
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
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Status: Approved, Date: 13 July 2023
10.14. Appendix 14: Long-term Extension Phase
The purpose of the Long-term Extension (LTE) Phase is to provide continued access to study drug,
while minimizing data collection burden. Subjects who are continuing to derive benefit from
erdafitinib or Investigator’s Choice of either intravesical gemcitabine or intravesical
MMC/hyperthermic MMC, as determined by their investigator, may have continued access to their
assigned study drug in the LTE Phase of this study (see Section 6.7). Note:
 
Subjects must be actively receiving study treatment to be able to transition to the LTE Phase.
Subjects who have already permanently discontinued treatment will not be permitted to enter
the LTE Phase.
 
Subjects eligible to enter the LTE Phase will continue to receive the study drug that they were
receiving at the time of Amendment 6 implementation; no additional crossover from
Investigator’s Choice to erdafitinib will be permitted (including in the LTE Phase).
 
Subjects who elect not to continue in the LTE Phase will be discontinued from the study.
As an alternative to entering the LTE Phase, subjects receiving erdafitinib may continue to receive
treatment on any other post-trial access program, when permitted by local regulations, or by
receiving commercially available drug.
Subjects may enter the LTE Phase following implementationof Amendment 6, provided they meet
the criteria for entry. LTE Figure 1 is a decision tree which depicts transition to the LTE Phase at
the individual subject level, according to the following factors: whether the subject has
experienced high-risk disease recurrence or progression at any point since the start of protocol
therapy, whether 18 or more months have elapsed since the subject received their first dose of
study drug (ie, Cycle 1 Day 1), and whether the subject is actively receiving study drug.
No data will be collected in the eCRF during the LTE Phase, and only SAEs will be reported to
the company safety repository. No analyses other than routine periodic safety review
encompassing reported SAEs are planned for the LTE Phase.
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Status: Approved, Date: 13 July 2023
LTE Figure 1: Decision Tree for Transition to LTE Phase
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Status: Approved, Date: 13 July 2023
10.15. Appendix 15: Protocol Amendment History
The Protocol Amendment Summary of Changes Table for the current amendment is located
directly before the Table of Contents (TOC).
Amendment 5 (24 September 2021)
Overall Rationale for the Amendment: A 
 utilizing
 is under development. The collection of an additional urine sample after disease
recurrence and before the TURBT, and another urine sample before the TURBT procedure at the
End of Treatment Visit were added to aid the
.
Section Number 
and Name
Description of Change 
Brief Rationale
1.3, 
Schedule 
of
Activities;
4.1, Overall Design;
8.1.1, Screening;
8.9, Biomarkers;
10.2, 
Regulatory,
Ethical, and Study
Oversight
Considerations
In the Schedule of Activities (under the new
“Voided urine sample for
” row)
and Section 8.9 (under the new subheader “Urine for
 (ie, for biomarker research)”),
instruction regarding collection of 2 voided urine
samples was added: one sample will be collected
after disease recurrence and before the TURBT
(except for patients being considered for study after
TURBT) and another sample will be collected at the
time of high-risk disease recurrence before the
TURBT procedure at the End of Treatment Visit. In
the Schedule of Activities added in the notes that the
pre-study urine samples for subjects who are found
to have low or intermediate risk disease recurrence
(except for eligible Cohort 3 subjects) must be
discarded as these patients would not be eligible for
the study. Also, an additional row for the “Urine
Sample for Assay Development ICF” was added to
the Schedule of Activities.
In section 4.1, added that subjects being considered
for the study before the TURBT, will provide a
voided urine sample after disease recurrence and
before TURBT. These subjects must sign the
Informed Consent Form (ICF) for Urine Sample for
Assay Development. Subjects being considered for
study after TURBT will not provide this urine
sample Also, mentioned at the end of the overview
that additional urine samples will be collected for
assay development.
The consent for the urine sample before screening is
added to Section 8.1.1 and Section 10.2 (Informed
Consent Process subheader).
In Section 8.9, the instrumented urine sample was
changed to voided urine sample.
The collection of 2 additional urine
samples, as described under the
“Description of Change” were
added to aid the
1.3, Schedule of
Activities;
4.1, Overall Design;
8.9, Biomarkers
In the Schedule of Activities, the row “Urine for
 was expanded to add “(ie,
for biomarker research”) and in the notes of this row
 
 was replaced with
Revisions were made to distinguish
urine 
samples 
for 
biomarker
research from urine samples for
assay development.
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section Number 
and Name
Description of Change 
Brief Rationale
“biomarker research” (as well as in the text of
Section 8.9).
In Section 4.1, mentioned that additional urine
samples may be collected for exploratory biomarker
research (these are not new samples, already listed
on the Schedule of Activities).
In Section 8.9, the subsection title
 From Urine” was revised to “Urine for
 
