A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two Different Dose Regimens of a Pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects With Metastatic or Surgically Unresectable Urothelial Cancer With FGFR Genomic Alterations
Phase: PHASE2
Conditions: Urothelial Cancer
Sponsor: Janssen Research & Development, LLC

CONFIDENTIAL – FOIA Exemptions Apply in U.S.
1
Status: Approved, Date: 4 October 2022
Janssen Research & Development *
Clinical Protocol
A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the 
Safety of Two Different Dose Regimens of a pan-FGFR Tyrosine Kinase Inhibitor 
JNJ-42756493 in Subjects with Metastatic or Surgically Unresectable Urothelial Cancer 
with FGFR Genomic Alterations
42756493BLC2001; Phase 2
Amendment 9
JNJ-42756493
*Janssen Research & Development is a global organization that operates through different legal entities in various
countries. 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 Sciences Ireland UC; 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.
This study will be conducted under US Food & Drug Administration IND regulations (21 CFR 
Part 312).
EudraCT NUMBER: 2014-002408-26
Status:
Approved
Date:
4 October 2022
Prepared by:
Janssen Research & Development, LLC
EDMS no.:
EDMS-ERI-85948746; 11.0
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.
NCT02365597

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TABLE OF CONTENTS
TABLE OF CONTENTS ............................................................................................................................... 2
LIST OF ATTACHMENTS............................................................................................................................ 7
LIST OF IN-TEXT TABLES AND FIGURES................................................................................................ 7
PROTOCOL AMENDMENTS....................................................................................................................... 9
SYNOPSIS.................................................................................................................................................. 27
TIME AND EVENTS SCHEDULES (For DDI Substudy – see Attachment 12)...................................... 30
ABBREVIATIONS AND DEFINITIONS OF TERMS.................................................................................. 41
1.
INTRODUCTION................................................................................................................................ 43
1.1.
Background .................................................................................................................................... 44
1.1.1.
Nonclinical Pharmacology .......................................................................................................... 44
1.1.2.
Pharmacokinetics and Product Metabolism in Animals.............................................................. 44
1.2.
Clinical Experience......................................................................................................................... 45
1.2.1.1.
Safety Experience ................................................................................................................... 46
1.2.1.2.
Clinical Pharmacokinetics........................................................................................................ 50
2.
OBJECTIVES AND HYPOTHESES.................................................................................................. 52
2.1.
Objectives ...................................................................................................................................... 52
2.1.1.
Primary........................................................................................................................................ 52
2.1.2.
Secondary................................................................................................................................... 52
2.2.
Hypotheses .................................................................................................................................... 53
2.3.
Overview of Study Design.............................................................................................................. 53
3.
STUDY DESIGN AND RATIONALE ................................................................................................. 56
3.1.
Overall Rationale for the Study...................................................................................................... 56
3.1.1.
Rationale for the Study in the Target Indication ......................................................................... 56
3.1.2.
Rationale for Phase 2 Dose Selection........................................................................................ 58
4.
SUBJECT POPULATION (For DDI Substudy – see Attachment 12)............................................ 63
4.1.
Inclusion Criteria ............................................................................................................................ 63
4.2.
Exclusion Criteria ........................................................................................................................... 64
5.
TREATMENT ALLOCATION AND BLINDING................................................................................. 66
6.
DOSAGE AND ADMINISTRATION .................................................................................................. 66
6.1.
Administration of Study Drug ......................................................................................................... 66
6.2.
Dose Up-titration Guidelines .......................................................................................................... 67
6.3.
Dose Modifications and Dose Delays ............................................................................................ 68
6.3.1.
Liver Event Safety Stopping Criteria........................................................................................... 70
6.3.2.
Guidelines for the Management of Elevated Phosphate Levels ................................................ 71
6.3.3.
Guidelines for the Management of Dry Mouth and Stomatitis.................................................... 73
6.3.4.
Guidelines for the Management of Dry Skin and Skin Toxicity .................................................. 75
6.3.5.
Guidelines for Management of Nail Toxicity (Onycholysis, Onychodystrophy, and 
Paronychia)................................................................................................................................. 76
6.3.6.
Guidelines for Eye Toxicity Associated With Vision Changes.................................................... 77
6.3.7.
Guidelines for the Management of Dry Eye................................................................................ 79
7.
TREATMENT COMPLIANCE............................................................................................................ 79
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8.
CONCOMITANT THERAPY.............................................................................................................. 80
8.1.
Permitted Medications.................................................................................................................... 80
8.2.
Prohibited Medications................................................................................................................... 81
8.3.
Precautions for Concomitant Medications ..................................................................................... 81
9.
STUDY EVALUATIONS .................................................................................................................... 82
9.1.
Study Procedures........................................................................................................................... 82
9.1.1.
Overview..................................................................................................................................... 82
9.1.2.
Screening Phase ........................................................................................................................ 82
9.1.3.
Treatment Phase ........................................................................................................................ 83
9.1.4.
End-of-Treatment Visit................................................................................................................ 83
9.1.5.
Follow-Up Phase ........................................................................................................................ 83
9.2.
Efficacy........................................................................................................................................... 84
9.2.1.
Evaluations ................................................................................................................................. 84
9.2.1.1.
Radiographic Images Assessment.......................................................................................... 84
9.2.1.2.
Definition of Measurable Disease............................................................................................ 85
9.2.2.
Endpoints.................................................................................................................................... 85
9.2.3.
Pharmacokinetics Evaluations.................................................................................................... 86
9.2.4.
Analytical Procedures................................................................................................................. 86
9.3.
Pharmacodynamic and Predictive Biomarker Evaluations ............................................................ 87
9.3.1.
Pharmacodynamic Biomarker Evaluations................................................................................. 87
9.4.
Safety Evaluations ......................................................................................................................... 89
9.4.1.
Adverse Events........................................................................................................................... 89
9.4.2.
Clinical Laboratory Tests ............................................................................................................ 89
9.4.3.
Renal Toxicity Evaluation ........................................................................................................... 90
9.4.4.
Urine or Serum Beta-hCG Pregnancy Test................................................................................ 90
9.4.5.
Electrocardiogram....................................................................................................................... 90
9.4.6.
Echocardiography Evaluation..................................................................................................... 91
9.4.7.
Ophthalmic Examination............................................................................................................. 91
9.4.8.
Vital Signs................................................................................................................................... 92
9.4.9.
Physical Examination.................................................................................................................. 92
9.4.10.
ECOG Performance Status ........................................................................................................ 92
9.4.11.
Symptomatic Measurement Questionnaire ................................................................................ 92
9.5.
Sample Collection and Handling.................................................................................................... 92
10.
SUBJECT COMPLETION/WITHDRAWAL....................................................................................... 93
10.1.
Completion ..................................................................................................................................... 93
10.2.
Discontinuation of Study Treatment............................................................................................... 93
10.3.
Withdrawal From the Study............................................................................................................ 93
10.3.1.
Withdrawal From the Use of Samples in Future Research ........................................................ 94
11.
STATISTICAL METHODS................................................................................................................. 94
11.1.
Sample Size Determination ........................................................................................................... 94
11.2.
Analysis Populations...................................................................................................................... 95
11.3.
Efficacy Analyses ........................................................................................................................... 95
11.3.1.
Primary Analysis ......................................................................................................................... 96
11.3.2.
Final Analysis.............................................................................................................................. 96
11.4.
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analyses........................................... 96
11.5.
Biomarker Analyses ....................................................................................................................... 97
11.6.
Safety Analyses ............................................................................................................................. 97
11.7.
Data Review Committee ................................................................................................................ 98
11.8.
Safety Monitoring Team................................................................................................................. 99
12.
ADVERSE EVENT REPORTING ...................................................................................................... 99
12.1.
Definitions ...................................................................................................................................... 99
12.1.1.
Adverse Event Definitions and Classifications ........................................................................... 99
12.1.2.
Attribution Definitions................................................................................................................ 100
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12.1.3.
Severity Criteria ........................................................................................................................ 101
12.2.
Special Reporting Situations........................................................................................................ 102
12.3.
Procedures................................................................................................................................... 102
12.3.1.
All Adverse Events.................................................................................................................... 102
12.3.2.
Serious Adverse Events ........................................................................................................... 103
12.3.3.
Pregnancy................................................................................................................................. 105
12.3.4.
Disease-related Events or Outcomes Not Qualifying as Adverse Events or Serious 
Adverse Events......................................................................................................................... 106
12.4.
Contacting Sponsor Regarding Safety......................................................................................... 106
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 106
13.1.
Procedures................................................................................................................................... 106
13.2.
Contacting Sponsor Regarding Product Quality .......................................................................... 107
14.
STUDY DRUG INFORMATION....................................................................................................... 107
14.1.
Physical Description of Study Drug.............................................................................................. 107
14.2.
Packaging .................................................................................................................................... 107
14.3.
Labeling........................................................................................................................................ 107
14.4.
Preparation, Handling, and Storage............................................................................................. 107
14.5.
Drug Accountability ...................................................................................................................... 107
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 108
16.
ETHICAL ASPECTS ....................................................................................................................... 108
16.1.
Study-Specific Design Considerations......................................................................................... 108
16.2.
Regulatory Ethics Compliance..................................................................................................... 109
16.2.1.
Investigator Responsibilities ..................................................................................................... 109
16.2.2.
Independent Ethics Committee or Institutional Review Board ................................................. 109
16.2.3.
Informed Consent ..................................................................................................................... 111
16.2.4.
Privacy of Personal Data .......................................................................................................... 112
16.2.5.
Long-Term Retention of Samples for Additional Future Research .......................................... 113
16.2.6.
Country Selection ..................................................................................................................... 113
16.2.7.
Protocol Clarification Communications..................................................................................... 113
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 114
17.1.
Protocol Amendments.................................................................................................................. 114
17.2.
Regulatory Documentation .......................................................................................................... 114
17.2.1.
Regulatory Approval/Notification .............................................................................................. 114
17.2.2.
Required Pre-study Documentation ......................................................................................... 114
17.2.3.
Financial Disclosure.................................................................................................................. 115
17.3.
Subject Identification, Enrollment, and Screening Logs .............................................................. 115
17.4.
Source Documentation................................................................................................................. 116
17.5.
Case Report Form Completion .................................................................................................... 116
17.6.
Data Quality Assurance/Quality Control ...................................................................................... 117
17.7.
Record Retention ......................................................................................................................... 117
17.8.
Monitoring .................................................................................................................................... 118
17.9.
Study Completion/Termination..................................................................................................... 118
17.9.1.
Study Completion ..................................................................................................................... 118
17.9.2.
Study Termination..................................................................................................................... 119
17.10.
On-Site Audits .............................................................................................................................. 119
17.11.
Use of Information and Publication.............................................................................................. 119
REFERENCES.......................................................................................................................................... 122
DRUG-DRUG INTERACTION (DDI) SUBSTUDY SUMMARY................................................................ 150
DEFINITION OF PHARMACOKINETIC PARAMETERS......................................................................... 156
1.
INTRODUCTION.............................................................................................................................. 157

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1.1.
Erdafitinib ..................................................................................................................................... 157
1.2.
Substudy Rationale...................................................................................................................... 158
1.3.
Study Purpose.............................................................................................................................. 159
1.4.
Study Design Rationale................................................................................................................ 160
1.5.
Background .................................................................................................................................. 162
1.6.
Dose Selection Rationale for Probe Drugs .................................................................................. 162
2.
OBJECTIVES AND ENDPOINTS ................................................................................................... 164
3.
STUDY DESIGN .............................................................................................................................. 164
4.
SUBJECT POPULATION................................................................................................................ 165
4.1.
Inclusion Criterion for the DDI Substudy...................................................................................... 166
4.2.
Exclusion Criterion for the DDI Substudy..................................................................................... 170
5.
TREATMENT ALLOCATION AND BLINDING............................................................................... 172
6.
DOSAGE AND ADMINISTRATION ................................................................................................ 172
6.1.
Administration of Study Drug ....................................................................................................... 172
6.2.
Dose Uptitration Guidelines ......................................................................................................... 173
6.3.
Dose Modifications and Dose Delays (Management of Toxicities) ............................................. 173
7.
TREATMENT COMPLIANCE.......................................................................................................... 173
8.
PROHIBITIONS AND RESTRICTIONS .......................................................................................... 173
9.
STUDY EVALUATIONS .................................................................................................................. 177
9.1.
Study Procedures......................................................................................................................... 177
9.1.1.
Molecular and DDI Substudy Screening................................................................................... 177
9.1.2.
Pretreatment with Probe Drugs ................................................................................................ 178
9.1.3.
Treatment Phase (DDI Treatment Phase Through Day 15)..................................................... 178
9.1.4.
Continued Treatment with Erdafitinib ....................................................................................... 179
9.1.5.
Long-Term Extension Phase .................................................................................................... 179
9.2.
Pharmacokinetic Evaluations....................................................................................................... 179
9.2.1.
Pharmacokinetic Evaluations ................................................................................................... 179
9.2.2.
Analytical Procedures............................................................................................................... 180
9.2.3.
Pharmacokinetic Parameters ................................................................................................... 180
9.2.4.
Sample Collection and Handling .............................................................................................. 180
9.2.5.
Criteria for PK Evaluability........................................................................................................ 181
9.3.
Safety Evaluations ....................................................................................................................... 181
9.3.1.
Physical Examinations.............................................................................................................. 181
9.3.2.
Vital Signs................................................................................................................................. 182
9.3.3.
Electrocardiograms................................................................................................................... 182
9.3.4.
Clinical Safety Laboratory Assessments .................................................................................. 182
9.3.5.
Ophthalmologic Examination.................................................................................................... 183
9.3.6.
Pregnancy Testing: Urine or Serum β-hCG ............................................................................. 183
9 3 7
ECOG Performance Status
183
9.5.
Radiologic Assessment for Identification of Disease Progression............................................... 185
10.
SUBJECT COMPLETION/WITHDRAWAL FOR THE DDI SUBSTUDY........................................ 185
10.1.
Completion ................................................................................................................................... 185
10.2.
Discontinuation of Study Treatment............................................................................................. 185
10.3.
Withdrawal From the Study.......................................................................................................... 186
11.
STATISTICAL METHODS............................................................................................................... 186
11.1.
Sample Size Determination ......................................................................................................... 186
11.2.
Pharmacokinetic Analyses........................................................................................................... 187
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12.
ADVERSE EVENT REPORTING .................................................................................................... 188
13.
PRODUCT QUALITY COMPLAINT HANDLING............................................................................ 189
14.
STUDY DRUG INFORMATION....................................................................................................... 189
14.1.
Physical Description of Study Drug.............................................................................................. 189
14.2.
Packaging .................................................................................................................................... 189
14.3.
Labeling........................................................................................................................................ 189
14.4.
Preparation, Handling, and Storage............................................................................................. 190
14.5.
Drug Accountability ...................................................................................................................... 190
15.
STUDY-SPECIFIC MATERIALS..................................................................................................... 190
16.
ETHICAL ASPECTS ....................................................................................................................... 190
17.
ADMINISTRATIVE REQUIREMENTS ............................................................................................ 190
INVESTIGATOR AGREEMENT ............................................................................................................... 191

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Status: Approved, Date: 4 October 2022
LIST OF ATTACHMENTS
Attachment 1: 
ECOG PERFORMANCE STATUS SCORES .......................................................... 124
Attachment 2: 
Cockcroft-Gault Formula For Estimated Creatinine Clearance (Crcl)...................... 125
Attachment 3: 
The Stages of Heart Failure – New York Heart Association (NYHA) 
Classification ............................................................................................................ 126
Attachment 4: 
Drugs Classified as Strong or Moderate In Vivo Inhibitors and Inducers of 
CYP3A4/2C9 Enzymes ............................................................................................ 127
Attachment 5: 
Amsler Grid............................................................................................................... 128
Attachment 8: 
Dose Up-titration Guidelines Made Obsolete by Amendment 3 and Regimen 
3................................................................................................................................ 140
Attachment 9: 
Statistical Methods Sections Made Obsolete by Amendment 3............................... 143
Attachment 10: 
Statistical Methods Sections Made Obsolete by Amendment 3............................... 146
Attachment 11: 
Guidance on Study Conduct During a National Disaster for Enrolled Subjects....... 147
Attachment 12: 
Drug-drug Interaction Substudy ............................................................................... 149
LIST OF IN-TEXT TABLES AND FIGURES 
TABLES
Table 1: 
REGIMEN 1 Time and Events Schedule (10 mg starting dose, 7 days on/7 days off) ............ 30
Table 2: 
REGIMEN 2 Time and Events Schedule (6 mg starting dose, 28 days continuous) ............... 33
Table 3: 
REGIMEN 3 Time and Events Schedule (8 mg starting dose, 28 days continuous) ............... 37
Table 4:
Pharmacokinetic Blood Sample Collection Schedule............................................................... 40
Table 5:
Biomarker Blood Sample Collection Schedule ......................................................................... 40
Table 6: 
Overall Summary of Treatment-Emergent Adverse Events: Study 42756493-EDI1001.......... 47
Table 7:
Treatment Emergent Adverse Events in Study 42756493EDI1001 for Dose Levels ≥6 
mg  (Any Grade, ≥10% Subjects) ............................................................................................. 49
Table 9:
Clinical Activity of JNJ-42756493 in Subjects with Urothelial Cancer (±FGFR 
Abnormality) Treated at 6 mg or Higher Dose (Study 42756493EDI1001).............................. 57
Table 10:
Dose Modification Guidelines ................................................................................................... 68
Table 11:
Dose Schedule and Dose Reductions - Regimen 1: Once Daily (QD) dosing, 7 days 
on / 7 days off in 28-day cycles ................................................................................................ 69
Table 12:
Dose Schedule and Dose Reductions - Regimen 2: 6 mg Once Daily (QD) dosing, 
continuous daily dosing in 28-day cycles ................................................................................. 69
Table 13:
Dose Schedule and Dose Reductions - Regimen 3: 8 mg Once Daily (QD) dosing, 
continuous daily dosing in 28-day cycles ................................................................................. 70
Table 14:
Guidelines for Management of Serum Phosphate Elevation.................................................... 72
Table 15:
Guidelines for Management of Dry Mouth (Xerostomia) .......................................................... 73
Table 16:
Guidelines for the Management of Oral Mucositis.................................................................... 74
Table 17:
Guidelines for Management of Dry Skin................................................................................... 75
Table 18:
Guidelines for Management of Nail Toxicity (Onycholysis/ Onychodystrophy)........................ 76
Table 19:
Guidelines for Management of Paronychia .............................................................................. 77
Table 20:
Guidelines for Management of Eye Toxicity ............................................................................. 78
Table 21:
Grading of Hyperphosphatemia and Nails Adverse Events ................................................... 102
Table 22:
Timepoint response:  patients with Target (+/- non-target) disease....................................... 131
Table 23:
Timepoint response:  patients with non-target disease only
132
Table 27: Interim Futility Boundaries ...................................................................................................... 144
DDI Table 28:
Time and Events Schedule (For Subjects Enrolled Under the DDI Substudy)............ 151
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DDI Table 29:
Time and Events Schedule (For Subjects Enrolled Under the DDI Substudy):
Long-Term Extension Phase .................................................................................................. 155
DDI Table 31:
List of Target Fibroblast Growth Factor Receptor (FGFR) Mutations.......................... 169
DDI Table 32:
Prohibited Concomitant Medications: Moderate to Strong CYP3A4 Inducers 
and Inhibitors .......................................................................................................................... 175
DDI Table 33:
Prohibited Concomitant Medications: Moderate CYP2C9 Inducers and 
Inhibitors and  OCT2 Inhibitors and Substrates...................................................................... 176
DDI Table 34:
Intra-subject Coefficient of Variation for the Probe Drugs and Their Metabolites
From  Previous Drug-Drug Interaction Studies and Publications............................................ 187
FIGURES
Figure 1: 
Mean (SD) Unbound JNJ-42756493 Plasma Concentration-time Profiles Following 
Oral Administrations of Drug at Indicated Doses (Study JNJ-42756493-EDI1001) ................. 51
Figure 2: 
Study Phases............................................................................................................................ 53
Figure 3: 
Study Design............................................................................................................................. 54
Figure 4: 
Dose Up-titration for Regimen 1 ............................................................................................. 140
Figure 5:
Dose Up-titration for Regimen 2 ............................................................................................. 141
Figure 6:
Dose Up-titration for Regimen 3 ............................................................................................. 142
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PROTOCOL AMENDMENTS
Protocol Version
Issue Date
Original Protocol
19 January 2015
Amendment 1
02 April 2015
Amendment 2
25 June 2015
Amendment 3
9 August 2016
Amendment 4
03 May 2017
Amendment 5
11 October 2017
Amendment 6
8 May 2019
Amendment 7
15 July 2020
Amendment 8
03 August 2021
Amendment 9
04 October 2022
Amendments below are listed beginning with the most recent amendment.
Amendment 9 (04 October 2022)
The overall reason for the amendment: To add a Long-term Extension (LTE) Phase with minimal assessments 
for subjects who have completed the Drug-drug Interaction (DDI) Substudy and who continue to derive benefit 
from treatment with erdafitinib.
Applicable Section(s)
Description of Change(s)
Rationale: The LTE Phase was added to reduce the burden of assessments for subjects who are continuing 
treatment with erdafitinib after completion of the DDI Substudy.
Synopsis,
2.3. Overview of Study Design,
Attachment 12: Drug-drug 
Interaction Substudy
   Drug-Drug Interaction (DDI) 
Substudy Summary
   DDI Table 29 (Added),
   3. Study Design,
   6.1. Administration of Study Drug, 
   9.1. Study Procedures,
   9.1.5. Long-Term Extension Phase
(Added)
   9.3. Safety Evaluations,
   9.5. Radiologic Assessment for 
Identification of Disease 
Progression,
   10.1. Completion,
   10.2. Discontinuation of Study 
Treatment,
   11. Statistical Methods
  12. Adverse Event Reporting
The LTE Phase was added to the main protocol sections and DDI Substudy 
in Attachment 12. The LTE Phase was the topic of Section 9.1.5, and the 
Time and Event Schedule was provided in DDI Table 29 (subsequent 
tables were renumbered). The end of study and study completion 
definitions were revised. The administration of study drug was updated. 
Aspects of the LTE phase including access to continue treatment with 
erdafitinib were mentioned as appropriate throughout the attachment.
Added that radiological assessments and safety assessments including 
laboratory assessments were to be performed based on the investigator’s 
discretion during the LTE phase, data for subjects in the LTE Phase were 
not to be added to the clinical database, and all SAEs and associated 
concomitant therapies were to be reported through the Company Safety 
Repository.
Rationale: To incorporate the Protocol Clarification from March 2022 regarding the Day −2, 0-hour 
pharmacokinetic (PK) sample during dosing with midazolam.
Attachment 12: Drug-drug 
Interaction Substudy
  DDI Table 28
Added additional PK sampling time under DDI Assessments, the PK 
blood sampling for midazolam, at Day −2, 0 hr (taken prior to 
administration of midazolam). 

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Applicable Section(s)
Description of Change(s)
Rationale: To incorporate the Protocol Clarification from July 2022 regarding the timing of the radiological 
assessment in relation to Cycle 1 Day 1 (C1D1).
Attachment 12: Drug-drug 
Interaction Substudy
  DDI Table 28
Added notation under Screening, the inclusion/exclusion criteria row, that 
the radiological assessment will be done within 35 days of C1D1.
Rationale: To provide clarity on usage of LTE Phase Time and Events Schedule for the subjects in the LTE Phase.
Attachment 12: Drug-drug 
Interaction Substudy
  DDI Table 28
Added a note explaining that LTE Phase Time and Events Schedule should 
be followed for the subjects who re-consent in the LTE Phase.
Rationale: To provide clarity on usage of LTE Phase Time and Events Schedule for the subjects in the LTE Phase 
and end of treatment (EoT) visit.
Attachment 12: Drug-drug 
Interaction Substudy
   DDI Table 28
Added a note explaining that LTE Phase Time and Events Schedule should 
be followed for the subjects who re-consent in the LTE Phase.
Added a footnote b explaining that EoT visit will not be required for 
subjects who re-consent to LTE phase.

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Status: Approved, Date: 4 October 2022
Amendment 8 (03 August 2021)
The overall reason for the amendment: To facilitate enrollment by expanding the enrollment criteria for the 
Drug-Drug Interaction (DDI) Substudy to include patients with advanced solid tumors, in addition to urothelial 
carcinoma, that harbor target fibroblast growth factor receptor (FGFR) mutations or FGFR gene fusions who have 
progressed after prior systemic therapy and who do not have standard of care options.
Applicable Section(s)
Description of Change(s)
Rationale: To facilitate enrollment, the DDI substudy population was expanded to patients with advanced solid 
tumors, in addition to urothelial carcinoma, that harbor target FGFR mutations or FGFR gene fusions who have 
progressed after prior systemic therapy and who do not have standard of care options. Also, the absolute neutrophil 
count (ANC) was made less restrictive for this population.
Synopsis;
2.3 Overview of Study Design;
Attachment 12 Drug-Drug 
Interaction Substudy,
   Title of Attachment 12;
   Substudy Summary;
   1.2 Substudy Rationale;
   
;
   2 Objectives and Endpoints;
   3 Study Design;   
   4 Subject Population;
   4.1 Inclusion Criterion for the
         DDI Substudy;
   4.2 Exclusion Criterion for the
        DDI Substudy;
   DDI Table 30;
   9.1.1 Molecular and DDI
         Substudy Screening
   
The Synopsis and Attachment 12 (DDI Substudy Title, Substudy 
Summary, and Sections 2 and 3) were revised to reflect the modified 
population to be enrolled in the DDI Substudy, ie, subjects with advanced 
solid tumors that harbor target FGFR mutations or FGFR gene fusions. 
Sections 2 and 3 provide a more detailed description of these subjects as 
those with an unresectable, locally advanced, or metastatic solid tumor 
malignancy. In addition, in Attachment 12, Section 4.1, the population was 
expanded as noted (Criterion 2, and revision of wording in Criterion 3). 
In Section 2.3, the duration of the DDI substudy was provided and 
distinguished from the main study.
The footnote in the introduction of Section 4 describing the population as 
similar to that of the main study was removed. In Attachment 12, Section 
4.1 (Criterion 4), molecular eligibility was expanded to target FGFR 
mutations or FGFR gene fusions. In Attachment 12, Section 4.2 (new 
Criterion 17 and 18), exclusions for FGFR gatekeeper and resistance 
alterations, and exclusions for pathogenic somatic mutations for non-small 
cell lung cancer (NSCLC), respectively, were added.  
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6.3.4 Guidelines for the
      Management of Dry Skin and
      Skin Toxicity; 
6.3.5 Guidelines for the 
      Management of Nail Toxicity
      (Onycholysis, Onychodystrophy,
      and Paronychia); 
6.3.6 Guidelines for Eye Toxicity 
      Associated With Vision Changes;
6.3.7 Guidelines for the Management
     of Dry Eye
consistency across the program. In Section 6.3.3, the prophylaxis 
measure for dry mouth related to mouthwash replaces “saline peroxide” 
with “salt and baking soda” (as in the stomatitis table).
In Section 6.3.5, Grade 4 was removed from the paronychia table, as well 
as the definition of grades.
In Section 6.3.7, artificial tear substitutes are recommended every 2 
hours during awake time under the prophylactic (the change also applies 
to ocular demulcents under this subsection) and reactive management 
sections.  
Rationale: The adverse event of special interest is termed “central serous retinopathy” (CSR, a grouped term). 
12.3 Procedures
Removed “adverse events of special interest” as a description of “corneal 
or retinal abnormalities”.
Rationale: To update the guidance for study conduct during a national disaster based on the updated company 
template (non-live vaccines).  
8.1 Permitted Medications;
Attachment 11 Guidance on Study
     Conduct During a National 
      Disaster for Enrolled Subjects
Guidance relating to administration of non-live vaccines was added.
Rationale: Provide overview of efficacy and safety information now available for Study 42756493BLC2001 
(Study BLC2001).
1.2.1.1 Safety Experience;
3.1.1 Rational for the Study in the 
Target Indication;
Provided an overview of efficacy and safety information from the primary 
analysis (clinical cutoff of 15 March 2018) and updated analysis (clinical 
cutoff of 09 August 2019) of Study BLC2001. Also, in Section 1.2.1.1 
referred the reader to the Erdafitinib Investigator’s Brochure for recent 
safety information. Also, in Section 3.1.1, referred the reader to the 
rationale for the treatment of subjects with advanced solid tumors in DDI 
Substudy Section 1.2.
Rationale: Change for consistency with protocol template
9.4.2 Clinical Laboratory Tests;
16.2.7 Protocol Clarification 
      Communications (new);
Attachment 12 Drug-Drug 
Interaction Substudy, Section 4.1 
Inclusion Criteria
In Section 9.4.2, added a mention of Hy’s Law and provided a reference 
to the reporting requirements.
Added text regarding protocol clarification communications as new 
Section 16.2.7.
In Attachment 12, Section 4.1 (Criterion 7), tubal closure was added as a 
contraceptives measure. 
Rationale: Editorial changes were made.
 Throughout the document
Editorial changes were made, ie, “he or she” changed to “the subject”. 
Tables and figures in the attachments were renumbered (were necessary) 
to flow with the main body of the protocol. The term FGFR-positive 
subject was revised to FGFR-eligible subject.

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Amendment 7 (15 July 2020)
The overall reason for the amendment: The overall reason for this amendment is to add the drug-drug interaction 
(DDI) substudy, to fulfill the US Food and Drug Administration (FDA) post-marketing requirement to evaluate the 
interaction of repeated doses of erdafitinib with a sensitive cytochrome 450 (CYP) 3A substrate, as well as the 
post-marketing commitment to evaluate the interaction of repeated doses of erdafitinib with an organic cation 
transporter 2 (OCT2) probe substrate. In addition, instructions for study conduct during a national disaster was 
added along with other updates.
Applicable Section(s)
Description of Change(s)
Rationale: The DDI substudy was added to the protocol for the purpose of evaluating the potential inhibition or 
induction effects of erdafitinib on the CYP3A-mediated metabolism of the probe drug midazolam and the potential 
inhibition effect on the OCT2-mediated transport of the probe drug metformin. The study results are intended to 
provide guidance that will enable an update to the erdafitinib labeling and will help guide recommendations for
administration of co-medications that are substrates for CYP3A4 or OCT2.
NOTE: Subjects entering under the DDI substudy will follow procedures as advised in Attachment 12. For these 
subjects, DO NOT USE the Time and Events Schedule and the Eligibility Criteria in the body of the protocol 
(referred to in Attachment 12 as the “Main Protocol”). 
Synopsis;
Time and Events Schedules;
3, Study Design and Rationale;
4, Subject Population;
Attachment 12
The DDI substudy has been added as Attachment 12. As this is an extensive 
attachment, a table of contents is provided. Subjects will be enrolled under the 
eligibility criteria provided in this attachment. Once subjects complete the DDI 
portion of the study, they will continue treatment with erdafitinib until disease 
progression, unacceptable toxicity, or until meeting another condition 
specified in the protocol. Safety assessments are continued, along with limited 
efficacy (for the purpose of signaling disease progression) 
 
. The assessments for the DDI substudy and thereafter 
during continued treatment with erdafitinib are provided in this attachment 
along with a Time and Events Schedule. Study participation ends with the End 
of Treatment Visit. 
The DDI substudy is mentioned in the synopsis. A reminder not to use the 
Time and Event Schedules and the eligibility criteria in the Main Protocol were 
added to these section headers, as well as mentioned at the beginning of 
Section 3.
Rationale: To add instructions to be followed during a national disaster.
Time and Event Schedules
(Table 2 and Table 3);
Attachment 11, Guidance on 
Study Conduct for Enrolled 
Subjects During a National 
Disaster (new);
2.3, Overview of Study Design
Instructions to be followed during a national disaster are provided in 
Attachment 11. This attachment was referenced in Section 2.3 as well as the 
Time and Events Schedules (Footnote “a”). As no subjects were ongoing on 
Regimen 1, ie, 10 mg starting dose, changes were not applied to this table. 
(This guidance is found in similar sections of the DDI Substudy attachment 
noted earlier.)
Rationale: Updated the description of fluconazole to a moderate (previously strong) CYP2C9 inhibitor, per FDA 
classification. Provided updated information and guidance for use of strong CYP2C9 or CYP3A4 inhibitors, as 
well as moderate CYP2C9 inducers and strong CYP3A4 inducers, and erdafitinib.
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Applicable Section(s)
Description of Change(s)
8.3, Precautions for Concomitant 
Medications;
Attachment 4, Drugs Classified 
as Strong or Moderate In Vivo 
Inhibitors and Inducers of 
CYP3A4/2C9 Enzymes
Updated fluconazole as a moderate CYP2C9 inhibitor (previously considered 
a strong inhibitor).
Provided information regarding use of strong inhibitors of CYP2C9 or 
CYP3A4 with erdafitinib, including specific guidance to use these agents with 
caution during erdafitinib treatment.  
Provided information regarding moderate CYP2C9 inducers (no drugs are 
classified as strong CYP2C9 inducers) and strong CYP3A4 inducers and 
interaction with erdafitinib. Provided specific guidance to avoid the use of 
these agents (moderate CYP2C9 inducers and strong CYP3A4 inducers) with 
erdafitinib, as well as guidance for the use of moderate CYP3A inducers with 
erdafitinib.
Attachment 4 was revised to provide drugs classified as strong or moderate 
in vivo inhibitors and inducers of CYP3A4/2C9. Previously moderate in vivo 
inhibitors of CYP3A4/2C9 were not included in the table.
Rationale: The management of elevated phosphate levels has been updated. To ensure consistency between the 
protocol and case report form (CRF) guidelines, harmonized rounding of phosphate values.
6.3.2, Guidelines for the 
Management of Elevated 
Phosphate Levels;
Table 14
Updated the management of elevated phosphate levels in Table 14. The values 
for grading of hyperphosphatemia have been revised throughout the protocol 
to include 2 decimals, for consistency with the CRF, and instructions for 
rounding the second decimal point were deleted. Also, small updates to the 
study and medical management were made and the toxicity grades (0 to 4) 
were added to the table. The update removed the information in the footnote
regarding re-introduction of study drug in subjects deriving benefit from 
treatment; however, the primary location of this information in Section 10.2 
remains.
Rationale: To update safety management guidelines for oral mucositis. 
6.3.3, Guidelines for the 
Management of Dry Mouth and 
Stomatitis;
Table 15, Guidelines for the 
Management of Dry Mouth 
(Xerostomia);
Table 16, General Prophylaxis 
and Guidelines for the 
Management of Oral Mucositis
Updated guidelines for general prophylaxis and management of oral mucositis 
were provided in Table 16. 
The general prophylaxis for dry mouth (which due to the above change now 
differs from oral mucositis) was removed from the text and was added to 
Table 15. 
Rationale: To update safety management guidelines for nail toxicity.
6.3.5, Guidelines for 
Management of Nail Toxicity 
(Onycholysis, Onychodystrophy, 
and Paronychia);
Table 18, General Prophylaxis 
and Guidelines for Management 
of Nail 
Discoloration/Loss/Ridging 
(Onycholysis/Onychodystrophy);
Table 19, Guidelines for 
Management of Paronychia
Updated guidelines for the management of nail toxicity in Table 18 (the new 
table format adds general prophylaxis to the table).
The general prophylaxis for the management of paronychia, previously in text 
was added to Table 19. Also, the descriptions of grades were removed from 
Table 19 for consistency across the program.  

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Applicable Section(s)
Description of Change(s)
Rationale: For the ophthalmic examination, tonometry was removed and slit lamp biomicroscopy was added. To 
clarify that all subjects must have an ophthalmologic examination performed at screening regardless of symptoms, 
and that a follow-up examination should be performed as clinically necessary based on clinical findings. To clarify 
that an Optical Coherence Tomography (OCT) will be performed. 
Time and Event Schedules
(Table 2 and Table 3);
9.4.7, Ophthalmic Examination 
On the Time and Events Schedules, the following notation has been added for 
the “Ophthalmologic Exam”: A follow-up examination should be performed 
as clinically necessary based on the findings of the Amsler grid tests and 
clinical assessment. (As no subjects were ongoing on Regimen 1, ie, 10 mg 
starting dose, changes were not applied to this table.)
Changed “should” to “must” in the first sentence as follows: “All subjects must 
have an ophthalmological examination performed at Screening by an 
ophthalmologist . . .”. Regarding the examination, “tonometry” was removed 
and “slit lamp biomicroscopy” was added. In addition, “where available, an 
Optical Coherence Tomography (OCT) should be performed [at Screening]” 
was replaced with simply “Optical Coherence Tomography (OCT)” at the end 
of the sentence that now clarifies that an OCT will also be performed at 
Screening. The Amsler grid test was removed from the list of assessments and 
this topic is addressed in a new sentence.
Rationale: The dose titration guidelines have been updated.
6.2, Dose Up-titration Guidelines
The dose titration guidelines have been updated (will be used by subjects 
enrolled under the DDI Substudy). The Regimen 3 guidelines have been 
moved to Attachment 8 (with Regimens 1 and 2).

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Status: Approved, Date: 4 October 2022
Rationale: Corneal or retinal abnormality of Grade 1 or 2 are reported as an adverse event. Updated information 
regarding Amsler grid testing. 
6.3.6, Guidelines for Eye 
Toxicity Associated With Vision 
Changes;
Table 20;
12.3, Procedures
Clarified that a corneal or retinal abnormality of Grade 1 or 2 is reported as an 
adverse event; previously text stated reporting as an adverse event of special 
interest. (These abnormalities of Grade 3 or higher continue to be reported as 
serious adverse events.) This revision was also added to Section 12.3.
The update to the Guidelines for Management of Eye Toxicity Table 20 
removed information in the footnote regarding re-introduction of study drug 
in subjects deriving benefit from treatment; however, the primary location of 
this instruction in Section 10.2 remains.
In Section 6.3.6, clarified text regarding instructions for an abnormal Amsler 
grid test as follows: However, if the subject has an abnormal Amsler grid test 
[added here “and otherwise normal ophthalmologic examination”] at baseline 
(during Screening), a repeat ophthalmic 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. Also, the description of a positive test 
was removed.
Rationale: Updated the management of dry eye.
6.3.7, Guidelines for the 
Management of Dry Eye
Ocular demulcents were included as a recommendation for prophylactic 
management. Also, ocular demulcents were added to reactive management 
(and the more descriptive text “hydrating/lubricating eye gels and ointments” 
was removed).
Rationale: The end of study has been redefined due to the addition of the DDI substudy.
Synopsis;
2.3, Overview of Study Design
Previous definition: The end of study is defined as the date when all subjects 
have completed the study treatment or 12 months after last subject is enrolled, 
whichever is later. 
New definition: The end of study is defined as the date when all subjects have 
completed the study treatment (Regimens 1 to 3) or until the last subject 
enrolled under the DDI substudy completes the end of treatment visit 
(whichever happens last).
Rationale: Updated text regarding disease-related events, per the protocol template. 
12.3.2, Serious Adverse Events;
12.3.4, Disease-related Events or 
Outcomes Not Qualifying as 
Adverse Events or Serious 
Adverse Events
Text regarding disease-related events was removed from Section 12.3.2 and 
the new template text was added as Section 12.3.4.
Rationale: Updated safety reporting with the addition anticipated events. 
12.3.2, Serious Adverse Events
Updated safety reporting with the addition of a list of anticipated events and 
related protocol template text.

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Throughout the document
Attachment 5
Minor editorial changes were made to improve clarity.
Subtitle at bottom of graph was removed.
Amendment 6 (8 May 2019)
The overall reason for the amendment: To modify the end of study definition in order to continue to provide 
access to study treatment for subjects still taking erdafitinib after the planned final analysis while limiting the scope 
of longer-term data collection after the time of final analysis to safety data (eg, AEs, SAEs).
.
Applicable Section(s)
Description of Change(s)
Rationale: The end of study definition was updated to extend access to erdafitinib for subjects still on study 
treatment at the time of final analysis.
Synopsis Overview of Study Design, 3.1 
Overview of Study Design
Text updated: The end of study is defined as the date when all 
subjects have completed the study treatment or 12 months after 
last subject is enrolled, whichever is later.
Rationale: The approximate duration of the study was updated due to the modification of the end of study 
definition.
3.1 Overview of Study Design
Text updated: The entire duration of the study will be 
approximately 3660 months to completion (first subject’s first 
visit to end of study).
Rationale: The definition of study completion was updated to reflect the updated end of study definition.
17.9.1 Study Completion
Text updated: The study is considered completed with the last 
follow up survival assessment for the last subject participating in 
the study when all subjects have completed the study treatment 
or 12 months after the last subject is enrolled, whichever is later.
Rationale: Provide extended access to study treatment for subjects still taking erdafitinib after the planned final 
analysis and limit the scope of data collection from the time of final analysis until the end of study.
11.3.2 Final Analysis
Text added: For subjects still on study treatment after the final 
analysis the study Sponsor will continue to provide access to 
erdafitinib and collect safety data (eg, AEs, SAEs) until the end 
of study.
Rationale: Updated text on PK and biomarker sample collection to conclude at the implementation of 
Amendment 6 at the local site level.
Time and Events Tables, Table 4, Table 5,
9.2.3 Pharmacokinetic Evaluations, 9.3.2 
Predictive Biomarker Evaluations
Added table text in Time and Events Schedule and updated table 
footnotes and text in the PK and biomarker sections to clarify the 
termination of routine PK and biomarker sample collection while 
still allowing the collection of additional PK samples at any time 
for assessment of adverse events as clinically appropriate.
Rationale: Information on study drug management of elevated phosphate levels was updated according to the latest 
guidelines.

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Status: Approved, Date: 4 October 2022
Applicable Section(s)
Description of Change(s)
Table 14; Table 21
Switched ordering of footnotes a and b according to updated 
table and updated the definition of persistent hyperphosphatemia 
in footnote a.
Updated study drug management for serum phosphate levels of 
7.0-9.0 mg/dL (2.3-2.9 mmol/L), >9.0-10 mg/dL (>2.9 mmol/L), 
>10.0 mg/dL (>3.2 mmol/L) and significant alteration in baseline 
renal function or Grade 3 hypocalcemia.
Rationale: Information on study drug management of eye toxicity was updated according to the latest guidelines.
Table 20
Added monitoring information for retinal epithelial detachment 
under Grades 1, 2, and 3 study drug management. Updated study 
drug management information for Grade 3 toxicity from 
“permanently discontinue” to “withhold” erdafitinib.
Rationale: Information on prohibited and concomitant medications were updated according to latest guidelines and 
study information.
8.2 Prohibited Medications; 
8.3 Precautions for Concomitant Medications; 
8.3.1 Concomitant Use of Strong CYP3A/2C9 
Inhibitors/Inducers
Removed medications that increase serum calcium and 
phosphate levels from the prohibited medications list.
Removed subsection “8.3.1 Concomitant Use of Strong 
CYP3A/2C9 Inhibitors/Inducers” and updated the text on 
potential strong inducers of CYP3A4 and CYP2C9 with the 
latest study information and source information.
Removed subheading “Concomitant Use of P-gp Substrates” and 
updated P-gp substrate text and source information.
Rationale: Updated wording to align with relevant changes to the protocol template since the last amendment was 
issued.
9.4 Safety Evaluations; 
17.3 Subject Identification, Enrollment, and 
Screening Logs
Updated wording: clinically stable endpoint condition
Updated wording: date of birth age at initial informed consent
Rationale: Minor errors were noted.
Throughout the document
Minor editorial changes were made to improve clarity. 
JNJ-42756493 and JNJ42756493 were replaced with erdafitinib
where applicable.

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Status: Approved, Date: 4 October 2022
Amendment 5 (11 October 2017)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: Precautionary language regarding concomitant medications was added, 
based on in vitro data showing that erdafitinib is a P-gp inhibitor.
.
Applicable Section(s)
Description of Change(s)
Rationale: Precautionary language was added regarding concomitant use of P-gp substrates.
8.3.2, Concomitant Use of P-gp Substrates 
(new section)
Text added:
Erdafitinib was shown to inhibit, in in vitro experiments, human 
P-glycoprotein (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. Therefore caution 
should be exercised for co-administered drugs that are P-gp 
substrates, such as digoxin, dabigatran, apixaban, etc.
Rationale: New food effect data show that erdafitinib may be taken with or without food.
6.1 Administration of Study Drug
Each dose should be taken at least 1 hour before eating or at least 
2 hours after a meal, at approximately the same time each day,
with or without food. In this same time frame, Subjects should 
avoid consuming grapefruit or Seville oranges due to CYP450 
3A4/5 inhibition
Amendment 4 (3 May 2017)
This amendment is considered to be nonsubstantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union in that it does not significantly 
impact the safety or physical/mental integrity of subjects, nor the scientific value of the study.
The overall reason for the amendment: To clarify the post treatment follow-up period and timing between 
enrollment and Cycle 1 Day 1 for Regimen 3 subjects.
.
Applicable Section(s)
Description of Change(s)
Rationale: To clarify the post treatment follow-up period, as the 6-month timeframe was confusing and 
unnecessary, and the timing between enrollment and Cycle 1 Day 1 for Regimen 3 subjects.
Time and Events Tables
3.1, Overview of Study Design
12.3.1, All Adverse Events
12.3.2, Serious Adverse Events
Clarified that follow-up for drug-related toxicity or serious 
adverse events was not restricted to a maximum of 6 months
following the end of study visit
10.1, Completion
Clarified that a subject will be considered to have completed the 
study if they have died, and deleted previous condition of 
follow-up for 6 months after disease progression
Time and Events Table, Regimen 3
Added sentence: Cycle 1 Day 1 must occur no more than 3 days 
after the Randomization transaction in IWRS

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Amendment 3 (9 August 2016)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: As recommended by the Data Review Committee (DRC) following their
review of Interim Analysis 1 (IA1) data for Study BLC2001, an analysis was conducted of safety and efficacy data 
in urothelial cancer of the 2 different dosing schedules (6 mg once daily continuous and 10 mg once daily intermittent 
[7-day-on/7-day-off] schedules; both with possible up-titration to 8 mg and 12 mg, respectively). From the BLC2001 
data no new safety signals were identified. Also, it was observed that, for subjects attaining a phosphate level of at 
least 5.5 mg/dL, the ORR was higher (57%, 4/7 subjects) as compared to those who did not attain this same level 
(21%, 3/14 subjects). From Study EDI1001, it was known that 6 mg once daily continuous was a well-tolerated 
schedule without significant unplanned treatment interruptions, while 9 mg once daily continuous in non-selected 
patients frequently led to treatment interruptions or dose reductions. Based on observed data and PK/PD modeling, it 
seemed possible to increase the highest continuous dose to 9 mg once daily in subjects who did not attain the target 
phosphate level of 5.5 mg/dL or higher. Furthermore, approximately half of the subjects starting at 6 mg once daily
were up-titrated to 8 mg once daily, and most tolerated this higher dose without the need for interruptions for 
hyperphosphatemia or other drug-related, mainly skin and nail, toxicity. Modeling was performed to assess different 
scenarios for dosing, including up-titration to 8 mg from a starting dose of 6 mg, or a starting dose of 8 mg with
potential up-titration to 9 mg in selected patients. Based on this modeling, the starting dose of the study will be 
increased to 8 mg once daily, with a provision for up-titration to 9 mg once daily for subjects whose serum phosphate
levels on Day 14 do not reach a target of at least 5.5 mg/dL, in the absence of drug related toxicity. Subjects will 
remain at 8 mg once daily if their serum phosphate levels on Cycle 1 Day 14 are within the target range of 5.5 to <7.0 
mg/dL. Any further elevations of serum phosphate will be managed as per protocol guidelines.
Applicable Section(s)
Description of Change(s)
Rationale: To implement procedures for Regimen 3, added T&E table (Table 3), revised description of study 
design, provided rationale, new dose up-titration guidelines and dose modification guidelines, 
Time and Events Table 3
New table added
1, Introduction
Added update on Regimen 3
2, Objectives and Hypotheses
Revised to reflect selected dose regimen, added secondary 
objective for other dose regimens
3.1, Overview of Study Design
9.1.2, Screening Phase
Revised text to include Regimen 3 after IA1, updated Figure 3
3.2.2, Rationale for Phase 2 Dose Selection
Updated with rationale for dose in Regimen 3
5, Treatment Allocation and Blinding
6.1, Administration of Study Drug
Updated with dose in Regimen 3
6.2, Dose Up-titration Guidelines
Moved guidelines for Regimen 1 and Regimen 2 to Attachment 
8, added guidelines for Regimen 3
6.3, Dose Modifications and Dose Delays
Updated with guidelines for Regimen 3
9.1.3, Treatment Phase
Added provision for subjects in Regimen 1 or Regimen 2 to 
move to Regimen 3
9.1.4, End-of-Treatment
9.1.5, Follow-up Phase
9.2, Efficacy
Added reference to Table 3
11.1, Sample Size Determination
Moved description for Regimen 1 and Regimen 2 to Attachment 
9, added description for Regimen 3

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Applicable Section(s)
Description of Change(s)
11.2, Analysis Populations
Specified that the Primary Efficacy (PE) analysis population will 
consist of all subjects who are treated by at least 1 dose of study 
drug in Regimen 3
11.3.1, Primary Analysis
Adjusted to Regimen 3
11.7, Interim Analysis
11.8, Dose Selection Criteria
Moved these former sections to Attachment 9 since Amendment 
3 rendered them obsolete 
16.1, Study Specific Design Considerations
Added additional considerations for new dose regimen
Attachment 8
New attachment for dose up-titration guidelines for Regimen 1 
and Regimen 2, since Amendment 3 rendered them obsolete
Attachment 9
New attachment for statistical methods (sample size 
determination, former sections 11.7 and 11.8) rendered obsolete 
by Amendment 3 
Rationale: Based on recent preclinical data, added warnings about CYP2C9 interactions.
8.3.1, Concomitant Use of Strong 
CYP3A4/2C9 Inhibitors/Inducers
Attachment 4, Drugs Classified as Strong in 
vivo Inhibitors…
Revised guidance to includeCYP2C9
Rationale: Biomarker section updated. Pre-treatment, on-treatment, and end of treatment biopsy collection added to 
support investigation of the impact of JNJ-42756493 on: tumor immune cell infiltrate, bladder cancer molecular 
profile; and to assess markers of response and acquired resistance to study drug. PD-L1 status and bladder cancer 
subtyping (molecular profile) will be assessed in archival tissue to better understand the immune marker status and 
molecular profile of FGFR alteration positive and negative samples. A statement is added to indicate that additional 
tissue may be requested, or retrieved from existing samples, at any point in the study to support protocol-specified 
analyses, or retrospective analyses. In particular, additional samples may be needed to support the development of 
the FGFR molecular screening assay as a companion diagnostic test (CDx).
Time and Events Table 3
Added pre-treatment, on-treatment, and end of treatment biopsy 
collection
Table 5, Biomarker Blood Sample Collection
Added blood sample on Cycle 2 Day 1 for subjects providing 
post treatment biopsy
2, Objectives and Hypotheses 
9.2.2, Endpoint
Added exploratory objectives, endpoints for PD-L1 status, 
molecular profile, impact on tumor immune cell infiltrate, 
changes to tumor molecular profile
9.3.2, Predictive Biomarker Evaluations
Added section on tissue biomarkers, request for additional tissue 
if needed
11.5, Biomarker Analysis
Updated to include analyses of tissue samples
Rationale: Symptom Management Questionnaire added to help evaluate and explore  the subject experience as part 
of the clinical study.
Time and Events Table 3
Added Symptom Management Questionnaire
2, Objectives and Hypotheses 
9.2.2 Endpoints
Added exploratory objective, endpoint, text for Symptom 
Management Questionnaire
9.4.11, Symptom Measurement Questionnaire
Added new section to describe questionnaire
Rationale: Clarifications to existing study procedures were made.
Table 2
Adjusted visit windows to match Table 3

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Status: Approved, Date: 4 October 2022
Applicable Section(s)
Description of Change(s)
Table 1, Table 2
Revised footnote “n” to match Table 3
6.3.2, Guidelines for the Management of 
Elevated Phosphate Levels
Added conversion to mmol/L and definitions of length of drug 
interruption and persistent hyperphosphatemia to Table 14
12.1.3, Severity Criteria
Added conversion to mmol/L to Table 22
6.3.6, Guidelines for Eye Toxicity Associated 
with Vision Changes
Clarified that Amsler grid test will be performed at the start of 
every cycle from Cycle 2 onwards
9.2.1.1, Radiographic Images Assessment
Clarified confirmatory scans are required for all unconfirmed 
PR/CR results
9.4.2, Clinical Laboratory Tests
Clarified alpha-1-glycoprotein performed by central lab using 2-
hour post-dose sample from Cycle 1 Day 1
12.3.1, All Adverse Events
Clarified that AEs are collected until 30 days after last dose of 
study drug
Rationale: Minor errors were noted
Throughout the protocol
Minor grammatical and formatting changes were made.
Amendment 2 (25 June 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
Applicable Section(s)
Description of Change(s)
Rationale: The T&E tables (Tables 1 & 2) were updated with additional visit windows to permit flexibility in 
scheduling radiology assessments and Cycle 1 Day 1 chemistry and hematology laboratory assessments. Table 4 
updated as a result of overall rationale (bridging to blood-based assay and assessment of molecular signature of 
response and resistance/progression). Bicarbonate and chloride removed from Section 9.4.2 due to absence of 
acid/base disturbances associated with JNJ-42756493 (data from ongoing phase 1 study).
Time and Events Table1 and Table 2
Updated footnotes to include window for Cycle 1 Day 1 
chemistry and hematology labs.
Updated footnotes to include visit window for radiology 
assessments.
Updated footnotes to exclude requirement of PTH value 
availability prior to dosing, as this value is not essential for 
screening safety of the subject but provides assessment of an 
additional potential biomarker linked to Ca-P homeostasis.
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Status: Approved, Date: 4 October 2022
Applicable Section(s)
Description of Change(s)
Time and Events Table 4, Section 11.5
Biomarker Analyses
Updated to include additional blood samples for biomarker 
research.
Synopsis, Section 9.3 Predictive and 
Pharmacodynamic Biomarker Evaluations
Added information on additional blood samples and intended 
analyses
Section 9.4.2 Clinical Laboratory Tests
Deleted bicarbonate and chloride from clinical chemistry table.
Rationale: Minor errors were noted
Minor grammatical, formatting, or spelling changes Minor grammatical and formatting changes were made.
Amendment 1 (2 April 2015)
This amendment is considered to be substantial based on the criteria set forth in Article 10(a) of Directive 
2001/20/EC of the European Parliament and the Council of the European Union.
The overall reason for the amendment: This amendment enables inclusion of up-titration of dose in both treatment 
Regimens, and changes Regimen 2 from an interrupted schedule to a continuous dosing schedule. 
Pharmacokinetic/pharmacodynamic modeling based on emerging data from Study42756493EDI1001 indicates that, 
at the 6 mg dose a 3-weeks on/1-week off dose regimen may be appropriate as it would avoid unscheduled 
interruptions due to hyperphosphatemia in approximately 25% of subjects. However, with dose reduction to 5 mg 
and 4 mg the number of subjects needing dose interruptions due to hyperphosphatemia is likely to be very small and 
therefore a 3-weeks-on/1-week-off dose regimen may not be necessary. Changing the schedule from the 3-weeks-
on/1-week-off dose regimen to continuous daily dosing will mitigate this effect, but may result in unscheduled 
interruptions in approximately 25% of subjects at the 6 mg starting dose level; this is considered manageable.
Moreover, further modeling also indicated that in both selected dose regimens (ie, 6 mg once daily continuous and 
10 mg once daily in a 7 days-on/7 days-off schedule) the dose can be further personalized based on the observed 
pharmacodynamic effect (phosphate level). Those subjects with suboptimal pharmacodynamic effect can be brought 
to target pharmacodynamic range (phosphate rage 5.5 to 7 mg/dL) by selective dose up-titration. Instituting these 
changes only in subjects with suboptimal pharmacodynamic effect who do not have significant toxicity will result in 
further dose optimization without significant increase in toxicity.
Applicable Section(s)
Description of Change(s)
Rationale: The T&E, Section 3.2.2 and Section 6 were adapted to reflect these changes.
Synopsis and throughout protocol: Changes pertaining to Regimen 2

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Status: Approved, Date: 4 October 2022
Applicable Section(s)
Description of Change(s)
T&E Tables
Abbreviations
Section 3.2.2 Rationale for Phase 2 Dose 
Selection
Section 4.1 &  4.2: Inclusion/Exclusion criteria
Section 6.2 Dose Up-titration Guidelines
(new section)
Section 6.3 Dose Modifications and Dose 
Delays
Split in two tables (one per regimen) and includes changes in 
assessments as necessitated by the dose and schedule change. 
Added increased frequency of pregnancy testing.
Several new abbreviations were added
Rationale for dose regimen selection and up-titration added
Updated inclusion 4 to clarify eligibility for subjects treated with 
anti-PDL1/PD1 antibodies. Updated exclusion 1 to include 
specific parameters for immunotherapy
Includes guidelines for up-titration.
Subsequent sections in Section 6 are renumbered
Tables specifying dose reduction levels for both regimens are 
provided.
Rationale:  The double barrier method is not considered to be an acceptable method by a Health Authority. 
Increased frequency of pregnancy testing recommended by Health Authority.
Section 4.1 Inclusion Criteria
Criterion 8
The double barrier method was removed
Rationale: Minor errors were noted
Th oughout the prot col
Minor grammatical and formatting changes were made.