 (ie, for Biomarker
Research)” and information related to the
 was moved to the new subjection titled
“Urine for Assay Development” described earlier in
this amendment table. As, a voided sample will be
collected rather than an instrumented urine sample
this notation was also made. Mentioned the urine
sample collected at the time of high-risk disease
recurrence before the TURBT procedure during the
study treatment phase. (This is not a new sample, ie,
previously shown on the Schedule of Activities.)
8.1.1.1, Molecular 
Eligibility Screening 
Phase (Cohort 1 and 
Cohort 2); 
8.9, Biomarkers 
Under the “Post-BCG Tissue Molecular Screening” 
subsection, removed the mention of signing the
Molecular Eligibility ICF, as this is not required for
patients for whom molecular eligibility was
determined based on a local (historical) report.
In 
Section 
8.9 
(“Circulating 
Biomarkers”
subsection), corrected the Phase 2 study number (ie,
42756493BLC2001).
Corrections
6.6.2.1.5, Guidelines 
for the Management 
of Eye Toxicity 
Associated with 
Vision Changes; 
8.4.7, Adverse 
Events of Special 
Interest; 
10.3 Appendix 3 
Adverse Events: 
Definitions and 
Procedures for 
Recording, 
Evaluating, Follow- 
up, and Reporting 
In Section 8.4.7, corneal or retinal abnormalities 
were removed as adverse events of special interest, 
as the adverse event of special interest is the 
combined term Central Serous Retinopathy. 
In Section 6.6.2.1.5, information regarding the 
adverse event of special interest and the special 
reporting requirement was removed as not 
applicable to this section. 
The reporting requirement for treatment-emergent 
retinal abnormalities (ie, Grade 3 or higher reported 
as a serious adverse event) was placed in        
Section 10.3, under Special Reporting Situations. 
Also, a reference to instructions for assessing visual 
abnormalities with a reference to the applicable
section was added. The special reporting
requirement was removed from Section 8.4.7.
The adverse event of special interest
(AESI) termed “Corneal or retinal
abnormalities” was replaced with
the AESI term “central serous
retinopathy”. Retinal toxicities have
been characterized as an adverse
AESI in the Erdafitinib Clinical
Development 
Program. 
Central
serous retinopathy is an umbrella
term 
being 
used 
to 
capture
treatment-emergent 
retinal
toxicities. 
However, 
retinal
abnormalities should continue to be
reported as serious adverse events if
the severity is Grade 3 or higher.
6.1.1, Erdafitinib 
Guidance for subjects with CYP2C9 *3/*3 genotype 
added. 
To provide guidance for subjects
with CYP2C9 *3/*3 genotype
6.5.3 Precautions for 
Concomitant 
Medications 
Edited precaution language in the first bullet for 
consistency with current Investigator Brochure. 
Guidance for use with CYP3A4 substrates and
OCT2 substrates added.
Aligned with updates to the current
Investigator’s Brochure.
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Status: Approved, Date: 13 July 2023
Section Number 
and Name
Description of Change 
Brief Rationale
6.5.1 Permitted 
Medications 
Text added relating to coronavirus disease 2019 
(COVID-19) vaccination. 
Guidance added relating to COVID-
19 vaccination.
6.6.2.1.2 Guidelines 
for the Management 
of Dry Mouth and 
Mucositis;
6.6.2.1.3 Guidelines
for the Management
of Dry Skin and
Skin Toxicity;
6.6.2.1.4 Guidelines
for the Management
of Nail Toxicity
(Onycholysis,
Onychodystrophy,
and Paronychia);
6.6.2.1.5 Guidelines
for the Management
of Eye Toxicity
Associated With
Vision Changes
Minor edits were added throughout these tables. 
Harmonization of presentation of
toxicity 
management 
guidance
across the development program.
4.2.2, Participant 
Input Into Design  
Explanation of how the results of the study may be 
made available to participants. 
To comply with an update to the
company template.
10.2, Regulatory 
and Ethical 
Considerations
Addition of text relating to protocol clarification 
communications 
Per update to company protocol
template.
10.3 Appendix 3 
Regarding Adverse 
Events
Clarification of text regarding disease progression. 
Per update to company protocol
template.
10.13 Appendix 13: 
Guidance on Study 
Conduct During a
National Disaster
for Enrolled
Subjects
Guidance relating to administration of non-live 
vaccines added.
Per program-wide change.
1.3, Schedule of 
Activities; 
6.1.2, Investigator’s 
Choice of Treatment 
- Cohort 1 Only  
In the Schedule of Activities (under the 
“Investigator Choice” row) and in Section 6.1.2, 
provided instruction regarding additional induction 
and maintenance doses and the timing of pre-dose 
assessments, if >4 induction doses are given and the 
start of the monthly maintenance dose falls on Day 
8, Day 15, or Day 22 of subsequent cycles. 
Added 
information 
from 
the
clarification memorandum issued 30
July 2021. This memorandum
clarifies the flexibility of giving
additional 
induction 
and
maintenance doses and the timing of
the 
corresponding 
predose
assessments.
Synopsis; 
4.1, Overall Design  
In the Synopsis and Section 4, removed text 
regarding no application of electricity around the 
tumor. 
Removed text that is no longer
applicable, as tumors are now
excised per standard practice as
mentioned in an earlier amendment.
Throughout the 
protocol 
Minor grammatical, formatting, or spelling changes 
were made.
Minor errors were noted.
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Status: Approved, Date: 13 July 2023
Amendment 4 (08 February 2021)
Overall Rationale for the Amendment:The erdafitinib dose is modified to 6 mg daily to improve
tolerability while maintaining activity to prevent disease recurrence in the non-muscle invasive
bladder cancer (NMIBC) population. The Independent Data Monitoring Committee (IDMC) for
this study reviewed safety data for the first 4 subjects treated with erdafitinib and recommended
that the change in dosing to 6 mg daily be implemented effective immediately to prevent any new
or ongoing subjects from discontinuing study treatment prematurely due to intolerance to therapy.
Further, the IDMC plans to review safety and tolerability data from approximately 5 to 10
additional subjects treated with the erdafitinib 6-mg daily regimen (without up-titration) and with
at least 2 months of data after initiation of study drug to determine whether up-titration is feasible
in this population. The erdafitinib dose of 6 mg daily (with and without up-titration) has
demonstrated clinical activity with lower rates of Grades 3 and 4 drug-related treatment-emergent
adverse events (TEAEs), drug-related TEAEs leading to dose interruptions, and drug-related
TEAEs leading to discontinuation in subjects with advanced or metastatic urothelial carcinoma in
Study 42756493BLC2001 (hereafter referred to as Study BLC2001). Therefore, the lower dosing
regimen of 6 mg daily (without up-titration) may be better suited, with respect to the 
 for this patient population without advanced, life-threatening disease. Due to
the modification to the dose of erdafitinib, the drug-drug interaction (DDI) substudy was removed,
as it was designed specifically for the 8-mg dosing regimen.
Section Number 
and Name
Description of Change 
Brief Rationale
Synopsis,
Treatment
Groups and
Duration;
1.3 Schedule of
Activities;
2.2.2 Erdafitinib;
4.1 Overall
Design;
4.3.1 Erdafitinib
Dose Selection;
6.1.1,
Erdafitinib;
6.6.1 Erdafitinib
Up-titration
Guidelines;
Table 2;
Appendix 10:
Erdafitinib
Crossover,
CO Table 1;
Appendix 12:
Guidance for 6
mg Daily Dose
with Up-titration
In the Synopsis, Schedule of Activities, Section 4.1
(Overall Design), Section 4.3.1 (Erdafitinib Dose
Selection), Section 6.1.1 (Erdafitinib), Section 6.6.1
(Erdafitinib Up-titration Guidelines) and Appendix 10
(the Crossover Schedule of Activities), the dosing
regimen was modified to 6 mg daily. These sections
also state that after review of safety and tolerability data
from approximately 5 to 10 additional subjects dosed
with the 6-mg daily regimen (without up-titration), the
IDMC may recommend a modification of the dosing
regimen to allow up-titration to the 8-mg daily regimen.
Sections 6.1.1 and 6.6.1 refer to information regarding
up-titration to the 8-mg daily dosing regimen in Section
10.12 (Appendix 12) and in Section 6.6.1 the former
up-titration information was removed. The Synopsis
(Overall Design) and Section 4.1 also mention that the
details of the IDMC recommendation will be
communicated in writing to the investigative sites and,
per local regulation, to health authorities. Also, Table 2
(Erdafitinib Dose Reduction Levels) was amended to
provide the sequence of reduction for the new dosing
regimen.
Section 2.2.2 provides data from BLC2001 reviewed in
consideration of the dose modification to 6 mg daily, ie,
data showing clinical activity in the dosing regimens
(6-and 8-mg daily regimens) with
 tolerability
for the 6-mg daily compared with the 8-mg daily dosing
regimen. Also, data from an analysis for subjects who
received the 6-mg daily dosing regimen (with and
The dosing regimen was modified to
6 mg daily without up-titration
(previously 8 mg daily with up-
titration to 9 mg daily) based on
IDMC recommendation after review
of safety data from subjects enrolled
in the BLC2003 study, thus far, and
data from the BLC2001 study.
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Status: Approved, Date: 13 July 2023
Section Number
and Name
Description of Change 
Brief Rationale
without 
up-titration) 
were 
provided 
showing
comparable results regardless of up-titration.
In addition to the dose modification, Section 4.3.1 also
highlights that based on efficacy and safety data from
patients with advanced or metastatic urothelial
carcinoma (BLC2001), the 6-mg dosing regimen may
be better suited with respect to
for the early bladder cancer population of NMIBC. Data
in Section 2.2.2 that support this position are
referenced. Background on the IDMC review is
mentioned. The former information supporting the
original 8-mg dosing regimen was removed.
Synopsis, Other
secondary
objectives for all
cohorts;
Synopsis,
Overall Design;
Synopsis,
Statistical
Methods;
Schedule of
Activities;
3 Objectives and
Endpoints;
4 Overall
Design;
4.2.1 Study-
specific Ethical
Design
Considerations;
5 Study
Population;
5.1 Inclusion
Criteria;
5.2 Exclusion
Criteria;
6 Study Drug;
The DDI Substudy presented in Appendix 10        
(Section 10.10) was removed. As a result, Inclusion 
Criteria 7.1 was modified to remove the creatinine 
requirement for the DDI substudy. Also, the note, after 
the list of exclusion criteria in Section 5.2, regarding
ensuring that enrollment criteria have been met at
screening was revised to remove instruction for the DDI
substudy. The information related to the DDI substudy
was removed from the Schedule of Activities, ie,
Inclusion/Exclusion Criteria, Randomization Cohort 1,
and Erdafitinib rows were modified to remove mentions
of the DDI substudy; and the DDI-substudy specific
rows were deleted. Throughout the protocol, the
mention of elements related to the DDI substudy have
been removed.
Due to the modification in the starting
dose of erdafitinib (to 6 mg daily), the
DDI substudy was removed as it was
designed for an 8-mg dose.
CCI
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section Number
and Name
Description of Change 
Brief Rationale
8 Study
Assessments and
Procedures;
8.1.2 Treatment
Phase;
8.6.1
Evaluations;
8.6.2 Analytical
Procedures;
9.4.6.1
Pharmacokinetic
Analyses;
10.10 (Appendix
10) Erdafitinib
Crossover
10.10 Drug-drug
interaction study
Due to the removal of the DDI substudy (Section 10.10,
Appendix 10) and the addition of the appendix for
up-titration if recommended by the IDMC (as Section
10.12, Appendix 
12) the remaining 
sections
(appendices) have been renumbered.
Renumbering of the appendices due
to removal of Appendix 10
containing the DDI substudy
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Amendment 3 (26 October 2020)
Overall Rationale for the Amendment:  The time point of the tissue collection for molecular eligibility
testing has been expanded to time before treatment with BCG (ie, previously required at the time of
recurrence after BCG therapy) to provide more opportunity for collection of a sufficient tumor sample.
Clarifications for histopathology sampling, bladder mapping for cross over study and acquisition of good
quality Optical Coherence Tomography (OCT) scan were added. Instructions on combination with
moderate CYP2C9 and strong CYP3A inhibitors or inducers was added. Other minor clarifications and
alignment with updated oncology protocol template text were also included.
Section number 
and Name
Description of Change 
Brief Rationale
1.3, Schedule of
Activities;
5.1, Inclusion
Criteria;
8.1.1.1 Molecular
Eligibility Phase;
Figure 2 (new);
8.1.1.2, Cohort 3
Molecular
Eligibility
Inclusion Criterion 3 (now numbered 3.2) was
revised to allow testing of molecular eligibility to
occur any time prior to enrollment by removing the
text, “at the time of recurrence after BCG therapy.”
This change was also reflected in the Schedule of
Activities (Notes for “Tumor tissue for molecular
eligibility...”) and in the sections regarding
molecular eligibility (8.1.1.1 and 8.1.1.2). In
Section 8.1.1.1, added that tissue obtained before
BCG treatment must also be submitted for central
confirmation of fibroblast growth factor receptor
(FGFR) status. A figure to depict the tissue testing
paradigm for this study (Figure 2) was also added to
Section 8.1.1.1.
To allow tissue testing for
molecular eligibility any time prior
to enrollment to provide more
opportunity for collection of a
sufficient tumor sample. The
consent instruction was changed
accordingly.
8.2.1.4,
Histopathologic
Assessment and
FGFR (All Cohorts)
In Section 8.2.1.4, revised instruction for Cohort 1
to add that it is the post-BCG specimen that will be
submitted to the central laboratory for central
histopathologic testing. Enrollment information
was removed. Added that if the central
histopathological assessment reveals T2 or higher
disease, the results will be communicated by the
medical monitor to the principal investigator.
Tissue samples for central
histopathologic assessment for
subjects in Cohort 1 will be post-
BCG specimens.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
151
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
1.3, Schedule of 
Activities 
8.1.2, Treatment 
Phase; 
8.2.1.5, Cystoscopy, 
Urine Cytology, 
Bladder Mapping, 
and CT/MRI 
Urogram; 
8.9, Biomarkers; 
CO Table 1,
Schedule of
Activities
In Section 1.3, the notes section of the cystoscopy 
and bladder mapping rows, specified that only 
positive biopsy samples should be sent for 
exploratory biomarker analysis and clarified that
this is for any grade of recurrence. This instruction
was also added to the last paragraphs of Sections
8.1.2 and 8.2.1.5.
Due to the above change and sentence structure in
Section 8.1.2, it was clarified that any tissue should
be sent for determination of the erdafitinib level.
Only tissue from positive biopsy
samples should be sent for
exploratory biomarker analysis.
CO Table 1, 
Schedule of 
Activities 
In Table 1, added that bladder mapping at 
screening will be done only if a prior history of 
carcinoma in situ (CIS). Also, note was moved to 
the “Note” column. 
For the cross over study, only
subjects with a history of CIS will
have bladder mapping performed at
screening.
CO Table 1, 
Schedule of 
Activities 
In Table 1, Cystoscopy, deleted the requirement to 
send tissue slides/blocks from subjects with locally 
confirmed recurrence for central histopathologic
review.
Central histopathologic review not
required in the crossover study
8.1.1.1 Molecular 
Eligibility Phase 
(Cohort1 and 
Cohort2)
For Cohort 2 with concurrent papillary disease, 
molecular eligibility can be determined from either 
the CIS specimen or the papillary lesion. 
For Cohort 2, clarified the type of
tissue specimens that may be used
to determine molecular eligibility.
1.3, Schedule of 
Activities (footnote 
b); 8.1.1.1 
Molecular 
Eligibility Screening 
Phase (Cohort1 and 
Cohort2); 
Figure 2 (new) 
In Section 8.1.1.1 removed the requirement to 
obtain sponsor approval prior to submitting a local 
next-generation sequencing (NGS)/tissue sample 
for confirmation of FGFR status.
Also added that pre-BCG tissue specimen and post-
BCG local NGS/PCR testing must also submit the
post-BCG tissue specimen tissue for central
confirmation of Molecular eligibility status.
The need for sponsor review and approval prior to
completion of the molecular eligibility requirement
and for resubmission of tissue that was of
insufficient quantity was removed.
Removed the requirement to have
sponsor approval for aspects of
molecular eligibility testing.
6.5.3 Precautions for 
Concomitant 
Medications; 
10.9, Drug 
Classified ... 
In Section 6.5.3, instruction for precaution with 
concomitant medications has been updated, ie, the 
combination of erdafitinib with moderate CYP2C9 
inhibitors or inducers or strong CYP3A inhibitors 
or inducers should be avoided. Also, additional 
information regarding erdafitinib and moderate 
CYP2C9 inhibitors or inducers and strong CYP3A 
inducers or inducers were added.
The combination of erdafitinib with
moderate CYP2C9 inhibitors or
inducers or strong CYP3A
inhibitors or inducers should be
avoided. Instruction for precaution
with concomitant medications was
updated.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
152
Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale 
5, Study Population; 
5.2, Exclusion 
Criteria; 
10.10, Drug-drug 
Interaction 
Substudy; 
10.11, Erdafitinib 
Crossover 
In Section 5.2, deleted Exclusion Criterion 13 from
the main study and the crossover study (Exclusion
Criterion 12). and updated the Drug-drug
Interaction (DDI) Substudy (Exclusion Criterion 1)
to read “Use of strong CYP3A4 inhibitors or
inducers” or “moderate CYP2C9 inhibitors or
inducers” (previously  “Medications known to
induce or inhibit CYP3A or CYP2C9”). Also edited
the DDI Exclusion Criterion 1 for clarity regarding
OCT2 use.
In Section 5, noted that additional eligibility criteria
for entry into the DDI Substudy is provided in
Appendix 10 under the “Subject Population”
subsection.
To remove Exclusion Criterion 13
(main study) and Exclusion
Criterion 12 (crossover study), as
this exclusion applies only to those
entering the DDI Substudy, to align
the DDI exclusion with the update
for CYP3A4/CYP2C9 inhibitors
and inducers, and to add a reminder
that additional eligibility criteria for
participation in the DDI Substudy is
provided in the substudy appendix.
5.2, Exclusion 
Criteria 
Exclusion Criterion15 was added to ensure washout
of any other investigational agent in another clinical
study within 30 days prior to randomization.
To clarify that subjects should have
adequate washout from prior use of
an investigational agent.
8.3.2, Vital Signs 
For the assessment of temperature, removed “oral
or tympanic”.
Temperature may be performed by
any method.
1.3, Schedule of 
Activities; 
4.1, Overall Design; 
8.1.2, Treatment 
Phase; 
8.6.1, Evaluations
Added that the 24-hour PK urine sample for
subjects receiving erdafitinib is done for the first
20 subjects in any cohort (previously all subjects in
Cohorts 2 and 3). Also added “approximately” 20
subjects will have the sample obtained.
As 20 subjects is sufficient for PK
evaluation of the 24-hour urine
sample, the requirement to test
further subjects was removed.
Testing was expanded to all
cohorts.
1.3, Schedule of 
Activities; CO 
Table 1, Schedule of 
Activities 
In the “Notes” column for the row
“Ophthalmologic examination” the following text
was added: “Repeat OCT scan in case of quality
issue.”
To ensure a quality OCT scan is
obtained.
1.3, Schedule of 
Activities; 
8.3.4, Clinical 
Safety Laboratory 
Assessments; CO 
Table 1, Schedule of 
Activities 
In Section 1.3, the “Notes” column for the rows
“Phosphate” and “Parathyroid hormone”, noted
that these tests are done for all subjects at
screening and for only subjects assigned to receive
erdafitinib after Cycle 1 Day 1 (C1D1). This
instruction was also added to Section 8.3.4.
In Section 1.3 (in the “Clinical Safety Laboratory
Assessments” subheader row) noted that results for
1,25-dihydroxyvitamin D do not need to be
available prior to the start of treatment at C1D1.
In Section 1.3 (screening results confirmed prior to
randomization) and Section 8.3.4, noted the
exception for parathyroid hormone and
1,25-dihydroxyvitamin D.
The clinical laboratory tests for
phosphate and parathyroid hormone
will be conducted for all subjects at
screening, as the treatment
assignment is not known at this
time.
It is not necessary to have results of
the 1,25-dihydroxyvitamin D and
parathyroid hormone tests prior to
dosing.
1.3, Schedule of 
Activities; 
In the “Notes” for the row “Cystoscopy (with
biopsy of visible lesions if present)” the following
change was made: “. . . Send tissue slides/blocks
from subjects with locally confirmed (“high-risk”
removed from this location) recurrence or
progression for central histopathologic review . . . “
Tissue slides/blocks from subjects
with locally confirmed recurrence
or progression of any grade will be
sent for central histopathologic
review.
1.3, Schedule of 
Activities 
Reordered the PK sample assessments to list blood
sampling first followed by tissue specimen
collection.
To improve readability.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
153
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
8.4.4, Regulatory 
Reporting 
Requirements for 
Serious Adverse
Events and 
Anticipated Events; 
8.4.6, Disease-
related Events and 
Disease-related 
Outcomes Not 
Qualifying as
Adverse Events or
Serious Adverse
Events;
10.3, Appendix 3,
Severity Criteria
subheader
The Section  8.4.4 header was revised to include 
Anticipated Events (per template); this topic is 
already provided in this section. 
In Section 8.4.6, the description of disease-related
events was updated.
In Section 10.3, the definitions of Grades 1 to 5 were
added (the mild, moderate, and severe definitions
were removed).
Aligned wording in several sections
with updated text common to the
oncology protocol template.
10.3, Appendix 3, 
Serious Adverse 
Events subheader 
Removed instructions for reporting of serious and 
unexpected adverse events that are a component of 
the study endpoint.
Not applicable to this study based
on study endpoints.
Synopsis, Overall 
Design; 
1.3, Schedule of 
Activities; 
8.1.1.3, Full-study 
Screening Phase
Clarified that the requirement for molecular 
screening to start within 12 weeks of transurethral 
resection of bladder tumor (TURBT) was done for
“high risk” recurrence “if molecular testing is being
done on post-BCG specimen”.
To clarify molecular screening
requirements.
5.4, Screen Failures 
In the last paragraph, it was clarified that subjects 
may be rescreened once for the main study. Also, 
the sentence was simplified by removing some of 
the detail that may result in rescreening. Instruction 
was added that for samples with insufficient tissue, 
another sample may be submitted, and this
submission is not considered rescreening.
Clarified that a subject may be
rescreened once for the main study.
Provided instruction for
resubmitting a tumor sample with
insufficient tissue.
1.3, Schedule of 
Activities; 
Section 8.1.1.1, 
8.1.1.1 Molecular 
Eligibility Screening 
Phase (Cohort1 and 
Cohort2);
10.2, Appendix 2,
Informed Consent
Process
Added that consent for molecular eligibility 
screening may be performed remotely  including 
consent by telephone or video consultation, unless 
not permitted according to local guidance. In
Section 10.2, noted that informed consent for
molecular eligibility may be obtained remotely.
Added remote consent to provide
more options for obtaining consent
for molecular eligibility.
8.2.1.3, Cohort 3 
Removed the following sentence from the first 
paragraph, “No electricity should be applied to a 1 
cm circumference around the tumor.” 
Tumors will be excised per
standard practice; therefore, extra
detail was removed.
Synopsis, Overall 
Design; 4.1, Overall 
Design; 6.5.1, 
Permitted 
Medications 
Moved the sentence regarding peri-operative
intravesical chemotherapy prior to study entry per
local standard of care from Section 6.5.1 to Section
4.1 (for Cohort 2) and added that prior
immunotherapy (eg, PD1 inhibitor etc) are also
allowed (for Cohort1 and Cohort 2). Also added that
for Cohort 2, subjects may receive chemotherapy as
bridging therapy after adequate BCG therapy while
being considered for trial.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
154
Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale 
1.3, Schedule of 
Activities; 8.9, 
Biomarkers 
In the Notes for “Urine for
”
added urine can be taken from excess “bladder
washing sample/” urine/cells remaining after urine
cytology “sample amount is aliquoted for testing: .
. In 8.9, FGFR alteration detection subsection,
included that voided urine specimen could be
assessed, although instrumented specimen is
preferred.
Clarified permitted methods of
urine sampling for diagnostic
development.
10.13, Appendix 13, 
Guidance . . .  
During a National 
Disaster 
Added text to the first paragraph to clarify that the
measures in this appendix are temporary and that
usual study conduct will resume once the national
situation allows.
The following text was added to clarify the consent
process during a national disaster: Consenting of
subjects for full-study screening and for molecular
eligibility screening will be performed as
applicable (including also remote consenting by
telephone or video consultation) according to local
guidance for the informed consent.
Clarified in the National Disaster
attachment that usual study conduct
resumes once the national situation
allows and added guidance for
consent during a national disaster.
Table 9 
For Grade 2 Management of Nail Discoloration/
Loss/Ridging (Onycholysis/ Onychodystrophy, the
instruction was changed as follows “Continue
holding study drug (previously “continue study
drug”) with reassessment in 1-2 weeks”.
Correction to Grade 2 instruction
for study drug management.
1.3, Schedule of 
Activities; 
8.1.1.3, Full-study 
Screening Phase 
In Section 1.3, added a notation to the Main-study
Informed Consent Form (ICF) row of the table that
procedures conducted, before signing the Main-
study ICF, as part of the subject’s routine clinical
management (eg, blood count, disease assessment)
may be used for screening or baseline purposes
provided the procedure meets the protocol-defined
criteria and has been performed within 35 days
prior to dosing.
In Section 8.1.1.3, added that test results may be
repeated once during screening if the underlying
issue has been resolved, as well as if the results are
believed to be in error.
Clarified the timing of procedures
conducted as part of patients’
routine clinical management that
can be used for screening purposes.
4.3.2, Gemcitabine 
Dose Selection  
Removed the lead sentence of the second paragraph
of this section: “Although gemcitabine and the
aforementioned dose is not labeled for use in
bladder cancer, it is considered standard to use as an
intravesical therapy and it is generally well-
tolerated.16”
General information was removed
from this section.
Table 3; 
Table 4 
Revised the serum phosphate levels in these tables
to align with the program-wide levels used for the
erdafitinib program.
The “Symptom Management” column for Grade 3
was revised as follows: Sevelamer up to 1,600 mg
TID with food until serum phosphate level “is”
[added “is” and deleted “returns to” <7.00 mg/dL.
Aligned rounding with other
protocols within the erdafitinib
program.
A minor correction was made to the
guidelines for the management of
elevated phosphate levels.
CCI
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
155
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
Figure 1; 8.1.1, 
Screening; 8.1.1.1, 
Molecular 
Eligibility Screening 
Phase (Cohort1 and 
Cohort2); 8.1.1.2, 
Cohort 3 Molecular 
Eligibility; Section 
8.1.1.3, Full-study 
Screening Phase 
Updated Figure 1 to reorder screening to display 
“Screening for FGFR . . .” first, followed by 
“NMIBC subjects .  . .” second. 
Reorganized the description for Screening (now
Section 8.1.1) as follows: Section 8.1.1.1,
“Molecular Eligibility Screening Phase (Cohort 1
and Cohort 2)”; Section 8.1.1.2, “Cohort 3
Molecular Eligibility”; and Section 8.1.1.3, “Full-
study Screening Phase.” Numbering for subsequent
headings in Section 8.1.1 were updated accordingly
(Section 8.1.2, Treatment Phase [was 8.1.3]; Section
8.1.3, Follow-up Phase [was 8.1.4]; and 8.1.4,
Unscheduled Visits [was 8.1.5]).
To clarify molecular screening and
full-study screening procedures and
improve readability.
1.1 Synopsis; 3 
Objectives and 
Endpoints; 9.4.3
Secondary Efficacy
Endpoints;
Switched order of secondary efficacy endpoints in
instances where “Time to progression” preceded
“Time to disease worsening.”
To align with the order in
hierarchical testing.
9.4.2 Primary 
Endpoints 
Added description of primary estimand. 
To align with ICH E9(R1)
Harmonised Guideline on
Estimands and Sensitivity Analysis
in Clinical Trials issued in 2019.
9.4.3 Secondary 
Efficacy Endpoints 
Modified Time to Disease Worsening definition to 
clarify components as (1) first documented 
evidence of cystectomy, (2) change in therapy
indicative of more advanced disease, including
systemic chemotherapy or radiotherapy, (3) death.
Also, changed phrase “radiation therapy” to
“radiotherapy” for consistency with case report
form (CRF).
To reduce ambiguity in the
definition of this endpoint.
9.4.5 Safety 
Analyses 
Added the sentence: “Clinically relevant ECG 
abnormalities are defined in the SAP." 
To clarify that these abnormalities
have been defined in the SAP.
9.4.6.1 
Pharmacokinetic 
Analyses
Included urine along with plasma and tissue as a 
potential source of PK data. 
To clarify that PK urine sample will
be included in listings.
9.4.6.1 
Pharmacokinetic 
Analyses 
Added description for how PK concentrations 
below the lower limit of quantitation will be 
displayed in listings. 
To clarify display of PK
concentrations below the lower
limit of quantitation.
9.4.6.3 Medical 
Resource Utilization 
Analyses (new) 
Added a separate section number for Medical 
Resource Utilization Analyses (formerly included
the Biomarkers Analyses section).
Minor correction.
9.5 Interim Analysis Added that if the hazard ratio at the interim 
analysis is ≥1, “the Independent Data Monitoring 
Committee (IDMC) may recommend” Cohort 1 to
be stopped for futility.
To clarify that that the IDMC
recommendation is not binding.
9.5 Interim Analysis Changed reference from interim analysis plan to 
statistical analysis plan. 
For consistency in including the
interim analysis plan in the
statistical analysis plan.
2.2.1, Fibroblast 
Growth Factor 
Receptors 
In the “FGFR Alterations in High-risk NMIBC” 
subsection, added recent data from the Breyer et al 
study regarding the prognostic and predictive value
of FGFR alterations in NMIBC for the real-world
patients.
To provide additional background
information.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
156
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
6.1.2, Investigator’s 
Choice of Treatment 
(Cohort 1 Only)
Add that subjects in Cohort 1 are not candidate for 
re-treatment with BCG. 
To clarify treatment options for
Cohort 1 subjects.
9.6 Independent 
Data Monitoring 
Committee 
Renamed the section from “Data Monitoring 
Committee or Other Review Board” to 
“Independent Data Monitoring Committee.”
To reflect the type of review board
used for the study.
10.2, Appendix 2, 
Committees 
Structure subsection 
Changed the number of medical experts on the 
IDMC from at least 2 to “at least 1.” 
Updated to reflect the required
number of medical experts (1) for
IDMC.
11, References 
Added references for Breyer 2020 and Gallagher 
2008. 
Updated to support protocol
revisions.
Title page and 
footer
Updated confidentiality information added. 
To align with updated statements.
Throughout the 
protocol; 
4.3.3, Mitomycin C 
Dose Selection;
8.1.1.1, Molecular
Eligibility Phase
(Cohort 1 and
Cohort 2); 
8.1.1.2, Cohort 3 
Molecular 
Eligibility; 
10.9, Drug 
Classified . . . 
Minor grammatical corrections were made. 
Added recurrence refers to “high risk” recurrence as 
applicable throughout the protocol.
In Section 4.3.3, removed redundant sentence:
“Additional doses of induction or maintenance are
allowed per local standard of care.”
In Section 8.1.1.1, moved the first paragraph
regarding the ANNAR protocol to the end of this
section.
In Section 8.1.1.2 the instruction in Number 5
regarding resection of the marker lesion when
molecular eligibility is not met was added to
Number 4.
In Section 10.9, provided correction to the Strong
CYP3A4 Inhibitor table, ie, Strong Inhibitors:
≥5-fold increase in area under the curve (AUC) or
≥80 % (previously >80%) decrease in CL.
In Section 10.10 under the Prohibition and
Restrictions subsection of the DDI substudy,
clarified subjects should not consume alcohol on
Day -3 and Day 12 (deleted “Day -3” and “Day 12”
from text regarding “no more than 1 drink”).
Minor clarifications and corrections
were made.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
157
Status: Approved, Date: 13 July 2023
Amendment 2 (26 March 2020)
Overall Rationale for the Amendment:  To address the shortage of Mitomycin C/MMC supply
Section number 
and Name
Description of Change 
Brief Rationale
Throughout the
protocol
The following bolded phrase was added:
The reason for not being eligible for cystectomy or
for refusing cystectomy…
As requested by the European
Medicines Agency (EMA)
Throughout the
protocol
The word “terminated” was replaced with “closed”
when referring to study discontinuation.
To provide clarity relative to
European guidance
Section 1.1
Synopsis;
Section 4.1 Overall
Design
The following sentence was added:
BCG strain administered will also be
documented in the eCRF.
As requested from the EMA
Section 1.1
Synopsis;
Section 4.1 Overall
Design
A statement was added to indicate that peri-
operative intravesical chemotherapy prior to study
entry is allowed per local standard of care.
To align with standard of care
practice
Section 1.3
Schedule of
Activities; Section
10.11 Appendix 11:
Erdafitinib
Crossover
Additional ocular examinations were added to the
ophthalmologic examination assessment.
As requested from the FDA
Section 1.3
Schedule of
Activities
The days of administration for the Investigator’s
Choice treatment were changed from C1D7,
C1D14, and C1D21 to C1D8, C1D15, and C1D22,
respectively.
To align with weekly 7-day dosing
The day for assessment was changed to C26D1 for
the following: cystoscopy, urine cytology, MRU
data collection, urine for
,
and blood (plasma) for ctDNA.
To address that each cycle is 28
days, and there are 13 cycles in 1
year
The notes section was modified for tumor tissue
for molecular eligibility, histopathology staging,
and biomarker testing.
To add clarity
Section 1.3.
Schedule of
Activities;
Section 8.3.4
Clinical Safety
Laboratory
Assessments;
Section 10.11
Appendix 11:
Erdafitinib
Crossover
Measurement of 1,25-dihydroxyvitamin D was
added for all subjects at specified time points.
To address a request from the
Italian regulatory authority
Section 1.3.
Schedule of
Activities; Section
8.6.1 Evaluations
PK urine sample was added for subjects in Cohorts
2 and 3.
To assess erdafitinib concentration
levels between tissue and urine
Section 1.3
Schedule of
Activities (footnote
a)
A footnote was added to refer to Appendix 13 for
guidance on national disasters.
To add instructions to be used
during national disasters
Section 4.3.2
Gemcitabine Dose
Selection
Clarified the dose of gemcitabine and removed 
language that was already included in the IPPI, 
which is referenced in this section.
To align and provide clarity with
the IPPI
CCI
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
Section 4.3.3
Mitomycin C Dose
Selection
Clarified the dose of MMC and added instruction 
to follow the IPPI.
To address a shortage ofMMC .
Section 5.1
Inclusion Criteria
For criterion #3, the following text was added:
Subjects enrolling as referrals from ANNAR
study do not need to submit tissue for central
confirmation.
Per the ANNAR protocol
procedures/processes
Section 5.1
Inclusion Criteria
For criteria #10, the time period was changed to 6
months after the last dose of study drug for the
following: to remain on a highly effective method
of contraception, to not donate eggs, not
breastfeeding, not planning to become pregnant,
not donate sperm, not planning to father a child.
Per the SmPC for gemcitabine.
To address a request from the
regulatory authorities in Germany
and Belgium
Section 5.1
Inclusion Criteria
For criteria #7, the calculation of renal function
was modified.
To add clarity
Section 5.2
Exclusion Criteria
An additional criterion was added relating to
contraindications to the use of gemcitabine or
MMC/hyperthermic MMC.
To address a request from the
German regulatory authority
Section 5.3 Lifestyle
Considerations
The following was added:
Male and female subjects should be advised on
sperm banking and egg preservation,
respectively, prior to entering the study, if
appropriate.
To address a request from the
Belgium regulatory authority
Section 6.1.3
Continuation of
Treatment After
Disease Recurrence
Text was added and deleted as shown below:
Subjects will not continue erdafitinib treatment
after disease recurrence or progression.  In
Cohort 1, erdafitinib may be continued after
disease recurrence if by the assessment of the
investigator it is the best treatment for the subject.
This should be discussed with and agreed to by the
sponsor’s medical monitor. Additionally, the
subject must agree to continue treatment and be
clinically stable.
To address a request from the
French regulatory authority
Section 6.3
Measures to
Minimize Bias:
Randomization and
Blinding
The following text was added:
All tissue samples with a local investigator
assessment ofany recurrence will be sent to
central lab for an independent pathologic
assessment regardless of risk category in order
to decrease bias.
To address a request from the FDA
to decrease bias
Section 6.5.3
Precautions for
Concomitant
Medications;
Section 10.9
Appendix 9: Drugs
Classified as Strong
In Vivo Inhibitors of
CYP3A4/2C9 or as
Moderate to Strong
Inducers of
CYP3A4/2C9
Enzymes; Section
10.10 Appendix 10:
Drug-drug
Interaction Substudy
Text related to CYP3A4 and CYP2C9 inhibitors
and inducers was added. Other edits were made to
the CYP3A4 and CYP2C9 tables.
To address a request from FDA by
adding a list of known CYP2C9
inhibitors and inducers; To indicate
that tables of inhibitors and
inducers provided is not an
exhaustive list. To reduce duplicity.
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
Section 6.6.2.1.1 
Guidelines for the 
Management of 
Elevated Phosphate 
Levels; Throughout
the protocol
The values for grading of hyperphosphatemia have 
been revised throughout the protocol to include 2 
decimals, for consistency with the CRF. 
Toxicity Grade 0 was added to Table 3. 
To ensure consistency between the
protocol and case report form
(CRF) guidelines, harmonize
rounding of phosphate values.
Section 6.6.2.1.2 
Guidelines for the 
Management of Dry 
Mouth and 
Mucositis 
Guidelines for general prophylaxis and 
management of mucositis (Table 6) were updated. 
To provide updated guidance for
specific erdafitinib toxicities for
additional clarification, and for
consistency with National Cancer
Institute Common Terminology
Criteria for Adverse Events (NCI-
CTCAE) guidelines.
Section 6.6.2.1.4 
Guidelines for 
Management of Nail 
Toxicity 
(Onycholysis, 
Onychodystrophy, 
and Paronychia) 
Guidelines for general prophylaxis and 
management of nail toxicities (Table 9) were 
updated. 
To provide updated guidance for
specific erdafitinib toxicities for
additional clarification, and for
consistency with National Cancer
Institute Common Terminology
Criteria for Adverse Events (NCI-
CTCAE) guidelines
Section 7.1 
Discontinuation of 
Study Drug, Section 
10.2 Appendix 2: 
Regulatory, Ethical,
and Study Oversight
Considerations
Text related to the sponsor’s right to discontinue 
the study was added. 
To address a request from the
German regulatory authority to add
criteria for discontinuation of the
study
Section 8.1.1.1, 
Molecular 
Eligibility Phase
(Cohort 1 and
Cohort 2)
Instructions for subjects from the ANNAR study 
were added. 
To indicate that FGFR testing may
come from the ANNAR study
Section 8.1.3 
Treatment Phase 
Text was deleted as shown: 
Subjects in Cohort 1 assessed with recurrent 
disease, but for whom the treating physician
strongly believes that continuation of study
treatment is in their best interest, may be allowed
to continue treatment with erdafitinib after
consultation with the sponsor’s medical monitor
(see Section 6.1.3). The subject will continue to
follow procedures as outlined in the Schedule of
Activities and receive treatment until the treating
physician and the sponsor’s medical monitor agree
that further continuation of treatment is no longer
providing benefit to the subject.
To address a request from the
French regulatory authority
Section 8.3.5 
Ophthalmologic 
Examination  
The following text was modified: 
All subjects should must have an ophthalmologic 
examination performed regardless of symptoms 
during the Screening Phase and during the
Treatment Phase as specified in the Schedule of
Activities (Section 1.3).
To clarify that assessments must be
performed according to the
Schedule of Activities
Section 8.3.5 
Ophthalmologic 
Examination  
Instructions for handling of angiograms, 
photographs, and OCT scans were added and the
frequency of ophthalmic examinations was
increased.
To address a request from the FDA
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
Section 8.4.5 
Pregnancy  
The following text was added: 
Male subjects receiving gemcitabine or MMC 
will refrain from sperm donation or fathering a 
child until 6 months after the last dose of study
drug.
To address a request from the
Belgium and German regulatory
authorities
Section 10.10 
Appendix 10: Drug- 
drug Interaction
Substudy
An additional exclusion criterion was added for the 
DDI substudy. 
To address a request from the
German regulatory authority
Section 10.11 
Appendix 11: 
Erdafitinib 
Crossover
Text was added to specify that the Amsler Grid 
Test is to be performed prior to beginning 
erdafitinib treatment.
To add clarity regarding
requirements
Section 10.11 
Appendix 11: 
Erdafitinib 
Crossover
Cross-over assessment timepoints at screening 
were added for the following: bladder mapping, 
urine cytology.
These timepoints were missing
from the schedule
Section 10.11 
Appendix 11: 
Erdafitinib 
Crossover; Section 
5.2 Exclusion 
Criteria
Exclusion criterion #12 was modified to add 
severe hypocalcemia (corrected serum calcium of 
<7 mg/dL), acute and unhealed bone fractures,
known underlying bone disease, or at an increased
risk of bone fracture.
To address a request from the
Italian regulatory authority
Appendix 13 
This appendix was added and provides guidance 
on study conduct in the event of a national disaster. 
To add instructions to be used
during national disasters
Throughout the 
protocol 
Minor grammatical, formatting, or spelling 
changes were made.
Minor errors were noted
Amendment 1 (06 November 2019)
Overall Rationale for the Amendment:To indicate that collection of a blood (plasma) sample for ctDNA
evaluation is required at specific time points before and during the first 2 years of the Treatment Phase.
This clarification is required to ensure relevant data are available for analysis. Additional revisions were
made throughout the protocol to facilitate study conduct.
Section number 
and Name
Description of Change 
Brief Rationale
Section 1.3. Schedule of 
Activities 
For the assessment “Blood (plasma) for ctDNA”, 
the following replacement text was provided for 
the description of Treatment Phase assessment
timing: “All Cohorts: C1D1 (predose), C3D1,
then every 12 weeks (±1 week) until C24D1 or
until disease recurrence/ progression.”
Text was missing from the
protocol.
Synopsis (Objectives and 
Endpoints [Cohort 1]); 
Section 3. Objectives and 
Endpoints; Section 9.4.3. 
Secondary Efficacy Endpoints 
The secondary endpoint of RFS by central 
histopathologic review was added for Cohort 1. 
A supportive analysis of
RFS by central
histopathologic review
provides additional
scientific rigor.
Synopsis (Overall Design); 
Section 4.1. Overall Design; 
Section 5.1. Inclusion Criteria 
(No. 4)
Text was added to state that subjects in Cohort 3 
have no predefined BCG or intravesical 
chemotherapy requirements.
To more clearly define the
study population.
Section 5.1. Inclusion Criteria 
(No. 4) 
Cross reference to Section 2.3 was added for a
description of “full dose” BCG. The word “OR”
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
was added between items 1 and 2 of 4b.
Clarification was added that maintenance doses
are given weekly. Note text was revised for
clarity.
Section 5.2. Exclusion
Criteria (No. 7); Section
10.11. Appendix 11
(Crossover Exclusion Criteria;
No. 6)
Clarification was added that subjects with known
HIV infection will be excluded. A timeframe for
CD4 count was provided (ie, in the last 6
months).
Section 5.2. Exclusion 
Criteria (No. 8); Section 
10.11. Appendix 11
(Crossover Exclusion Criteria;
No. 7)
Text was revised. Subjects with evidence of
hepatitis B or C infection will be excluded.
Section 10.11. Appendix 11 
(Crossover Inclusion) 
Erdafitinib Crossover inclusion criterion no. 6
was added: “Locally confirmed high-risk
recurrence while receiving Investigator’s Choice,
and the subject has all visible tumor resected
completely prior to enrollment and documented
at baseline cystoscopy.”
Text was revised in the general description of the
Erdafitinib Crossover: “Subjects who were
randomized in Cohort 1 to either gemcitabine or
MMC/hyperthermic MMC, who have
investigator assessed locally confirmed
recurrence or progression…” Treatment may
continue for “up to a maximum of 2 years or
until disease recurrence or progression…”
Section 1.3. Schedule of 
Activities; Section 8.3.4. 
Clinical Laboratory 
Assessments; Section 10.11. 
Appendix 11 (Crossover 
Schedule of Activities) 
Presentation of clinical laboratory assessments 
was reorganized to clarify timing and subjects 
affected. Phosphate was removed from the
Comprehensive Metabolic Panel; alkaline
phosphatase and magnesium were added
(Section 8.3.4). Phosphate and parathyroid
hormone were identified as analytes measured
only for subjects receiving erdafitinib. EoT Visit
assessment of phosphate and parathyroid
hormone was deleted. Text describing chemistry
analytes for subjects receiving erdafitinib was
deleted (Section 8.3.4).
Reorganized for improved
understanding.
Section 8.1.3. Treatment 
Phase; Section 8.2.1.5. 
Cystoscopy, Urine Cytology, 
Bladder Mapping, and 
CT/MRI Urogram
Clarification was added that pharmacokinetic 
assessment for erdafitinib level will be 
performed only for subjects receiving erdafitinib. 
To limit the possibility of
unnecessary sampling for
pharmacokinetic
assessment.
Section 4.3.2. Gemcitabine 
Dose Selection 
Text was revised: “Gemcitabine will be provided 
by the sponsor as 2,000 mg/vial powder in a 
100 mL vial.” 
Additional detail was added
to the description of
gemcitabine.
Section 6.1.2.1. Gemcitabine 
Administration 
Text was revised: “Gemcitabine will be
administered as an intravesical instillation with
2,000 mg in ~50 52.6 mL NSS once weekly…”
Section 1.3. Schedule of 
Activities 
For “Main-study ICF” the “X” was removed 
from the Molecular Eligibility Phase column. 
To clarify informed consent
requirements.
Section 10.11. Appendix 11 
(Crossover Schedule of 
Activities) 
For the task “Review Erdafitinib Crossover
appendix of the ICF”, the text “and sign to
enroll” was added.
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JNJ-42756493 (erdafitinib)
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
Synopsis (Overall Design);
Section 1.3. Schedule of
Activities; Section 8.1.2.
Screening Phase
Text was revised: “Screening must occur start
within 12 weeks after the last TURBT done for
recurrence.”
To clarify activity or
assessment timing.
Section 1.3. Schedule of
Activities; Section 10.11.
Appendix 11 (Crossover
Schedule of Activities)
The interval for Disease Assessment Follow-up
during the Follow-up Phase was specified as
every 24 weeks ±2 weeks.
Section 1.3. Schedule of
Activities
For “Inclusion/exclusion criteria” and
“Randomization Cohort 1” text was added to the
grid to reiterate that these activities will be done
on Day -3 for subjects in the DDI substudy.
Section 1.3. Schedule of
Activities
Presentation of assessment/activity timing and
cohorts affected during the Treatment Phase and
Follow-up Phase (including NOTE text where
applicable) was revised for clarity for the
following: “Ophthalmologic evaluation”,
“Physical examination”, “12-lead ECG”, “Urine
or serum β-hCG pregnancy test”, “Bladder
mapping”, “Urine cytology”, “MRU data
collection”, “Urine for 
”,
and “Blood (plasma) for ctDNA”.
Section 1.3. Schedule of
Activities
For “Erdafitinib”, detail on erdafitinib
discontinuation was replaced with cross-
reference to Section 6.1.1. Clarification was
added that treatment may continue until
“…disease recurrence or progression…”
Section 1.3. Schedule of
Activities
For “Investigator’s Choice”, specific time points
were given for induction doses (C1D1, C1D7,
C1D14, C1D21[±2 days]) and maintenance
doses (C2D1, C3D1, C4D1, C5D1, C6D1, C7D1
[±2 days]).
Section 1.3. Schedule of
Activities
For “Tumor tissue for molecular eligibility…”,
NOTE text was revised to provide detail on
sample handling and testing requirements by
cohort.
Section 1.3. Schedule of
Activities; Section 10.11.
Erdafitinib Crossover
(Schedule of Activities)
For “Review adverse events”, detailed text in the
NOTE was deleted.
Section 1.3. Schedule of
Activities; Section 8.2.1.5.
Cystoscopy, Urine Cytology,
Bladder Mapping, and
CT/MRI Urogram; Section
10.11. Appendix 11
(Crossover Schedule of
Activities)
For “Cystoscopy”, NOTE text regarding activity
during the Molecular Eligibility Phase was
replaced with the following: “At screening, if
TURBT was done within 6 weeks before
randomization, then the findings of the complete
resection from TURBT can be used instead of
Screening cystoscopy.” Corresponding text was
added to Section 8.2.1.5.
CCI
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
Section 1.3. Schedule of 
Activities; Section 8.1.3. 
Treatment Phase; Section 
8.2.1.4. Histopathologic 
Assessment; Section 8.2.1.5. 
Cystoscopy, Urine Cytology, 
Bladder Mapping, and 
CT/MRI Urogram; Section 
8.9. Biomarkers (Tissue 
Biomarkers); Section 10.11.
Appendix 11 (Crossover
Schedule of Activities)
For “Cystoscopy”, NOTE text in the Schedule of
Activities regarding activity during the
Treatment Phase was revised for clarity and
added to Section 8.1.3 and Section 8.9.
Instruction was provided for handling biopsy
samples for biomarker analysis (corresponding
revision to Section 8.2.1.5 and Section 8.9) and
tissue for central histopathologic review
(corresponding text added to Section 8.2.1.4).
Section 1.3. Schedule of 
Activities (Cystoscopy); 
Section 8.2.1.5. Cystoscopy, 
Urine Cytology, Bladder 
Mapping, and CT/MRI
Urogram
Cystoscopy assessments for Cohort 3 at C1D28,
C2D28, and C3D28 (±1 week) were changed to
align with planned visits on C2D1, C3D1, and
C4D1 (±1 week).
Section 1.3. Schedule of 
Activities (TURBT); Section
10.11. Appendix 11
(Crossover Schedule of
Activities)
“TURBT” was added as an assessment.
Section 1.3. Schedule of 
Activities 
For “Bladder mapping”, NOTE text was revised
to change the word “patient” to “subject”. Cross
reference to Section 8.2.1.5 was added. Cohort 2
assessment at C12D1 was repositioned within
the grid.
Section 1.3. Schedule of 
Activities (urine cytology); 
Section 8.2.1.5. Cystoscopy, 
Urine Cytology, Bladder
Mapping, and CT/MRI
Urogram
Clarification was added that urine cytology is
only required for Cohort 1 and Cohort 2. Urine
cytology will not be done for Cohort 3.
Section 1.3. Schedule of 
Activities (Urine cytology, 
Urine for 
 
); Section 
8.2.1.5. Cystoscopy, Urine 
Cytology, Bladder Mapping,
and CT/MRI Urogram;
Section 8.9. Biomarkers
(FGFR Alteration)
Text was added stating that “A voided urine
specimen for urine cytology is acceptable at
screening if no screening cystoscopy is
performed (due to TURBT within 6 weeks
prior)”.
Section 1.3. Schedule of 
Activities; Section 8.10. 
Medical Resource Utilization 
and Health Economics 
For the assessment “MRU Data Collection”,
clarification was added that the assessment was
applicable to Cohort 1 and Cohort 2 only. The
start of MRU data collection was changed from
C3D1 to Screening. Text was aligned in Section
8.10.
Section 1.3. Schedule of 
Activities; Section 8.2.1.5. 
For “CT/MRI Urogram”, assessment will occur
until recurrence/progression. The window for
CCI
CCI
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
Cystoscopy, Urine Cytology,
Bladder Mapping, and
CT/MRI Urogram; Section
10.11. Appendix 11
(Crossover Schedule of
Activities)
CT/MRI urogram assessment was changed from
±1 week to ±2 weeks.
Section 1.3. Schedule of
Activities; Section 8.2.2.
Patient-reported Outcomes
(Follow-up Phase ePRO
Assessments)
For the assessment “PGIS, EORTC QLQ-C30,
EORTC QLQ-NMIBC24, EQ-5D-5L” Follow-
up Phase assessment was limited to the 30-day
Safety Follow-up Visit, and the following text
was deleted from the NOTE: “In addition to the
required assessments per this SoA. A total of 3
ePRO assessments will be conducted after the
subject has ended treatment.” Corresponding text
describing Follow-up Phase PRO assessment in
Section 8.2.2 was deleted.
Section 1.3. Schedule of
Activities
For “Urine for 
”,
clarification was added that urine will be
collected “…during cystoscopy for all cohorts”.
Section 1.3. Schedule of
Activities
For “PK: tissue specimen for erdafitinib”, PK:
blood sample for erdafitinib”, “Protein binding
blood sample” and “Blood sample for CYP2C9
genotyping”, NOTE text was revised to add
“Subjects receiving erdafitinib only”.
Section 2.3. Benefit-Risk
Assessment
A definition of full dose of BCG therapy was
added.
Section 4.1. Overall Design;
Section 10.10. Appendix 10;
Section 10.11. (Erdafitinib
Crossover)
Clarification was added that subjects who
participate in the Erdafitinib Crossover will not
participate in the DDI substudy.
Section 4.4. End of Study
Definition (Treatment and
Study Completion)
The stated minimum duration of gemcitabine or
MMC/hyperthermic MMC was changed from 6
months to 7 months per local standard of care
site practice.
Section 8.2.1.5. Cystoscopy, 
Urine Cytology, Bladder 
Mapping, and CT/MRI 
Urogram
Text was revised: “…for Cohort 2, urine
cytology does not have to be negative at
screening.”
Text was revised: “All scheduled CT/MRI
urograms assessments of disease status will be
performed within 1 week before or after the
timepoint as indicated in the Schedule of
Activities (Section 1.3).”
Text was revised: “Subjects with a positive urine
cytology (not atypical cells) but with negative
cystoscopic biopsy cystoscopy will continue
treatment until next scheduled evaluation in 12
weeks.”
8.1.3. Treatment Phase 
Text was revised: “Subjects in Cohort 1 assessed
with recurrent or progressive disease, but for
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NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
whom the treating physician strongly
believes…”
Section 8.1.4.2.2. Survival
Follow-up
Text was added that survival follow-up begins
when a subject has confirmed disease recurrence
or progression or starts new anticancer therapy.
Text was added that new anticancer therapy will
be collected in the eCRF.
Section 10.10. Appendix 10
(DDI Substudy)
Reference to metformin as a 500-mg tablet
presentation was deleted.
Section 10.11. Appendix 11
(Erdafitinib Crossover)
For “Ophthalmologic examination”, screening
examination is “Only required if last
ophthalmologic examination was more than 2 1
months prior“
Section 10.11. Appendix 11
(Erdafitinib Crossover)
For “Cystoscopy”, screening cystoscopy was
added to the Schedule of Activities. The
following text was added to the NOTE: “At
Screening, if TURBT was done within 6 weeks
before randomization, then the findings of the
complete resection from TURBT can be used
instead of Screening cystoscopy.”
Section 10.11. Appendix 11
(Erdafitinib Crossover)
For “Bladder mapping”, screening bladder
mapping was deleted. “NOTE” text was moved
into the grid for the Treatment Phase.
Synopsis (Treatment Groups);
Section 6.1.2. Investigator’s
Choice of Treatment
Text was aligned between sections: “(All) dose 
modifications or omissions will be managed by 
the treating physician per local standard of care
after discussion with the sponsor.”
Consistency within the
protocol.
Synopsis (Overall Design);
Section 4.1. Overall Design;
Section 10.2. Regulatory,
Ethical, and Study Oversight
Considerations
The following text was added: “(T)he reason for 
not being eligible for cystectomy will be entered
into the eCRF.”
.
Synopsis (Evaluations);
Section 1.3. Schedule of
Activities (Cystoscopy);
Section 4.1. Overall Design;
Section 8.1.3. Treatment
Phase; Section 8.2.1.4.
Histopathologic Assessment;
Section 8.2.1.5. Cystoscopy,
Urine Cytology, Bladder
Mapping, and CT/MRI
Urogram; Section 10.11.
Appendix 11 (Crossover
Schedule of Activities)
Clarification was made that biopsied tumor
tissue will be sent for “central histopathologic
review” for subjects in Cohort 1. Tissue
slides/blocks from subjects in Cohort 1 with
locally confirmed high-risk recurrence or
progression will be sent for central
histopathologic review.
Section 1.2. Schema 
Cohort 3 exploratory endpoint was changed to
“CR Rate”
Section 6.1.4. Erdafitinib 
Crossover 
Text was replaced: “…and demonstrate a
recurrence via investigator disease assessment..”
was changed to “…and demonstrate locally
confirmed high-risk recurrence while receiving
study drug…”
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale 
Section 6.6.2.1.5. Guidelines 
for the Management of Eye 
Toxicity Associated With
Vision Changes; Section
8.1.3. Treatment Phase;
Section 8.1.4.2.1. Disease
Assessment Follow-up
“Study therapy” or “erdafitinib therapy” was
changed to “study drug”.
Section 8.1.2. Screening 
Phase 
Clarification was added that PGIC is only
assessed during the Treatment Phase.
Clarification was added: “The PRO measures
will be electronically (ePRO) collected,
according to the Schedule of Activities (Section
1.3), to understand change over time (all cohorts)
and difference between treatment groups (Cohort
1).”
Section 8.2.1.5. Cystoscopy, 
Urine Cytology, Bladder 
Mapping, and CT/MRI 
Urogram  
The description of cystoscopy timing was
aligned with the revised Schedule of Activities.
Text related to cystoscopy was kept together.
The definition of recurrence was restated as
histologically proven first appearance of “high-
grade Ta or T1 lesion bladder cancer…”
Section 4.1. Overview of 
Study Design  
Text was revised: “All subjects randomized and
enrolled to erdafitinib… Subjects receiving
erdafitinib…”
Section 4.1. Overall Design. 
Text was revised: “Total subject involvement in
the main study is up to 4 years from the day of
randomization (Cohort 1) or enrollment (Cohort
2 and Cohort 3).”
Section 8.1.3. Treatment 
Phase 
Clarification was made that treatment with
Investigator’s Choice will follow guidance in
Section 6.1.2. Reference to standard local
practice was deleted.
Section 8.2.1.1. Cohort 1 
Text was revised: “If there are no muscle fibers
in the biopsy, subjects must undergo re-TURBT
before randomization or enrollment.”
Section 8.2.1.3. Cohort 3 
Text was revised: “Subjects with stable disease
or disease progression will must undergo
TURBT of the marker lesion and discontinue
erdafitinib. Subjects with PR may, at the
investigator’s discretion, either continue
treatment with erdafitinib or discontinue
erdafitinib and undergo TURBT of the marker
lesion.”
Section 8.3.5. 
Ophthalmologic Examination  
A description of assessment timing was replaced
with a cross reference to the Schedule of
Activities.
Section 8.9. Biomarkers 
(
 