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Status: Approved, Date: 4 October 2022
SYNOPSIS
A Phase 2, Two-arm Multicenter, Open-Label Study to Determine the Efficacy and the Safety of Two 
Different Dose Regimens of a pan-FGFR Tyrosine Kinase Inhibitor JNJ-42756493 in Subjects with 
Metastatic or Surgically Unresectable Urothelial Cancer with FGFR Genomic Alterations
JNJ-42756493 (erdafitinib) is a selective and potent pan fibroblast growth factor receptor (FGFR) inhibitor 
with demonstrated clinical activity in patients with solid tumors with alterations in the FGFR pathway 
including urothelial carcinoma,1 indicating the potential to be a new therapeutic option for these patients. 
In the proposed Phase 2 study, the efficacy and safety of erdafitinib in urothelial carcinomas harboring 
select FGFR aberrations will be evaluated at 3 dose regimens. The selected dose regimen upon 
implementation of Amendment 3 is 8 mg continuous daily dosing (Regimen 3).
OBJECTIVES AND HYPOTHESES
Primary Objective

To evaluate the objective response rate (complete response [CR]+ partial response [PR]) of the selected 
dose regimen in subjects with metastatic or surgically unresectable urothelial cancers that harbor 
specific FGFR genomic alterations.
Secondary Objectives

To evaluate the objective response rate of the selected dose regimen in chemo-refractory subjects

To evaluate progression-free survival (PFS), duration of response, and overall survival of the selected 
dose regimen in all and chemo-refractory subjects

To evaluate the response rate in biomarker-specific subgroups (translocations versus mutations) with
the selected dose regimen

To evaluate the objective response rate, PFS, duration of response, and overall survival of the other 
dose regimens tested

To evaluate the safety and pharmacokinetics of erdafitinib of all dose regimens
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Status: Approved, Date: 4 October 2022
OVERVIEW OF STUDY DESIGN
This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of 2 different dose 
regimens (Regimen 1: 10 mg oral study drug once daily on an intermittent schedule [Days 1 through 7 and 
Days 15 through 21 of a 28-day cycle]; Regimen 2: 6 mg oral study drug once daily on a continuous 
schedule [Days 1 through 28 of a 28-day cycle]), and selection of a more favorable dose regimen for 
erdafitinib in subjects with metastatic or surgically unresectable urothelial cancer with select FGFR genetic 
alterations. Based on analysis of data up to Interim Analysis 1 (IA1), the Data Review Committee (DRC)
decided to terminate further enrollment to the intermittent schedule and select the continuous schedule with 
a starting dose of 8 mg and possible up-titration to 9 mg (Regimen 3) for further enrollment. It is expected 
that approximately 180 subjects with specified FGFR genetic alterations will be enrolled in the study, of 
which about 30 subjects will be treated with Regimen 1, about 50 subjects will be treated with Regimen 2, 
and approximately 100 subjects will be treated with Regimen 3. When approximately 88 subjects have been 
treated in Regimen 3, if less than 80 subjects are chemo-refractory, then enrollment of chemo-naïve subjects 
in Regimen 3 will be stopped but enrollment of chemo-refractory subjects will continue until at least 80 
chemo-refractory subjects are treated in Regimen 3 or a total of approximately 100 subjects are treated with 
Regimen 3.
The study comprises a Screening Phase (molecular screening and full study screening), a Treatment Phase, 
and a post-treatment Follow-up Phase. Prior to IA1, subjects were randomized to 1 of 2 treatment regimens 
and stratified according to Eastern Cooperative Oncology Group (ECOG) performance status, hemoglobin 
level, FGFR alteration type, pretreatment status, and disease distribution. After IA1, subjects will be
assigned to Regimen 2. Following implementation of Amendment 3, all new subjects will be assigned to 
Regimen 3.
Subjects will be assessed for disease response according to the Response Evaluation Criteria in Solid 
Tumors (RECIST; version 1.1) guidelines. The end of study is defined as the date when all subjects have 
completed the study treatment (Regimens 1 to 3) and all subjects enrolled under the drug-drug interaction 
(DDI) substudy are no longer receiving treatment with erdafitinib.
SUBJECT POPULATION
Key inclusion criteria include the following: ≥18 years of age with histologic demonstration of metastatic 
or surgically unresectable transitional cell carcinoma of the urothelium 
 ECOG 
performance status score 0, 1, or 2; measurable disease according to the RECIST guidelines, version 1.1 at 
baseline; progressive disease after receiving at least 1 prior systemic chemotherapy; or ineligible for 
cisplatin per full inclusion criteria. 
DOSAGE AND ADMINISTRATION
The erdafitinib study drug is formulated as 3-, 4-, and 5-mg tablets for oral use. Prior to IA1, subjects were
randomized to receive 10 mg of oral study drug once daily on Days 1 through 7 and Days 15 through 21 of 
a 28-day cycle (Regimen 1) or 6 mg of oral study drug once daily on Days 1 through 28 of a 28-day cycle 
(Regimen 2). After IA1, subjects will receive 6 mg of oral study drug once daily on Days 1 through 28 of 
a 28-day cycle (Regimen 2). Following implementation of Amendment 3, subjects will receive 8 mg oral 
study drug once daily on Days 1 through 28 of a 28 day cycle (Regimen 3).
EFFICACY EVALUATIONS
Subjects will have response evaluations performed by radiographic image assessments according to 
RECIST version 1.1 guidelines until disease progression, initiation of subsequent anticancer therapy, or 
withdrawal of consent, whichever occurs first.
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Status: Approved, Date: 4 October 2022
c Only available tumor tissue (quantity as noted in the Laboratory Manual) should be sent for analysis.  No biopsies will be performed for purposes of molecular eligibility until 
approval is given by local regulatory agencies where applicable (e.g. approval of an Investigational Device Exemption (IDE) by the FDA/Center for Devices and Radiological Health 
(CDRH).
d Randomization will occur within 3 days prior to Cycle 1 Day 1. All information required for randomization purposes must be available at the time of randomization including: 
ECOG performance status score, hemoglobin value, FGFR alteration type (communicated by sponsor by time of randomization), disease distribution (presence or absence of visceral 
metastases: lung, liver, and bone) based upon baseline radiographic imaging performed during screening window, and pretreatment status (chemo-refractory versus chemo-naive) 
obtained by subject history/medical records.
e At Screening, a complete physical examination will be performed including height, weight, and oral/tympanic temperature. During the treatment period, limited physical examination 
of affected organs will be done, including weight and oral/tympanic temperature.
f
Including heart rate, systolic and diastolic blood pressure.
g On the day of visits with multiple measurements (clinical laboratory testing, ECG, PK/PD, and vital signs), the order of assessments will be per local site standards.
h ECOG performance status score of 0, 1, or 2 required within the 14 days prior to Cycle 1 Day 1, up until pre-dose of Cycle 1. 
i
Urine or serum β-hCG test, for women of childbearing potential and when sexually active at screening, at Day 1 of each subsequent cycle (following C1D1) and the end of treatment. 
Enrolled subjects should be counselled regarding appropriate contraception as required on Day 1 of every cycle. 
j
Clinical laboratory test results (except PTH) and ECG results must be available in real time prior to dosing with study drug as required in the schedule. Values/results of previous 
testing should be available for comparison as clinically necessary.
k If echocardiogram is not available, MUGA can be used.
l
Ophthalmological examinations should be performed by an ophthalmologist and should include assessment of visual acuity, tonometry, fundoscopy (examination of both central and 
peripheral zones should be performed), and where available Optical Coherence Tomography (OCT).
m Amsler grid testing should be performed by study physician or nurse (as directed by specific site instructions); please see Attachment 5 for Amsler grid pictorial
n Radiological assessment of response using imaging technology. Identical methodology should be used for disease assessment at baseline and throughout the study whenever possible. 
Baseline radiological assessment (refer to Section 9.2) will be obtained within 30 days before administration of the first dose of study drug. Radiological assessment will be
performed once every 6 weeks (+/-3 days, -14 to +3 days for scans confirming initial response) during the first 3 months, then once every 12 weeks (+/-1week) for the next 9 months, 
and once every 4 to 6 months until disease progression. All unconfirmed PR/CR require confirmation of response within 4 to 6 weeks of first assessment, as per RECIST 1.1.
o Pharmacokinetic sampling schedule is provided in Table 4.
p Biomarker sampling schedule is provided in Table 5.
q Adverse events will be collected from the day of the full study ICF signing until 30 days after the subject’s last dose of study drug. Adverse events may be collected by telephone 
call, and clinic visits.
r  Subjects who discontinue study drug due to drug-related toxicity will continue to be monitored for this toxicity until the toxicity resolves to baseline, stabilizes, or is deemed 
irreversible, the subject dies, or subsequent therapy is started, whichever occurs first.
s  May be assessed via telephone call.
t
The End-of-Treatment Visit must occur within 30 days after subject discontinues treatment last dose of study drug. 
u All subjects are to have a Follow-up Visit every 12 weeks (±7 days) in the Follow-Up Phase. For subjects who discontinue study drug before disease progression, tumor assessment 
should be continued as if the subject is still on treatment.
v Pre-dose
w To be performed 2 hours post-dose, at approximately the same time of day as the Day 1 ECG was performed
x Every third cycle starting on Cycle 3 Day 1: white blood cell count, absolute neutrophil count, hemoglobin, and platelet count
y Parathyroid hormone (PTH) will only be assessed pre-dose on Cycle 1 Day 1, Cycle 1 Day 21, Cycle 2 Day 1, and Cycle 3 Day 1.
z  Decision to up-titrate to 12 mg 7 days on/7 days off should be determined based on C1D21 phosphate value, and as per dose up-titration guidelines in Section 6.2.
aa Cycle 1 Day 1 chemistry and hematology may be performed the day prior to Cycle 1 Day 1.

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Status: Approved, Date: 4 October 2022
Table 2: 
REGIMEN 2 Time and Events Schedule (6 mg starting dose, 28 days continuous)
Parameter
Molecular 
Eligibility 
Assessment
Full Study 
Screening
Treatment C1 – ALL subjects
Treatment C2 & 3 – ONLY up-
titrated (8mg/day) subjectsa
Subsequent Cycles:
Day 1
(starting at C2 for subjects 
non up-titrated; starting at 
C4 for subjects up-titrated 
to 8 mg daily)a
Subsequent cycles
(C2 and C3): 
Day 14
(ONLY
non up-titrated 
subjects that 
continue at 
6mg/day)a
End-of-
Treatmenta,t
Follow-
Up 
Phasea,u
Day 1
Day 
7(-1)
Day 
21(-2)
Abbreviations: C=Cycle; CDRH=Center for Devices and Radiological Health; ECG=electrocardiogram; ECOG=Eastern Cooperative Oncology Group; FGFR=fibroblast growth factor 
receptor; ICF=informed consent form; MUGA=multi-gated acquisition scan; PD=pharmacodynamics; Phos=phosphate; PK=pharmacokinetic 
a Guidance for study conduct for ongoing subjects in the event of a national disaster is provided in Attachment 11.
b   Subjects may be presented with a molecular eligibility ICF to allow for the assessment of archived tumor tissue. Subjects who meet the tumor molecular eligibility criteria will be 
    further screened for full study eligibility, for which subjects may be presented a separate Full-Study ICF within 30 days prior to Cycle 1 Day 1.
c Only available tumor tissue (quantity as noted in the Laboratory Manual) should be sent for analysis.  No biopsies will be performed for purposes of molecular eligibility until 
approval is given by local regulatory agencies where applicable (e.g. approval of an Investigational Device Exemption (IDE) by the FDA/Center for Devices and Radiological Health 
(CDRH).
d Randomization  will occur within 3 days prior to Cycle 1 Day 1. All information required for randomization purposes must be available at the time of randomization including: 
ECOG performance status score, hemoglobin value, FGFR alteration type (communicated by sponsor by time of randomization), disease distribution (presence or absence of visceral 
metastases: lung, liver, and bone) based upon baseline radiographic imaging performed during screening window, and pretreatment status (chemo-refractory versus chemo-naive) 
obtained by subject history/medical records.
e At Screening, a complete physical examination will be performed including height, weight, and oral/tympanic temperature. During the treatment period, limited physical examination 
of affected organs will be done, including weight and oral/tympanic temperature.
f
Including heart rate, systolic and diastolic blood pressure.
g On the day of visits with multiple measurements (clinical laboratory testing, ECG, PK/PD, and vital signs), the order of assessments will be per local site standards.
h ECOG performance status score of 0, 1, or 2 required within the 14 days prior to Cycle 1 Day 1, up until pre-dose of Cycle 1. 
i
Urine or serum β-hCG test, for women of childbearing potential and when sexually active: at screening, at Day 1 of each subsequent cycle (following C1D1) and end of treatment. 
Enrolled subjects should be counselled regarding appropriate contraception as required on Day 1 of every cycle.
j
Clinical laboratory test results (except PTH) and ECG results must be available in real time prior to dosing with study drug as required in the schedule. Values/results of previous 
testing should be available for comparison as clinically necessary.
k If echocardiogram is not available, MUGA can be used.
l
Ophthalmological examinations must be performed at Screening by an ophthalmologist and should include assessment of visual acuity, fundoscopy (examination of both central and 
peripheral zones should be performed), and slit lamp biomicroscopy and Optical Coherence Tomography (OCT).
m Amsler grid testing should be performed by study physician or nurse (as directed by specific site instructions); please see Attachment 5 for Amsler grid pictorial
n Radiological assessment of response using imaging technology. Identical methodology should be used for disease assessment at baseline and throughout the study whenever possible. 
Baseline radiological assessment (refer to Section 9.2) will be obtained within 30 days before administration of the first dose of study drug. Radiological assessment will be 
performed once every 6 weeks (+/-3 days, -14 to +3 days for scans confirming initial response) during the first 3 months, then once every 12 weeks (+/-1week) for the next 9 months, 
and once every 4 to 6 months until disease progression. All unconfirmed PR/CR require confirmation of response within 4 to 6 weeks of first assessment, as per RECIST 1.1.
o Pharmacokinetic sampling schedule is provided in Table 4.
p Biomarker sampling schedule is provided in Table 5.
q Adverse events will be collected from the day of the full study ICF signing until 30 days after the subject’s last dose of study drug. Adverse events may be collected by telephone 
call, and clinic visits.

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Status: Approved, Date: 4 October 2022
Table 2: 
REGIMEN 2 Time and Events Schedule (6 mg starting dose, 28 days continuous)
Parameter
Molecular 
Eligibility 
Assessment
Full Study 
Screening
Treatment C1 – ALL subjects
Treatment C2 & 3 – ONLY up-
titrated (8mg/day) subjectsa
Subsequent Cycles:
Day 1
(starting at C2 for subjects 
non up-titrated; starting at 
C4 for subjects up-titrated 
to 8 mg daily)a
Subsequent cycles
(C2 and C3): 
Day 14
(ONLY
non up-titrated 
subjects that 
continue at 
6mg/day)a
End-of-
Treatmenta,t
Follow-
Up 
Phasea,u
Day 1
Day 
7(-1)
Day 
21(-2)
r  Subjects who discontinue study drug due to drug-related toxicity will continue to be monitored for this toxicity until the toxicity resolves to baseline, stabilizes, or is deemed 
irreversible, the subject dies, or subsequent therapy is started, whichever occurs first.
s  May be assessed via telephone call.
t
The End-of-Treatment Visit must occur within 30 days after the subject discontinues treatment. 
u All subjects are to have a Follow-up Visit every 12 weeks (±7 days) in the Follow-Up Phase. For subjects who discontinue study drug before disease progression, tumor assessment 
should be continued as if the subject is still on treatment.
v Pre-dose
w To be performed 2 hours post-dose, at approximately the same time of day as the Day 1 ECG was performed
x Every third cycle starting on Cycle 3 Day 1: white blood cell count, absolute neutrophil count, hemoglobin, and platelet count
y Parathyroid hormone (PTH) will only be assessed pre-dose on Cycle 1 Day 1, Cycle 1 Day 21, Cycle 2 Day 1, and Cycle 3 Day 1.
z  Decision to up-titrate to 8 mg daily should be determined based on the C2D1 pre-dose phosphate value, and as per dose up-titration guidelines in Section 6.2
aa Cycle 1 Day 1 chemistry and hematology may be performed the day prior to Cycle 1 Day 1.
bb Histological documentation of specific tumor type and prior anticancer therapy. Record demographic information.

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Status: Approved, Date: 4 October 2022
j
Clinical laboratory test results (except PTH) and ECG results must be available in real time prior to dosing with study drug as required in the schedule. Values/results of 
previous testing should be available for comparison as clinically necessary.
k Cycle 1 Day 1 chemistry and hematology may be performed the day prior to Cycle 1 Day 1.
l  Every third cycle starting on Cycle 6 Day 1: white blood cell count, absolute neutrophil count, hemoglobin, and platelet count
m Parathyroid hormone (PTH) will only be assessed pre-dose on Cycle 1 Day 1, Cycle 1 Day 21, Cycle 2 Day 1, and Cycle 3 Day 1.
n Decision to up-titrate to 9 mg daily should be determined based on the C1D14 phosphate value, and as per dose up-titration guidelines in Section 6.2 
o If echocardiogram is not available, MUGA can be used.
p Ophthalmological examinations must be performed at Screening by an ophthalmologist and should include assessment of visual acuity, fundoscopy (examination of both 
central and peripheral zones should be performed), and slit lamp biomicroscopy and Optical Coherence Tomography (OCT).
q Amsler grid testing should be performed by study physician or nurse (as directed by specific site instructions); please see Attachment 5 for Amsler grid pictorial
r  Radiological assessment of response using imaging technology. Identical methodology should be used for disease assessment at baseline and throughout the study 
whenever possible. Baseline radiological assessment (refer to Section 9.2) will be obtained within 30 days before administration of the first dose of study drug. 
Radiological assessment will be performed once every 6 weeks (+/-3 days, -14 to +3 days for scans confirming initial response) during the first 3 months, then once every 
12 weeks (+/-1week) for the next 9 months, and once every 4 to 6 months until disease progression. All unconfirmed PR/CR require confirmation of response within 4 to 6 
weeks of first assessment, as per RECIST 1.1.
s Pre-treatment and post-treatment tumor biopsies, if feasible, for patients deemed eligible by investigator (refer to Section 9.1). Not applicable for existing subjects who 
switch to Regimen 3.
t  Adverse events will be collected from the day of the full study ICF signing until 30 days after the subject’s last dose of study drug. Adverse events may be collected by 
telephone call, and clinic visits.
u Subjects who discontinue study drug due to drug-related toxicity will continue to be monitored for this toxicity until the toxicity resolves to baseline, stabilizes, or is 
deemed irreversible, the subject dies, or subsequent therapy is started, whichever occurs first.
v All subjects are to have a Follow-up Visit every 12 weeks (±7 days) in the Follow-Up Phase. All subjects will enter the Follow-Up Phase to assess survival status and start 
of alternate anticancer therapy until death, the subject withdraws consent, or the end of study, whichever occurs first. This information may be collected via telephone call. 
For subjects who discontinue study drug before disease progression, tumor assessment should be continued as if the subject is still on treatment.
w Histological documentation of specific tumor type and prior anticancer therapy. Record demographic information.

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Status: Approved, Date: 4 October 2022
Table 4:
Pharmacokinetic Blood Sample Collection Schedule
Cycle and Daya
Number of samples at each 
time point
Volume (mL)
Predose
(within 30 minutes prior 
to dose)
2 h
4 h
Cycle 1 Day 1
1
3 or 7b
X
Xb
X
Cycle 1 Day 21
1
3
X
X
X
Every other cycle, starting Cycle 
3
1
3
X
a
3 mL blood sample will be collected at each time point. The sampling schedule may be adjusted based on pharmacokinetic analysis output generated during the study or in case of 
vomiting or other safety concerns.
b   an additional 4 mL blood sample will be collected for determination of FU (fraction of the unbound erdafitinib) and protein levels (total protein, albumin, and alpha-1-acid 
glycoprotein) on Cycle 1 Day 1, 2 hours post dose
Note: Routine sample collection will be terminated once protocol Amendment 6 is approved at the site, as required by local regulations. Additional samples may be collected at any 
time for assessment of adverse events as clinically appropriate.
Table 5:
Biomarker Blood Sample Collection Schedule
Time Point
Number of samples at each time point
Total Volume (mL) a
Screening 
1+1
22.5 mL
Cycle 1 Day 1 (predose)
1
2.5 mL
Cycle 2 Day 1 (predose) b
1+1
22.5 mL
Cycle 3 Day 1 (predose)
1
2.5 mL
Cycle 5 Day 1 (predose) c
1+1
22.5 mL
Day 1 of every other cycle (predose) starting Cycle 7
1
2.5 mL
End of Treatment Visit c
1+1
22.5 mL
a Total volume composed of 2.5 mL sample, and, where applicable, additional 20 mL sample.
b Subjects providing post-treatment biopsy only
c When possible, additional 20mL sample to be collected.
Note: Routine sample collection will be terminated once protocol Amendment 6 is approved at the site, as required by local regulations. 

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Status: Approved, Date: 4 October 2022
ABBREVIATIONS AND DEFINITIONS OF TERMS
ALP
alkaline phosphatase
ALT
alanine aminotransferase
AMD
age-related macular degeneration
ANC
absolute neutrophil count
AST
aspartate aminotransferase
AUC
area under the serum concentration versus time curve
AUCu
area under the serum concentration versus time curve for unbound drug
BCOP
bovine corneal opacity and permeability
β-hCG
beta human chorionic gonadotropin
BUN
blood urea nitrogen
Cavg
average plasma concentrations
CED
the total concentration of erdafitinib in the plasma
Cmax
maximum plasma concentration
Cmin
minimum plasma concentration
CPK
creatine phosphokinase
CR
complete response
CRF
Case Report Form
CSR
central serious retinopathy
CT
computed tomography
ctDNA
circulating tumor DNA
Cu
unbound concentration of erdafitinib
%CV
coefficient of variation
CYP
cytochrome P
DDI 
drug-drug interaction
DLT
dose-limiting toxicity
DRC
Data Review Committee
ECG
electrocardiogram
ECOG
Eastern Cooperative Oncology Group
eCRF
electronic case report form
eDC
electronic data capture
ESA
erythropoiesis-stimulating agent
FDA
Food and Drug Administration (United States)
FDG-PET
fluorine 18-fluorodeoxyglucose positron emission tomography
FGFR
fibroblast growth factor receptor
FU
fraction of the unbound erdafitinib
GCP
Good Clinical Practice
GFR
glomerular filtration rate
HIV
human immunodeficiency virus
IA1
Interim Analysis 1
IA2
Interim Analysis 2
IC50
half maximal inhibitory concentration
ICF
informed consent form
ICH
International Conference on Harmonisation
IEC
Independent Ethics Committee
IgM
Immunoglobulin M
IHC
immunohistochemistry 
INR
international normalized ratio
IRB
Institutional Review Board
IRC
Independent Review Committee
IWRS
Interactive Web Response System
LDH
lactate dehydrogenase
LC-MS/MS
liquid chromatography-mass spectrometry
LTE
Long-Term Extension
LVEF
left ventricular ejection fraction

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MAPK
Ras/mitogen-activated protein kinase
MedDRA
Medical Dictionary for Regulatory Activities
MTD
maximum tolerated dose
MRI
magnetic resonance imaging
MUGA
multi-gated acquisition scan
MVAC
methotrexate/vinblastine/doxorubicin/cisplatin
NCI-CTCAE
National Cancer Institute Common Terminology Criteria for Adverse Events
NSCLC
non-small cell lung cancer
OCT
Optical Coherence Tomography 
OCT2
organic cation transporter 2 
ORR
overall response rate
PD
disease progression
PE
Primary Efficacy (analysis population)
PFS
progression-free survival
P-gp
P-glycoprotein
PK
pharmacokinetics
PQC
Product Quality Complaint
PR
partial response
PTH
parathyroid hormone
RANO
Revised Assessment in Neuro-Oncology
RE
Response Evaluable (population)
RECIST
Response Evaluation Criteria in Solid Tumors
RPED
retinal pigment epithelial detachments
RVO
retinal vascular occlusion
SD
stable disease
SMT
Safety Management Team
SPF
skin protection factor
TDI
time-dependent inhibitor
tmax
median time to maximum concentration
ULN
upper limit of normal
US
United States
WBC
white blood cell (count)

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1.
INTRODUCTION
Urothelial carcinoma is a highly prevalent disease, with an estimated 74,700 new cases and 15,600 
deaths in the United States (US) in 2014.27 For metastatic urothelial cancer, platinum-based 
chemotherapy is the main therapeutic option for front-line therapy and there is no accepted 
standard of care for second-line therapy. 
First-line chemotherapy for metastatic disease includes a combination of gemcitabine and cisplatin 
or methotrexate/vinblastine/doxorubicin/cisplatin (MVAC).20 With cisplatin-based treatment, the 
median survival for patients with surgically unresectable or metastatic urothelial carcinoma is only 
approximately 14 months,3 and 5-year survival is 13%.30 Gemcitabine in combination with 
cisplatin showed a similar effect on overall survival (median: 14 months versus 15 months) and 
response rate (49% versus 46%) compared with MVAC with a better safety profile.24,29
There is a need to develop new therapeutic options capitalizing on the molecular aberration driving 
urothelial malignancy. Overexpression of fibroblast growth factor receptors (FGFRs), or aberrant 
regulation of their activity, has been implicated in many forms of human malignancies including 
urothelial carcinoma.22
Fibroblast growth factor receptors are protein tyrosine kinases and consist of 4 members (FGFR1 
to FGFR4).22 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.11,22 The result is FGFR stimulation of cell growth, survival, migration, and 
differentiation depending on the cell type. 
Fibroblast growth factor receptors are present in many types of normal and tumor cells and have 
been shown to play an important role in tumor cell growth, survival, and migration as well as in 
maintaining tumor angiogenesis. Overexpression of FGFRs, or aberrant regulation of their activity, 
has been implicated in many forms of human malignancies.13 Fibroblast growth factor receptor
activating mutation, gene amplification, and translocation have been associated with neoplastic 
progression and tumor vascularization in multiple cancer types, including breast, lung, prostate, 
endometrial, gastric, and urothelial carcinoma.22 Therefore, targeting FGFRs in urothelial cancer 
with a small molecule kinase inhibitor is an attractive strategy for the development of a novel 
cancer treatment.13
JNJ-42756493 (erdafitinib) is a selective and potent pan FGFR inhibitor with demonstrated clinical
activity in patients with alterations in the FGFR pathway including urothelial carcinoma,1
indicating the potential to be a new therapeutic option for these patients. In the proposed study, the 
efficacy and safety of erdafitinib in urothelial carcinomas harboring select FGFR aberrations will 
be evaluated at 2 dose regimens, and a more favorable dose regimen will be selected. Based on 
analysis of data up to Interim Analysis 1 (IA1), the Data Review Committee (DRC) decided to 

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terminate further enrollment to the intermittent schedule and select the continuous schedule with 
a starting dose of 8 mg and possible up-titration to 9 mg (Regimen 3) for further enrollment.
For the most comprehensive nonclinical and clinical information regarding erdafitinib, refer to the 
latest version of the Investigator’s Brochure.13
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.
1.1.
Background
1.1.1.
Nonclinical Pharmacology
Erdafitinib is an FGFR1, 2, 3, and 4 inhibitor with nanomolar affinity (biochemical half maximal 
inhibitory concentration [IC50] values of <1 nM for FGFR1, <1 nM for FGFR2, 1.05 nM for 
FGFR3, and <1 nM for FGFR4). It has demonstrated potent inhibition of cell proliferation with 
IC50 values ranging from <1 nM to 100 nM in cell lines harboring activating FGFR alterations, 
including squamous non-small cell lung cancer (NSCLC), gastric, breast, and bladder. Non-FGFR 
driven cell lines require significantly higher drug concentration for inhibition of cell proliferation 
to be observed. Target inhibition and pathway modulation have been demonstrated in cellular 
models at the active cellular concentrations. A separate experiment demonstrated rapid lysosomal 
uptake of erdafitinib, which enables sustained intracellular release and long-lasting target 
engagement. Brief exposure (1 hour) to erdafitinib has been demonstrated to result in long term (8 
to 16 hours) target inhibition due to drug accumulation in the lysosomes.13 Furthermore, erdafitinib
has demonstrated potent inhibition of growth of both xenograft tumors and patient-derived tumor 
samples implanted in immunodeficient mice and rats, including gastric, breast, lung, and bladder 
tumors harboring activating FGFR alterations. 
1.1.2.
Pharmacokinetics and Product Metabolism in Animals
In pharmacokinetic experiments in mice, rats, and dogs, erdafitinib showed high clearance, fast 
oral absorption, and short elimination half-life; the volume of distribution was higher than the total 
body water indicating extensive tissue distribution. The highest tissue exposures were observed in 
lung and liver and the lowest exposures were observed in skin and muscle, resulting in tissue to 
plasma ratios between 133 and 6.0.13
Cytochrome P450 (CYP) 3A4 was identified as the most important CYP enzyme involved in the 
metabolism of erdafitinib. Other minor routes involved in the microsomal metabolism of 
erdafitinib were CYP2C8 and CYP2D6.14 Furthermore, erdafitinib shows weak inhibition 
potential towards CYP1A2, CYP2C9, CYP2C19, CYP2D6, and CYP3A reflected in IC50 values 
>15 µM, suggesting a low drug-drug interaction potential.13
Large species differences in unbound fraction in plasma were observed. The free fraction in human 
samples ranged between 0.55% and 0.74%. In animals, the free fraction ranged between 2.2% 
(nude rat) to 13.7% (dog). In human blood, erdafitinib was mainly bound to plasma proteins (about 

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95%). Strong binding of 3H-JNJ-42756493 to human purified alpha-1-acid glycoprotein was 
observed which was dependent on the protein concentration.13
In both rat and dog, less than 5% of the dose was excreted unchanged, indicating extensive 
metabolism in vivo. Fecal excretion of drug-related material was higher (88% and >75%, 
respectively) than urinary excretion (2.5% and ≤5.5%, respectively), implying hepatic clearance 
plays more dominate role than renal clearance.15
Toxicology
Toxicology studies were conducted in rats, dogs, and male mice. Cartilage dysplasia and soft tissue 
mineralization were observed as primary drug-related toxicities in all species. Erdafitinib showed 
no genotoxic properties in in- vitro genotoxicity screening assays. Soft tissue mineralizations were 
associated with a disturbance of vitamin D and phosphate homeostasis, characterized by elevated 
levels of 1,25-dihydroxyvitamin D3, serum phosphate and, to a much lesser extent, calcium. 
Chondroid dysplasia and soft tissue mineralization were shown to be slowly and partially 
reversible, except for the aorta mineralization in dogs that did not show recovery after a 4-week 
washout period. Additionally mammary gland atrophy was noted in male rats in a 1-month 
repeated dose study. In the ongoing 3-month repeated dose studies in rats and dogs, at the end of 
treatment corneal atrophy was seen in rats and lacrimal gland atrophy in rats and dogs. 
Reversibility was not evaluated. Erdafitinib showed no genotoxic properties in in vitro 
genotoxicity screening assays. It was classified as a very severe eye irritant at a high concentration 
in the in-vitro bovine corneal opacity and permeability (BCOP) test. At clinically relevant 
concentrations it did not induce vascular irritation in the in vitro HET-CAM test. Erdafitinib was 
evaluated in mice as having a skin sensitizing potential. No phototoxicity was observed in a 
pigmented rat study.
Erdafitinib is an intrinsic hERG blocker with a proarrhythmia liability which translates into a 
prolonged repolarization (QTc) after i.v. dosing in the anesthetized dog and guinea pig, and after 
oral dosing in the conscious dog. A total plasma concentration of 770 ng/mL or unbound 
concentration of 81 ng/mL is considered to be the cardiovascular threshold for of this liability. In 
a modified Irwin’s test in rats, erdafitinib showed minimal neurofunctional aberrations (impaired 
wire maneuvers and flaccid body tone) from a mean maximal plasma concentrations (Cmax) of 12.1 
ng/ml, considered an indirect effect of treatment.13
Holter monitoring was terminated in Parts 2 and 3 of Study 427856493EDI1001 after no clinically 
significant cardiovascular findings were noted in 37 consecutive subjects. In addition the 
concentration of free drug was never recorded above 1/20th of the threshold level for potential 
cardiac events.13
1.2.
Clinical Experience
Study 42756493EDI1001 is a Phase 1, first-in-human, open-label, multicenter, 4-part, dose-
escalation study to explore the safety, pharmacokinetics, pharmacodynamics, and clinical activity
of erdafitinib in subjects 18 years of age or older with advanced or refractory solid malignancies 
or lymphoma who are not candidates for approved or available therapies. Part 1 is the Dose-

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Escalation Phase based on safety and pharmacokinetics. Part 2 is the Dose-Confirmation Phase, 
consisting of pre- and post-treatment tumor biopsy cohorts to confirm the recommended Phase 2 
dose based on the pharmacodynamic effect of erdafitinib on the FGFR signaling pathway in 
tumors. Part 3 is the first Dose-Expansion Phase, designed to evaluate inclusion biomarkers and 
preliminary clinical activity at the first recommended Phase 2 dose of 9.0 mg daily, and Part 4 is 
the second Dose-Expansion Phase, designed to evaluate clinical activity at the second 
recommended Phase 2 dose of 10 mg intermittent dosing schedule.
Study 42756493EDI1001 has evaluated erdafitinib in daily dosing cohorts from 0.5 mg to 12 mg, 
and 10 mg intermittent and 12 mg intermittent doses. As of 15 October 2014, 96 subjects have 
received treatment with erdafitinib in 8 cohorts: 0.5, 2.0, 4.0, 6.0, 9.0, and 12.0 mg daily, and 
10.0 mg and 12.0 mg given on an intermittent schedule. One dose-limiting toxicity (DLT) was 
observed to date in a 40-year-old woman with breast cancer in the 12.0 mg daily dosing cohort. 
The event was a reversible and asymptomatic Grade 3 hepatic function abnormal/alanine 
aminotransferase (ALT) increase on Study Day 15 in Cycle 1. Based on the DLT, higher incidence 
of hyperphosphatemia requiring dose interruption, and overall tolerability, a decision to stop dose 
escalation beyond 12.0 mg was made and 12 mg was declared the maximum administered daily 
dose. A true maximum-tolerated dose (MTD) was not established in the Part 1 dose-escalation 
component. However, based on the safety, pharmacokinetic/ pharmacodynamics and preliminary 
clinical response data, 9 mg daily was selected as the first recommended Phase 2 dose. Additional 
doses such as a 6-mg continuous dose and 10-mg and 12-mg intermittent doses were considered 
possible Phase 2 doses for further evaluation.
1.2.1.1.
Safety Experience
Safety data for 96 treated subjects was available at the October 2014 data cut-off. The median drug 
exposure for all 96 subjects was 2.0 cycles (range: 1 to 13 cycles) or 1.6 months. Across all dose 
cohorts, the median total number of cycles of treatment ranged from 2.0 to 4.0, and the median 
total duration of treatment ranged from 1.4 to 2.8 months, suggesting similar tolerability to the 
drug.
Of the 96 subjects treated with erdafitinib in Study 42756493EDI1001, 91 subjects (94.8%) 
experienced any treatment-emergent adverse event; 43 subjects (44.8%) experienced a Grade 3 or 
higher adverse event. Thirty-one subjects (32.3%) experienced a serious adverse event with 
8 subjects (8.3%) experiencing a drug-related serious treatment-emergent adverse event. Six
subjects (6.3%) discontinued treatment due to an adverse event. Seven subjects (7.3%) experienced 
adverse events leading to death (Table 6).

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Table 6: 
Overall Summary of Treatment-Emergent Adverse Events: Study 42756493-EDI1001
6.00 mg 
(QD) 
9.00 mg 
(QD) 
10.00 mg (7d 
on/7d off) 
12.00 mg 
(QD) 
12.00 mg (7d 
on/7d off) 
Total
(all doses
0.5-12 mg)
Population: safety
9
47
6
7
13
96
Any adverse event (AE)
9 (100.0%)
44 (93.6%)
5 (83.3%)
7 (100.0%)
13 (100.0%)
91 (94.8%)
Grade 3 or higher
3 (33.3%)
21 (44.7%)
4 (66.7%)
3 (42.9%)
7 (53.8%)
43 (44.8%)
Any drug-relateda AE
9 (100.0%)
39 (83.0%)
5 (83.3%)
7 (100.0%)
13 (100.0%)
82 (85.4%)
Grade 3 or higher
1 (11.1%)
13 (27.7%)
0
3 (42.9%)
4 (30.8%)
21 (21.9%)
Any serious AE
2 (22.2%)
18 (38.3%)
2 (33.3%)
1 (14.3%)
4 (30.8%)
31 (32.3%)
Drug-relateda
0
8 (17.0%)
0
0
0
8 (8.3%)
AE leading to treatment 
discontinuation
1 (11.1%)
3 (6.4%)
0
0
1 (7.7%)
6 (6.3%)
Hyperphosphatemia
7 (77.8%)
30 (63.8%)
4 (66.7%)
4 (57.1%)
10 (76.9%)
60 (62.5%)
Hyperphosphatemia leading 
to dose interruption
2 (22.2%)
23 (48.9%)
1 (16.7%)
4 (57.1%)
4 (30.8%)
34 (35.4%)
Hyperphosphatemia leading 
to dose reduction
0
6 (12.8%)
0
3 (42.9%)
0
9 (9.4%)
AE with outcome of deathb
0
4 (8.5%)
0
0
1 (7.7%)
7 (7.3%)
a
Adverse event reported as very likely, possibly or probably related to erdafitinib.
b
Death within 30 days of last treatment dose are included.
Note: Adverse events reported any time from the first treatment dose to within 30 days of last treatment dose are 
included.
Note: Incidence is based on the number of subjects experiencing at least one adverse event, not the number of 
events.
Note: Percentages calculated with the number of subjects in safety population of each group as denominator.
Subject.
was assigned to the liquid group since the subject took only 1 capsule dose then switched to
liquid doses.
Sources: TSFAE01S; TSFAE02S; TSFAE42S, TSFAE04S
Treatment-emergent adverse events experienced by at least 10% of subjects in 
Study 42756493EDI1001 as of October 2014 are summarized in Table 7. The most commonly 
reported adverse events by preferred terms (>20% of subjects) were hyperphosphatemia (62.5%), 
dry mouth (44.8%), asthenia (42.7%), constipation (38.5%), stomatitis (33.3%), decreased appetite 
(29.2%), vomiting (28.1%), dysgeusia (26.0%), and diarrhea (20.8%).
Central serous retinopathy (CSR)/retinal pigment epithelial detachments (RPED) were observed 
in 3 subjects. One subject (9 mg daily dose) experienced Grade 2 CSR and Grade 1 retinal 
detachment. This subject had complete resolution of the Grade 2 CSR/Grade 1 RPED within 
30 days, however upon study drug reintroduction at a lower dose had recurrent Grade 1 
CSR/RPED, which resolved upon on re-interruption. Two other subjects, 1 treated at 12 mg, 7 days 
on/7 days off, and 1 treated at 9 mg daily, respectively, experienced Grade 1 CSR and Grade 2 
retinal edema, which were considered probably related to study drug and resolved after drug 
interruption.
Prior experiences with CSR with kinase inhibitors, primarily MEK inhibitors have indicated that 
CSR/RPEDs are generally reversible. In the case of trametinib, a Food and Drug Administration 
(FDA)-approved MEK inhibitor, instances of CSR have generally resolved completely by 
withholding drug and required no additional treatment. Permanent ocular sequelae have also not 
been reported in patients that have experienced CSR due to MEK inhibitors.18,19,33 Based on 
PPD

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emerging data more stringent eye examination and eye toxicity management guidelines have been 
instituted in this study.
Thirty-one subjects (32.3%) experienced serious adverse events. The most commonly reported 
serious adverse events (preferred terms) were general physical health deterioration, abdominal 
pain, intestinal obstruction, and hyponatremia, experienced by 3 subjects (3.1%) each. Forty-
three subjects (44.8%) experienced a Grade 3 or higher adverse event; 21 subjects (21.9%) 
experienced Grade 3 or higher events considered drug-related (Table 7). These events included 
5 events each of onycholysis and Palmar-plantar erythrodysesthesia syndrome; 4 events of fatigue; 
3 events each of AST increased, onychalgia, and ALT elevation; 2 events each of onychomycosis
and decreased appetite; and 1 event each of acute pancreatitis, stomatitis dyspnea, hyponatremia, 
atrophic rhinitis, asthenia, anemia, and paronychia.
Eighteen subjects (18.8%) experienced adverse events which led to dose reductions. Adverse 
events leading to treatment discontinuation were reported for 6 subjects (6.3%): 1 subject in each 
of the 0.5 mg and 6.0 mg daily dosing groups, 3 subjects in the 9.0 mg daily dosing group, and 
1 subject in the 12 mg (7 days on/7 days off) dosing group. Only 1 subject in the 9 mg daily dosing 
group discontinued treatment due to an adverse event which was considered drug related (Palmar-
plantar erythrodysesthesia syndrome). 
Dose selection rationale is described in Section 3.1.2.

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Table 7:
Treatment Emergent Adverse Events in Study 42756493EDI1001 for Dose Levels ≥6 mg 
(Any Grade, ≥10% Subjects)
Dose
6 mg
(QD)
9 mg
(QD)
10.00 mg (7 
d on/7 d off)
12.00 mg 
(QD)
12.00 mg (7 
d on/7 d off)
Total
(all doses
0.5-12 
mg)
Total no. of subjects 
treated
9
47
6
7
13
96
Total no. subjects with 
adverse events
9 (100.0%)
44 (93.6%)
5 (83.3%)
7 (100.0%)
13 (100.0%)
91 (94.8%)
Hyperphosphataemia
7 (77.8%)
30 (63.8%)
4 (66.7%)
4 (57.1%)
10 (76.9%)
60 (62.5%)
Dry mouth
7 (77.8%)
19 (40.4%)
3 (50.0%)
6 (85.7%)
5 (38.5%)
43 (44.8%)
Asthenia
6 (66.7%)
11 (23.4%)
4 (66.7%)
7 (100.0%)
6 (46.2%)
41 (42.7%)
Constipation
3 (33.3%)
20 (42.6%)
0
4 (57.1%)
5 (38.5%)
37 (38.5%)
Stomatitis
3 (33.3%)
19 (40.4%)
2 (33.3%)
5 (71.4%)
2 (15.4%)
32 (33.3%)
Decreased appetite
2 (22.2%)
11 (23.4%)
3 (50.0%)
2 (28.6%)
7 (53.8%)
28 (29.2%)
Vomiting
4 (44.4%)
15 (31.9%)
1 (16.7%)
1 (14.3%)
3 (23.1%)
27 (28.1%)
Dysgeusia
1 (11.1%)
12 (25.5%)
3 (50.0%)
4 (57.1%)
4 (30.8%)
25 (26.0%)
Diarrhoea
3 (33.3%)
10 (21.3%)
1 (16.7%)
1 (14.3%)
2 (15.4%)
20 (20.8%)
Dry skin
1 (11.1%)
8 (17.0%)
0
6 (85.7%)
3 (23.1%)
19 (19.8%)
Nausea
3 (33.3%)
10 (21.3%)
0
1 (14.3%)
2 (15.4%)
19 (19.8%)
Alopecia
1 (11.1%)
8 (17.0%)
0
5 (71.4%)
2 (15.4%)
16 (16.7%)
Anaemia
1 (11.1%)
4 (8.5%)
3 (50.0%)
0
5 (38.5%)
16 (16.7%)
Abdominal pain
1 (11.1%)
7 (14.9%)
0
2 (28.6%)
0
14 (14.6%)
Dry eye
1 (11.1%)
8 (17.0%)
0
2 (28.6%)
3 (23.1%)
14 (14.6%)
Arthralgia
2 (22.2%)
8 (17.0%)
0
0
0
12 (12.5%)
Hepatic function 
abnormal
1 (11.1%)
2 (4.3%)
1 (16.7%)
1 (14.3%)
4 (30.8%)
12 (12.5%)
Fatigue
0
9 (19.1%)
0
0
1 (7.7%)
11 (11.5%)
Hypomagnesaemia
3 (33.3%)
4 (8.5%)
1 (16.7%)
1 (14.3%)
1 (7.7%)
11 (11.5%)
Abdominal pain upper
2 (22.2%)
4 (8.5%)
1 (16.7%)
0
2 (15.4%)
10 (10.4%)
Dyspnoea
0
5 (10.6%)
0
1 (14.3%)
4 (30.8%)
10 (10.4%)
Pyrexia
2 (22.2%)
6 (12.8%)
0
1 (14.3%)
0
10 (10.4%)
Urinary tract infection
2 (22.2%)
3 (6.4%)
2 (33.3%)
1 (14.3%)
0
10 (10.4%)
AE=adverse event; QD=once daily
Note: Adverse events reported any time from the treatment dose to within 30 days of last treatment dose are included.
Note: Incidence is based on the number of subjects, not the number of events.
Note: Percentages calculated with the number of subjects in safety population of each group as denominator.
Note: Recurring events are counted only once for each subject.
Subjetc
was assigned to liquid group since the subject took only one capsule dose then switched to liquid doses.
Source: [TSFAE02ES.rtf] [JNJ-42756493\EDI1001\DBR_FDA_BB_2014\RE_FDA_BB_2014\TSFAE02es.sas] 15OCT2014, 15:28
The overall safety profile for Study 42756493EDI1001 at the time of the final report was 
essentially identical to the safety reported for the primary analysis. There were no new safety 
signals observed after the cut-off date for the primary CSR. The most commonly reported AEs, 
after hyperphosphatemia (65%), were dry mouth (46%), asthenia (45%), stomatitis (39%), 
constipation (37%), decreased appetite (34%), and diarrhea (30%). One hundred sixteen subjects 
(62%) experienced a Grade 3 or higher AE. Twenty-three subjects (12%) discontinued treatment 
due to an AE.
Erdafitinib for the treatment of patients with metastatic urothelial carcinoma that harbor select 
FGFR alterations received accelerated approval in the United States based on the primary analysis 
of Study BLC2001. At the time of the primary analysis (clinical cutoff of 15 March 2018), 
210 subjects had been treated: 33 subjects in the 10 mg intermittent dosing regimen, 78 subjects 
in the 6 mg daily regimen, and 99 subjects in the 8 mg daily regimen (selected dose regimen). The 
most frequently reported adverse events in the 8 mg once daily regimen, most of which were Grade 
PPD

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1 or 2 in severity, were hyperphosphatemia (77%), stomatitis (58%), diarrhea (51%), and dry 
mouth (46%). Twenty-one subjects (21%) discontinued treatment due to adverse events. The most 
common reason for discontinuation was general physical health deterioration. The frequency of 
reported adverse events and discontinuations across all dose regimens combined was similar to 
that seen in the 8 mg once daily regimen.
An updated analysis has also been completed for Study BLC2001 (clinical cutoff of 
09 August 2019). The median follow-up for 101 subjects treated in the erdafitinib 8 mg regimen 
was approximately 24 months. The erdafitinib safety profile was consistent with the primary 
analysis. No new treatment-emergent adverse events were seen with longer follow-up. Central 
serious retinopathy events occurred in 27% (27/101) of subjects; 85% (23/27) were Grade 1 or 2. 
Dosage was reduced in 13 subjects with CSR, interrupted in 8 subjects, and discontinued for 3 
subjects. On the data cutoff date, 63% (17/27) CSR events had resolved; 6 of 10 of the ongoing 
CSR events were Grade 1. There were no treatment-related deaths.
Also, please refer to the current Erdafitinib Investigator’s Brochure for recent safety information.
1.2.1.2.
Clinical Pharmacokinetics
Erdafitinib plasma pharmacokinetics has been assessed in Study 42756493EDI1001 with oral 
doses ranging from 0.5 mg to 12 mg. Erdafitinib is highly and tightly bound to alpha-1-acid 
glycoprotein (orosomucoid) leading to low and variable free-drug fraction in cancer-patient 
circulation (mean: 0.0035; range: 0.0012 to 0.0083). Unbound drug is detailed here as this is the 
relevant pharmacologically active moiety. Erdafitinib absorption is fast following oral intake of 
oral solution or immediate-release capsule formulation. Maximal plasma concentrations (Cmax) 
and area under the serum concentration versus time curve (AUC) values increased approximately 
linearly with increasing doses across the dose range tested, after both single- and multiple-dosing 
(Select doses are shown in Figure 1 and 
). There is no indication of time-dependent 
pharmacokinetics on multiple dosing of erdafitinib.
CCI

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Figure 1: 
Mean (SD) Unbound JNJ-42756493 Plasma Concentration-time Profiles Following Oral 
Administrations of Drug at Indicated Doses (Study JNJ-42756493-EDI1001)
The apparent terminal half-life of erdafitinib is variable and ranges from 50 to 60 hours and 
possibly up to 3 days. Oral clearance (based on total plasma drug concentrations) of the drug is 
low in the range of 0.3 (L/h) and central volume of distribution (based on total drug concentrations) 
is also low at approximately 20 (L).
Based on a population-based approach, analysis of current clinical exposure data demonstrates 
2 significant co-variates in the determination of pharmacokinetic parameters. Erdafitinib is highly 
protein bound including plasma alpha-1-acid glycoprotein. Alpha-1-acid glycoprotein plasma 
levels and bodyweight have influence on the pharmacokinetics of erdafitinib.

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With a median drug exposure at the October 2014 data cut-off for the total population of
1.6 months (2.0 cycles), there does not appear to be substantial differences in mean or median drug 
exposure in dose cohorts comparing higher doses with lower doses considering the number of 
subjects who are continuing treatment, suggestive of tolerability to the drug. 
2.
OBJECTIVES AND HYPOTHESES
2.1.
Objectives
2.1.1.
Primary
The primary objective of the study is:

To evaluate the objective response rate (complete response [CR]+ partial response [PR]) of 
the selected dose regimen in subjects with metastatic or surgically unresectable urothelial 
cancers that harbor specific FGFR genomic alterations.
2.1.2.
Secondary
The secondary objectives of the study are:

To evaluate the objective response rate of the selected dose regimen in chemo-refractory 
subjects

To evaluate the progression-free survival (PFS), duration of response, and overall survival of 
the selected dose regimen in all and in chemo-refractory subjects

To evaluate the response rate in biomarker-specific subgroups (translocations versus 
mutations) with the selected dose regimen

To evaluate the objective response rate, PFS, duration of response, and overall survival of the 
other dose regimens tested

To evaluate the safety and pharmacokinetics of erdafitinib of all dose regimens
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2.2.
Hypotheses
The primary hypothesis is that the selected dose regimen of erdafitinib has an overall response rate
(ORR) >25% in subjects with metastatic or surgically unresectable urothelial cancer harboring 
select FGFR alterations.
2.3.
Overview of Study Design
This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of single-agent
erdafitinib in subjects with metastatic or surgically unresectable urothelial cancer harboring select 
FGFR genetic alterations.
The study comprises a Screening Phase (both molecular screening and full-study screening), a 
Treatment Phase, and a post-treatment Follow-up Phase (Figure 2). Molecular screening will occur
any time prior to the first dose; the full-study Screening Phase will be up to 30 days prior to the 
first dose. The Treatment Phase will extend from the administration of the first dose until the End-
of-Treatment Visit. The post-treatment Follow-up Phase will extend from the End-of-Treatment 
Visit until the subject has died, withdraws consent, is lost to follow-up, or the end of study, 
whichever comes first. The end of study is defined as the date when all subjects have completed 
the study treatment (Regimens 1 to 3) and all subjects enrolled under the drug-drug interaction 
(DDI) substudy are no longer receiving treatment with erdafitinib.
Figure 2: 
Study Phases
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Study treatment will be administered on a 28-day cycle. Prior to IA1, there were 2 treatment 
regimens: Regimen 1 (10 mg once daily, 7 days on/7 days off); Regimen 2 (6 mg once daily for 
28 days). Following IA1 and implementation of Amendment 3, Regimen 3 (8 mg once daily for 
28 days) will be instituted. It is expected that approximately 180 subjects with specified FGFR 
genetic alterations will be enrolled in the study, of which about 30 subjects will be treated with 
Regimen 1, about 50 subjects will be treated with Regimen 2, and approximately 100 subjects will 
be treated with Regimen 3. When approximately 88 subjects have been treated in Regimen 3, if 
less than 80 subjects are chemo-refractory, then enrollment of chemo-naïve subjects in Regimen 
3 will be stopped but enrollment of chemo-refractory subjects will continue until at least 80 chemo-
refractory subjects are treated in Regimen 3 or a total of approximately 100 subjects are treated 
with Regimen 3.
Dose up-titration and dose reductions for each treatment group are described in Sections 6.2 and 
6.3, respectively. Prior to IA1, randomization was stratified according to Eastern Cooperative 
Oncology Group (ECOG) performance status (0-1 versus 2), hemoglobin value (<10 g/dL versus
≥10 g/dL), FGFR alteration type (translocation versus mutation), pretreatment status 
(chemo-refractory versus chemo-naive), and disease distribution (presence or absence of visceral 
metastases: lung, liver, and bone). Covariate-adaptive randomization method was used to allocate 
subjects into treatment regimens. Randomization continued until a preferred dose regimen was
selected on the basis of activity and tolerability.
A diagram of the study design is provided below in Figure 3.
Figure 3: 
Study Design

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The study will be conducted in an outpatient setting. Subjects will be seen at the study center on 
the pre-specified days for safety monitoring, pharmacokinetic sample collection, and provision of 
clinical supplies. More frequent study center visits may be scheduled, if deemed necessary, on the 
basis of emerging safety observations. Subjects will be issued diary cards to record study drug 
dosing time and meal time.
Subjects will be assessed for disease response every 6 weeks during the first 3 months. Thereafter, 
scans will be performed every 12 weeks for the next 9 months, then every 4 to 6 months until 
disease progression.
All subjects are to have a Follow-up Visit (telephonic or in person) every 12 weeks (±7 days) for 
survival status update and start of subsequent anticancer therapy in the Follow-up Phase. The post-
treatment Follow-up Phase will extend from the End-of-Treatment Visit until the subject has died, 
withdraws consent, is lost to follow-up, or the end of study, whichever comes first. Additional 
information may be gathered in the Follow-up Phase in the following 2 situations:

If a subject discontinues study drug due to drug-related toxicity which has not resolved by the 
End-of-Treatment Visit, the subject will continue to be monitored for this toxicity as clinically 
appropriate until the toxicity resolves to baseline, stabilizes, or is deemed irreversible; the 
subject dies; or subsequent therapy is started; whichever occurs first. 

If a subject discontinues study drug before disease progression, tumor assessments should be 
continued as usual, as if the subject is still on study treatment until disease progression is 
documented, subsequent therapy is started, the subject dies, or the end of study, whichever 
occurs first.
The entire duration of the main study will be approximately 60 months to completion (first 
subject’s first visit to end of study), while the duration of the DDI substudy will be approximately 
16 months.
Safety will be monitored by the sponsor’s medical monitor or study responsible physician 
throughout the study. In addition, the sponsor’s Safety Management Team (SMT), a multi-
disciplinary team including an internal safety physician will review the safety data routinely and 
will investigate specific safety queries. The SMT will review all serious adverse events. In the 
event a significant safety issue is identified, both the internal safety team and the responsible 
investigators will convene to discuss the safety data and to make a recommendation on the future 
conduct of the study. All decisions will be documented and will be distributed to investigators. 
The Institutional Review Board (IRB) or Independent Ethics Committee (IEC) will be notified if 
required.
Guidance for study conduct for ongoing subjects in the event of a national disaster is provided in 
Attachment 11.

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3.
STUDY DESIGN AND RATIONALE
For subjects enrolled under the DDI substudy (with continued erdafitinib treatment until disease 
progression), follow Attachment 12; DO NOT USE the eligibility criteria or the Time and Events 
Schedules in the main protocol. 
3.1.
Overall Rationale for the Study
3.1.1.
Rationale for the Study in the Target Indication
Urothelial carcinoma of the bladder is a common malignancy causing approximately 165,000 
deaths per year worldwide.12 The median survival for patients with recurrent or metastatic 
urothelial carcinoma is only 14 to 15 months.24 Treatments for muscle-invasive urothelial 
carcinoma have not improved beyond cisplatin-based combination chemotherapy and surgery in 
the past 30 years, and no new drugs making a significant impact on the disease have been approved 
in that time. In fact, there is no approved standard of care therapy for surgically unresectable or 
metastatic patients who have disease recurrence after treatment with a platinum-containing therapy 
(in the US). Objective response rates ranging from 10% to 20% have been observed with single-
agent and combination therapies in patients who have progressed following platinum-based 
chemotherapy regimens.6,16,17,28,32
Vinflunine is approved only in Europe for treatment of metastatic urothelial cancer in the second 
line setting, based upon results of a Phase 3 study in which subjects were randomized to either 
vinflunine plus best supportive care or best supportive care alone, and demonstrated a 9% objective 
response rate and increase in median overall survival (6.9 versus 4.3 months) in the vinflunine 
arm.2,4 Vinflunine has not been evaluated for efficacy and safety in patients with a performance 
status of ≥2.23
Moreover, a significant proportion of patients have poor performance status and compromised 
renal function and need targeted therapies with relatively benign safety profiles.20 Due to age, 
disease-associated impairment in renal function, as well as comorbidities and specific treatment 
related toxicities, approximately 30 to 50% of patients are ineligible for treatment with cisplatin.9
For patients unfit to receive cisplatin-containing chemotherapy in the first line, 2 carboplatin-based 
regimens (gemcitabine/carboplatin and methotrexate/carboplatin/vinblastine) demonstrated 
objective response rates as low as 26% and 20% in patients with a glomerular filtration rate less 
than 60 and a performance status of 2.7
Thus far, no molecularly targeted agents have been approved for the treatment of the disease.
However, recent advances in genomic profiling of urothelial carcinomas have identified potential 
therapeutic molecular targets in 69% of the tumors. The genomic alterations identified involve the 
PI(3)K/AKT/mTOR, CDKN2A/CDK4/CCND1 and RTK/RAS pathways, including ERBB2, 
ERBB3, and FGFR3, most of which are potentially targetable.5
Of the molecular alterations identified, FGFR signaling in particular is altered in a high proportion 
of bladder tumors in both muscle invasive and non-invasive tumors. The FGFR pathway is thought 
to play an important role in promoting cancer. Multiple alterations have been identified in this 

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pathway including FGFR gene translocations, activating mutations, gene amplifications, and 
overexpression of FGFRs or their ligands. Mutations in FGFR3 are found in 12% of all patients 
with high-grade muscle-invasive urothelial bladder carcinomas.5 Translocations of FGFR reported 
in urothelial carcinoma have been demonstrated to play a key role in transforming normal cells.31
Our internal data and external data have indicated the presence of multiple FGFR translocations 
in bladder cancer such as, FGFR2-BICC1, FGFR2-AFF3, FGFR2-CASP7, FGFR2-CCDC6, 
FGFR2-OFD1, FGFR3-TACC3, and FGFR3-BAIAP2L1. Based on a small sample size, 
approximately 50% of urothelial carcinomas could potentially harbor these translocations. 
However, the clinical sensitivity of all these alterations to an FGFR inhibitor is not yet fully known. 
Pre-clinical studies have demonstrated that urothelial carcinoma cell lines RT-4 and RT-112 
carrying the FGFR3-TACC3 translocation are sensitive to erdafitinib, with IC50 values of 0.1 and 
0.01 nM, respectively. The ability of each translocation to respond to erdafitinib is currently being 
investigated.
The ongoing Phase 1 study of erdafitinib has demonstrated anti-tumor activity in subjects with 
urothelial carcinoma. Of the 12 subjects with urothelial carcinoma who were treated at doses 
≥9 mg, 4 had confirmed or unconfirmed partial response (PR), 6 had stable disease (SD), 1 had 
progressive disease (PD), and the results for 1 subject were not applicable (Table 9). All the 
responses occurred in subjects with FGFR aberrations and included subjects with FGFR3-TACC3, 
FGFR2-BICC1 translocations or FGFR3 mutations such as S249C, R248C and G370C. Another 
FGFR inhibitor, BGJ 398, has been reported to produced responses in patients with urothelial 
carcinoma with FGFR3 mutations; a response rate of 40% was observed in the 5 FGFR3-mutant 
patients treated.26 All of these factors emphasize the importance of targeting the FGFR pathway in 
urothelial carcinomas with a potent pan FGFR inhibitor such as erdafitinib. Therefore, a clinical 
study to test the efficacy of erdafitinib in urothelial carcinomas is merited
Table 9:
Clinical Activity of JNJ-42756493 in Subjects with Urothelial Cancer (±FGFR 
Abnormality) Treated at 6 mg or Higher Dose (Study 42756493EDI1001)
Dose 
Molecular Status
Activity
9 mg daily
FGFR3-TACC3
PR (-39%)
9 mg daily
FGFR2-BICC1/FGFR2-CASP7
PR (-79%)
9 mg daily
FGFR3 mut
SD (-19% )
9 mg daily
FGFR3 mut (R248C)
SD (-21%)
9 mg daily
FGFR3 mut (G370C)/FGF3,4,19 amp
PR (-45%)
9 mg daily
FGFR3 mut (S249C)
PR (-73%)
9 mg daily
FGFR3 (S249C)
NA
9 mg daily
FRS2 amp/MDM2 amp
SD (-25%)
10 mg, 7 days on 7 days off
FGFR3:BIAP2L1/ FGFR2:BICC1/ 
FGFR2:CASP7/ FGFR2:OFD1
SD (+7)
10 mg, 7 days on 7 days off
Unknown
PD
12 mg, 7 days on 7 days off
FGFR3-TACC3/FGFR3 amp
SD (-10% )
12 mg daily
No FGFR alteration
SD (FDG-PET complete 
response)
Abbreviations: PD=progressive disease; PR=partial response; NA=not applicable; SD=stable disease
Total (n=12): PR 4, SD 6, PD 1, NA 1; FGFR+ (n= 9): PR 4, SD 5