From Urine) 
Clarifying text was added: “Instrumented (ie,
urine samples collected during cystoscopy)urine
samples…”
CCI
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
167
Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
Section 10.8. Appendix 8
(Amsler Grid)
Information to be collected on the Amsler
Recording Chart page was limited to subject
number, date, and examiner.
Section 10.11. Appendix 11
(Crossover Schedule of
Activities)
For the assessments “Physical examination”,
“12-lead ECG”, “Urine or serum β-hCG
pregnancy test”, “Ophthalmologic evaluation”,
“Cystoscopy”, “Urine cytology”, and “Blood
(plasma) for ctDNA” the description of
Treatment Phase and Follow-up Phase
assessment timing was aligned with changes to
the main Schedule of Activities. For the
assessments “Cystoscopy” and “Urine cytology”
reference to Cohort 1 and Cohort 2 was deleted.
Synopsis (Overall Design,
Treatment Groups); Section
4.1 (Overall Design); Section
6.1.2. Investigator’s Choice;
Section 6.1.3. Continuation of
Treatment; Section 8.2.1.5.
Cystoscopy, Urine Cytology,
Bladder Mapping, and
CT/MRI Urogram; Section
10.11. Appendix 11
(Erdafitinib Crossover)
Clarification was added that assessment of
recurrence, progression, and disease response
will be based on locally confirmed
histopathologic evaluation.
To clarify an assessment,
activity, analysis, or study
design element
Synopsis (Overall Design,
Treatment Groups); Section
1.3. Schedule of Activities
(Cystoscopy); Section 4.1
(Overall Design); Section
6.1.2. Investigator’s Choice;
Section 6.1.3. Continuation of
Treatment; Section 10.11.
Appendix 11 (Erdafitinib
Crossover)
Clarification was made that subjects in Cohort 1
will be monitored for high-risk grade
recurrence.
Synopsis (Treatment Groups);
Section 4.1. Overall Design;
Section 6.1.1. Erdafitinib;
Section 8.1.3. Treatment
Phase; Section 8.2.1.5.
Cystoscopy, Urine Cytology,
Bladder Mapping, and
CT/MRI Urogram
The description of treatment for Cohort 3 after
the first 3 months of the Treatment Phase was
revised for completeness based on response to
treatment.
Section 4.1. Overall Design  
Clarification was made: “Subjects will be
assessed for disease response by cystoscopy and
bladder mapping for detection and tracking of
new lesions…”
Clarification was made: “An IDMC will be
commissioned to review safety and efficacy data
during the study primarily for Cohort 1…” Cross
reference to a description of interim analysis was
added, and the following text was deleted: “The
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
168
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
IDMC will review safety and efficacy results of
both interim analyses (see Section 9.5).”
Clarification was made that “Subjects who
receive erdafitinib during the main study will
have plasma erdafitinib concentration
measurements during the Treatment Phase for
pharmacokinetic assessment.”
Section 4.1; Overall Design  
Clarification made that biomarker assessments
will be performed for all subjects receiving
erdafitinib.
Section 4.2. Scientific 
Rationale (Blinding); Section 
6.3. Measures to Minimize 
Bias
Clarification was added that the sponsor (as well
as investigators and subjects) is not blinded to
treatment assignment.
Section 4.2. Scientific 
Rationale (MRU Data 
Collection)
The description of planned MRU analyses was
rephrased.
Section 4.2.1. Study-Specific 
Ethical Design 
Considerations; Section 8. 
Study Assessments and 
Procedures; Section 10.11. 
Appendix 11 (Erdafitinib 
Crossover) 
The total blood volume collected during the
main study was revised from 407 mL to 682 mL.
Detailed collection volumes were revised in
Section 8. Total blood volume for subjects also
participating in the DDI substudy increased from
493 mL to 768 mL. Text was added to
acknowledge that the blood volume actually
collected may vary for reasons such as “a
subject’s visit schedule and childbearing
potential”. Total and detailed blood volumes
collected during the Erdafitinib Crossover were
added in Section 10.11.
Section 6. Study Drug 
Clarification was added that erdafitinib
administered during the Erdafitinib Crossover is
considered study drug.
Section 6.5. Concomitant 
Therapy  
Emphasis was added that all prior anticancer
therapy will be recorded in the eCRF.
Section 6.6.3. Investigator’s 
Choice Dose Modification  
Detail was added: “Changes to intravesical
gemcitabine or intravesical MMC/hyperthermic
MMC dose or regimen for subjects in Cohort 1
assigned to receive Investigator’s Choice (ie,
additional doses of induction or maintenance)
will be directed by local standard practice of
care...”
8.1.2. Screening Phase; 
Section 10.10. Drug-drug 
Interaction Substudy  
Text was added to specify the role of an
independent witness to assist with PRO
questionnaires during the main study and
completion of diary cards during the DDI
substudy.
Section 8.1.4.2.1. Disease 
Assessment Follow-up 
Text was added that other assessments, in
addition to disease assessment, will be
performed during the Disease Assessment
Follow-up period.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
169
Status: Approved, Date: 13 July 2023
Section number
and Name
Description of Change 
Brief Rationale
Section 8.2.1.5. Cystoscopy,
Urine Cytology, Bladder
Mapping, and CT/MRI
Urogram; Section 10.11.
Appendix 11 (Crossover
Schedule of Activities);
Section 10.12. Appendix 12
(Bladder Map)
Detail was provided on requirements for bladder
mapping, and a new Bladder Map Appendix
(Appendix 12) was added.
Section 9.4.3. Secondary
Efficacy Endpoints
The definition of RFS2 was modified as follows:
“RFS2 is defined as the time from the date of
randomization until the date of the reappearance
of high-risk disease (high-grade Ta, T1 or CIS)
on the first subsequent non-surgical anticancer
treatment, or death, whichever is reported first.”
Section 10.10. Appendix 10
(Drug-drug Interaction
Substudy)
Statements were added stating that residual
plasma samples and residual urine samples from
the DDI substudy may be used for exploratory
analysis of endogenous drug disposition
biomarkers if there is sufficient sample
remaining.
Section 10.2. Appendix 2.
Regulatory, Ethical, and
Study Oversight
Considerations (Committee
Structure)
Text was revised: “Based on the results from
these scheduled safety review meetings, the
IDMC chair may request additional safety
interim analyses and more frequent monitoring”.
The IDMC chair is not
limited in the type of
additional interim analyses
that may be requested.
Section 6.2.
Preparation/Handling/Storage/
Accountability
Clarification of supplemental Investigational
Product Preparation Instructions and
Investigational Product Procedures Manual
materials was provided.
To clearly identify all
supplemental pharmacy
manual material provided.
Section 7.1. Discontinuation
of Study Drug
The following reason for discontinuation of
study drug was deleted: “Investigator decision”.
Text was redundant, no
longer relevant, or
unnecessary for endpoint
analysis
Section 8.2.1.3. Cohort 3 
The following text was deleted: “No biopsy will
be done if the tumor is not visible and urine
cytology is negative.”
Section 8.2.1.5. Cystoscopy, 
Urine Cytology, Bladder 
Mapping, and CT/MRI 
Urogram  
The following text was deleted: “If a subject 
demonstrates progression, a tissue sample should
be collected for biomarker analysis.” and
“Additionally, at the time of disease recurrence
or progression, the decision for next treatment
option (therapy, cystectomy or both) will be
entered in the eCRF. If the subject declines
cystectomy, the reason will be entered into the
eCRF.”
.
Section 10.13. Appendix 13 
(Protocol Amendment 
History) 
Text was modified to direct readers to the 
Protocol Amendment Summary of Changes
Table for a description of this protocol
amendment.
Document version control.
Section 10.1. Appendix 1 
The list of abbreviations was updated. 
To define abbreviations
used in text.
Section 3. Objectives and 
Endpoints 
For the MRU Exploratory Endpoint: “Evaluation 
of all the health states generated by the EQ-5D- 
5L utility and including visual analogue scale
(VAS)”
Typographical error was
corrected.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
170
Status: Approved, Date: 13 July 2023
Section number 
and Name
Description of Change 
Brief Rationale
Section 5.1. Inclusion Criteria 
(No. 2) 
For inclusion criterion no. 2, part b, the
following typographical error was corrected:
“Papillary disease (Cohort 1) must be high-risk
disease, defined as high-grade disease Ta/T1
lesion.”
Section 8.2.1.3. Cohort 3 
Text revised: “Subjects in Cohort 3 with PR or
CR at within 3 months…”
Section 10.10. Appendix 10 
(DDI Table 2) 
The Study Day 1 time point was corrected to
show it is in the DDI Treatment Phase.
Section 4.3.3. Mitomycin C 
Dose Selection
“40 mL mg in 40 mL”
Throughout the protocol 
Minor grammatical, formatting, or spelling 
changes were made. Abbreviation usage was
updated.
Minor errors were noted.
NCT04172675


JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
11. 
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Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
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CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
39. Sockett LJ, Borwell J, Symes A, Parker T, Montgomery BSI, Barber NJ. Electro-motive drug administration
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JNJ-42756493 (erdafitinib)
Clinical Protocol 42756493BLC2003 –Amendment 6
CONFIDENTIAL –FOIA Exemptions Apply in U.S. 
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Status: Approved, Date: 13 July 2023
INVESTIGATOR AGREEMENT
I have read this protocol and agree that it contains all necessary details for carrying out this study. I will
conduct the study as outlined herein and will complete the study within the time designated.
I will provide copies of the protocol and all pertinent information to all individuals responsible to me who
assist in the conduct of this study. I will discuss this material with them to ensure that they are fully informed
regarding the study intervention, the conduct of the study, and the obligations of confidentiality.
Coordinating Investigator (where required):
Name (typed or printed):
Institution and Address:
Signature: 
Date:
(Day Month Year)
Principal (Site) Investigator:
Name (typed or printed):
Institution and Address:
Telephone Number:
Signature: 
Date:
(Day Month Year)
Sponsor's Responsible Medical Officer:
Name (typed or printed): 
 MD
Institution: 
Janssen Research & Development
Signature: electronic signature appended at the end of the protocol 
Date:
(Day Month Year)
Note: If the address or telephone number of the investigator changes during the study, written notification will be
provided by the investigator to the sponsor, and a protocol amendment will not be required.
PPD
NCT04172675


Signature
User 
Date 
Reason
 
13-Jul-2023
14:27:33
(GMT)
Document Approval
PPD
NCT04172675

SAP_001.pdf: 
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Final, Date: 17 April 2023
Janssen Research & Development
Statistical Analysis Plan
A Randomized Phase 2 Study of Erdafitinib Versus Investigator Choice of Intravesical 
Chemotherapy in Subjects Who Received Bacillus Calmette-Guérin (BCG) and Recurred 
With High Risk Non-Muscle-Invasive Bladder Cancer (NMIBC) and FGFR Mutations and 
Fusions
Protocol 42756493BLC2003
Original Protocol 24-September-2019
Amendment 1 05-November-2019
Amendment 2 26-March-2020
Amendment 3 26-October-2020
Amendment 4 08-February-2021
Amendment 5 24-September-2021
Amendment 6 11-November-2022
JNJ-42756493  (erdafitinib)
Status:
Final
Date:
17 April 2023
Prepared by:
Janssen Research & Development, LLC  
Document No.: EDMS-ERI-203723576, 4.0
Compliance: The study described in this report was performed according to the principles of Good Clinical Practice (GCP). 
Confidentiality Statement
The information in this document contains trade secrets and commercial information that are privileged or confidential and 
may not be disclosed unless such disclosure is required by applicable law or regulations. In any event, persons to whom the 
information is disclosed must be informed that the information is privileged or confidential and may not be further disclosed 
by them. These restrictions on disclosure will apply equally to all future information supplied to you that is indicated as 
privileged or confidential.
NCT04172675


JNJ-42756493  (erdafitinib)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
2
Status: Final, Date: 17 April 2023
TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
AMENDMENT HISTORY.............................................................................................................................. 4
ABBREVIATIONS ........................................................................................................................................ 6
INTRODUCTION........................................................................................................................................... 8
1.1.
Trial Objectives ................................................................................................................................ 8
1.1.1.
Primary Objective (Cohort 1: Papillary disease only) ................................................................... 8
1.1.2.
Secondary Objectives................................................................................................................... 8
1.1.2.1.
Secondary Objectives for Cohort 1............................................................................................ 8
1.1.2.2.
Other Secondary Objectives for All Cohorts.............................................................................. 8
1.1.3.
Exploratory Objectives.................................................................................................................. 8
1.1.3.1.
Cohort 2 (Carcinoma in situ (CIS) with or without papillary disease)........................................ 8
1.1.3.2.
Cohort 3 (Intermediate-risk marker lesion)................................................................................ 9
1.2.
Trial Design ...................................................................................................................................... 9
1.3.
Statistical Hypotheses for Trial Objectives..................................................................................... 12
1.4.
Sample Size Determination ........................................................................................................... 12
1.5.
Randomization and Blinding .......................................................................................................... 13
2.
GENERAL ANALYSIS DEFINITIONS .............................................................................................. 13
2.1.
Visit Windows................................................................................................................................. 13
2.2.
Pooling Algorithm for Analysis Centers.......................................................................................... 14
2.3.
Analysis Sets.................................................................................................................................. 14
2.3.1.
Efficacy Analysis Set(s) .............................................................................................................. 14
2.3.1.1.
Intent-to-Treat Analysis Set..................................................................................................... 14
2.3.2.
Safety Analysis Set..................................................................................................................... 14
2.3.3.
PK Evaluable Analysis Set ......................................................................................................... 15
2.4.
Definition of Subgroups.................................................................................................................. 15
2.5.
Study Day and Relative Day .......................................................................................................... 16
2.6.
Baseline ......................................................................................................................................... 16
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution ................................................. 16
2.7.1.
Methods of Handling Missing Data............................................................................................. 16
2.7.2.
Missing/Partial Dates.................................................................................................................. 17
3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW....................................... 18
4.
SUBJECT INFORMATION................................................................................................................ 18
4.1.
Demographics and Baseline Characteristics ................................................................................. 18
4.2.
Disposition Information................................................................................................................... 19
4.3.
Treatment Compliance................................................................................................................... 19
4.4.
Extent of Exposure......................................................................................................................... 20
4.5.
Protocol Deviations ........................................................................................................................ 21
4.6.
Prior and Concomitant Medications ............................................................................................... 21
5.
EFFICACY ......................................................................................................................................... 22
5.1.
Analysis Specifications................................................................................................................... 22
5.1.1.
Level of Significance................................................................................................................... 22
5.1.2.
General Analysis Considerations ............................................................................................... 22
5.2.
Primary Efficacy Endpoint(s).......................................................................................................... 22
5.2.1.
Recurrence-free Survival............................................................................................................ 22
5.2.1.1.
Definition.................................................................................................................................. 22
5.2.1.2.
Estimand.................................................................................................................................. 23
5.2.1.3.
Analysis Methods .................................................................................................................... 23
5.2.1.4.
Subgroup Analyses ................................................................................................................. 24
5.3.
Secondary Efficacy Endpoints (Cohort 1)...................................................................................... 24
NCT04172675