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Study 42756493BLC2001 was designed to confirm the significance of selecting FGFR fusions 
and activating mutations as predictive markers when treated with erdafitinib in the metastatic
urothelial carcinoma population. This study prospectively screens and evaluates the significance 
of these FGFR aberrations when subjects are treated with erdafitinib. Erdafitinib for the treatment 
of this population received accelerated approval in the United States based on the primary analysis. 
At the primary analysis (clinical cutoff of 15 March 2018), 210 subjects had been treated: 
33 subjects in the 10 mg intermittent dosing regimen, 78 subjects in the 6 mg daily regimen, and 
99 subjects in the 8 mg daily regimen (selected dose regimen). Of the 99 subjects in the primary 
efficacy population in the 8 mg regimen, 87 (90%) subjects were chemo-refractory and 12 (10%) 
subjects were chemo-naïve. Confirmed ORR based on investigator assessment (CR+PR), was 
40.4% in the 8 mg once daily regimen. 
An updated analysis has also been completed for Study BLC2001 (clinical cutoff of 
09 August 2019), the median follow-up for 101 subjects treated in the erdafitinib 8 mg regimen 
was approximately 24 months. The confirmed ORR by investigator assessment was 40%. The 
median duration of response (DOR) was 5.98 months. Thirty-one percent of responders had DOR 
of 1 year or more. The median PFS was 5.52 months. The median OS was 11.3 months. The 
12- and 24-month survival rates were 49% and 31%, respectively. Median treatment duration was 
5.4 months.
The rationale for the treatment of subjects with advanced solid tumors in the DDI substudy is 
provided in DDI Substudy Section 1.2.
3.1.2.
Rationale for Phase 2 Dose Selection
In the proposed erdafitinib Phase 2 study, the sponsor will explore 3 different active dosing 
regimens, in 28-day cycles.
1.
Sustained Inhibition Regimen: 6 mg once daily continuously for 28 days 
2.
Intermittent High-Dose Regimen: 10 mg once daily 7 days on 7 days off
3.
Sustained Inhibition Regimen: 8 mg once daily continuously for 28 days
The first 2 dose regimens were selected to test whether high exposure levels with intermittent 
dosing could maximize antitumor effects while minimizing drug-related toxicities as compared 
with moderate exposures sustained over a longer period. A randomized comparison of the safety 
and clinical activity of these regimens allowed for the selection of an optimal regimen for an 
expansion cohort of patients. After IA1, a third regimen is instituted to evaluate 8 mg once daily 
continuous dosing.
Recent data with targeted therapies indicate that intermittent dosing may enhance efficacy, delay 
the emergence of resistance, and improve safety profiles.10,16,26,27 The dose and schedules of these 
3 different regimens are supported (as described below) by emerging pharmacokinetic, 
pharmacodynamic, safety, and clinical activity data.
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Choice of the Sustained Dosing Regimen: 6 mg Daily with Flexibility to Up-titrate to 8 mg 
Daily
Pharmacokinetics: The 6 mg daily regimen is the lowest dose that achieves sustained exposures 
in the efficacious range, 
. At the 6 mg dose, 
based on pharmacokinetic simulations, the expected mean unbound Cavg plasma concentrations in 
patients during the 28 day cycle period is 
. The mean unbound average plasma 
concentration of urothelial cancer patients with clinical activity (partial responses) in the Phase 1 
study was 
, which is also consistent with the preclinical target window. Antitumor 
activity is anticipated to correlate with preclinical AUC for unbound drug (AUCu), and at the 6 mg
dose level, 90% of patients will have unbound trough plasma concentrations and AUCu levels 
within the target window by day 2. At doses lower than 6 mg daily, trough plasma concentrations 
will fall below the effective range in approximately 50% or more of patients. Thus, 6 mg daily is 
the lowest sustained dose that is predicted to generate continuously efficacious drug concentrations 
for the majority of patients. 
Pharmacodynamics: Hyperphosphatemia is a common drug-induced toxicity due to renal tubular
FGFR inhibition and, thus, it can serve as a pharmacodynamic marker of drug activity. Dose-
dependent elevations in serum phosphate occurred in all patients starting at 4 mg daily. Because 
this represents a target-mediated drug effect, one of the Phase 1 study goals was to select a dose 
regimen that consistently induced manageable hyperphosphatemia but did not exceed a critical 
level requiring cessation of therapy, which in the Phase 1 study was 7 mg/dL. Emerging data from 
the ongoing Phase 1 study indicates that a phosphate increase of at least 35% over baseline level 
may be required for anti-tumor response. Therefore a pharmacodynamic objective of 50% increase 
in phosphate level over baseline was felt to be appropriate. Considering the median phosphate 
level of 3.6 mg/dL in the Phase 1 study, a 50% increase would correspond to an absolute phosphate 
level of 5.5 mg/dL (which is also 35% over the phosphate ULN). Subjects achieving a phosphate 
level of less than 5.5mg/dL by the end of first cycle dosing period (day 28) would be considered 
to have had inadequate PD effect and be subject to dose escalation to 8 mg daily to achieve an 
optimum PD effect (phosphate range 5.5-7mg/dL).
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 40% of subjects would have serum 
phosphate levels < 5.5 mg/dL (on Day 28) and would potentially benefit from dose up-titration. 
Additionally, approximately 25% may reach a phosphate level >7 mg /dL and thus need an 
unscheduled interruption of up to 7 days to maintain the phosphate level in the target range of 5.5 
to 7 mg/dL. A 3-weeks on/1-week off regimen may be suitable at the 6 mg starting dose, but such 
scheduled dose interruption might well be unnecessary when the dose is reduced to below 6 mg 
daily. The latter was observed in Phase 1 at the 4 mg dose level, and further confirmed in modeling. 
Thus, continuous dosing is attainable for the proposed 6 mg, 5 mg, and 4 mg dose levels.
Clinical safety: The 6 mg daily dose is the highest continuous regimen that was well tolerated 
without treatment interruptions. In the Phase 1 study at this dose level, there were no dose 
reductions and only one subject (11%) was removed from the study due to a non-drug-related AE 
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of abdominal pain. However, 44.4% of subjects treated with 6 mg daily continuously required 
treatment interruptions, generally after several weeks of dosing. Escalation of dose from 6 mg to 
8 mg in 40% of subjects with suboptimal pharmacodynamic effect, ie, phosphate below 5.5 mg/dL 
at the end of the first treatment cycle and who do not have any significant drug related toxicity 
(Grade ≥2 toxicity or Grade ≥1 central serious retinopathy or retinal pigment epithelial 
detachments) is unlikely to significantly change the overall tolerability profile.
Clinical activity: Assessment of clinical activity at the 6 mg dose has been limited by the paucity 
of treated subjects with tumors bearing FGFR aberrations. To date, the only subject treated at this 
dose with a known FGFR aberration had an adrenal cortical carcinoma that harbored both 
. This patient achieved stable disease for 
9 months on erdafitinib. Clinical activity has been noted at 9 mg daily, but 70% of the subjects 
treated at this dose needed unscheduled treatment interruptions. Selective dose escalation to 8 mg 
for optimization of the pharmacodynamic effect in approximately 40% of subjects is likely to 
increase the potential for clinical activity without significantly increasing dose interruptions or 
toxicity. In addition, the mean dose intensity of this continuous 6 mg regimen (with flexibility to 
up-titrate) is likely to be closer to the 6.8 (± 2.37) mg/day as observed with the 9 mg daily schedule 
in Phase 1 as compared to the observed 5.4 (± 0.63) mg/day reported with the 6 mg daily schedule 
in Phase 1, thereby increasing the potential for clinical activity.
Choice of the Intermittent Dosing Regimen: 10 mg on a 7 Days-on/7 Days-off Schedule with 
Flexibility to Up-titrate to 12 mg 7 days-on/7 days-off
Pharmacokinetics: An intermittent regimen of 10 mg is expected to generate a mean unbound Cavg
plasma concentration of 
 during the 28-day cycle period. This is in the upper range of 
exposures associated with preclinical efficacy and similar to geometric mean observed in clinical 
urothelial partial responders. In simulation studies, 100% of patients after Day 1 will have unbound 
trough plasma concentrations and AUCu values within the target window. Doses lower than 10 mg 
intermittently are associated with plasma concentrations below the minimum thresholds needed to 
inhibit FGFR in preclinical models in approximately 35% or more of patients. Therefore, 10 mg 
is the lowest intermittent dose given for a 1 week on/1 week off schedule that generates drug 
exposures continuously in the efficacious range for most patients.
Pharmacodynamics: Nearly 70% of patients on the 10 mg intermittent regimen developed 
hyperphosphatemia consistent with FGFR target engagement. This was the lowest intermittent 
dose that achieved serum phosphate levels that rapidly approached but did not consistently exceed 
the critical threshold of 7 mg/dL. Only 16% of the subjects required treatment interruptions due to 
hyperphosphatemia and none needed dose reductions. However, based on emerging 
pharmacokinetic/pharmacodynamic modeling, 35% of subjects are likely to have a phosphate level 
<5.5mg/dL at the end of the Cycle 1 dosing period (Day 21), indicating the need to optimize the 
dose by up-titrating the dose to 12 mg in these selected subjects.
Clinical safety: The 10 mg dose is the highest intermittent regimen with acceptable tolerability 
proposed for further evaluation in Phase 2 and 3 studies. At the 10 mg dose, drug-related 
interruptions occurred in 33.3% of subjects; however, only 16.7% required dose reduction and 
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none (0%) were terminated from the study. In contrast, the 12 mg intermittent regimen was less 
well tolerated, with 46.2% of patients requiring treatment interruptions, 15.4% requiring dose 
reductions, and 7.7% requiring complete discontinuation due to drug-related AEs.
Additional toxicities were also more common on the 12 mg intermittent schedule as compared 
with the 10 mg dose.  In the 12 mg and 10 mg intermittent dose cohorts, eye toxicities occurred in 
38.5% (one case of Grade 1 central serous retinopathy) and 16.7%, respectively, liver function 
abnormalities 
were 
noted 
in 
38% 
and 
16.7%, 
respectively, 
nail 
disorders/
onychodystrophy/onycholysis were present in 30.8% and 16.7%, respectively, and alopecia was 
reported in 15.4% and 0% of subjects, respectively. However, escalation of dose from 10 mg to 12 
mg in approximately 35% of subjects with suboptimal pharmacodynamic effect and who do not 
have any significant drug related (≥Grade 2 toxicity or ≥Grade 1 CSR/RPED) toxicity is unlikely 
to significantly change the overall tolerability profile. This approach is safer than starting at 12 mg 
in all subjects and de-escalating to 10 mg based on toxicity. Thus, the 7 days on/7 days-off 
schedule at 10 mg (with the flexibility to up-titrate) is a regimen with acceptable clinical 
tolerability.
Clinical activity: It is clear that an intermittent regimen can be active. At 12 mg on the intermittent 
schedule, a subject with glioblastoma harboring an 
 achieved a PR 
(-58% tumor reduction) by RANO criteria, and a second subject with a uterine neuroendocrine 
tumor (FGFR status unknown) demonstrated a PR (-70% tumor reduction). Clinical activity 
evaluation in patients treated with the 10 mg intermittent regimen is ongoing; however, early but 
as yet unconfirmed assessments suggest that this regimen will also be clinically active. Further 
optimization of the dose with up-titration to 12 mg in approximately 35% of subjects with 
suboptimal pharmacodynamic effect is likely to increase the potential for clinical activity.
Selected dose regimen: Choice of the Sustained Dosing Regimen: 8 mg Daily with 
Flexibility to Up-titrate to 9 mg Daily
Pharmacokinetics: At the 8 mg dose, based on pharmacokinetic simulations, the expected mean 
unbound Cavg plasma concentrations in patients during the 28 day cycle period is 
. The 
mean unbound average plasma concentration of urothelial cancer patients with clinical activity 
(partial responses) in the Phase 1 study was 
, which is also consistent with the preclinical 
target window. Antitumor activity is anticipated to correlate with preclinical AUC for unbound 
drug (AUCu), and at the 8 mg dose level, 90% of patients will have unbound trough plasma 
concentrations and AUCu levels within the target window 
 by Day 3. Thus, 8 
mg daily is predicted to generate continuously efficacious drug concentrations for the vast majority 
of patients. 
Pharmacodynamics: Hyperphosphatemia is a common drug-induced toxicity due to renal tubular 
FGFR inhibition and, thus, it can serve as a pharmacodynamic marker of drug activity. 
Dose-dependent elevations in serum phosphate occurred in all patients starting at 4 mg daily. 
Because this represents a target-mediated drug effect, one of the Phase 1 study goals was to select 
a dose regimen that consistently induced manageable hyperphosphatemia but did not exceed a 
critical level requiring cessation of therapy, which in the Phase 1 study was 7 mg/dL. Emerging 
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data from the ongoing Phase 1 study indicates that a phosphate increase of at least 35% over 
baseline level may be associated with anti-tumor response. Therefore a pharmacodynamic 
objective of 50% increase in phosphate level over baseline was felt to be appropriate. Considering 
the median phosphate level of 3.6 mg/dL at baseline in the Phase 1 study, and of 3.3 mg/dL at 
baseline in the Phase 2 study (IA1 data) an increase of at least 50% for the majority of subjects 
would correspond to an absolute phosphate level of around 5.5 g/dL (which is also 35% over the 
phosphate ULN). Subjects achieving a phosphate level of less than 5.5mg/dL by the end of first 
cycle dosing period (day 28) would be considered to have had inadequate PD effect and would be 
candidates for dose escalation to 9 mg daily to achieve an optimum PD effect (phosphate range 
5.5-7mg/dL).
Overall, emerging pharmacokinetic/pharmacodynamic (PK/PD) modeling suggests that 
approximately 60% of subjects would have serum phosphate levels < 5.5 mg/dL (on Day 28) when 
dosed with 6 mg and would potentially benefit from dose up-titration. Additionally, by Day 28 
approximately 13% of subjects may reach a phosphate level ≥7 mg /dL and thus need an 
unscheduled interruption of up to 7 days to maintain the phosphate level in the target range of 5.5 
to <7 mg/dL.
Clinical safety: The 8 mg daily dose is the continuous regimen that, based on modelling, would 
likely be well tolerated without significant treatment interruptions (approximately 10% to 15% 
anticipated early interruptions) and for which the majority of subjects would tolerate the sustained 
dose of 8 mg once daily. Escalation on Day 15 of the first treatment cycle of daily dose from 8 mg 
QD to 9 mg QD in the subjects with both phosphate below 5.5 mg/dL (suboptimal 
pharmacodynamic effect; about 40% of subjects), and without significant drug related toxicity 
(Grade ≥2 toxicity or Grade ≥1 central serious retinopathy or retinal pigment epithelial 
detachments) is unlikely to significantly change the overall tolerability profile.
Clinical activity: Assessment of clinical activity at the 6 mg dose and in up-titrated subjects at IA1 
is limited by the paucity of treated subjects, but 3 PR were observed in 14 subjects with phosphate 
level below 5.5 mg/dL and 4 PR in 7 subjects with phosphate level over 5.5 mg/dL, pointing to 
the potential importance of attaining full pharmacodynamic effect. Hence the aim is to bring a 
maximal number of subjects within the target phosphate range of 5.5 mg/dL to less than 7 mg/dL 
in order to attain maximal sustained inhibition of target, and thereby allow for potential 
optimization of efficacy, given the observed correlation thus far between clinical response and the
pharmacodynamic effect on phosphate. Selective dose escalation to 9 mg for optimization of the 
pharmacodynamic effect in approximately 40% of subjects is likely to increase the potential for 
clinical activity without significantly increasing dose interruptions or toxicity. In addition, the 
mean dose intensity of the continuous 8 mg regimen (with flexibility to up-titrate) based on PK/PD 
model based simulations is likely to be 6.7 mg /day, which would be close to the 6.8 (±2.37) 
mg/day as observed with the 9 mg daily schedule in Phase 1 as compared to the observed 5.4 (± 
0.63) mg/day reported with the 6 mg daily schedule in Phase 1, thereby increasing the potential 
for clinical activity.

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4.
SUBJECT POPULATION (For DDI Substudy – see Attachment 12) 
The inclusion and exclusion criteria for enrolling subjects in this study are described in the 
following 2 subsections. If there is a question about the inclusion or exclusion criteria below, the 
investigator should consult with the appropriate sponsor representative before enrolling a subject 
in the study.
4.1.
Inclusion Criteria
Potential subjects must meet all of the inclusion criteria to be eligible to participate in the study:
1.
Must be 18 years of age or older
2.
Must have histologic demonstration of metastatic or surgically unresectable urothelial 
cancer
 Minor components (<50% overall) of variant histology such 
as glandular or squamous differentiation, or evolution to more aggressive phenotypes 
such as sarcomatoid or micropapillary change are acceptable.
3.
Must have measurable disease according to the Response Evaluation Criteria in Solid 
Tumors (RECIST, version 1.1) at baseline.
4.
Must have shown disease progression according to RECIST, version 1.1, following 
prior chemotherapy for metastatic or surgically unresectable urothelial cancer. Subjects 
who received neoadjuvant or adjuvant chemotherapy and showed disease recurrence or 
progression according to RECIST, version 1.1, within 12 months of the last dose are 
considered to have received chemotherapy in the metastatic setting. These subjects will 
be referred to as chemo-refractory subjects. (Subjects who have shown disease 
progression according to RECIST, version 1.1 following prior treatment with 
anti-PDL1/PD1 antibodies are also eligible).
OR
Subjects who have not yet received chemotherapy for metastatic or surgically
unresectable urothelial cancer, and are ineligible for cisplatin based upon impaired renal 
function defined as a glomerular filtration rate (GFR) <60 mL/min/1.73 m2 by 24-hour 
urine measurement or calculated by Cockcroft-Gault (Attachment 2), or Grade 2 or 
higher peripheral neuropathy per CTCAE version 4.0.9,10These subjects will be referred 
to as chemo-naïve subjects.
5.
Subjects must meet 1 of the following molecular eligibility criteria based on evaluation 
of appropriate tumor tissue (only available tumor tissue should be sent for analysis; 
please see Section 9.1.2 for details):

Tumors must have at least 1 of the following translocations:, FGFR2-BICC1, 
FGFR2-CASP7, FGFR3-TACC3, FGFR3-BAIAP2L1; or

One of the following FGFR3 gene mutations: R248C, S249C, G370C, Y373C.
6.
Must have an ECOG performance status score 0, 1, or 2 (Attachment 1).
7.
Must have adequate bone marrow, liver, and renal function as described below:

Bone marrow function (without the support of cytokines and/or erythropoiesis-
stimulating agent [ESA] in preceding 2 weeks):
CCI

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
Absolute neutrophil count (ANC) >1500/mm3

Platelet count >75,000/mm3

Hemoglobin >8.5 g/dL (without transfusion or demonstrate stability, i.e., 
no significant decline in hemoglobin, for 2 weeks after transfusion)

Liver function:

Total bilirubin ≤1.5 x institutional upper limit of normal (ULN), unless 
know to have Gilbert’s disease.

Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) 
≤2.5 x institutional ULN.

Albumin ≥2.0 g/dL

Renal function: Creatinine clearance ≥40 mL/min/1.73 m2 either directly measured 
via 24-hour urine collection or calculated using Cockroft-Gault. (Attachment 2) 

Electrolytes: Magnesium within 0.85 to 1.25 x institutional normal limits; sodium 
≥130 mEq/L; and potassium within institutional normal limits.
8.
Female subjects (if of child bearing potential and sexually active) must use medically 
acceptable methods of birth control before study entry, during the study, and until
3 months after taking the last dose of study drug. Male subjects must use a condom with 
spermicide when sexually active and must not donate sperm from the first dose of study 
drug until 5 months after the last dose of study drug. Medically acceptable methods of 
contraception that may be used by the subject and/or his/her partner include hormonal 
prescription oral contraceptives, contraceptive injections, contraceptive patch, 
intrauterine device, true sexual abstinence, and surgical sterilization (e.g., confirmed 
successful vasectomy or tubal ligation). True sexual abstinence is defined as refraining 
from heterosexual intercourse during the entire period of the study, including up to 
3 months for females and 5 months for males after the last dose of study drug is given. 
Periodic abstinence (calendar, symptothermal, post-ovulation methods) is not 
considered an acceptable contraceptive method.
9.
Negative pregnancy test (urine or serum beta human chorionic gonadotropin [β-hCG]) 
at Screening for women of child bearing potential who are sexually active.
10.
Subject (or his/her legally acceptable representative) must sign the informed consent 
documents indicating that they understand the purpose of and procedures required for 
the study and are willing to participate in the study.
4.2.
Exclusion Criteria
Potential subjects who meet any of the following criteria will be excluded from participation in 
the study:
1.
Received chemotherapy, targeted therapies, definitive radiotherapy, or treatment with 
an investigational anticancer agent within 2 weeks (in the case of nitrosoureas and 
mitomycin C, within 6 weeks; in the case of immunotherapy, within 4 weeks) before 
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Localized palliative radiation therapy (but should not include radiation to target lesions) 
and ongoing bisphosphonates and denosumab, are permitted.
2.
Has persistent phosphate level >ULN during screening (within 14 days of treatment and 
prior to Cycle 1 Day 1) and despite medical management 
3.
Has a history of or current uncontrolled cardiovascular disease including:

unstable angina, myocardial infarction, or known congestive heart failure Class II-
IV (Attachment 3) within the preceding 12 months; cerebrovascular accident or
transient ischemic attack within the preceding 3 months, pulmonary embolism 
within the preceding 2 months.

any of the following: sustained ventricular tachycardia, ventricular fibrillation, 
Torsades de Pointes, cardiac arrest, Mobitz II second degree heart block or third 
degree heart block; known presence of dilated, hypertrophic, or restrictive 
cardiomyopathy. 

Left ventricular ejection fraction (LVEF) <50% as assessed by echocardiography 
(or multi-gated acquisition scan [MUGA]) performed at screening.

QTc prolongation as confirmed by triplicate assessment at screening (Fridericia; 
QTc >480 milliseconds).
4.
Any reason that in the view of investigator would substantially impair the ability of the 
subject to comply with study procedures and increase the risk to the subject. Examples 
include poorly controlled diabetes (HbA1c >8), and ongoing active infection requiring 
IV antibiotics.
5.
Females who are pregnant, breast-feeding, or planning to become pregnant within 
3 months after the last dose of study drug and males who plan to father a child while 
enrolled in this study or within 5 months after the last dose of study drug
6.
Has not recovered from reversible toxicity of prior anticancer therapy (except toxicities 
which are not clinically significant such as alopecia, skin discoloration, or Grade 1
neuropathy).
7.
Has impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg 
ulcers, known gastric ulcers, or unhealed incisions
8.
Had major surgery within 4 weeks before enrollment
9.
Has known human immunodeficiency virus (HIV) infection, or active hepatitis B or C
infection (subjects with history of hepatitis C infection but negative hepatitis C virus
polymerase chain reaction (PCR) test and subjects with hepatitis B with positive 
hepatitis B surface antibody are allowed.)
10.
Has active, symptomatic, or untreated brain metastases (subject with prior brain 
metastases treated at least 3 weeks prior to signing the full-study Informed Consent 
Form (ICF) or that are clinically and radiographically stable for at least 1 month prior 
to Cycle 1 Day 1 and do not require chronic corticosteroid treatment are allowed to be 
enrolled).
11.
Received prior FGFR inhibitor treatment or if the subject has known allergies, 
hypersensitivity, or intolerance to erdafitinib or its excipients.13
12.
Any corneal or retinal abnormality likely to increase the risk of eye toxicity, i.e.:

History of or current evidence of CSR or retinal vascular occlusion (RVO)

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
Active wet, age-related macular degeneration (AMD)

Diabetic retinopathy with macular edema

Uncontrolled glaucoma (per local standard of care)

Corneal pathology such as keratitis, keratoconjunctivitis, keratopathy, corneal 
abrasion, inflammation or ulceration.  
13.
Subjects with evidence of active malignancies other than urothelial cancer (except 
definitively treated early stage cancer such as resected skin cancers and/or completely 
resected prostate cancer)
Investigators should ensure that all study enrollment criteria have been met at screening. If a 
subject's status changes (including laboratory results or receipt of additional medical records) after 
Screening but before the first dose of study drug is given such that the subject no longer meets all 
eligibility criteria, then the subject should be excluded from participation in the study. 
Section 17.4, Source Documentation, describes the required documentation to support meeting the 
enrollment criteria.
5.
TREATMENT ALLOCATION AND BLINDING
As this is an open-label study, blinding procedures are not applicable.
Before IA1, central randomization was implemented in this study. Subjects were randomly 
assigned to treatment Regimen 1 or 2 via a web-based and computer-generated randomization 
method. Subjects were randomized to receive Regimen 1: 10 mg of oral study drug once daily on 
Days 1 through 7 and Days 15 through 21 of a 28-day cycle; or Regimen 2: 6 mg of oral study 
drug once daily on Days 1 through 28 of a 28-day cycle. Randomization was stratified according 
to ECOG performance status (0-1 versus 2), hemoglobin level (<10 g/dL versus ≥10 g/dL), FGFR 
alteration type (translocation versus mutation), pretreatment status (chemo-refractory versus 
chemo-naive), and disease distribution (presence or absence of visceral metastases: lung, liver, and 
bone). Covariate-adaptive randomization was used to allocate subjects between Regimens 1 and 2 
until a favorable dose was selected. The interactive web response system (IWRS) assigned a 
unique treatment code, which dictated the treatment assignment for the subject. The requestor must 
use his or her own user identification and personal identification number when contacting the 
IWRS, and then gave the relevant subject details to uniquely identify the subject.
After IA1, all subjects will be assigned to Regimen 2. After implementation of Amendment 3, all 
subjects will be assigned to Regimen 3.
6.
DOSAGE AND ADMINISTRATION
6.1.
Administration of Study Drug
The study drug will be provided as a tablet for oral administration. Subjects assigned to Regimen 1
will be instructed to take 10 mg of the study drug orally each day on an intermittent dosing schedule 
of 7 days on and 7 days off on a 28-day cycle. Subjects assigned to Regimen 2 will be instructed 
to take 6 mg of study drug orally once daily for 28 days on a 28-day cycle. Subjects assigned to 
Regimen 3 will be instructed to take 8 mg of study drug orally once daily for 28 days on a 28-day 

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cycle. The study drug is to be taken with approximately 240 mL (8 ounces) of water. The tablets
should be swallowed intact and subjects should not attempt to dissolve them in water. Each dose 
should be taken at approximately the same time each day with or without food. Subjects should 
avoid consuming grapefruit or Seville oranges due to CYP450 3A4/5 inhibition.
If a dose is missed, it can be taken up to 6 hours after the scheduled time; the subject may return 
to the normal schedule the following day. If it has been more than 6 hours since the missed dose, 
then that dose should be skipped and the subject should continue treatment at the scheduled time 
the next day.
The study drug will be dispensed at the first visit of each cycle. All study drug doses dispensed
must be captured in the source documents, including the subject’s diary card, and the electronic 
case report form (eCRF). 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 cannot be re-issued in this study or outside the study
(follow study drug accountability guidelines in the Site Investigational Product Manual). Missed 
doses will not be replaced and the next dose will remain unchanged. If vomiting occurred with 
drug administration, no replacement dose will be taken and any such event that occurs up to 4 
hours following dose administration must be recorded on the subject’s diary card and the eCRF.
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 the
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.
6.2.
Dose Up-titration Guidelines
Subjects in Regimen 1 and Regimen 2 followed dose up-titration guidelines as specified in 
Attachment 8 (Regimen 3 moved in this attachment).
For subjects enrolled under the DDI Substudy, the erdafitinib dose may be up-titrated to 9 mg or 
maintained at 8 mg based on the Cycle 1 Day 14 phosphate level taking into account observed 
toxicity to that day. 

Subjects with serum phosphate levels higher than 9.00 mg/dL (>2.91 mmol/L) will withhold 
erdafitinib treatment, with at least weekly assessment of serum phosphate until it returns to 
less than 7.00 mg/dL (<2.25 mmol/L) while initiating treatment with a phosphate binder such 
as sevelamer. Use of phosphate binder must be recorded as concomitant medication in the 
eCRF. (See Section 6.3.2 for detailed guidelines regarding further treatment).

Subjects with serum phosphate levels between 7.00 to 9.00 mg/dL (2.25 mmol/L to 
2.90 mmol/L) should increase the erdafitinib dose to 9 mg once daily, while concurrently 
initiating treatment with a phosphate binder such as sevelamer (see Section 6.3.2 for details).

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
Subjects with serum phosphate level less than 7.00 mg/dL (<2.25 mmol/L) will increase the 
erdafitinib dose to 9 mg once daily. No concomitant treatment is required for these subjects.
6.3.
Dose Modifications and Dose Delays
Treatment can be modified or terminated based on toxicity as described in Table 10. For eye, 
skin/nail, dry mouth/mucositis, liver, and phosphate toxicity, specific recommendations in the 
management guidelines are provided in Sections 6.3.1 through 6.3.7.
Table 10:
Dose Modification Guidelines
Toxicity 
Grade 
Action 
Dose Modification After Resolution of Adverse Event
1
None 
Continue same dose
2
None or consider interruption
If interrupted, restart at same dose or 1 dose lower, if necessary.
3
Interrupt drug
Restart at 1 or 2 doses lower if recovery (to ≤Grade 1 or back to 
baseline for non-hematologic toxicity) is within 28 days. 
Discontinue drug if unresolved for >28 days. 
4
Interrupt drug or discontinue
Discontinue*
For general toxicity management:

Subjects with any grade of toxicity (Grade 1 to 4) should be provided symptomatic treatment 
when applicable. 

Subjects should follow the guidelines in Table 11 or Table 12 or Table 13 for dose reduction 
recommendations and may have more than 1 dose reduction.

If erdafitinib must be withheld for more than 28 days for a drug-related adverse event that 
fails to resolve to acceptable level (e.g., ≤Grade 1 non-hematologic toxicity or back to 
baseline), treatment with erdafitinib should be discontinued with the exception noted below.*

If the subject achieves calcium-phosphate product >70 mg2/dL2 for 2 consecutive weeks 
despite phosphate lowering therapy or >90 mg2/dL2 any time during treatment despite 
phosphate lowering therapy, erdafitinib should be withheld until recovery to calcium-
phosphate product <55 mg2/dL2. Treatment may be reintroduced at the first reduced dose 
level.

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 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.
*Exception: if a subject has been deriving benefit from treatment, and the investigator can 
demonstrate that re-introduction of study drug is in the best interest of the subject considering the 
terminal nature of the disease, the drug may be re-introduced at a lower dose and/or intensity if the 
medical monitor is in agreement with this assessment. With appropriate re-consenting, the subject 
can be retreated with a 1- or 2-dose level reduction as appropriate, along with appropriate clinical 
follow-up as designated by the investigator. Please see Section 16.2.3 for details.

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resolution, stabilization, or return to subject’s baseline values. Monitor clinical condition 
closely.

Draw blood samples for random pharmacokinetic analysis.

Record use of concomitant medications, acetaminophen, herbal remedies, other over-the-
counter medications, or known hepatotoxins.

Record alcohol use on the liver event alcohol intake Case Report Form (CRF).

Serum creatine phosphokinase (CPK) and lactate dehydrogenase (LDH).

Check the viral hepatitis serology as appropriate and include:

Hepatitis A IgM antibody;

Hepatitis B surface antigen and Hepatitis B core antibody (IgM); 

Hepatitis C RNA;

Hepatitis E IgM antibody (appropriate for subjects traveling outside North America);

Cytomegalovirus IgM antibody; and

Epstein-Barr viral capsid antigen IgM antibody (or equivalent test).

Anti-nuclear antibody, anti-smooth muscle antibody, and type 1 anti-liver kidney microsomal 
antibodies 

Liver imaging (ultrasound, magnetic resonance, or computerized tomography) to evaluate 
liver disease
Liver Event Re-challenge Requirements
If a subject meets the liver event stopping criteria, the study drug should not be re-administered. 
In the case in which Hy’s law (refer to Section 6.3.1) is not met and the investigator can 
demonstrate that re-introduction of study drug is in the best interest of the subject considering the 
terminal nature of the disease, the drug may be re-introduced at a lower dose and/or intensity if the 
medical monitor is in agreement with this assessment. With appropriate re-consenting, the subject 
can be retreated with a 1- or 2-dose level reduction as appropriate, along with appropriate clinical 
follow-up as designated by the investigator. Prior to re-introduction, the investigator should obtain 
written permission from the study medical monitor and the IRB. The investigator should also have 
the subject re-consent, explaining that re-introduction of study drug could lead to liver damage, 
which may be serious and/or may even result in death (please see Section 16.2.3 for details).
6.3.2.
Guidelines for the Management of Elevated Phosphate Levels
Guidelines for the clinical management of elevated serum phosphate levels are presented in
Table 14.

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Table 14:
Guidelines for Management of Serum Phosphate Elevation
Serum Phosphate 
Level
Study Drug Management
Medical 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
≥7.00 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 3 
times a day with food until 
phosphate level is <7.00 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 <7.00 mg/dL (weekly testing recommended).
Re-start treatment at the same dose level. 
A dose reduction will be implemented for persistenta 
hyperphosphatemia (defined as serum phosphate 
≥9.00 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 3 times 
a day with food until serum 
phosphate level returns to 
<7.00 mg/dL
>10.00 mg/dL 
(>3.20 mmol/L)
(Grade 4)
Withholdb erdafitinib treatment until serum phosphate level 
returns to 7.00 mg/dL (weekly testing recommended).
Re-start treatment at the first reduced dose level.
If persistenta hyperphosphatemia (≥10.00 mg/dL) for
>2 weeks, erdafitinib should be discontinued
permanently.
Medical management as clinically
appropriate.
Significant 
alteration in 
baseline renal 
function and/or 
Grade 3 
hypocalcemia
Erdafitinib should 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 re-started at 2 dose levels lower if 
appropriate. Follow other recommendations described 
above, Section 6.3)
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 phosphate management and diet can be found 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 duration.

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6.3.3.
Guidelines for the Management of Dry Mouth and Stomatitis
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 15:
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 16:
Guidelines for the Management of Oral Mucositis
Grade
Study Drug (Erdafitinib) Management
SymptomManagement
Grade 1
Continue erdafitinib at current
dose.

Continue general prophylaxis 
recommendations

Dexamethasone solution (0.5 mg/ 5mL 
solution) swish and spit QID 
or similar solution that is available in 
your country 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/5mL 
solution) swish and spit QID or similar 
solution that is available in your country 
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/ 5mL 
solution) swish and spit QID or similar 
solution that is available in your country 
and lidocaine 2%-5% jelly or solution.

Consider pain management strategies.

Consider IV hydration.
Grade 4
Discontinue erdafitinib.
Evaluation and therapy as clinically
indicated.
AE=adverse event; QID= four times a day.

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6.3.4.
Guidelines for the Management of Dry Skin and Skin Toxicity
Guidelines for the management of dry skin are provided in Table 17.
General prophylaxis for dry skin and skin toxicity:
-
Avoid unnecessary exposure to sunlight and excessive use of soap.
-
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 17:
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 steroid 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 Steroid Ointments: Clobetasol 0.05%, Betamethasone 0.05%, Fluocinonide 0.05%

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6.3.5.
Guidelines for Management of Nail Toxicity (Onycholysis,
Onychodystrophy, and Paronychia)
Guidelines for management of nail discoloration/loss/ridging (onycholysis/onychodystrophy) are 
provided in Table 18. Guidelines for the management of paronychia are provided in Table 19.
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

Wearing comfortable shoes (wide sized shoes with room for the toes)
Table 18:
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 polyurea-urea
urethane nail lacquer (Nuvail™) OR diethylene glycol
monoethylether nail lacquer (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 (periungual 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/trimethoprimBID).
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/polymixins B
BID=bis in die (two times each day).

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Table 19:
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 (periungual 
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 (periungual 
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
6.3.6.
Guidelines for Eye Toxicity Associated With Vision Changes
If a subject experiences an event of confirmed new corneal or retinal abnormality while on study 
drug, the event should be reported as an adverse event (if Grade 1 or 2) or a serious adverse event
(if Grade 3 or higher) as appropriate. Any new and clinically significant symptoms, such as but 
not limited to, 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 
below.
Amsler grid (illustrated in Attachment 5) testing will be performed (by the study physician or 
nurse) at Screening, at the beginning of every new cycle from Cycle 2 onwards and at the 
End-of-Treatment Visit. 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 

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ophthalmic 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.
Table 20:
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 exam cannot be performed within 7 days, 
withhold treatment of erdafitinib until an examination can 
be performed.
If there is no evidence with 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 
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 
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Grade and Definition
Study Drug (Erdafitinib) Management
Symptom Management
recurrence, then re-escalation can be considered in 
consultation with the medical monitor.
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 1 to 2 weeks for a month and as clinically 
appropriate thereafter. For cases of recurrence, consider 
permanent discontinuation.
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 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
6.3.7.
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 
are strongly recommended, ie, every 2 hours during awake time.

Reactive management: 

Withhold erdafitinib for Grade 3 toxicity 

Artificial tear substitutes if not started, every 2 hours during awake time

Ocular demulcents 

Severe treatment-related dry eye should be evaluated by an ophthalmologist 
7.
TREATMENT COMPLIANCE
The investigator or designated study personnel will maintain a log of the amount of study drug 
dispensed and returned. Drug supplies will be inventoried and accounted for throughout the study.
Subjects will receive instructions on compliance with study treatment at the screening visit. A 
diary card will be given to the subject to record intake at home. On days when the subject visits 
the study center for dose administration or pharmacokinetic sampling, the investigator or designee 

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will supervise administration of the study drug and the exact time of administration will be 
recorded in the eCRF. During the course of 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.
8.
CONCOMITANT THERAPY
Concomitant therapies are to be recorded at the time of screening (within 14 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.
All therapies (prescriptions 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 documented in the concomitant 
therapy section of the eCRF. Caution should be exerted for subjects taking anti-coagulant 
therapies. Frequent monitoring for international normalized ratio (INR) is allowed at the treating 
physician’s discretion.
The sponsor must be notified in advance, or as soon as possible thereafter, of any instances where 
prohibited medications are administered.
8.1.
Permitted Medications
Permitted medications are to be recorded at the time of screening (within 14 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, diet, 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 at the treating physician’s 
discretion, as clinically indicated.
Prophylactic medications: Appropriate prophylactic antiemetic regimens may be provided if 
required, in accordance with institutional practice and current European Society of Medical 
Oncology guidelines.
Chronic supportive therapies: Ongoing bisphosphonates and denosumab or other supportive 
therapies are permitted.  
Palliative radiotherapy: Localized radiotherapy for symptomatic control is permitted, but should 
not include definitive radiation to target lesions.
COVID-19 vaccination: Administration of non-live vaccines approved or authorized for 
emergency use by local health authorities are allowed before or during this study. (For additional 
information, please refer to Attachment 11.)

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8.2.
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

Concurrent antineoplastic agents or hormonal anticancer therapy
8.3.
Precautions for Concomitant Medications

Based on in vitro data, erdafitinib is metabolized by cytochrome CYP3A4 and CYP2C9. A 
clinical drug-drug interaction study showed that on average, erdafitinib exposure (Cmax and 
AUC) was increased 5% to 34% when co-administered with itraconazole (a strong inhibitor 
of CYP3A4) and 21% to 49% 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 Attachment 4). Consider alternative therapies that are not strong
CYP3A4 or moderate CYP2C9 inhibitors during treatment with erdafitinib. If co-
administration of strong CYP3A4 or moderate CYP2C9 inhibitors 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. 
Based on in vitro data, erdafitinib is metabolized by cytochrome CYP2C9 and CYP3A4. The 
impact of moderate CYP2C9 inducers and strong CYP3A4 inducers (such as rifampin) on 
erdafitinib was not clinically studied. The concomitant use of these agents with erdafitinib 
should be avoided (see Attachment 4).
Co-administration of erdafitinib with moderate CYP3A4 inducers may decrease erdafitinib 
exposure. Caution should be exercised for concomitant administration of erdafitinib and these 
agents. A comprehensive list of CYP450 isoenzymes and CYP3A4/2C9 inhibitors and 
inducers 
is 
provided 
in 
Attachment 
4
and 
in 
http://medicine.iupui.edu/CLINPHARM/ddis/main-table; however, 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 strong inducers of CYP3A4 and CYP2C9.

Until further data become available, concomitant use of erdafitinib with CYP3A4 substrates 
with narrow therapeutic indices should be avoided (Attachment 4).
In in vitro experiments, erdafitinib was shown to inhibit human P-glycoprotein (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. Therefore, caution should be exercised for co-administered drugs that 
are 
P-gp 
substrates, 
such 
as 
digoxin, 
dabigatran, 
and
fexofenadine 
(https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf); in addition, drugs with a 
narrow therapeutic index should only be used where the benefit outweighs the potential risk.

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. 

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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 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 
levels.
9.
STUDY EVALUATIONS
9.1.
Study Procedures
9.1.1.
Overview
The Time and Events Schedules (Table 1, Table 2, Table 3, Table 4, and Table 5) summarize the 
frequency and timing of safety, efficacy, pharmacokinetic, biomarker, and other measurements 
applicable to this study.
Pre-treatment and post-treatment tumor biopsies will be collected where feasible.  Feasibility may 
include but is not limited to: accessible tumor location; subject deemed clinically appropriate by 
investigator; subject is willing to comply with the procedure.
The number of blood samples, volume of blood, and amount of tissue that will be required from 
each subject for the various study procedures is outlined in the Laboratory Manual. The number 
of samples and the blood volume will vary depending on the number of cycles of the study drug
that the subject receives. Unscheduled blood samples may be required for safety issues of
individual subjects.
9.1.2.
Screening Phase
The Screening Phase will consist of a molecular eligibility assessment period and a study screening 
period. The molecular eligibility assessment period starts with the signing of a molecular eligibility 
Informed Consent Form (ICF) and can occur at any time prior to administration of study drug. 
During this period, a central laboratory will evaluate subjects for molecular eligibility by analyzing
appropriate tumor specimens.
The Sponsor will communicate results of the testing to the site. If a subject meets the molecular 
eligibility criteria, the subject can continue full-study screening under the full-study ICF for 
determination of full-study eligibility.
Subjects must meet all of the inclusion and none of the exclusion criteria in Section 4, as well as 
the molecular eligibility criteria. During the Screening Phase, prior to IA1, subjects were randomly 
assigned to Regimen 1 or 2. After IA1, newly enrolled subjects will be assigned to Regimen 2. 
After implementation of Amendment 3, all newly enrolled subjects will be assigned to Regimen 
3. All information required for randomization purposes must be available at the time of 
randomization including: ECOG performance status, hemoglobin value, FGFR alteration type, 
disease distribution (presence or absence of visceral metastases: lung, liver, and bone) based upon 

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baseline radiographic imaging performed during screening window, and pretreatment status 
(chemo-refractory versus chemo-naive) obtained by subject history/medical records.
9.1.3.
Treatment Phase
The Treatment Phase will begin with the administration of the first dose of erdafitinib and will 
continue until disease progression or unacceptable toxicity (based on investigator assessment) 
occurs. Subjects with progressive disease or unacceptable toxicity will be withdrawn from 
treatment. If a subject has progressive disease per RECIST version 1.1, but the treating physician 
strongly believes that continuation of study treatment is in the best interest of the subject, then, in 
consultation with the medical monitor, the subject may be allowed to continue on the study drug.
The subject may receive treatment until such time as the treating physician and the medical monitor 
agree that further continuation of treatment is no longer thought to benefit the subject. The subject 
must follow the procedures as outlined in the Time and Events Schedule (Table 1, Table 2, and
Table 3) as if the subject has not progressed.
Subjects who have been treated on Regimens 1 or 2 (and who have not already been up-titrated to 
8 mg in Regimen 2) may be considered for treatment in Regimen 3 (8 mg, without the provision 
for up-titration), based on fulfillment of specific clinical elements as determined by the sponsor, 
and furthermore based upon agreement between the sponsor and treating physician. These subjects 
will follow the Time and Events schedule for Regimen 3, and will start treatment at the new dose 
at the start of their next subsequent cycle based on approval by the medical monitor in discussion 
with the treating physician.
Adverse events occurring any time after the subject signs the full-study ICF and up to 30 days after 
the last dose of erdafitinib are to be recorded for all subjects (no adverse events will be collected 
for subjects signing the molecular ICF only). Adverse event information will be graded using the 
National Cancer Institute Common Terminology Criteria for Adverse Events (NCI-CTCAE), 
Version 4.0. See Section 12 for complete details on adverse event reporting. Concomitant 
medications used will also be recorded throughout this time period. 
Throughout the Treatment Period, the investigator will assess subject response to therapy using 
the RECIST Version 1.1.8 Efficacy evaluations are described in Section 9.2.
9.1.4.
End-of-Treatment Visit
The End-of-Treatment Visit will be performed after the last dose of erdafitinib is administered and 
will include End-of-Treatment procedures as outlined in the Time and Events Schedule (Table 1, 
Table 2, and Table 3). All subjects should have the End-of-Treatment Visit completed within 
30 days after the last dose of study drug, and prior to starting any subsequent cancer treatment, 
except for those who have withdrawn consent, died, or have been lost to follow-up. 
Additional information on reporting of adverse events can be found in Section 12.
9.1.5.
Follow-Up Phase
The Follow-up Phase is the time between the End-of-Treatment Visit and the end of study 
participation or end of study. All subjects who enter the Follow-up Phase will have a Follow-up 

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Visit every 12 weeks (±7 days) after the End-of-Treatment Visit to assess survival status and start 
of alternate anticancer therapy until death, the subject withdraws consent, or the end of study, 
whichever occurs first as outlined in the Time and Events Schedules (Table 1, Table 2, and Table 
3). Assessments of survival status and alternate anticancer therapies must be recorded in the eCRF. 
If necessary, this visit can occur telephonically.
9.2.
Efficacy
Disease assessments will be performed according to the Time and Events Schedules (Table 1, 
Table 2, and Table 3). Assessment of responses for solid tumors will be performed according to 
RECIST (version 1.1)8 by investigators. For subjects who discontinue study drug before disease 
progression, tumor assessments should be continued per this schedule, as if the subject is still on 
study treatment.
More frequent radiological assessments are allowed, if clinically indicated/desirable. Identical 
methodology (computed tomography [CT] scan or magnetic resonance imaging [MRI]) should be 
used for disease assessment at baseline, and throughout the course of the study, to characterize 
each identified and reported lesion to document disease status. Ultrasound, fluorine-18-
fluorodeoxyglucose positron emission tomography (FDG-PET), and plain x-rays are not 
acceptable methods of evaluating disease response in the absence of CT or MRI scans.
If symptomatic deterioration (on the basis of global deterioration of health status) occurs without 
documentation of radiographic progression, the clinical findings used to make this determination 
must be specified in the eCRF and documented in the source documents. Every effort should be 
made to document the objective progression even after discontinuation of treatment for 
symptomatic deterioration. Tumor response will be reported by the investigator in the eCRF.
9.2.1.
Evaluations
9.2.1.1.
Radiographic Images Assessment
Computed tomography (CT) scans of the chest, abdomen, pelvis, and any other location where 
disease is present will be performed at Screening. During the study, disease response will be 
assessed using CT scans of the locations of known disease. Magnetic resonance imaging may be 
used to evaluate sites of disease that cannot be adequately imaged using CT (in cases where MRI 
is desirable, the MRI must be obtained at baseline and at all subsequent response evaluations or in 
cases where use of CT scan is clinically contraindicated). For all other sites of disease, MRI studies 
do not replace the required chest, abdomen, and pelvic CT scans. Brain MRI and lumbar puncture 
are required, only if clinically indicated.
All unconfirmed PR/CR results require confirmation of response within 4 to 6 weeks of first 
assessment of response, as per RECIST 1.1.
After disease progression is documented, subjects will be monitored as outlined in Section 9.1.5.

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9.2.1.2.
Definition of Measurable Disease
Subjects will have response assessments performed by radiographic image assessments (CT or 
MRI) as described in Section 9.2.1.1. Disease assessment procedures must be consistent with 
RECIST version 1.1 guidelines for radiographic assessment, as outlined in Attachment 6. The 
same method of assessment and the same technique should be used to characterize each identified 
and reported lesion at baseline and during follow-up. Imaging based evaluation should always be 
done rather than clinical examination alone.
9.2.2.
Endpoints
Primary Endpoint
The primary endpoint is the best objective response.
Secondary Endpoints

Progression-free survival, defined as the duration from the date of the first dose of study drug 
until the date of first documented evidence of progressive disease (or relapse for subjects who 
experience CR during the study) or death, whichever comes first. Data from subjects who are 
progression-free and alive or have unknown status will be censored at the last tumor 
assessment.

Duration of response (CR or PR), calculated from the date of initial documentation of a 
response to the date of first documented evidence of progressive disease (or relapse for 
subjects who experience CR during the study) or death. Data from subjects who are 
progression-free and alive or have unknown status will be censored at the last tumor 
assessment.

Overall survival, measured from the date of first dose of study drug to the date of the subject’s 
death. If the subject is alive or the vital status is unknown, the subject’s data will be censored 
at the date the subject was last known to be alive.

The safety profile of erdafitinib

The response rate in biomarker-specific subgroups

Pharmacokinetics of erdafitinib: population (typical) and individual pharmacokinetic 
parameters of JNJ 42756493 (for instance, plasma clearance, volumes of distribution, etc.) 
will be estimated from the available JNJ 42756493 plasma concentration-time observations
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9.2.3.
Pharmacokinetics Evaluations
Venous blood samples will be collected for determination of plasma concentrations of erdafitinib
at the time points specified in the Pharmacokinetic Time and Event Schedule 
(Table 4). On Cycle 1 Day 1, a 4-mL venous blood sample will be taken together with the 2-hour 
postdose pharmacokinetic blood sample for the determination of the plasma protein binding of 
erdafitinib. Total protein, albumin, and alpha-1-acid glycoprotein levels will be determined as 
well. If indicated by the emerging safety findings or if the scheduled pharmacokinetic samples are 
not collected due to treatment interruption, unscheduled blood samples may be collected to study 
the relationship between drug exposure and adverse events to support the decision of dose 
reduction or modification. The total number of samples and blood volume will not be substantially 
increased without IEC approval. The estimated volume of blood required for the pharmacokinetic
evaluations is summarized in Table 4. The dates and times of venous blood sample collection will
be recorded on the laboratory requisition form or in the eCRF. At the time of implementation of 
Amendment 6 at the local site level, routine PK samples will no longer be collected; PK samples 
may still be collected for assessment of adverse events as clinically appropriate.
The Laboratory Manual provides further information regarding handling and shipment of 
blood/plasma samples.
9.2.4.
Analytical Procedures
Blood samples will be processed to obtain plasma for measurement of erdafitinib by validated 
analytical methods under the direction of the sponsor. For total plasma concentrations of 
erdafitinib, the samples will be analyzed using a validated liquid chromatography-mass 
spectrometry (LC-MS/MS) method under the direction of the sponsor. Plasma protein binding will 
be determined by equilibrium dialysis. The Cycle 1 Day 1, 2-hour plasma samples will be 
subjected to equilibrium dialysis against phosphate buffer. After dialysis, the buffer and plasma 
samples will be analyzed for erdafitinib content using a qualified LC-MS/MS method by the 
sponsor's Bioanalytical Laboratory. The fraction of the unbound erdafitinib (FU) will be calculated 
as the ratio of the unbound concentration (Cu) in the buffer, to the total concentration (CED) in the 
plasma (formula: FU = Cu/CED).
Based on the metabolite profiling data, the need for further metabolite assessment in the clinical 
samples will be evaluated. If further metabolite quantification is needed it will be done by a 
qualified method. After these analyses, the remaining plasma will be retained and may be used for 
future metabolite identification, or profiling (to be reported either together with or separate from 
the clinical study report).
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9.3.
Pharmacodynamic and Predictive Biomarker Evaluations
9.3.1.
Pharmacodynamic Biomarker Evaluations
For pharmacodynamic biomarker evaluation, serum phosphate levels will be monitored in subjects 
treated with the study drug. The Phase 1 Study EDI1001 demonstrated that the phosphate levels 
tend to correlate with the activity of erdafitinib. 
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9.4.
Safety Evaluations
This study will be monitored in accordance with the sponsor’s Pharmacovigilance Committee
procedures. Adverse event and serious adverse event data will be reviewed internally on an 
ongoing basis to identify safety concerns by the study medical monitor. In addition, the sponsor’s 
SMT will review the safety data routinely and will investigate specific safety queries. The SMT 
will review all serious adverse events. Periodic conference calls with the study investigators will 
be conducted to discuss study progress, obtain investigator feedback, and discuss study-specific 
issues including adverse events and serious adverse events.
Safety assessments will be based on medical review of adverse event reports and the results of 
vital sign measurements, electrocardiograms (ECGs), physical examinations, clinical laboratory 
tests, ECOG performance status, and other safety evaluations at specified time points as described 
in the Time and Events Schedules (Table 1, Table 2, and Table 3).
Any clinically significant abnormalities or toxicities persisting at the end of the study will be 
followed by the investigator until resolution or until reaching a clinically stable condition. For 
adverse events such as skin/nail and mucosal toxicity, upon subjects consent, photographs may be 
taken for assessment and monitoring of the toxicity.
9.4.1.
Adverse Events
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. The incidence of 
adverse events will be tabulated and reviewed for potential significance and clinical importance. 
Adverse events will be graded according the NCI-CTCAE, Version 4.0. Adverse events will be 
followed by the investigator as specified in Section 12, Adverse Event Reporting.
9.4.2.
Clinical Laboratory Tests

Blood samples for serum chemistry and hematology will be collected according to the Time 
and Events Schedules (Table 1, Table 2, and Table 3). 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 report, document this review, and record any 
clinically relevant changes occurring during the study in the adverse event section of the 
eCRF. 
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
Laboratory test results completed on Cycle 1 Day 1 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 locally:

Hematology Panel

-hemoglobin

-platelet count

-white blood cell (WBC) count and ANC only

Serum Chemistry Panel 
-alanine aminotransferase (ALT)
-creatinine
-albumin
-magnesium
-alkaline phosphatase
-alpha-1-acid glycoprotein1
-aspartate aminotransferase (AST)
-phosphate
-blood glucose
-potassium

-blood urea nitrogen (BUN)
-sodium

-total bilirubin
-total protein

-calcium
-parathyroid hormone (PTH)
1.
Testing of alpha-1-acid glycoprotein will be performed by a central lab using the 2-hour post dose 
blood sample from Cycle 1 Day 1. This test is not performed locally. Please refer to Table 4 for 
additional details.
Potential Hy’s Law case reporting requirements are defined in Section 6.3.1.
9.4.3.
Renal Toxicity Evaluation
Serum creatinine clearance will be calculated
according to Cockcroft-Gault Formula 
(Attachment 2) or measured by 24-hour urine collection.
9.4.4.
Urine or Serum Beta-hCG Pregnancy Test
A urine or serum sample will be obtained for a pregnancy test in sexually active female subjects 
of child-bearing potential at pre-specified time points (β-hCG). Additional serum or urine 
pregnancy tests may be performed, 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.
9.4.5.
Electrocardiogram
Electrocardiograms will be performed according to the Time and Events Schedule at the study site.
Subjects should reside in a quiet setting for the duration of serial ECG recordings, without 
distractions, at each scheduled time point for ECG measurements. The subject should rest in a 
supine position for at least 5 minutes before each serial ECG recording, and should refrain from 
talking or moving arms or legs. Skin preparation should be optimal to obtain high quality of ECGs; 
if deemed appropriate, the chest should be shaved and prepped with light abrasion. Serial triplicate 
ECGs should be performed with 5 minute intervals between each assessment, at approximately the 

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same time of day for each required study visit (as outlined in the Time and Events Schedules).
Serial triplicate 12-lead ECGs will be recorded and 1 printout produced and stored in the subject’s 
source documents. The data will also be stored digitally and sent to the central laboratory for 
storage (as described in the ECG manual) periodically. All 12-lead ECG recorder devices should 
have been recently serviced and calibrated. The following variables should be measured: heart 
rate, RR, QT, PR, QRS, QTc (Fridericia) intervals. QTcF (Fridericia) will be used for assessment 
of QTc interval prolongation. The investigator will review the results, including ECG morphology, 
for immediate management. A description of the overall assessment (i.e., normal or abnormal plus 
reason) will be made along with the clinical investigator’s signature and date.
Abnormal and clinically significant ECG results will be reported to the Sponsor within 72 hours. 
Screening ECG results will be used to determine subject eligibility. The investigator will comment 
on the clinical relevance and document this in the eCRF (along with details of clinically significant 
findings). Any clinically significant worsening from baseline or new finding after the first study 
drug administration will be recorded as an adverse event and will be followed up to resolution or 
until an adequate explanation for the abnormality is found.
9.4.6.
Echocardiography Evaluation
Echocardiography (ECHO) will be conducted and assessed by a local cardiologist during the full-
study Screening. Echocardiography may be repeated at any time during the study at the discretion 
of investigators to assess for any potential cardiovascular toxicity. Screening ECHO results will 
be used to determine subject eligibility. In the event that ECHO is not available or not interpretable, 
MUGA is an acceptable alternative.
9.4.7.
Ophthalmic Examination
All subjects must have an ophthalmological examination performed at Screening by an 
ophthalmologist, which should include assessment of visual acuity, fundoscopy (examination of 
both central and peripheral zones should be performed), slit lamp biomicroscopy and an Optical 
Coherence Tomography (OCT). The Amsler grid test will also be administered by the treating 
study physician or nurse at screening and other timepoints, as indicated in the Time and Events 
Schedule. A follow-up examination should be performed as clinically necessary based on the 
findings of the Amsler grid tests and clinical assessment.
When Central Serous Retinopathy (CSR)/Retinal Pigment Epithelial Detachments (RPED) is 
suspected, an OCT should be performed. Fluorescein angiography could be considered appropriate 
in conditions such as suspected Retinal Vein Occlusion (RVO). It is also recommended that color 
fundus photos or OCT images be obtained and stored in the subject’s records for future reference. 
In subjects with suspected retinal pathology such as CSR or RVO, a consultation with a retina 
specialist should be considered.
Amsler grid testing will be administered by the treating physician or nurse according to the Time 
and Events Schedules (Table 1, Table 2, and Table 3). 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 exam within 7 days.

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However, if the subject has an abnormal Amsler grid test at baseline (during Screening), then a 
repeat ophthalmic 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 (specific guidelines outlined in Section 6.3.6).
9.4.8.
Vital Signs
Blood pressure (systolic and diastolic) and heart rate measurements will be assessed with a 
completely automated device consisting of an inflatable cuff and an oscillatory detection system 
according to the Time and Events Schedules (Table 1, Table 2, and Table 3). 
9.4.9.
Physical Examination
A full physical examination will be performed at screening according to the Time and Events 
Schedule. Limited physical examinations of involved organs will be performed at subsequent visits
as outlined in the Time and Events Schedules (Table 1, Table 2, and Table 3).
9.4.10.
ECOG Performance Status
Eastern Cooperative Oncology Group performance status score will be determined at pre-specified 
time points listed in the Time and Events Schedules (Table 1, Table 2, and Table 3). Eastern 
Cooperative Oncology Group scoring information is provided in Attachment 1.
9.4.11.
Symptomatic Measurement Questionnaire
An abbreviated set of self-reported questions will be administered to rate the subject’s experience 
focusing on disease- and treatment-related symptoms. Symptoms reflect a subject’s experience of 
treatment-related side effects and disease-related symptoms that may impact treatment decisions. 
Subjects will be asked to rate their symptoms on a scale ranging from 0 to 10, with higher scores 
indicating a more severe degree of symptoms. The Symptom Measurement Questionnaire (e.g. 
pain, fatigue, cough, breathing) was developed by reviewing clinical reports from the subjects 
treated thus far in BLC2001.  The questionnaire time recall period for this instrument is 1 week 
(the past week) and it will be administered in this study to perform Patient-Reported Outcomes 
(PRO) analysis.  The Symptom Measurement Questionnaire will be completed by the subject at 
the timepoints specified in the Time and Events Schedule (Table 3). The Symptom Measurement 
Questionnaire will be provided as part of the CRF.  The Symptom Measurement Questionnaire 
will be analyzed by measuring change from baseline to determine if response to therapy and side 
effects of therapy are accompanied by measurable changes in the symptoms reported.
This questionnaire will be in English only, and will be completed only by subjects who can read
English. Subjects who switch to Regimen 3 from Regimen 1 or 2 are not required to complete the 
questionnaire.
9.5.
Sample Collection and Handling
The actual dates and times of sample collection must be recorded in the laboratory requisition 
form/source documentation. Refer to the Time and Events Schedules for the timing and frequency 
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Instructions for the collection, handling, and shipment of samples are found in the Laboratory 
Manual.
10.
SUBJECT COMPLETION/WITHDRAWAL
10.1.
Completion
A subject will be considered to have completed the study if the subject has died.
10.2.
Discontinuation of Study Treatment 
A subject's study treatment will be discontinued for any of the following reasons:

Concurrent medical conditions or unmanageable disease–related events for which the 
investigator believes that it is in the best interest of the subject to stop treatment

The subject becomes pregnant

Disease progression (Exception: if the investigator and medical monitor agree that 
continuation of treatment is acceptable and in the best interest of the subject considering the 
terminal nature of the underlying disease, he/she may receive treatment until such time as the 
treating physician and the medical monitor agree that further continuation of treatment is no 
longer beneficial to the subject.)