JNJ-42756493  (erdafitinib)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
3
Status: Final, Date: 17 April 2023
5.3.1.
Time to Progression (TTP) ......................................................................................................... 24
5.3.1.1.
Definition.................................................................................................................................. 24
5.3.1.2.
Analysis Methods .................................................................................................................... 24
5.3.2.
Overall Survival........................................................................................................................... 25
5.3.2.1.
Definition.................................................................................................................................. 25
5.3.2.2.
Analysis Methods .................................................................................................................... 25
5.3.3.
RFS Rate .................................................................................................................................... 25
5.3.3.1.
Definition.................................................................................................................................. 25
5.3.3.2.
Analysis Methods .................................................................................................................... 25
5.3.4.
RFS2........................................................................................................................................... 25
5.3.4.1.
Definition.................................................................................................................................. 25
5.3.4.2.
Analysis Methods .................................................................................................................... 25
5.4.
Exploratory Efficacy Endpoints ...................................................................................................... 26
5.4.1.
All Cause RFS (Cohort 1)........................................................................................................... 26
5.4.1.1.
Definition.................................................................................................................................. 26
5.4.1.2.
Analysis Methods .................................................................................................................... 26
5.4.2.
Complete Response Rate at 8 weeks and 32 weeks  (Cohort 2)............................................... 26
5.4.2.1.
Definition.................................................................................................................................. 26
5.4.2.2.
Analysis Methods .................................................................................................................... 27
5.4.3.
Duration of Response (Cohort 2)................................................................................................ 27
5.4.3.1.
Definition.................................................................................................................................. 27
5.4.3.2.
Analysis Methods .................................................................................................................... 27
5.4.4.
Complete Response Rate (Cohort 3) ......................................................................................... 27
5.4.4.1.
Definition.................................................................................................................................. 27
5.4.4.2.
Analysis Methods. ................................................................................................................... 27
5.4.5.
Best Overall Response (Cohort 3).............................................................................................. 27
5.4.5.1.
Definition.................................................................................................................................. 27
5.4.6.
Duration of Response (Cohort 3)................................................................................................ 27
5.4.6.1.
Definition.................................................................................................................................. 27
5.4.6.2.
Analysis Methods .................................................................................................................... 28
6.
SAFETY............................................................................................................................................. 28
6.1.
Adverse Events .............................................................................................................................. 28
6.1.1.
All Adverse Events...................................................................................................................... 28
6.1.2.
Anticipated/Unlisted (unexpected) Adverse Event ..................................................................... 29
6.1.3.
Adverse Events of Special Interest and other safety observations ............................................ 29
6.2.
Deaths............................................................................................................................................ 30
6.3.
Clinical Laboratory Tests................................................................................................................ 30
6.4.
Electrocardiogram.......................................................................................................................... 30
6.5.
Eastern Cooperative Oncology Group (ECOG) Performance Status............................................ 31
6.6.
Other Safety Parameters ............................................................................................................... 31
7.
PHARMACOKINETICS/PHARMACODYNAMICS ........................................................................... 31
7.1.
Pharmacokinetics........................................................................................................................... 31
8.
BIOMARKERS................................................................................................................................... 31
REFERENCES............................................................................................................................................ 32
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ABBREVIATIONS
AE
adverse event
ALT
alanine aminotransferase
AST
aspartate aminotransferase
ATC
anatomic and therapeutic class
AUC
area under the curve
BCG
Bacillus Calmette-Guérin
BOR
best overall response
C1D1
Cycle 1 Day 1
CFA
Confirmatory factor analysis
CI
confidence interval
CIS
carcinoma in situ
CR
complete response
CRF
case report form
CSR
Clinical Study Report
CTCAE
Common Terminology Criteria for Adverse Events
CV
coefficient of variation
DBP
diastolic blood pressure
DOR
duration of response
DPS
Data Presentation Specifications
eCDF
Empirical Cumulative Distribution Function
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
EFA
Exploratory factor analysis
EORTC
European Organisation for Research and Treatment of Cancer
EOT
End of Treatment
EU
European Union
eCRF
electronic case report form
EQ-5D-5L
EuroQol-5 Dimension 5-Level Instrument
FDA
Food and Drug Administration
FGFR
fibroblast growth factor receptor
GHS
Global Health Status
HR
hazard ratio
HRQoL
health-related quality of life
IAP
interim analysis plan
ICH
International Conference on Harmonisation
IDMC
Independent Data Monitoring Committee
IEC/IRB
Independent Ethics Committee/Institutional Review Board
IQ
interquartile
IR
intermediate risk
ITT
intent-to-treat
KM
Kaplan-Meier
LS
Least Squares
MCID
Minimum Clinically Important Difference
MedDRA
Medical Dictionary for Regulatory Activities
MMC
mitomycin C
NA
North America
NCI
National Cancer Institute
NMIBC
non-muscle invasive bladder cancer
OS
overall survival
PD
pharmacodynamic(s)
PD
progressive disease
PGIC
Patient Global Impression of Change
PGIS
Patient Global Impression of Severity
PI
principal investigator
PK
pharmacokinetic(s)
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PP
per protocol
PR
partial response
PRO
patient-reported outcome
PT
preferred term
QLQ-C30
Quality of Life Questionnaire Core-30 Items
RFS
recurrence-free survival
RFS2
recurrence-free survival on subsequent anticancer therapy
ROW
rest of the world
RS
Raw Score
SAE
serious adverse event
SAP
Statistical Analysis Plan
SBP
systolic blood pressure
SD
standard deviation
SD
stable disease
SOC
system organ class
SUSAR
sudden unexpected serious adverse reaction
TEAE
treatment-emergent adverse event
TTP
time to progression
TUR
transurethral resection
US NCI
United States National Cancer Institute
VAS
Visual Analogue Score
WBC
white blood cell
WHO
World Health Organization
WHO-DD
World Health Organization Drug Dictionary
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INTRODUCTION
The purpose of the statistical analysis plan (SAP) is to lay out key elements including definitions 
and statistical methods for the planned analyses for efficacy, safety, and other endpoints. The SAP 
was
based 
upon 
the
fifth 
amended 
version 
of 
the 
study 
protocol 
42756493BLC2003<clinical_trial_id> (dated 24 September 2021) and further updated 
according to an internal decision to terminate the study’s enrollment earlier than original planned 
at the study design.  
1.1.
Trial Objectives
1.1.1.
Primary Objective (Cohort 1: Papillary disease only)
For Cohort 1, the primary objective of the study is to evaluate recurrence-free survival (RFS) in 
subjects treated with erdafitinib vs Investigator’s Choice, for subjects with high-risk NMIBC who 
harbor FGFR mutations or fusions, and who recurred after BCG therapy.
1.1.2.
Secondary Objectives 
1.1.2.1.
Secondary Objectives for Cohort 1 
The secondary objectives for Cohort 1 are the following:

To evaluate time to progression.

To evaluate overall survival (OS).

To evaluate RFS rate at 6 and 12 months. 
1.1.2.2.
Other Secondary Objectives for All Cohorts
The following secondary objectives will be evaluated for all cohorts:

To evaluate erdafitinib PK.

To evaluate safety and tolerability of erdafitinib.
1.1.3.
Exploratory Objectives
1.1.3.1.
Cohort 2 (Carcinoma in situ (CIS) with or without papillary disease)
The efficacy objectives for Cohort 2 are to evaluate the efficacy of erdafitinib based on the 
following: 

Complete response (CR) rate at 8 weeks.

CR rate at 32 weeks

Duration of response (DOR)
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1.1.3.2.
Cohort 3 (Intermediate-risk marker lesion)
The efficacy objective for Cohort 3 as an exploratory endpoint is to evaluate the efficacy of 
erdafitinib based on the following:

CR rate 

Best overall response (BOR)

DOR
1.2.
Trial Design
This is an open-label, global, multicenter, randomized, Phase 2 study of the safety and efficacy of 
erdafitinib in subjects with NMIBC and FGFR mutations or fusions (see protocol Section 5.1). 
Cohort 1 was planned to enroll approximately 240 subjects with high-risk NMIBC presenting as 
papillary tumor only, with disease recurrence after BCG therapy, and who either refuse or are not 
eligible for cystectomy The reason for not being eligible for cystectomy or for refusing cystectomy 
are entered into the electronic case report form (eCRF). Subjects are assigned randomly 2:1 to 
treatment with erdafitinib or the investigator’s choice of either intravesical gemcitabine or 
intravesical mitomycin C (MMC)/hyperthermic MMC, respectively. Randomization is stratified 
by tumor stage (Ta vs T1) and type of prior BCG therapy (BCG-unresponsive vs BCG-
experienced). BCG strain administered is also be documented in the eCRF. Subjects in the BCG-
experienced strata are capped at approximately 50% of the total study population (See protocol 
Section 6.3). Investigators must choose between intravesical gemcitabine or intravesical 
MMC/hyperthermic MMC for each subject at screening, and the choice of the agent must take 
prior exposure into consideration. Subjects in Cohort 1 with locally confirmed high-risk recurrence 
on Investigator’s Choice may cross over to treatment with erdafitinib. Molecular screening must 
start within 12 weeks after the last transurethral resection of bladder tumor (TURBT) done for 
high-risk recurrence if molecular testing is being done on post-BCG specimen. Peri-operative 
intravesical chemotherapy prior to study entry per local standard of care and prior immunotherapy 
(e.g., PD1 inhibitor, etc.) are allowed.
The enrollment of Cohort 1 was terminated in later 2022 due to poor accrual. At the enrollment 
termination, 73 subjects were randomized into the Cohort 1 according to the study design and they 
were treated and followed per protocol.
Cohort 2 and Cohort 3 are exploratory. 
Cohort 2 was planned to enroll approximately 20 subjects with high-risk, BCG-unresponsive 
NMIBC presenting as CIS with or without concurrent papillary tumor, and who either refuse or 
are not eligible for cystectomy. The reason for not being eligible for cystectomy or for refusing 
cystectomy will be entered into the eCRF. All subjects enrolled in Cohort 2 will receive treatment 
with erdafitinib. Peri-operative intravesical chemotherapy prior to study entry per local standard 
of care and prior immunotherapy (e.g., PD1 inhibitor, etc.) are allowed. Additionally, subjects in 
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this cohort may receive chemotherapy as bridging therapy after adequate BCG therapy while being 
considered for trial.
Cohort 3 was planned to enroll approximately 20 subjects at select study sites and will include 
subjects with intermediate-risk NMIBC presenting as papillary disease only. All previous tumors 
for these subjects must be low grade (G1-G2), Ta, or T1, with no previous CIS. Furthermore, 
subjects must have a risk of progression less than 5% for 2 years, and the risk of recurrence must 
be greater than 50% as calculated using the European Organisation for Research and Treatment of 
Cancer (EORTC) risk calculator.4 There are no predefined BCG or intravesical chemotherapy 
requirements for subjects enrolled in Cohort 3. All tumors must be removed except for a single, 
untouched 5 to 10 mm lesion. All subjects enrolled in Cohort 3 will receive treatment with 
erdafitinib. 
The enrollment of both exploratory cohorts was terminated in December 2022 as enrollment 
approached approximate target. At the enrollment termination, 16 subjects were enrolled into 
Cohort 2 and 18 subjects were enrolled into Cohort 3 according to the study design and they were 
treated and followed per protocol.
Molecular eligibility will be determined before screening for remaining eligibility criteria. The 
Treatment Phase will begin on Day 1 for subjects meeting all eligibility criteria. The Follow-up 
Phase includes a 30-day Safety Follow-up Visit, disease assessment follow-up, and survival 
follow-up. An Independent Data Monitoring Committee (IDMC) was commissioned for Cohort 
1 and dissolved after the Cohort 1 termination of enrollment.
A diagram of the study design is provided in 
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Figure 1. Details about the study design can be found in the study protocol.  
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Figure 1: Schematic Overview of the Study (original design prior to the termination of 
enrollment)
BCG= bacillus Calmette-Guérin; CIS=carcinoma in situ; CR=complete response; FGFR= fibroblast growth factor receptor; 
HR=high risk; IR=intermediate risk; MMC=mitomycin C; NMIBC=non-muscle-invasive bladder cancer; RFS=recurrence-free-
survival; TUR=transurethral resection
1.3.
Statistical Hypotheses for Trial Objectives
No hypothesis testing will be performed for Cohort 1, Cohort 2, or Cohort 3.
1.4.
Sample Size Determination
Cohort 1 was planned to enroll approximately 240 subjects in a 2:1 randomization ratio. The 
primary efficacy analysis was planned to be performed when approximately 160 recurrence events 
were observed. This plan was based on the assumption of 67% improvement in the median RFS 
of the erdafitinib arm over the control arm, i.e., a hazard ratio (HR) of 0.60 for the erdafitinib arm 
relative to the control arm, improving the median RFS from 6 months to 10 months, 160 recurrence 
events would provide approximately 86% power to achieve a statistically significant difference 
between the treatment arms in RFS (2-sided alpha=0.05). 
The termination of Cohort 1 enrollment resulted in a sample size of approximately 73 for the 
purpose of summarizing the data descriptively. With a total number of 73 subjects under the 2:1 
randomization ratio, the 95% CIs for the possible hazard rations assumed to be observed at the end 
of the study are presented as follows:
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Hazard Ratio Confidence Intervals
Number of Events
20
30
40
50
Hazard Ratio
0.4
(0.16, 1.01)
(0.19, 0.85)
(0.21, 0.77)
(0.22, 0.72)
0.5
(0.20, 1.27)
(0.23, 1.07)
(0.26, 0.96)
(0.28, 0.90)
0.6
(0.24, 1.52)
(0.28, 1.28)
(0.31, 1.16)
(0.33, 1.08)
Cohort 2 was planned to enroll approximately 20 subjects. As suggested by the International 
Bladder Cancer Group1, a 40% CR rate at 6 months would be clinical meaningful. With 20 
subjects, the cohort would have produced a 2-sided 95% CI of (16%, 64%) when the observed CR 
rate is 40%. The termination of enrollment resulted in a Cohort 2 sample size of 16. 
Cohort 3 was planned to enroll approximately 20 subjects. A CR rate of 30% to 50% has been 
reported in most previous marker lesion studies2 With 20 subjects, the lower bound of the 95% 
CIs would exclude 0 if the observed CR rate is at least 30%. The 95% CIs for different observed 
CR rates based on 20 subjects are as follows:  
Observed rate
95% CI
30%
(7%, 53%)
40%
(16%, 64%)
50%
(26%, 74%)
60%
(36%, 84%)
The termination of enrollment resulted in a Cohort 3 sample size of 18.
1.5.
Randomization and Blinding
This is an open-label study; neither the sponsor, investigators, nor subjects will be blinded to 
assigned treatment. Central randomization will be implemented in this study. In Cohort 1, subjects 
will be randomly assigned to 1 of 2 treatment groups in a 2:1 randomization ratio (erdafitinib: 
Investigator’s Choice) based on a computer-generated randomization schedule prepared before the 
study by or under the supervision of the sponsor. The randomization will be balanced by using 
randomly permuted blocks and will be stratified by the type of resected papillary disease (Ta vs 
T1) and type of prior BCG therapy (BCG-unresponsive vs BCG-experienced). Subjects in the 
BCG-experienced strata will be capped at approximately 50% of the total study population. 
Investigators must indicate their Investigator’s Choice selection for each subject during screening.
All subjects in Cohort 2 and Cohort 3 will be assigned to treatment with erdafitinib.
2.
GENERAL ANALYSIS DEFINITIONS
2.1.
Visit Windows
Visit windowing will be based on the following phases and cycles: 
Screening Phase: The Full-Study Screening Phase includes the interval between signing the 
Main-study ICF and the day the subject is randomized (Cohort 1) or receives the first dose of study 
drug (Cohort 2 and Cohort 3). The full Screening Phase should not exceed 35 days. Assessments 
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that are required to demonstrate eligibility may be performed over the course of 1 or more days 
during the screening process. In specific, for Cohort 1, the Screening Phase is a period of 35 days 
before the subject is randomized.  For Cohort 2 and 3, the Screening Phase is a period of 35 days 
before the subject receives the first dose of study drug.  
Treatment Phase: The Treatment Phase will begin on Cycle 1 Day 1 following the first dose of 
study drug, and end at the date of end of treatment (EoT) visit. If the date of the end of treatment 
is not available, the date of last dose of study medication + 7 days will be used.
The Treatment Phase will be subdivided by cycles, based on the nominal treatment cycles as 
defined in protocol and recorded on the Case Report Form (CRF). A treatment cycle is defined as 
28 days.  
Follow-up Phase: After EoT until the study cutoff. The Follow-up Phase includes a 30-day (+ 7 
days) Safety Follow-up Visit, disease assessment follow-up (every 24±2 weeks), and survival 
follow-up (every 12±2 weeks). Total subject involvement in the study is up to 4 years from the 
day of randomization (Cohort 1) or enrollment (Cohort 2 and Cohort 3). 
Cycle-based analysis may be performed for safety parameters during the Treatment Phase up to 
date of last dose + 7 days or End-of-Treatment visit whichever comes later.  
2.2.
Pooling Algorithm for Analysis Centers
All participating study sites will be pooled together for analysis.
2.3.
Analysis Sets
2.3.1.
Efficacy Analysis Set(s)
2.3.1.1.
Intent-to-Treat Analysis Set
In Cohort 1, the Intent-to-Treat (ITT) Analysis Set includes all randomized subjects. Subjects in 
this group will be primarily analyzed by the treatment to which they are assigned, regardless of 
the actual treatment received. 
In Cohort 2 and 3, the ITT Analysis Set includes all treated subjects.
Primary efficacy analyses, secondary efficacy endpoints, and summary of subject disposition, 
demographics and baseline characteristics will be based on the ITT Analysis Set. 
2.3.2.
Safety Analysis Set
The Safety Analysis Set includes all subjects who received at least 1 dose of study drug. This 
analysis set will be used for exposure and safety analyses. Safety data will be analyzed according 
to the actual treatment received.
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2.3.3.
PK Evaluable Analysis Set
The PK Evaluable Analysis Set includes all subjects who have received at least 1 dose of 
erdafitinib and had at least 1 PK sample obtained post-treatment.
The Erdafitinib plasma PK analysis set is defined as subjects (FGFR+): 

who have received at least 1 dose of study drug;

who have at least one evaluable PK sample
A plasma PK sample is considered to be not evaluable if 

there are e.g., missing information of dosing and sampling times

vomiting occurs within the first 2.5 hours following the last dose intake prior to the predose 
PK sample draw

vomiting occurs within first 2.5 hours after Cycle 2 Day 1 dose

the patient does not take study drug according to the originally assigned dose and assigned 
dose post up-titration for at least 5 consecutive days without interruption or dose 
modification prior to the PK sampling day

For the predose PK sample, the draw occurs outside the 18-30 hours window after the last 
dose intake

For the predose PK sample, the draw occurs after the next dose  
A tissue or a urine erdafitinib PK sample is considered to be not evaluable if 

there are e.g., missing information of dosing and sampling times
2.4.
Definition of Subgroups
Subgroup analyses will be performed as appropriate to evaluate the consistency in the selected 
efficacy and safety endpoints. Table 1 below provides the categorical variables for subgroup 
analysis.
Table 1
Categorical variables used for subgroup analyses
Subgroup
Definition
Analysis Type
Region
North America (NA)
Europe (EU)
Rest-of-the-World (ROW)
E, S
Prior BCG Therapy
Unresponsive
Experienced
E, S
Tumor Stage
Ta
T1
E
Baseline ECOG Status
0
1
E
FGFR Alteration Type
Mutations
Fusions
E
PD-L1 Status
Positive 
Negative 
E
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Subgroup
Definition
Analysis Type
Baseline Creatinine 
Clearance
< 30 mL/min
30 - <60 mL/min
≥60 mL/min
E, S
Age Group
<65
≥65
E, S
Gender
Female
Male
E, S
Race

White

Non-white
E, S
2.5.
Study Day and Relative Day
A treatment cycle for a specific drug is defined as a cycle in which the subject received any amount 
of the specific drug. The cycle number will be named according to the sequence of every 28-day 
cycle for study drug administration.
Assessments will be presented chronologically by study day and/or cycle day as described below:
The reference date is defined as the date of the initial study agent administration of any study 
agent. If the subject was not dosed, then the visit date should be used. If the visit date is not
available, then the randomization date should be used. Otherwise reference date will be missing.
Study Day = assessment date – reference date + 1 for assessment performed on or after the 
reference date; assessment date – reference date for assessment performed before the reference 
date.
Cycle Day = assessment date – date of first day of the cycle + 1.
The full study screening period is 35 days before the randomization or first dose of the study drug 
on Cycle 1 Day 1. Randomization will occur within 3 days prior to Cycle 1 Day 1. 
There is no “Day 0”.
2.6.
Baseline 
Baseline is defined as the last non-missing observation on or prior to the start of the first study 
drug administration. For subjects who have been randomized but not treated with any dose, 
randomization date will be used as the reference date for baseline value calculation. Change from 
baseline will be defined as the difference between post-baseline value and baseline value.
2.7.
Imputation Rules for Missing AE Date/Time of Onset/Resolution
2.7.1.
Methods of Handling Missing Data
In general, missing data will be treated as missing and no data imputation will be applied, unless 
otherwise specified.
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2.7.2.
Missing/Partial Dates
In general, imputation of missing dates will be made for AE onset date, AE resolution date, date
of death, start and end dates of prior, concomitant, and subsequent therapies, and date of initial 
diagnosis according to the following rules.

Start date will be imputed before end date.

If date is completely missing, no imputation will be made.

If year is missing, no imputation will be made.

If only year is present, but month and day are missing, then June 30th will be used.

If only day is missing but year and month are available, then the 15th of the month will be 
used.
For initial diagnosis if such imputed date is on or after the reference date, then reference date – 1 
will be used. If such imputed date for prior therapies or initial diagnosis is on or after the reference 
date, then reference date – 1 will be used. If such imputed date for subsequent therapies is before 
date of last dose, then date of last dose +1 will be used. The imputed start date for subsequent 
therapies will be adjusted sequentially using the following steps:

If the imputed start date is before the last dose date but in the same year and month, then the 
last dose date will be used.

If subsequent therapy end date is not missing and is before the imputed subsequent therapy 
start date, then the subsequent therapy end date will be used as the start date.

If the imputed date is for a date of death and is before the last date that the subject is known 
to be alive, the latter date will be used. If the last known alive date is beyond the clinical cutoff 
date, use the clinical cutoff date.
The imputed AE start date will be adjusted sequentially using the following steps:

If the imputed date is in the same year and month as but day before the first dose date, then 
the first dose date will be used, or if it is in the same year and month as but day after the last 
dose date + 30 days, then the last dose date + 30 days will be used.

If AE end date is not missing and the imputed AE start date is after the AE end date, then the 
AE end date will be used.

If the imputed AE start date and is after date of death, then date of death will be used

If the imputed AE start date is in the same month and year but after the 1st subsequent therapy 
start date, then 1st subsequent therapy start date will be used.

If the imputed date is for an AE end date and is after the death date, then the death date will 
be used, or if the imputed AE end date is before the AE start date, then the AE start date will 
be used.
The AE imputation rule will be used for concomitant medication.
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3.
INTERIM ANALYSIS AND DATA MONITORING COMMITTEE REVIEW
Two interim analyses were originally planned. Due to the change in the conduct of the study, they 
will no longer be included.
An IDMC was commissioned for reviewing safety data at various intervals outlined in the IDMC 
Charter. 
The IDMC monitored data to ensure the safety of the subjects enrolled in this study. The safety 
review focused on deaths, treatment discontinuations, serious adverse events, Grade ≥3 events, 
and events of special interest. Based on the results from these scheduled safety review meetings, 
the IDMC chair could have requested additional interim analyses and more frequent monitoring. 
All deaths, treatment discontinuations and serious adverse events were reviewed by the sponsor’s 
medical monitor on an ongoing basis to identify safety concerns, and the IDMC was informed of 
any new potential signals.
The IDMC was composed of at least 2 medical experts in the relevant therapeutic area and at least 
1 statistician. Refer to the IDMC charter for detailed procedures.
Prior to the termination of enrollment, an independent third-party Statistical Support Group (SSG) 
prepared the unblinded data packages, which included tables, listings and/or figures, and sent the 
packages to the IDMC for several safety review meetings. Due to the termination of enrollment in 
all cohorts of the study and since a recent IDMC found the safety of erdafitinib in BLC2003
consistent with the known safety profile of erdafitinib, no further monitoring by the IDMC will be 
conducted.
4.
SUBJECT INFORMATION
The number of subjects in each analysis set will be summarized and listed by treatment group and 
overall within each cohort. 
4.1.
Demographics and Baseline Characteristics
Subject demographics and baseline disease characteristics will be summarized using descriptive 
statistics, which include the following items:

Demographics and baseline characteristics: 
o
age, sex, race, ethnicity, geographic region, height (cm), weight (kg), systolic blood 
pressure/diastolic pressure (SBP/DBP) (mmHg)

Baseline disease characteristics: 
o
Baseline ECOG (0, 1)
o
Prior BCG therapy (unresponsive, experienced)
o
Tumor stage (Ta, T1)
o
FGFR alteration type 
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o
Specific Mutation (FGFR3 S249C, R248C, G370C, Y373C
o
Specific Gene Fusions (FGFR2-BICC1, FGFR2-CASP7, FGFR3-TACC3, FGFR3-
BAIAP2L1)
o
PD-L1 status (Positive, Negative)

Hematology: hemoglobin, platelet count, white blood cell (WBC) count, absolute neutrophil 
count (ANC)

Comprehensive Metabolic: alanine aminotransferase (ALT), aspartate aminotransferase 
(AST), total bilirubin, creatinine, sodium, calcium, potassium, albumin, bicarbonate, alkaline 
phosphatase, magnesium

1,25-Dihydroxyvitamin D

Phosphate (all subjects at screening; subjects receiving erdafitinib only after screening)

Parathyroid hormone (PTH) (all subjects at screening; subjects receiving erdafitinib only after 
screening)
4.2.
Disposition Information
All enrolled subjects will be summarized overall based on the following:

Subjects completing the study

Subjects who terminated study prematurely

Reasons for termination of study

Subjects who completed study drug

Subjects who discontinued study drug

Reasons for discontinuation of study drug

Treatment disposition

Screen Failures
4.3.
Treatment Compliance
Study drug compliance will be summarized descriptively based on the Safety Analysis Set.
For subjects on erdafitinib (all cohorts), study drug compliance will be calculated as follows:

Study drug compliance (%) = (actual dose taken/total dose prescribed) x100.
For subjects on comparator drugs (gemcitabine or MMC/hyperthermic MMC for Cohort 1), study 
drug compliance will be calculated as follows:

Study drug compliance (%) = (actual number of intravesical infusions /total number of 
infusions prescribed) x100.
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4.4.
Extent of Exposure
The number and percentage of subjects who receive the study drug (the Safety Analysis Set) will 
be summarized by treatment group (erdafitinib vs Investigator’s Choice) for Cohort 1, and for 
Cohorts 2 and 3. The administration of study drugs will be presented, by medication administered 
within each treatment group and will be described in terms of total number of cycles administered, 
the median of cycles administered, dose intensity, dose modifications, dose withholdings, and dose 
interruptions.
For daily dosing, treatment duration for the study will be calculated as date of last dose of study 
drug – date of first dose of study drug + 1. For non-daily dosing, if subjects died before end date 
of last cycle (incomplete last cycle), use death date – date of first dose of study drug + 1.
Descriptive statistics for treatment duration (N, mean, SD, median, and range [minimum, 
maximum]) will be presented by treatment group using the safety population. Subject-years of 
exposure are calculated as days of exposure/365.25. Subject-years will be presented by treatment 
group.
Duration of treatment will be summarized by treatment group. Subjects may be included in more 
than one category if they are administered different treatments, i.e. subjects assigned to 
Investigator’s Choice that cross over to Erdafitinib. Subjects randomized but not dosed will be 
summarized in a separate line.
Total dosing days are defined as the total number of days that study drug (erdafitinib) has been
administered to the subject (excluding days of study drug interruption).
The number (%) of subjects with a dose adjustment will be summarized by treatment group and 
cycle. Reasons for dose adjustments will also be summarized.
Descriptive statistics will be presented for study drug (erdafitinib) using the following parameters:

Number of study drug administrations

Cumulative total dose

Mean daily dose

Relative dose intensity
The mean daily dose of study drug is calculated as (sum of total daily dose during the treatment 
phase)/treatment duration.
Relative dose intensity is defined as cumulative total dose/planned total dose which is based on 
initial planned dose displayed as percentages.
A by-subject listing will present all the study drugs that have been taken by the subject, which 
include cohort, treatment group, study day, cycle day, name of study drug and doses. Any dose 
adjustment/withhold/delays and the reasons need to be presented accordingly.
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4.5.
Protocol Deviations
In general, the following list of major protocol deviations may have the potential to impact 
subjects’ safety or well-being, or the integrity and/or result of the clinical study. Subjects with 
major protocol deviations need to be identified prior to database lock and summarized by the 
following categories:

Informed consent not signed

Entered the study but did not satisfy I/E criteria

Developed withdrawal criteria but not withdrawn

Received wrong study treatment or incorrect dose

Received a disallowed concomitant treatment

Developed AEs that met the criteria for discontinue/interrupt drug but not 
discontinued/interrupted 

Received erroneous test or procedure

Visit schedule outside of the Protocol defined visit windows

Others
A Protocol Deviation Specification (PDS) has been developed to provide more information about 
the major protocol deviations. Periodic meetings are required to investigate each potential protocol 
deviation.
4.6.
Prior and Concomitant Medications
Prior and Concomitant medications will be coded using the World Health Organization Drug 
Dictionary (WHO-DD). Prior medications are defined as any therapy used before the day of first 
dose (partial or complete) of study drug. Concomitant medications are defined as any therapy used 
on or after the same day as the first dose of study drug, including those that started before and 
continue on after the first dose of study drug.
The number and percentage of subjects taking concomitant medications from the first dose through 
the end of the on-treatment period (up to 30 days after the last dose of study drug) will be tabulated 
by the Anatomical Therapeutic Chemical (ATC) classification pharmacological subgroup and 
WHO drug generic term for each treatment group in the safety population. The proportion of 
subjects who receive each concomitant medication will be summarized as well as the proportion 
of subjects who receive at least one concomitant medication. A by-subject listing will also be 
presented for concomitant medication.
Prior medications will be summarized by treatment group and ATC terms. 
Summaries of concomitant medications of special interest may be provided: CYP3A4 and 
CYP2C9 inhibitors and inducers, P-glycoprotein (P-gp) substrates, and medications known to 
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increase serum levels of phosphate such as potassium phosphate supplements (oral or IV), vitamin 
D supplements, antacids, and phosphate-containing enemas and laxatives (oral/rectal).
5.
EFFICACY
5.1.
Analysis Specifications
5.1.1.
Level of Significance
Because of the nature of the modified study, no hypothesis testing will be performed for Cohort 1,
Cohort 2, or Cohort 3. Descriptive statistics will be used to summarize the study endpoints.
5.1.2.
General Analysis Considerations
The cohorts will be analyzed separately. Descriptive statistics and subject listings will be used to 
summarize the data. For continuous variables, number of observations, means, standard deviations, 
medians, interquartiles (IQs), and ranges will be used.  For discrete variables, frequency will be 
summarized.  
The comparisons between the 2 treatment groups in Cohort 1 will be performed using descriptive 
statistics.
Subjects who have crossed over from treatment with Investigator’s Choice to treatment with 
Erdafitinib will have crossover status indicated in the listings. In the tables, subjects will be 
summarized based on the information collected prior to crossover. If a substantial number of 
subjects cross over, then a category for crossover subjects may be added to the tables.
5.2.
Primary Efficacy Endpoint(s)
5.2.1.
Recurrence-free Survival
5.2.1.1.
Definition
For Cohort 1, the primary endpoint is recurrence-free survival (RFS). RFS is defined as the time 
from randomization until the date of the reappearance of high-risk disease (high grade Ta, T1, or 
CIS), or death, whichever is reported first. At the cutoff date for analysis, subjects who are 
recurrence-free and alive or have unknown status will be censored at the last tumor assessment. In 
addition, subjects without any postbaseline disease assessment will be censored at the 
randomization. Subjects who withdrew consent from the study before RFS event will be censored 
at the last tumor assessment. Subjects who are lost to follow-up will be censored at the last tumor 
assessment before subjects are lost to follow-up. Subjects who start subsequent anticancer 
therapies without RFS event will be censored at the last disease assessment before the start of 
subsequent anticancer therapies. 
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Table 2: 
RFS Event and Censoring Method
Situation
Outcome
Date of Event or Censoring
Reappearance of high-risk disease (high grade Ta, 
T1, or CIS)
RFS event
Earliest date that indicates recurrence
Death* 
RFS event
Date of death
No postbaseline disease assessment
Censored
Date of randomization
Other, such as:
Withdrawal of consent to study 
participation 
Lost to follow-up
Start of subsequent anticancer therapy 
prior to reappearance of high-risk disease or 
death
Censored
Date of last tumor assessment prior to 
withdrawal of consent to study 
participation, lost to follow-up, or 
start of subsequent anticancer therapy, or 
cross over from comparator to erdafitinib  
*Subjects who died after consent withdrawal will be censored at the date of consent withdrawal for RFS analysis
RFS is calculated in months as follows:
RFS = (date of RFS event or censoring – date of randomization + 1) / (365.25/12).
5.2.1.2.
Estimand
The primary estimand, the main clinical quantity of interest to be estimated in the study, is defined 
by the following 4 components:

Population: all randomized subjects, with high-risk NMIBC who harbor FGFR mutations or 
fusions, and who recurred after BCG therapy.

Variable: time to event, RFS.

Intercurrent event: 

Treatment discontinuation. Treatment policy approach is used, where the occurrence of 
the intercurrent event is irrelevant: the value of the event is used regardless of treatment 
discontinuation occurring. 

Subsequent anticancer therapy. While on treatment strategy will be used, that is, RFS will 
be censored at the start date of anticancer therapy. Note that for subjects randomized to 
Investigator’s Choice in Cohort 1, the treatment of erdafitinib after cross over is 
considered as use of subsequent therapy and the while on treatment strategy will be used.