Unacceptable toxicity (Exception: If a subject has been deriving benefit from treatment, and 
the investigator can demonstrate that re-introduction of study drug is in the best interest of the 
subject considering the terminal nature of the disease, the drug may be re-introduced at a lower 
dose and/or intensity if the medical monitor is in agreement with this assessment. With 
appropriate re-consenting, the subject can be retreated with a 1- or 2-dose level reduction as 
appropriate, along with appropriate clinical follow-up as designated by the investigator (please 
see Section 16.2.3 for details.)

The subject refuses further treatment with the study drug

The sponsor terminates the study

Investigator decision approved by the sponsor
If a subject discontinues treatment, an End-of-Treatment visit should be conducted within 30 days 
of the subject’s last dose of study drug. The primary reason for treatment discontinuation will be 
clearly documented in the subject’s medical record and recorded in the eCRF. Once a subject 
discontinues treatment with the study drug, the subject will not be permitted to be retreated.
10.3.
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
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.

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When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn subject 
may not be assigned to another subject.
A subject may be replaced if the subject withdraws prior to study drug administration or prior to 
the first disease assessment for reasons other than toxicity or disease progression.
10.3.1.
Withdrawal From the Use of Samples in Future Research
The subject may withdraw consent for use of samples for research (refer to Section 16.2.5, 
Long-Term Retention of Samples for Additional 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 full study ICF.
11.
STATISTICAL METHODS
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. 
In the original protocol, 2 interim analyses were planned. After Interim Analysis 1 was completed 
and Amendment 3 written, no further interim analyses were needed. The original protocol sections 
describing the interim analyses and dose selection criteria were moved to Attachment 9, along with 
the original sample size calculations.
11.1.
Sample Size Determination
Sample size determination prior to IA1 is described in Attachment 9.
After IA1, it is expected that approximately 180 subjects with specified FGFR genetic alterations 
will be enrolled in the study. Of these, about 30 subjects will be treated with Regimen 1, about 50 
subjects will be treated with Regimen 2, and approximately 100 subjects will be treated with
Regimen 3. When approximately 88 subjects have been treated in Regimen 3, if less than 
80 subjects are chemo-refractory, then enrollment of chemo-naïve subjects in Regimen 3 will be 
stopped but enrollment of chemo-refractory subjects will continue until at least 80 
chemo-refractory subjects are treated in Regimen 3 or a total of approximately 100 subjects are 
treated with Regimen 3.
The number of subjects to be treated with Regimen 3 (at least 88) was based on sample size 
calculations using the following assumptions: 
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After a total of approximately 88 subjects are treated with Regimen 3, enrollment will be stopped 
if at least 80 chemo-refractory subjects have been treated with Regimen 3. However, if the number 
of chemo-refractory subjects treated with Regimen 3 is less than 80, then the enrollment will 
change as follows:
1.
Enrollment of chemo-naïve subjects will be stopped.
2.
Enrollment of chemo-refractory subjects will continue until a total of at least 80 chemo-
refractory subjects are treated or a total of 100 subjects are treated with Regimen 3. 
Enrollment of at least 80 chemo-refractory subjects will provide at least 80% power to reject the 
null hypothesis within the chemo-refractory subgroup under the above assumptions.  
11.2.
Analysis Populations
The analysis populations for this study are defined as the following: 

The Primary Efficacy (PE) analysis population will consist of all subjects who are treated by 
at least 1 dose of study drug in Regimen 3. 

The Treated Population will consist of all subjects who receive at least 1 dose of study drug. 
All safety analyses will be performed using the Treated Population.

The Response-Evaluable (RE) population will include all subjects who satisfy all of the
following:

Met all eligibility criteria for the study;

Received at least 1 dose of study drug;

Had a baseline and at least 1 adequate post-treatment disease evaluation, have had clinical 
signs and/or symptoms of disease progression or died prior to the first post-treatment 
disease evaluation (these subjects will be considered non-responders). Adequate disease 
assessment is defined as having sufficient evidence to correctly indicate that progression 
has or has not occurred.
The efficacy analyses at IA1 and IA2 will be performed using the RE population. 

The Pharmacokinetic/Pharmacodynamic Population will consist of all subjects who received 
at least 1 dose of erdafitinib and had at least 1 sample collected during treatment to determine 
the drug concentration or pharmacodynamic biomarker response.
11.3.
Efficacy Analyses 
Efficacy will be evaluated using the RECIST version 1.1 and current disease specific solid tumor 
response criteria.8 Response may be assessed by investigators and by an Independent Radiologic 
Review Committee (IRRC). Independent Radiologic Review Committee assessment may not be 
performed if the investigator assessments indicate that the primary objective has not been met 
(IRRC assessment will not be performed for IA1 and IA2). If response is assessed by an IRRC, 
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the IRRC assessment of response will be used for the primary and final analyses, and the response
assessed by the investigators will be used for supportive analyses.
11.3.1.
Primary Analysis
The primary analysis will be conducted 6 months after enrollment of the last subject in the selected 
dose regimen. The primary efficacy analyses will be based on the PE analysis population. 
The response rate for both the chemo-naïve and chemo-refractory subjects will be analyzed at the 
time of primary analysis. The null hypothesis will be rejected using normal approximation to the 
binomial distribution. The response rate and its 95% 2-sided confidence interval will be calculated 
using normal approximation to the binomial distribution as well.
The response rate of the chemo-refractory subgroup in Regimen 3 will be analyzed at the time of 
the primary analysis. Only chemo-refractory subjects who have received at least 1 dose of study 
drug will be included in this analysis. The null hypothesis for the chemo-refractory subjects is that 
the response rate is less than or equal to 25%; this will be rejected using normal approximation to 
the binomial distribution. Efficacy on response rate within the chemo-refractory subgroup will be 
claimed if the null hypothesis on response rate on the combined chemo-naive and chemo-refractory 
group is rejected and the null hypothesis on response rate on the chemo-refractory subgroup is also 
rejected.
Analysis of duration of response, PFS, and overall survival will be conducted at the same cutoff 
date of the primary analysis. The distribution (median and Kaplan-Meier curves) of duration of 
response will be provided using Kaplan-Meier estimates for subjects who achieved a response 
during the study. Biomarker-specific response rates will also be evaluated, including differences 
between translocations and mutations.
Exploratory analyses will be performed on response rate, duration of response, PFS, overall 
survival based on the treated population. 
Similar exploratory efficacy analyses on Regimen 1 and Regimen 2 will be performed as well.
11.3.2.
Final Analysis
The final analysis will be performed 12 months after last subject is enrolled. All analyses on 
efficacy endpoints will be updated based on the treated population. For subjects still on study 
treatment after the planned final analysis the study Sponsor will continue to provide access to 
erdafitinib and collect safety data (eg, AEs, SAEs) until the end of study (see Section 2.3 for the 
end of study definition).
11.4.
Pharmacokinetic and Pharmacokinetic-Pharmacodynamic Analyses 
Population pharmacokinetic analysis of plasma concentration-time data of erdafitinib will be 
performed using nonlinear mixed-effect modeling. Data from this study may be combined with 
those from a selection of Phase 1 studies to support a relevant structural model. This model will 
be used to predict pharmacokinetic parameters at steady-state. Descriptive statistics, including 

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mean, standard deviation, coefficient of variation (%CV), median, minimum, and maximum will 
be applied for estimated pharmacokinetic parameters. Graphical exploration of data may be 
performed if deemed useful. In addition, available subjects’ characteristics (demography, such as 
body weight; laboratory data, such as alpha-1-acid glycoprotein; and genotype) may be tested as 
potential covariates affecting pharmacokinetic parameters.
Relationships between plasma concentrations or metrics of systemic exposure and markers of 
pharmacological activities, efficacy or treatment-emergent adverse events could also be explored 
as data allow using population approaches (e.g., non-linear mixed effects approaches). For 
example, Pharmacokinetic-phosphate relationships will be explored, also evaluating the potential 
effect of baseline phosphate level as influential covariate.
11.5.
Biomarker Analyses
All FGFR alterations in tumor will be tested at the central laboratory and biomarker eligibility will 
be determined using the accepted criteria developed in the central laboratory.
Blood samples will be collected as outlined in Table 5. Blood samples will be tested for the 
presence of the FGFR translocations or mutations to determine if they correlate with sensitivity to 
the compound. A laboratory-developed test will be used for this exploratory endpoint. 
Phosphate will be tested at local laboratories using the test developed there. Analysis will be 
performed and total levels of phosphate in serum will be determined for each subject.
11.6.
Safety Analyses
Safety analyses will be performed using the treated population. Safety will be evaluated using the
NCI-CTCAE, Version 4.0. All safety analyses will be performed using data from the safety 
population. The safety parameters to be evaluated are the incidence, intensity, and type of adverse 
events, clinically significant changes in the subject’s physical examination findings, vital signs 
measurements, and clinical laboratory results. Exposure to investigational product and reasons for 
discontinuation of study treatment will be tabulated.
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Adverse Events
Treatment-emergent adverse events are adverse events that occur after the first dose of study drug, 
through the Treatment Phase, and for 30 days following the last dose of study drug; any adverse 
event considered study drug-related regardless of the start date of the event; or any event that is 
present at baseline but worsens in severity or is subsequently considered drug-related by the 
investigator. The number and percent of subjects with treatment-emergent adverse events will be 
summarized according to intensity (NCI-CTCAE, Version 4.0) and drug relationship as well as 
categorized by System Organ Class and preferred term by treatment group.
The verbatim terms used in the CRF by investigators to identify adverse events will be coded using 
the Medical Dictionary for Regulatory Activities (MedDRA). All reported adverse events with 
onset during the treatment phase (i.e., treatment-emergent adverse events, and adverse events that 
have worsened since baseline) 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.
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 included in the summary of 
laboratory data. Descriptive statistics will be calculated for each laboratory analyte at baseline.
Parameters with predefined NCI-CTCAE Version 4.0 toxicity grades will be summarized. Change 
from baseline to the worst adverse event grade experienced by the subject during the study will be 
provided as shift tables.
Electrocardiogram
The effects of erdafitinib on ECGs (QT, QTc, PR, QRS, heart rate) will be evaluated by means of 
descriptive statistics and frequency tabulations. These tables will include observed values and 
changes from baseline values (the Day 1 pre-dose ECG will be used as baseline) to allow detection 
of clinically relevant changes in individuals.
Vital Signs
Descriptive statistics of pulse/heart rate and blood pressure (systolic and diastolic) values and 
changes from baseline will be summarized. The percentage of subjects with clinically important 
changes from baseline will be summarized.
11.7.
Data Review Committee 
The DRC will be conducting all interim analyses (IA1 and IA2 prior to Amendment 3, please refer 
to Attachment 9) and further safety analyses. Details of the composition of the DRC and their 
operational procedures will be specified in the DRC charter.

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11.8.
Safety Monitoring Team
Safety will be monitored by the sponsor’s medical monitor or study responsible physician 
throughout the study. In addition, the sponsor’s SMT, a multi-disciplinary team including an 
internal safety physician, will review the safety data and will investigate specific safety queries. In
addition, the SMT will review all serious adverse events. In the event a significant safety issue is 
identified, both the internal safety team and the responsible investigators will convene to discuss 
the safety data and to make a recommendation on the future conduct of the study. All decisions 
will be documented and will be distributed to investigators. The IRB or IEC will be notified if 
required.
12.
ADVERSE EVENT REPORTING
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 
information; all clinical studies conducted by the sponsor or its affiliates will be conducted in 
accordance with those procedures.
12.1.
Definitions
12.1.1.
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 treatment. 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 
Section 12.3.1, All Adverse Events, for time of last adverse event recording).
Serious Adverse Event
A serious adverse event based on ICH and European Union Guidelines on Pharmacovigilance for 
Medicinal Products for Human Use is any untoward medical occurrence that at any dose:

Results in death

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
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.
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 Investigator's Brochure. 
Adverse Event Associated With the Use of the Drug
An adverse event is considered associated with the use of the drug if the attribution is possible, 
probable, or very likely by the definitions listed in Section 12.1.2.
12.1.2.
Attribution Definitions
The attribution definitions (ie, assessment of causality) have been updated for the DDI Substudy 
and are provided in DDI Substudy Attachment 12, Section 12. 
Not Related
An adverse event that is not related to the use of the drug.
Doubtful
An adverse event for which an alternative explanation is more likely, e.g., concomitant drug(s), 
concomitant disease(s), or the relationship in time suggests that a causal relationship is unlikely.
Possible
An adverse event that might be due to the use of the drug. An alternative explanation, 
eg, concomitant drug(s), concomitant disease(s), is inconclusive. The relationship in time is 
reasonable; therefore, the causal relationship cannot be excluded.

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Probable
An adverse event that might be due to the use of the drug. The relationship in time is suggestive 
(e.g., confirmed by dechallenge). An alternative explanation is less likely, eg, concomitant drug(s), 
concomitant disease(s).
Very Likely
An adverse event that is listed as a possible adverse reaction and cannot be reasonably explained 
by an alternative explanation, e.g., concomitant drug(s), concomitant disease(s). The relationship 
in time is very suggestive (e.g., it is confirmed by dechallenge and rechallenge).
12.1.3.
Severity Criteria
The severity criteria have been updated for the DDI Substudy and are provided in the DDI 
Substudy Attachment 12, Section 12; the DDI Substudy will be using the NCI-CTCAE, 
Version 5.0.
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 4.0. Any adverse event or serious adverse event not listed in the NCI-CTCAE, 
Version 4.0 will be graded according to the investigator clinical judgment by using the standard 
grades as follows:
Grade 1, Mild: Awareness of symptoms that are easily tolerated causing minimal discomfort and 
not interfering with everyday activities
Grade 2, Moderate: Sufficient discomfort is present to cause interference with normal activity
Grade 3, Severe: Extreme distress causing significant impairment of functioning or 
incapacitation; prevents normal everyday activities
Grade 4, Life-threatening: Requires urgent medical intervention
Grade 5, Death: Death
The investigator should use clinical judgment in assessing the severity of events not directly 
experienced by the subject (e.g., laboratory abnormalities).
Hyperphosphatemia and adverse events related to nails are to be graded using
Table 21. 

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Table 21:
Grading of Hyperphosphatemia and 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
Hyperphosphatemia
5.5-6.9 mg/dl
1.8-2.2 mmol/L
7.0-8.9 mg/dl
2.3-2.9 mmol/L
9.0-10.0 mg/dl
(>2.9-3.2 mmol/L), 
or asymptomatic 
soft tissue 
calcification with 
any phosphate level
>10 mg/dl (>3.2 
mmol/L), or 
symptomatic soft 
tissue calcification 
with any phosphate 
level
12.2.
Special Reporting Situations
Safety events of interest on a sponsor study drug that may require expedited reporting and/or safety 
evaluation include, but are not limited to:

Overdose of a sponsor study drug

Suspected abuse/misuse of a sponsor study drug

Inadvertent or accidental exposure to a sponsor study drug

Medication error involving a sponsor product (with or without subject/patient exposure to the 
sponsor study drug, e.g., name confusion)
Special reporting situations should be recorded in the eCRF. Any special reporting situation that 
meets the criteria of a serious adverse event should be recorded on the serious adverse event page 
of the eCRF.
12.3.
Procedures
Corneal or retinal abnormalities for subjects receiving erdafitinib should be reported as adverse 
events (if Grade 1 or 2) and or as serious adverse events if the severity is Grade 3 or higher.
12.3.1.
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 full-study ICF (no adverse events will be collected for subjects 
signing the molecular ICF only) is obtained until 30 days after last dose of study drug. Subjects 
who discontinue study drug due to drug-related toxicity will continue to be monitored for this 
toxicity until the toxicity resolves to baseline, stabilizes, or is deemed irreversible, the subject dies, 
or subsequent therapy is started, whichever occurs first. 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 

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that is spontaneously reported by an investigator beyond the time frame specified in the protocol.
Adverse events that occur between after signing the ICF for assessment of the molecular eligibility 
and before signing the full study eligibility screening ICF will not be collected.
All events that meet the definition of a serious adverse event will be reported as such.
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 eCRF. Whenever 
possible, diagnoses should be given when signs and symptoms are due to a common etiology 
(e.g., cough, runny nose, sneezing, sore throat, and head congestion should be reported as "upper 
respiratory infection"). Investigators must record in the eCRF 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.
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 serious adverse events that are unlisted (unexpected) and associated 
with the use of the study drug. The investigator (or sponsor where required) must report these 
events to the appropriate IEC/IRB that approved the protocol unless otherwise required and 
documented by the IEC/IRB.
Subjects (or their designees, if appropriate) must be provided with a "study card" indicating the 
following:

Subject's name

Subject number

Subject's date of birth

Study site number

Investigator's name and 24-hour contact information

Local sponsor's name and 24-hour contact information

Statement that the subject is participating in a clinical trial.
12.3.2.
Serious Adverse Events
All serious adverse events occurring during the study must be reported to the appropriate sponsor 
contact person by study-site personnel within 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, which must be completed and signed 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 made by facsimile (fax).

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All serious adverse events that have not resolved by the End-of-Treatment Visit, or that have not 
resolved upon discontinuation of the subject's participation in the study, must be followed until 
any of the following occurs (whichever occurs first):

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); or

The subject dies.
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 the course of 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 (e.g., 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 eCRF). 

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 (e.g., 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 (i.e., 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.)

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Anticipated Events
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 SAEs 
will be considered anticipated events: 

Cauda equina syndrome

Haematuria

Urinary incontinence

Lymphedema

Pathological fracture

Spinal cord compression

Urinary hesitation

Ureteric obstruction

Hydronephrosis

Urine flow decreased, including oliguria

Urinary retention

Urinary tract obstruction

Urinary tract stoma complication

Urinary tract pain

Urinary tract infection

Urosepsis
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 intervention 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 in which the studies are conducted.
12.3.3.
Pregnancy
All initial reports of pregnancy must be reported to the sponsor by the investigational staff within 
24 hours of their knowledge of the event using the appropriate pregnancy notification form. 
Abnormal pregnancy outcomes (e.g., spontaneous abortion, stillbirth, and congenital anomaly) are 

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considered serious adverse events and must be reported using the Serious Adverse Event Form. 
Any subject who becomes pregnant during the study must be promptly withdrawn from the study.
Because the effect of the study drug on sperm is unknown, pregnancies in partners of male subjects 
included in the study will be reported by the investigational staff within 24 hours of their knowledge 
of the event using the appropriate pregnancy notification form.
Follow-up information regarding the outcome of the pregnancy and any postnatal sequelae in the 
infant will be required.
12.3.4.
Disease-related Events or Outcomes Not Qualifying as Adverse 
Events or Serious Adverse Events
All events that meet the definition of a serious adverse event will be reported as serious adverse 
events, regardless of whether they are protocol-specific assessments.
Progression of disease should not be considered nor should be reported as an adverse event (or 
serious adverse event). 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 (refer to 
Adverse Event Definitions and Classifications in Section 12.1.1).
12.4.
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 on the Contact Information 
page(s), which will be provided as a separate document.
13.
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.
13.1.
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 

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Section 12.3.2, Serious Adverse Events). A sample of the suspected product should be maintained 
for further investigation if requested by the sponsor.
13.2.
Contacting Sponsor Regarding Product Quality
The names (and corresponding telephone numbers) of the individuals who should be contacted 
regarding product quality issues are listed on the Contact Information page(s), which will be 
provided as a separate document.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The erdafitinib study drug supplied for this study is formulated as 3-, 4-, and 5-mg tablets for oral 
use. Refer to the Investigator’s Brochure for a list of excipients.
14.2.
Packaging
The tablets for oral use in this study will be packaged in child-resistant bottles.
14.3.
Labeling
Study drug labels will contain information to meet the applicable regulatory requirements. No 
medication can be relabeled without prior approval from the sponsor.
14.4.
Preparation, Handling, and Storage
The tablets for oral use should be stored at room temperature. Dosing instructions are provided in 
by the investigator and on the study drug labeling.
The study drug must be stored as specified at delivery and in the original packaging.
14.5.
Drug Accountability
The clinical 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, must be documented on the drug accountability form. 
Subjects (or, when appropriate, by a caregiver or surrogate) must be instructed to return all original 
containers, whether empty or containing study drug. Study drug returned by study subjects will be 
stored and disposed of according to the sponsor’s instructions. Site staff must not combine contents 
of the study drug containers.
Study drug must be handled strictly in accordance with the protocol and the container label and 
will be stored 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 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 site is an authorized destruction unit and study drug supplies are 
destroyed on site, this must also be documented on the Drug Return Form.

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Hazardous materials such as used ampoules, needles, syringes and vials containing hazardous 
liquids, should be disposed of immediately in a safe manner and therefore will not be retained for 
drug accountability purposes. The immediate destruction of these drug supplies should be 
documented in the drug accountability records on site.
Study drug should be dispensed under the supervision of the investigator, a qualified member of 
the investigational staff, 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. 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.
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Protocol

Investigator’s Brochure

Electronic CRFs and electronic data capture (eDC) manual

Site Investigational Product Manual

Laboratory manual

ECG manual 

Kits for pharmacokinetic, pharmacodynamics/biomarker, safety, and tissue sample
assessments

Subject diary card and information booklet

Investigator binder to store all documents concerning the study. This is a confidential binder 
and only personnel involved in the study should have access to it.
16.
ETHICAL ASPECTS
16.1.
Study-Specific Design Considerations
This is a Phase 2, multicenter, open-label study to evaluate the efficacy and safety of 2 different dose 
regimens (Regimen 1: 10 mg oral study drug once daily on an intermittent schedule [Days 1 through 
7 and Days 15 through 21 of a 28-day cycle]; Regimen 2: 6 mg oral study drug once daily on a 
continuous schedule [Days 1 through 28 of a 28-day cycle]), and selection of a more favorable dose 
regimen for erdafitinib in subjects with metastatic or surgically unresectable urothelial cancer with 
select FGFR genetic alterations. Based on analysis of data up to Interim Analysis 1 (IA1), the Data 
Review Committee (DRC) decided to terminate further enrollment to the intermittent schedule and 
select the continuous schedule with a starting dose of 8 mg and possible up-titration to 9 mg 
(Regimen 3) for further enrollment.  
The collective experience from both the Phase I and current ongoing global Phase 2 trials, in addition 
to emerging pharmacokinetic/pharmacodynamic (PK/PD) modeling, suggest that the 8 mg daily 

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dose as the continuous regimen is likely to be well tolerated without significant treatment 
interruptions. In addition, the majority of subjects would tolerate the sustained 8 mg daily dose, while 
maximizing the chance for potential efficacy, based on observations to date of responses being most 
associated with reaching the target therapeutic window for serum phosphate (5.5 - 7mg/dL). 
Selective dose up-titration to 9 mg for optimization of the pharmacodynamic effect based on 
individual tolerance in subjects is likely to increase the potential for clinical activity without 
significantly increasing dose interruptions or toxicity.
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.
All participating subjects will receive full supportive care and will be followed closely for safety and 
efficacy throughout the trial, as outlined in the Time and Events Schedules.
The total blood volume to be collected is considered to be within the normal range allowed for this 
adult subject population over this time frame.21
16.2.
Regulatory Ethics Compliance
16.2.1.
Investigator Responsibilities
The investigator is responsible for ensuring that the study is performed in accordance with the 
protocol, current International Conference on Harmonisation (ICH) guidelines on Good Clinical 
Practice (GCP), and applicable regulatory and country-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.
16.2.2.
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)

Investigator's Brochure (or equivalent information) and amendments/addenda

Sponsor-approved subject recruiting materials

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
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), 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.
Approval for the collection of optional samples for research and for the corresponding ICF text 
must be obtained from the IEC/IRB.
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 Investigator's Brochure 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

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 

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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. The re-approval 
should be documented in writing (excluding the ones that are purely administrative, with no 
consequences for subjects, data, or study conduct).
At the end of the study, the investigator (or sponsor where required) will notify the IEC/IRB about 
the study completion. 
16.2.3.
Informed Consent
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.
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 they will receive. 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, including permission to 
obtain information about his or her survival status. agrees to allow his or her study physician to 
recontact the subject for the purpose of obtaining consent for additional safety evaluations, if 
needed, subsequent disease-related treatments, or to obtain information about his or her survival 
status.
Each 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 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 ICF if the rescreening occurs within 
30 days from the previous ICF signature date.

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Subjects will be asked for consent to provide optional samples for research where local regulations 
permit.
Where local regulations require, a separate ICF may be used for the required DNA component of 
the study.
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.
When prior consent of the subject is not possible (and the subject's legally acceptable 
representative is not available), enrollment procedures should be described in the protocol with 
documented approval/favorable opinion by the IEC/IRB to protect the rights, safety, and well-
being of the subject and to ensure compliance with applicable regulatory requirements. The subject
(or legally acceptable representative) must be informed about the study as soon as possible and 
give consent to continue.
In the event of re-introduction of study drug after drug has been withdrawn due to an adverse event 
requiring drug discontinuation, the investigator must demonstrate that re-introduction of study 
drug is in the best interest of the subject considering the terminal nature of the disease, and the 
drug may be re-introduced at a lower dose and/or intensity if the medical monitor is in agreement 
with this assessment. Prior to re-introduction, the investigator should obtain written permission 
from the study medical monitor and the IRB. The investigator should also have the subject re-
consent using the appropriate re-challenge ICF, explaining that re-introduction of study drug could 
lead to increased risk of recurrent toxicities or death. With appropriate re-consenting, the subject 
can be retreated with a 1- or 2-dose level reduction as appropriate, along with appropriate clinical 
follow-up as designated by the investigator. Subjects who are already being treated at the lowest 
dose level are not permitted to have re-introduction of study drug at this level. Also cross-over to 
a different dose regimen is not permitted.
16.2.4.
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.
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 

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monitoring, audit, IEC/IRB review, and regulatory inspection. This consent also addresses the 
transfer of the data to other entities and to other countries.
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 pharmacodynamics, biomarker, and pharmacokinetics 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.
16.2.5.
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 
differential drug responders, and to develop tests/assays related to erdafitinib. 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 research (refer to Section 10.3, Withdrawal from the Study).
16.2.6.
Country Selection
This study will only be conducted in those countries where the intent is to launch or otherwise help 
ensure access to the developed product, unless explicitly addressed as a specific ethical 
consideration in Section 16.1, Study-Specific Design Considerations.
16.2.7.
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 (LTMs), Clinical Trial Managers 
(CTMs), and/or Contract Research Organizations (CROs) who will ensure that the PCC 
explanations are followed by the investigators.
The PCC Document may be shared by the sites with Independent Ethics Committees/Institutional 
Review Boards (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.

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17.
ADMINISTRATIVE REQUIREMENTS
17.1.
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) involves only logistic or administrative aspects of the study, the IRB (and IEC where 
required) only needs to be notified.
During the course of 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 
(see Contact Information page(s) provided separately). 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 eCRF and source documents will reflect any 
departure from the protocol, and the source documents will describe this departure and the 
circumstances requiring it.
17.2.
Regulatory Documentation
17.2.1.
Regulatory Approval/Notification
This protocol and any amendment(s) must be submitted to the appropriate regulatory authorities 
in each respective country, if applicable. A study may not be initiated until all local regulatory 
requirements are met.
17.2.2.
Required Pre-study 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 

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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 (e.g., Form FDA 1572), if applicable

Documentation of investigator qualifications (e.g., 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 sub-investigators

Documentation of sub-investigator qualifications (e.g., 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

Local 
laboratory 
documentation 
demonstrating 
competence 
and 
test 
reliability 
(e.g., accreditation/license), if applicable.
17.2.3.
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 course of 
the study and for 1 year after completion of the study.
Refer to Required Prestudy Documentation in Section 17.2.2 and contracts for details on financial 
disclosure.
17.3.
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.
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 (subjects enrolled 
under the DDI substudy will not be randomized) into the study, the date seen and age at initial 
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The investigator must also complete a subject screening log, which reports on all subjects who 
were seen to determine eligibility for inclusion in the study.
Individuals who do not meet the criteria for participation in this study (screen failure) may be 
rescreened.
17.4.
Source Documentation
At a minimum, source documentation must be available for the following to confirm data collected 
in the eCRF: 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; 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. 
In addition, the author of an entry in the source documents should be identifiable.
At a minimum, the type and level of detail of source data available for a subject should be 
consistent with that commonly recorded at the study site as a basis for standard medical care. 
Specific details required as source data for the study 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 Inclusion Criteria and 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
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.
17.5.
Case Report Form Completion
Case report forms are provided for each subject in electronic format.
Electronic Data Capture will be used for this study. The study data will be transcribed by study-
site personnel from the source documents onto an electronic CRF, and transmitted in a secure 

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manner to the sponsor within the timeframe agreed upon between the sponsor and the study site. 
The electronic file will be considered to be the eCRF.
Worksheets may be used for the capture of some data to facilitate completion of the eCRF. Any 
such worksheets will become part of the subject's source documentation. All data relating to the 
study must be recorded in eCRFs prepared by the sponsor. Data must be entered into eCRFs in 
English. Study site personnel must complete the eCRF as soon as possible after a subject visit, and 
the forms should be available for review at the next scheduled monitoring visit.
All subjective measurements (e.g., pain scale information or other questionnaires) will be 
completed by the same individual who made the initial baseline determinations whenever possible.
All eCRF entries, corrections, and alterations must be made by the investigator or other authorized 
study-site personnel. The investigator must verify that all data entries in the CRF are accurate and 
correct.
If necessary, queries will be generated in the eDC tool. If corrections to an eCRF are needed after 
the initial entry into the eCRF, this can be done in 3 different ways:

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).

Study site manager can generate a query for resolution by the study-site personnel.

Clinical data manager can generate a query for resolution by the study-site personnel.
17.6.
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, and periodic monitoring visits by the sponsor. Written 
instructions will be provided for collection, handling, storage, and shipment of samples. 
Guidelines for eCRF completion will be provided and reviewed with study-site personnel before 
the start of the study. The sponsor will review eCRFs 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.
17.7.
Record Retention
In compliance with the ICH/GCP guidelines, the investigator/institution will maintain all eCRFs 
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.