Population-level summary: Descriptive statistics.
5.2.1.3.
Analysis Methods
The primary efficacy analysis on RFS will be based on the ITT population in Cohort 1. The
Kaplan-Meier method will be used to estimate the distribution of overall RFS for each treatment 
group. The median RFS with 95% CI will be provided. In addition, the number and percentage of 
subjects who had an RFS event or were censored will be reported. The reasons for RFS censoring 
will be summarized accordingly. The Kaplan-Meier RFS curve will also be plotted by treatment 
group.
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5.2.1.4.
Subgroup Analyses
Subgroup analysis may be performed for the selected potential prognostic variables (as listed in 
Table 1) to assess the consistency and robustness of the treatment benefit for RFS if sufficient data 
are captured. 
Subgroup analysis on selected secondary endpoints may be generated.
5.3.
Secondary Efficacy Endpoints (Cohort 1)
5.3.1.
Time to Progression (TTP)
5.3.1.1.
Definition
For Cohort 1, time to progression (TTP) is defined as the time from the date of randomization until 
the date of first documented evidence of any of the following disease progression or death:

Development of or increase in stage to lamina propria invasion (e.g., increase from Ta to 
T1)

Development of or increase in stage to muscle-invasive disease (stage ≥T2)

Development of or increase in stage to lymph node (N+) or distant metastasis (M1) 
disease (subject must have previously been diagnosed with N0 and/or M0 disease)

Increase in tumor grade from low to high (including CIS)

Death 
At the cutoff date for analysis, subjects who are progression free and alive or have unknown status 
will be censored at the date of the last tumor assessment. Subjects who withdraw consent to study 
or are lost to follow-up will be censored at the last disease assessment. Subjects without any post-
baseline disease assessment will be censored at the randomization.
Table 3: 
TTP Event and Censoring Method
Situation
Outcome
Date of Event or Censoring
Disease progression prior to start of subsequent 
anticancer therapy
TTP event
Earliest date that indicates disease 
progression
Death* 
TTP event
Date of death
No postbaseline disease assessment
Censored
Date of randomization
Other, such as:
Withdrawal of consent to study 
participation 
Lost to follow-up
Censored
Date of last tumor assessment prior to 
withdrawal of consent to study 
participation, lost to follow-up, or 
start of subsequent anticancer therapy, or 
cross over from comparator to erdafitinib  
*Subjects who died after consent withdrawal will be censored at the date of consent withdrawal for TTP analysis
5.3.1.2.
Analysis Methods
. Descriptive statistics will be used to assess TTP of the two treatment groups for the ITT 
population in Cohort 1. The Kaplan-Meier TTP curve will  be plotted by treatment group.
l be plotted by treatment group.
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5.3.2.
Overall Survival
5.3.2.1.
Definition
For Cohort 1, overall survival (OS) is defined as the time from the date of randomization to the 
date of the subject’s death resulting from any cause. Subjects who are alive or have unknown vital 
status will be censored at the date the subject was last known to be alive. Subjects who withdraw
consent from the study or are lost to follow-up will be censored at the time of withdrawal or lost 
to follow-up.
5.3.2.2.
Analysis Methods
OS will be analyzed using descriptive statistics for the ITT population in Cohort 1. The Kaplan-
Meier method will be used to estimate the distribution of OS for each treatment group. The Kaplan-
Meier OS curve will be plotted by treatment group.
5.3.3.
RFS Rate
5.3.3.1.
Definition
See Section 5.2.1 for RFS definition and analysis method. The RFS rate at 6 and 12 months with
95% CI will be estimated by Kaplan-Meier method and reported for each treatment group in 
Cohort 1.
5.3.3.2.
Analysis Methods
The RFS rate will be calculated with its associated 2-sided 95% CIs.
5.3.4.
RFS2
5.3.4.1.
Definition
For Cohort 1, RFS2 is defined as the time from the date of randomization until the date of the 
reappearance of high-risk disease (high grade Ta, T1, or CIS) on the first subsequent non-surgical
anticancer treatment, or death due to any cause, whichever is reported first. Subjects who are 
recurrence-free, or who have a recurrence event but do not receive subsequent anticancer therapy 
and who are alive or have unknown status will be censored at the last tumor assessment. Subjects 
who have a recurrence event and have received subsequent anticancer therapy, but do not have a 
recurrence event on the subsequent therapy and are alive or have unknown status will be censored 
at the last tumor assessment.
5.3.4.2.
Analysis Methods
Descriptive statistics will be used to assess RFS2 for the two treatment groups. The Kaplan-Meier 
RFS2 curve will be plotted by treatment group.
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5.4.
Exploratory Efficacy Endpoints
5.4.1.
All Cause RFS (Cohort 1)
5.4.1.1.
Definition
All Cause RFS is defined as the time from randomization until the date of the reappearance of any 
of the following, whichever is reported first:

Low- or high-grade Ta

Low- or high-grade T1 or higher

CIS

N+

M+

Death 
At the cutoff date for analysis, subjects who are recurrence-free and alive or have unknown status 
will be censored at the last tumor assessment. In addition, subjects without any postbaseline 
disease assessment will be censored at the randomization. Subjects who withdrew consent from 
the study before All Cause RFS event will be censored at the last tumor assessment. Subjects who 
are lost to follow-up will be censored at the last tumor assessment before subjects are lost to follow-
up. Subjects who start subsequent anticancer therapies without All Cause RFS event will be 
censored at the last disease assessment before the start of subsequent anticancer therapies. 
All Cause RFS is calculated in months as follows:
All Cause RFS = (date of event or censoring – date of randomization + 1) / (365.25/12).
5.4.1.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the distribution of All Cause RFS for each 
treatment group. The median All Cause RFS with 95% CI will be provided. In addition, the number 
and percentage of subjects who had an All Cause RFS event or were censored will be reported. The 
Kaplan-Meier All Cause RFS curve will also be plotted by treatment group.
5.4.2.
Complete Response Rate at 8 weeks and 32 weeks  (Cohort 2)
5.4.2.1.
Definition
For Cohort 2, exploratory endpoints include complete response (CR) rate at 8 weeks and CR rate 
at 32 weeks. CR is defined as at least one of the following: 1) negative cystoscopy and negative 
(including atypical) urine cytology; or 2) positive cystoscopy with biopsy-proven benign or low-
grade NMIBC and negative cytology. Only CRs prior to the start of subsequent anticancer therapy
will be considered for this endpoint. CR rate at 8 weeks is calculated as the number of patients 
who report a CR on or after 50 days following treatment start divided by the number of treated 
patients in Cohort 2. CR rate at 32 weeks is calculated as the number of patients who report a CR 
on or after 218 days following treatment start divided by the number of treated patients in Cohort 2.
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5.4.2.2.
Analysis Methods
The CR rate at 8 weeks and the CR rate at 32 weeks will be calculated with their associated 2-
sided 95% CIs.
5.4.3.
Duration of Response (Cohort 2)
5.4.3.1.
Definition
Duration of response will be analyzed for subjects in Cohort 2 with a BOR of CR only and is 
defined as the interval between the date of initial documentation of a response and the first 
documented evidence of PD, recurrence, or death due to any cause. Subjects who are 
progression- and recurrence-free and alive or have unknown status will be censored at the last 
tumor assessment. Subjects who had disease progression or death event but started a subsequent 
anti-cancer therapy before disease progression or death event will be censored at the last disease 
assessment before the subsequent therapy. 
5.4.3.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the median DOR with 95% CI. 
5.4.4.
Complete Response Rate (Cohort 3)
5.4.4.1.
Definition
For Cohort 3, an exploratory endpoint is CR rate. CR is defined as the disappearance of the marker 
lesion without any new lesions; and if any remnant of the marker lesion, no viable tumor seen on 
histopathological examination. Only CRs prior to the start of subsequent anticancer therapy will 
be considered for this endpoint. The CR rate is calculated as the number of patients who report at 
least one CR divided by the number of treated patients.
5.4.4.2.
Analysis Methods.
The CR rate will be calculated with its associated 2-sided 95% CIs.
5.4.5.
Best Overall Response (Cohort 3)
5.4.5.1.
Definition
For Cohort 3, the best overall response (BOR) is defined as the best response documented after 
start of study treatment. CR for Cohort 3 is defined above. A partial response (PR) for Cohort 3 is 
defined as marker lesion reduction by 50%. Stable disease (SD) for Cohort 3 is defined as marker 
lesion reduction by less than 50%. Progressive disease (PD) for Cohort 3 is defined as any marker 
lesion growth beyond baseline.
5.4.6.
Duration of Response (Cohort 3)
5.4.6.1.
Definition
Duration of response will be analyzed for subjects in Cohort 3 with a BOR of CR or PR and is 
defined as the interval between the date of initial documentation of a response and the first 
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documented evidence of PD, recurrence, or death due to any cause. Subjects who are 
progression- and recurrence-free and alive or have unknown status will be censored at the last 
tumor assessment. Subjects who had disease progression or death event but started a subsequent 
anti-cancer therapy before disease progression or death event will be censored at the last disease 
assessment before the subsequent therapy.
5.4.6.2.
Analysis Methods
The Kaplan-Meier method will be used to estimate the median DOR with 95% CI. 
6.
SAFETY
All safety analyses will be based on the Safety Analysis Set based on actual treatment received, 
unless otherwise specified.
Safety assessments will be based on medical review of adverse event reports and the results of 
vital sign measurements, 12-lead electrocardiogram (ECG), physical examinations, clinical 
laboratory tests, ophthalmologic examinations, and other safety evaluations at specified time 
points as described in the Schedule of Activities in protocol Section 1.3.
For all continuous safety variables, descriptive statistics will include the N, mean, standard 
deviation, median, minimum, and maximum. Categorical variables will be summarized using 
frequency counts and percentages.
6.1.
Adverse Events
The verbatim terms used in the eCRF by investigators to identify adverse events (AEs) will be 
coded using the Medical Dictionary for Regulatory Activities (MedDRA). These coded AE terms 
are referred to as preferred terms (PT); classification into System Organ Class (SOC) is a result of 
the coding process. 
6.1.1.
All Adverse Events
Treatment-emergent AEs (TEAEs) are defined as 1) those that first occur in TEAE period (defined 
as the time from first dose date through 30 days after last dose date, or day before subsequent 
anticancer therapy, whichever occurs first); 2) present before first dose, but worsened in toxicity 
grade during TEAE period; 3) had missing start date and its end date is during the TEAE period; 
4) was a drug-related event. To determine TEAE, partially missing AE start dates will be imputed 
according to the rules stated in section 2.7.2.
Treatment-emergent AEs will be summarized by system organ class and preferred terms, by NCI 
toxicity grade, by relationship to erdafitinib, and by action taken.
The severity of AEs will be graded on a scale of 1 to 5 according to the adult NCI Common 
Terminology Criteria for Adverse Events (NCI CTCAE Version 5.0) where higher grades indicate 
events of higher severity.
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For each TEAE, the percentage of subjects who experience at least 1 occurrence of the given event 
will be summarized. Tables will be sorted by frequency in incidence (the highest to lowest 
incidence). 
6.1.2.
Anticipated/Unlisted (unexpected) Adverse Event
The sponsor assumes responsibility for appropriate reporting of adverse events to the regulatory 
authorities. The sponsor will also report to the investigator (and the head of the investigational 
institute where required) all suspected unexpected serious adverse reactions (SUSARs). The 
investigator (or sponsor where required) must report SUSARs to the appropriate Independent 
Ethics Committee/Institutional Review Board (IEC/IRB) that approved the protocol unless 
otherwise required and documented by the IEC/IRB. 
An anticipated event is an adverse event that commonly occurs in the study population independent 
of exposure to the drug under investigation. Anticipated and unlisted (unexpected) AEs by SOC, 
PT and toxicity grade will be summarized by treatment group. 
An adverse event is considered unlisted if the nature or severity is not consistent with the applicable 
product reference safety information. For erdafitinib, the expectedness of an adverse event will be 
determined by whether or not it is listed in the IB. For gemcitabine or MMC/hyperthermic MMC, 
the expectedness of an adverse event will be determined by whether or not it is listed in the 
applicable package insert or summary of product characteristics. 
For the purposes of this study the following serious adverse events will be considered anticipated 
events: 

hematuria

dysuria

nocturia

bladder perforation 

ureteric stenosis 

urinary incontinence

urinary hesitation

stranguria

ureteric obstruction 

urine flow decreased

urinary retention

urinary tract obstruction

urinary tract pain

urinary tract infection

urosepsis
6.1.3.
Adverse Events of Special Interest and other safety observations
Central Serous Retinopathy for subjects receiving erdafitinib is considered an adverse event of 
special interest. These occurrences should be reported as an event of special interest (if Grade 1 or 
2) and as serious adverse events if the severity is Grade 3 or higher. 
Adverse events of interest will be summarized.
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Other safety observations are defined as: Hyperphosphatemia (serum phosphate elevation), Nail 
Disorders such as Onycholysis/Onychodystrophy and Paronychia; dry mouth, mucositis, dry 
skin/skin toxicities and dry eye.
6.2.
Deaths
A summary of all deaths, deaths within 60 days after treatment, and deaths during the treatment 
and up to 30 days after last dose will be provided, along with the primary cause of death. In 
particular, frequencies of deaths due to study treatment-related adverse events will also be 
reported. A death is study medication-related death if the primary cause is a drug related AE.
6.3.
Clinical Laboratory Tests
Number and percentage of subjects with post-baseline clinically important laboratory values 
and/or markedly abnormal post-baseline values will be presented by treatment group.
The clinically important laboratory findings to be reported are described below:

AST (U/L): ≥2x ULN

ALT (U/L): ≥2x ULN

Alkaline phosphatase (U/L): High (≥3xULN)

Bilirubin (total) ≥2x ULN 
Markedly abnormal laboratory findings to be reported are described below:

AST (U/L) or ALT(U/L): ≥3x ULN

AST(U/L) or ALT (U/L): ≥5x ULN

Grade 4 NCI-CTCAE
Applicable laboratory results will be graded according to NCI-CTCAE version 5.0.
A listing for all subjects with clinically important laboratory values will be provided and a 
summary table of the number of such subjects will be provided by treatment group.
6.4.
Electrocardiogram
All clinically relevant abnormalities in ECG waveform that are changes from the baseline readings 
will be reported (e.g., changes in T wave morphology or the occurrence of U waves). Clinically 
relevant ECG abnormalities are defined as follows:

Heart rate (bpm): Low < 50; High > 100

RR Interval (msec): Low < 600; High > 1000

QT Interval (msec): High > 500

QTcF Interval (msec): High (Males) > 450; High (Females) > 470; Very High > 500
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6.5.
Eastern Cooperative Oncology Group (ECOG) Performance Status
Screening ECOG performance status will be summarized for each cohort. 
6.6.
Other Safety Parameters
Pregnancy testing results will be presented in a by-subject listing.
7.
PHARMACOKINETICS/PHARMACODYNAMICS
7.1.
Pharmacokinetics
Erdafitinib pharmacokinetic data in different metrices (plasma, urine, and tissue) will be listed for 
all subjects with available erdafitinib concentrations. Concentration values below the lower limit 
of quantitation (LLOQ) will be displayed in listings as zero with a flag and handled as zero in the
calculations for mean, CV for mean, standard deviation, minimum, median, maximum, but 
handled as missing for the calculation of the geometric means and their CV.
If appropriate, descriptive statistics, including arithmetic and geometric mean, median, standard 
deviation, coefficient of variation (CV), geometric CV, minimum and maximum, will be tabulated 
for erdafitinib PK concentrations and protein binding data by time point if provided. 
8.
BIOMARKERS
FGFR variant type will be summarized by treatment group. Primary and key secondary efficacy 
endpoints will be summarized with the subgroups of FGFR Alteration Type (mutations vs. 
fusions). A subgroup analysis on the specific variants may be performed if a large number of 
subjects possess the variant.
Results of exploratory biomarker analyses may be presented in a separate report. Planned 
biomarker analyses may be deferred if emerging study data show no likelihood of providing useful 
scientific information.
NCT04172675


JNJ-42756493  (erdafitinib)
Statistical Analysis Plan      
CONFIDENTIAL – FOIA Exemptions Apply in U.S.
32
Status: Final, Date: 17 April 2023
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NCT04172675