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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.
17.8.
Monitoring
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 eCRFs with the hospital or clinic records (source 
documents). The nature and location of all source documents will be identified to ensure that all 
sources of original data required to complete the eCRF 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 documentation (medical records) must be allowed for the purpose of 
verifying that the data recorded in the CRF are consistent with the original source data. Findings 
from this review of CRFs and source documents 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 documentation 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.
17.9.
Study Completion/Termination
17.9.1.
Study Completion
The study is considered completed when all subjects have completed the study treatment or 12 
months after last subject is enrolled, whichever is later. The final data from the study site will be 
sent to the sponsor (or designee) after completion of the final subject follow-up survival 
assessment at that study site, in the time frame specified in the Clinical Trial Agreement.

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17.9.2.
Study Termination
The sponsor reserves the right to close the study site or terminate the study at any time for any 
reason at the sole discretion of the sponsor. 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
17.10. 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 and comparison with the eCRFs. 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 the subject has
been contacted by a regulatory agency concerning an upcoming inspection.
17.11. Use of Information and Publication
All information, including but not limited to information regarding erdafitinib or the sponsor's 
operations (e.g., 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 pharmacogenomic or exploratory 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 

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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. 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. Results of pharmacogenomic or exploratory 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 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.
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 the 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 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.

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Registration of Clinical Studies and Disclosure of Results
The sponsor will register and/or 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.

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http://www.ema.europa.eu/docs/en_GB/document_library/EPAR_-_Product_Information/human/000983/ 
WC500039604.pdf. Accessed on 29 October 2014.
24.
Roberts JT, von der Maase H, Sengelov L, et al. Long-term survival results of a randomized trial comparing 
gemcitabine/cisplatin and methotrexate/vinblastine/doxorubicin/cisplatin in patients with locally advanced and 
metastatic bladder cancer.  Ann Oncol. 2006; 17 (Suppl 5):v118-22.
25.
Rosell R, Carcereny E, Gervais R, et al. Erlotinib versus standard chemotherapy as first-line treatment for 
European patients with advanced EGFR mutation-positive non-small-cell lung cancer (EURTAC): a 
multicentre, open-label, randomised phase 3 trial. Lancet Oncol. 2012;13(3):239-46.
26.
Sequist LV, Cassier P, Varga A, et al. Phase I study of BGJ398, a selective pan-FGFR inhibitor in genetically 
preselected advanced solid tumors [Abstract CT326]. In: Proceedings of the 105th Annual Meeting of the 
American Association for Cancer Research; 08 Apr 2104; San Diego, CA. 
27.
Surveillance, Epidemiology, and End Results Program. SEER stat fact sheets: Bladder cancer. Available at: 
http://seer.cancer.gov/statfacts/html/urinb.html. Accessed on 30 June 2014.
28.
Sweeney CJ, Roth BJ, Kabbinavar FF, et al. Phase II study of pemetrexed for second-line treatment of 
transitional cell cancer of the urothelium. J Clin Oncol. 2006;24(21):3451-7.
29.
von der Maase H, Hansen SW, Roberts JT, et al. Gemcitabine and cisplatin versus methotrexate, vinblastine, 
doxorubicin, and cisplatin in advanced or metastatic bladder cancer: results of a large, randomized, 
multinational, multicenter, phase III study. J Clin Oncol. 2000:18(17):3068-77.
30.
von der Maase H, Sengelov L, Roberts JT, et al. Long-term survival results of a randomized trial comparing 
gemcitabine plus cisplatin, with methotrexate, vinblastine, doxorubicin, plus cisplatin in patients with bladder 
cancer. J Clin Oncol. 2005:23(21):4602.
31.
Williams SV, Hurst CD, Knowles MA. Oncogenic FGFR3 gene fusions in urothelial carcinoma. Human 
Molecular Genetics. 2013; 22:795-803. EDMS-ERI-58940056
32.
Witte RS, Elson P, Bono B, et al. Eastern Cooperative Oncology Group phase II trial of ifosfamide in the 
treatment of previously treated advanced urothelial carcinoma. J Clin Oncol. 1997;15(2):589-93.
33.
Zhao Y, Adjei AA. The clinical development of MEK inhibitors. Nat Rev Clin Oncol. 2014;11(7):385-400.
34.
Damrauer, J. S., et al. (2014). "Intrinsic subtypes of high-grade bladder cancer reflect the hallmarks of breast 
cancer biology." Proc Natl Acad Sci U S A 111(8): 3110-3115.
35.
Choi, W., et al. (2014). "Identification of distinct basal and luminal subtypes of muscle-invasive bladder cancer 
with different sensitivities to frontline chemotherapy." Cancer Cell 25(2): 152-165.

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Attachment 1: ECOG PERFORMANCE STATUS SCORES
Grade 
ECOG Performance Status Scores
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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Attachment 2: Cockcroft-Gault Formula For Estimated Creatinine Clearance (Crcl)
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 men and 1.04 for women
http://www.mdcalc.com/creatinine-clearance-cockcroft-gault-equation/

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Attachment 3: 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.
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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Attachment 4: Drugs Classified as Strong or Moderate In Vivo Inhibitors and Inducers of 
CYP3A4/2C9 Enzymes
Strong CYP3A4 Inhibitors
Boceprevir
Conivaptan
Clarithromycin
Indinavir
Grapefruit juice
Itraconazole
Lopinavir
Ketoconazole
Mibefradil
Ritonavir
Nefazodone
Nelfinavir
Posaconazole
Erythromycin
Saquinavir
Troleandomycin
Telaprevir
Telithromycin
Voriconazole
Fluconazole
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
Ataciguat
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/ucm093664 htm#4
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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Attachment 5: Amsler Grid 

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Attachment 6: RECIST GUIDELINES
Response Evaluation Criteria in Solid Tumors (RECIST) Version 1.1
The following information was extracted from Section 3, Section 4, and Appendix I of the New response evaluation 
criteria in solid tumours: revised RECIST guideline (version 1.1) authored by Eisenhauer et al (2009). Refer to the 
European Journal of Cancer article (2009;45(2):228-247) for the complete publication. 
Measurability of tumor at baseline
Definitions
At baseline, tumor lesions/lymph nodes will be categorized measurable or non-measurable as follows:
Measurable:
Tumor lesions:  Must be accurately measured in at least one dimension (longest diameter in the plane of measurement 
is to be recorded) with a minimum size of:

10 mm by CT scan (CT scan slice thickness no greater than 5 mm)

10 mm caliper measurement by clinical exam (lesions which cannot be accurately measured with calipers should 
be recorded as non-measurable)

20 mm by chest X-ray 

Lymph nodes to be considered pathologically enlarged and measurable. A lymph node must be ≥15 mm 
in the short axis when assessed by CT scan (CT scan slice thickness is recommended to be a maximum 
of 5 mm). At baseline and follow-up, only the short axis will be measured and followed.
Non-measurable:
All other lesions, including small lesions (longest diameter <10 mm or pathological lymph nodes with 10 to <15 mm 
short axis) as well as truly non-measurable lesions. Lesions considered truly non-measurable include: leptomeningeal 
disease, ascites, pleural or pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not measurable by reproducible 
imaging techniques.
Specifications by methods of measurements
The same method of assessment and the same technique should be used to characterize each identified and reported 
lesion at baseline and during follow-up. Imaging based evaluation should always be done rather than clinical 
examination unless the lesion(s) being followed cannot be imaged but are assessable by clinical exam. 
Clinical lesions:  Clinical lesions will only be considered measurable when they are superficial and 10 mm diameter 
as assessed using calipers (e.g. skin nodules). For the case of skin lesions, documentation by color photography 
including a ruler to estimate the size of the lesion is suggested. As noted above, when lesions can be evaluated by both 
clinical exam and imaging, imaging evaluation should be undertaken since it is more objective and may also be 
reviewed at the end of the study. 
Chest X-ray:  Chest CT is preferred over chest X-ray, particularly when progression is an important endpoint, since 
CT is more sensitive than X-ray, particularly in identifying new lesions. However, lesions on chest X-ray may be 
considered measurable if they are clearly defined and surrounded by aerated lung. See Appendix II for more details. 
CT, MRI:  CT is the best currently available and reproducible method to measure lesions selected for response 
assessment. This guideline has defined measurability of lesions on CT scan based on the assumption that CT slice 
thickness is 5 mm or less. As is described in Appendix II, when CT scans have slice thickness greater than 5 mm, the 
minimum size for a measurable lesion should be twice the slice thickness. MRI is also acceptable in certain situations 
(e.g. for body scans). More details concerning the use of both CT and MRI for assessment of objective tumor response 
evaluation are provided in Appendix II. 

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Ultrasound:  Ultrasound is not useful in assessment of lesion size and should not be used as a method of measurement. 
Ultrasound examinations cannot be reproduced in their entirety for independent review at a later date and, because 
they are operator dependent, it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next. If new lesions are identified by ultrasound in the course of the study, confirmation by CT 
or MRI is advised. If there is concern about radiation exposure at CT, MRI may be used instead of CT in selected 
instances. 
Endoscopy, laparoscopy:  The utilization of these techniques for objective tumor evaluation is not advised. However, 
they can be useful to confirm complete pathological response when biopsies are obtained or to determine relapse in 
trials where recurrence following complete response or surgical resection is an endpoint. 
Tumor markers:  Tumor markers alone cannot be used to assess objective tumor response. If markers are initially 
above the upper normal limit, however, they must normalize for a patient to be considered in complete response (CR). 
Cytology, histology:  These techniques can be used to differentiate between PR and CR in rare cases if required by 
protocol (for example, residual lesions in tumor types such as germ cell tumors, where known residual benign tumors 
can remain). When effusions are known to be a potential adverse effect of treatment (e.g. with certain taxane 
compounds or angiogenesis inhibitors), the cytological confirmation of the neoplastic origin of any effusion that 
appears or worsens during treatment can be considered if the measurable tumor has met criteria for response or stable 
disease in order to differentiate between response (or stable disease) and progressive disease.
Tumor response evaluation
Assessment of overall tumor burden and measurable disease
To assess objective response or future progression, it is necessary to estimate the overall tumor burden at baseline
and use this as a comparator for subsequent measurements. Measurable disease is defined by the presence of at least 
one measurable lesion 
Baseline documentation of ‘target’ and ‘non-target’ lesions
When more than one measurable lesion is present at baseline all lesions up to a maximum of five lesions total (and a 
maximum of two lesions per organ) representative of all involved organs should be identified as target lesions and 
will be recorded and measured at baseline. 
Target lesions should be selected on the basis of their size (lesions with the longest diameter), be representative of all 
involved organs, but in addition should be those that lend themselves to reproducible repeated measurements. It may 
be the case that, on occasion, the largest lesion does not lend itself to reproducible measurement in which circumstance 
the next largest lesion, which can be measured reproducibly, should be selected. 
A sum of the diameters (longest for non-nodal lesions,) for all target lesions will be calculated and reported as the 
baseline sum diameters. The baseline sum diameters will be used as reference to further characterize any objective 
tumor regression in the measurable dimension of the disease. 
All other lesions (or sites of disease) should be identified as non-target lesions and should also be recorded at baseline. 
Measurements are not required and these lesions should be followed as ‘present’, ‘absent’, or in rare cases 
‘unequivocal progression. In addition, it is possible to record multiple nontarget lesions involving the same organ as 
a single item on the case record form (e.g. ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’). 
Response criteria
This section provides the definitions of the criteria used to determine objective tumour response for target lesions.
Evaluation of target lesions
Complete Response (CR):  Disappearance of all target lesions. 
Partial Response (PR):  At least a 30% decrease in the sum of diameters of target lesions, taking as reference the 
baseline sum diameters.

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Progressive Disease:  At least a 20% increase in the sum of diameters of target lesions, taking as reference the smallest 
sum on study (this includes the baseline sum if that is the smallest on study). In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm. (Note:  the appearance of one or more new 
lesions is also considered progression). 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient increase to qualify for progressive 
disease, taking as reference the smallest sum diameters while on study.
Evaluation of non-target lesions
Complete Response (CR):  Disappearance of all non-target lesions and normalization of tumor marker level. 
Non-CR/Non-progressive disease:  Persistence of one or more non-target lesion(s) and/or maintenance of tumor 
marker level above the normal limits. 
Progressive Disease:  Unequivocal progression of existing non-target lesions. (Note:  the appearance of one or more 
new lesions is also considered progression).
Evaluation of best overall response
The best overall response is the best response recorded from the start of the study treatment until the end of treatment 
taking into account any requirement for confirmation. On occasion a response may not be documented until after the 
end of therapy so protocols should be clear if post-treatment assessments are to be considered in determination of best 
overall response. The patient’s best overall response assignment will depend on the findings of both target and non-
target disease and will also take into consideration the appearance of new lesions. 
Timepoint response
It is assumed that at each protocol specified timepoint, a response assessment occurs. Table 22 on the next page 
provides a summary of the overall response status calculation at each timepoint for patients who have measurable 
disease at baseline. 
When patients have non-measurable (therefore non-target) disease only, Table 23 is to be used. 
Best overall response:  all timepoints
The best overall response is determined once all the data for the patient is known. 
Best response determination in trials where confirmation of complete or partial response IS NOT required:  Best 
response in these trials is defined as the best response across all timepoints (for example, a patient who has SD at first 
assessment, PR at second assessment, and progressive disease on last assessment has a best overall response of PR). 
When SD is believed to be best response, it must also meet the protocol specified minimum time from baseline. If the 
minimum time is not met when SD is otherwise the best timepoint response, the patient’s best response depends on 
the subsequent assessments. For example, a patient who has SD at first assessment, progressive disease at second and 
does not meet minimum duration for SD, will have a best response of progressive disease. The same patient lost to 
follow-up after the first SD assessment would be considered inevaluable.
Table 22:
Timepoint response:  patients with Target (+/- non-target) disease
Target lesions
Non-target lesions
New lesions
Overall response
CR
CR
No
CR
CR
Non-CR/non-PD
No
PR
CR
Not evaluated
No
PR
PR
Non-PD or not all evaluated
No
PR
SD
Non-PD or not all evaluated
No
SD
Not all evaluated
Non-PD
No
NE
PD
Any
Yes or No
PD
Any
PD
Yes or No
PD
Any
Any
Yes
PD
CR = complete response; PR = partial response; SD = stable disease; PD = progressive disease; NE = inevaluable.

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Table 23:
Timepoint response:  patients with non-target disease only
Non-target lesions
New lesions
Overall response
CR
No
CR
Non-CR/non-PD
No
Non-CR/non-PDa
Not all evaluated
No
NE
Unequivocal PD
Yes or No
PD
Any
Yes
PD
CR = complete response; PD = progressive disease; NE = inevaluable.
a Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly used as endpoint for 
assessment of efficacy in some trials so to assign this category when no lesions can be measured is not advised.
Patients with a global deterioration of health status requiring discontinuation of treatment without objective evidence 
of disease progression at that time should be reported as ‘symptomatic deterioration’. Every effort should be made to 
document objective progression even after discontinuation of treatment. Symptomatic deterioration is not a descriptor 
of an objective response:  it is a reason for stopping study therapy. The objective response status of such patients is to 
be determined by evaluation of target and non-target disease as shown in Table 22 and Table 23.
Conditions that define ‘early progression, early death and inevaluability’ are study specific and should be clearly 
described in each protocol (depending on treatment duration, treatment periodicity). 
In some circumstances it may be difficult to distinguish residual disease from normal tissue. When the evaluation of 
complete response depends upon this determination, it is recommended that the residual lesion be investigated (fine 
needle aspirate/biopsy) before assigning a status of complete response. FDG-PET may be used to upgrade a response 
to a CR in a manner similar to a biopsy in cases where a residual radiographic abnormality is thought to represent 
fibrosis or scarring. The use of FDG-PET in this circumstance should be prospectively described in the protocol and 
supported by disease specific medical literature for the indication. However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy resolution/ sensitivity. 
For equivocal findings of progression (e.g. very small and uncertain new lesions; cystic changes or necrosis in existing 
lesions), treatment may continue until the next scheduled assessment. If at the next scheduled assessment, progression 
is confirmed, the date of progression should be the earlier date when progression was suspected.
Duration of overall response 
The duration of overall response is measured from the time measurement criteria are first met for CR/PR (whichever 
is first recorded) until the first date that recurrent or progressive disease is objectively documented (taking as reference 
for progressive disease the smallest measurements recorded on study). 
The duration of overall complete response is measured from the time measurement criteria are first met for CR until 
the first date that recurrent disease is objectively documented. 
Duration of stable disease 
Stable disease is measured from the start of the treatment (in randomised trials, from date of randomisation) until the 
criteria for progression are met, taking as reference the smallest sum on study (if the baseline sum is the smallest, this 
is the reference for calculation of progressive disease). 
The clinical relevance of the duration of stable disease varies in different studies and diseases. If the proportion of 
patients achieving stable disease for a minimum period of time is an endpoint of importance in a particular trial, the 
protocol should specify the minimal time interval required between two measurements for determination of stable 
disease. 

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Summary of major changes RECIST 1.0 to RECIST 1.1a
RECIST 1.0
RECIST 1.1
Rationale
Minimum size 
measurable lesions
CT:  10 mm spiral;
20 mm non-spiral
CT 10 mm; delete reference 
to spiral scan
Most scans used have 5 mm or less 
slice thickness Clearer to give 
instruction based on slice interval if 
it is greater than 5 mm
Clinical: 20 mm
Clinical:  10 mm (must be 
measurable with calipers)
Caliper measurement will make this 
reliable.
Lymph node:  not 
mentioned
CT:
15 mm short axis for target
10 - <15 mm for non-target
<10 mm is non-pathological
Since nodes are normal structure 
need to define pathological 
enlargement. Short axis is most 
sensitive.
Special considerations 
on lesion measurability
-
Notes included on bone 
lesions, cystic lesions
Clarify frequently asked questions.
Overall tumour burden
10 lesions (5 per 
organ)
5 lesions (2 per organ)
Data warehouse analysis shows no 
loss of information if lesion number 
reduced from 10 to 5. A maximum 
of 2 lesions per organ yields 
sufficient representation per disease 
site.
Response criteria 
target disease
CR lymph node 
not mentioned
CR lymph nodes must be 
<10 mm short axis
In keeping with normal size of 
nodes.
PD 20% increase 
over smallest sum 
on study or new 
lesions
PD 20% increase over 
smallest sum on study 
(including baseline if that is 
smallest) and at least 5 mm 
increase or new lesions
Clarification that if baseline 
measurement is smaller than any on 
study measurement, it is reference 
against which PD is assessed 5 mm 
absolute increase to guard against 
over calling PD when total sum is 
very small and 20% increase is 
within measurement error.
Response criteria 
non-target disease
‘unequivocal 
progression’ 
considered as PD
More detailed description of 
‘unequivocal progression’ to 
indicate that it should not 
normally trump target disease 
status. It must be 
representative of overall 
disease status change, not a 
single lesion increase
Confusion with RECIST 1.0 where 
some were considering PD if 
‘increase’ in any non-target lesion, 
even when target disease is stable or 
responding.
New lesions
New section on New lesions
To provide guidance on when a 
lesion is considered new (and thus 
PD).
Overall response
Table integrated 
target and non-
target lesions
Two tables:  one integrating 
target and non-target and the 
other of non-target only  
To account for the fact that RECIST 
criteria are now being used in trials 
where PFS is the endpoint and not 
all patients have measurable (target) 
disease at baseline.
Special notes:
How to assess and measure 
lymph nodes;
CR in face of residual tissue;
Discussion of  ‘equivocal’ 
progression
Frequently asked questions on these 
topics.

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Summary of major changes RECIST 1.0 to RECIST 1.1a (Continued)
RECIST 1.0
RECIST 1.1
Rationale
Confirmatory measure
For CR and PR:  
criteria must be 
met again 4 weeks 
after initial 
documentation
Retain this requirement 
ONLY for non-randomised 
trials with primary endpoint 
of response
Data warehouse shows that response 
rates rise when confirmation is 
eliminated, but the only 
circumstance where this is important 
is in trials where there is no 
concurrent comparative control and 
where this measure is the primary 
endpoint.
Progression-free 
survival
General comments 
only
More specific comments on 
use of PFS (or proportion 
progression-free) as phase II 
endpoint. 
Greater detail on PFS 
assessment in phase III trials
Increasing use of PFS in phase III 
trials requires guidance on 
assessment of PD in patients with 
non-measurable disease
Reporting of response 
results
9 categories 
suggested for 
reporting phase II 
results
Divided into phase II and 
phase III;  
9 categories collapsed into 5;
In phase III, guidance given 
about reporting response
Simplifies reporting and clarifies 
how to report phase II and III data 
consistently. 
Response in phase III 
trials
More relaxed 
guidelines possible 
if protocol 
specified
This section removed and 
referenced in section above:  
no need to have different 
criteria for phase II and III
Simplification of response 
assessment by reducing number of 
lesions and eliminating need for 
confirmation in randomized studies 
where response is not the primary 
endpoint makes separate ‘rules’ 
unnecessary.
Imaging appendix
Appendix I
Appendix II:  updated with 
detailed guidance on use of 
MRI, PET/CT. 
Other practical guidance 
included
Evolving use of newer modalities 
addressed. Enhanced guidance in 
response to frequent questions and 
from radiology review experience.
New appendices
Appendix I:  comparison of 
RECIST 1.0 and 1.1; 
Appendix III:  frequently 
asked questions
PD = progressive disease
a See publication for references applicable to this table.

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CCI

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Attachment 9: Statistical Methods Sections Made Obsolete by Amendment 3
Section 11.1, Sample Size Determination
Approximately 165 subjects with select FGFR genetic alterations may be enrolled in the study on 
treatment Regimen 1 or 2. There are 2 planned interim analyses (IA1 and IA2), which will be 
performed for safety, futility, and dose selection. Approximately 110 subjects will be treated at the 
selected dose regimen and up to 55 subjects may be treated at the dropped dose regimen.   
After a total of 110 subjects are treated at the selected dose regimen, enrollment will be stopped if 
at least 80 chemo-refractory subjects have been treated at the selected dose regimen. However, if 
the number of chemo-refractory subjects treated at the selected dose regimen is less than 80, then 
the enrollment will change as follows:
1) Enrollment of chemo-naïve subjects will be stopped.
2) Enrollment of chemo-refractory subjects may continue until a total of 80 chemo-refractory 
subjects are treated. 
Enrollment of at least 80 chemo-refractory subjects will provide at least 79% power to reject the 
null hypothesis within the chemo-refractory subgroup under the above assumptions.  
At IA1, a sample size of at least 20 response-evaluable subjects per treatment regimen will have 
at least an 80% probability of selecting the preferred dose regimen, assuming the following: 1) the 
true response rates of one or both regimens is at least 10%; 2) the preferred dose has at least a 30% 
higher response rate than the other dose; and 3) the dose selection criteria as specified in 
Section 11.8 are followed.  
If both dose regimens are continued until IA2, a sample size of at least 40 response-evaluable 
subjects will be enrolled in each regimen and will have at least an 80% probability of selecting the 
preferred dose regimen if 1 dose regimen has at least a 15% greater response rate than the other 
regimen and both dose regimens have at least a 20% response rate.  
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The statistical technical details are described in Attachment 7.
Subjects will be randomly assigned to treatment Regimen 1 or 2. Covariate-adaptive 
randomization will be used to allocate subjects between Regimen 1 and Regimen 2 until a 
favorable dose is selected. Randomization will be stratified according to ECOG performance status 
(0-1 versus 2), hemoglobin level (<10 g/dL versus ≥10 g/dL), FGFR alteration type (translocation 
versus mutation), pretreatment status (chemo-refractory versus chemo-naive), and disease 
distribution (presence or absence of visceral metastases: lung, liver, and bone). Randomization 
will continue until a favorable dose regimen is selected (up to a maximum of 110 subjects total). 
Section 11.7, Interim Analysis
There will be 2 planned interim analyses (IA1 and IA2), which will be performed for safety, 
futility, and dose regimen selection.
The interim safety analyses will be based on the Treated Population (as defined in Section 11.2). 
The interim analyses for futility and the efficacy portion of dose regimen selection will be based 
on the RE population (as defined in Section 11.2).
In IA1 and IA2, subjects with unconfirmed response (CR or PR) will be considered responders for 
futility and dose selection only. However, subjects who have initially demonstrated a CR or PR 
but on subsequent evaluation have shown PD will not be considered responders. Response will be 
assessed by the investigators. The Sponsor’s Data Review Committee (DRC) will be conducting 
the interim analyses.
The interim futility boundary will be derived using East® software version 5.3 to control the 
1-sided Type-2 error of 0.14. The Type-2 error spending function is from Rho family with 
parameter of 1.8. Enrollment may be stopped if the pre-specified futility boundary is crossed. 
However, enrollment will not be stopped for efficacy at these interim analyses (IA1 and IA2). 
The interim futility boundaries at IA1 and IA2 are listed in Table 27 below. 
Table 27: 
Interim Futility Boundaries
N
(number of subjects in the 
response-evaluable population)
Declare futility if the number of 
responders is less than or equal to 
(≤)
20 – 22
3
23 – 25
4
40 – 41
10
42 – 43
11
44 – 45
12
IA1 will be conducted after at least 20 subjects have been treated per dose regimen and are 
considered evaluable. The enrollment may continue until 30 subjects per dose regimen have been 

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treated. The enrollment will be held pending the outcome of the interim analysis, unless the 
decision is already clear based on available data prior to the interim analysis. 
IA2 will be conducted after at least 40 subjects have been treated per dose regimen and considered 
evaluable (if both dose regimens continue at IA1) or in the selected dose regimen only. The 
enrollment may continue until 55 subjects have been treated per dose regimen. The enrollment will 
be held pending the decision of the interim analysis unless the decision is already clear based on 
available data before the interim analysis.  
Section 11.8, Dose Selection Criteria
The Sponsor’s DRC will make dose selection decisions, taking into consideration elements of 
safety, tolerability, and efficacy. Safety and tolerability of each dose regimen will be assessed by 
consideration of the following (including but not limited to): overall and Grade 3 or higher adverse 
events, any and Grade 3 or higher drug-related adverse events, any and drug-related serious 
adverse events, adverse events leading to treatment interruption, dose reduction or treatment 
discontinuation, percent of planned dose administered, overall tolerability, and mean exposure. 
If a dosing regimen is deemed unsafe or intolerable by the DRC, further enrollment into that dosing 
regimen will be discontinued, and that dose regimen will not be considered for further dose 
regimen selection. 
1. If only 1 dose regimen is safe and tolerable, that dose regimen will be evaluated by efficacy 
parameters (including, but not limited to, response rate, PFS, and overall survival) to decide if the 
enrollment into that dose regimen should continue.  
2. If both dose regimens are considered to be safe and tolerable, then further evaluation will be 
made based on efficacy parameters (including, but not limited to, response rate, PFS, and overall 
survival). The guidelines for dose selection based on response rate alone are outlined in the study 
. 
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Attachment 10: 
Statistical Methods Sections Made Obsolete by Amendment 3

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Attachment 11: 
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 

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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.

Consenting of subjects for full study screening will be performed as applicable (including 
also remote consenting by telephone or video consultation) according to local guidance for 
the informed consent. (Remote consenting for molecular eligibility screening is described 
in the DDI substudy attachment.)
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. 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 ESMO 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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Attachment 12: 
Drug-drug Interaction Substudy
Drug-drug Interaction Substudy to Assess the Effect of Repeated Doses of 
Erdafitinib on the Single-dose Pharmacokinetics of Midazolam and Metformin 
in Subjects with Advanced Solid Tumors that Harbor Target FGFR Mutations 
or FGFR Gene Fusions at Selected Sites

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DRUG-DRUG INTERACTION (DDI) SUBSTUDY SUMMARY
This drug-drug interaction (DDI) substudy will assess the effect of repeated doses of erdafitinib 
on the single-dose pharmacokinetics (PK) of midazolam and metformin in subjects with advanced 
solid tumors including those with metastatic or surgically unresectable urothelial cancer that 
harbor target fibroblast growth factor receptor (FGFR) mutations or FGFR gene fusions. This 
substudy is designed to fulfill the Food and Drug Administration (FDA) post-marketing 
requirement to evaluate the interaction of repeated doses of erdafitinib with a sensitive cytochrome 
450 (CYP) 3A substrate, as well as the post-marketing commitment to evaluate the interaction of 
repeated doses of erdafitinib with an organic cation transporter 2 (OCT2) probe substrate.
The DDI substudy is described in this attachment, as well as continued treatment with erdafitinib 
until disease progression or unacceptable toxicity. The Time and Events Schedule for subjects 
enrolled at the time of the DDI substudy are provided in this attachment (DDI Table 28), as well 
as the Time and Events Schedule for subjects in the DDI Substudy Long-Term Extension (LTE) 
Phase (DDI Table 29, Section 9.1.5), with reference to the main study protocol for specific 
additional information.  
Detailed introductory information regarding erdafitinib (nonclinical pharmacology, PK, and 
clinical experienced) is provided in the Main Protocol Section 1. 

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Blood (plasma) for ctDNA
See Main Protocol, Section 9.3.2.
X
C2D1, C5D1
X
β-hCG=beta-human chorionic gonadotropin; C=cycle; ctDNA=circulating tumor DNA; CXDX=Cycle X Day X; D=day; DDI=drug-drug interaction; ECG=electrocardiogram; ECOG=Eastern Cooperative 
Oncology Group; EoT=End of Treatment; FGFR=fibroblast growth factor receptor; ICF=informed consent form; LTE=long-term extension; PK=pharmacokinetic; SoA=Schedule of Activities;  
a Guidance for study conduct for ongoing subjects in the event of a national disaster is provided in Attachment 11.
b Subjects who re-consent to LTE Phase will not be required to complete EoT visit.

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DEFINITION OF PHARMACOKINETIC PARAMETERS
The definition of the PK parameters is as follows: 
Cmax
maximum observed analyte concentration
Ctrough
observed analyte concentration just prior to the beginning or at the end of 
a dosing interval
tmax
the actual sampling time to reach the maximum observed analyte 
concentration
AUClast
area under the analyte concentration versus time curve (AUC) from time 0 
to the time of the last measurable (non-below quantification limit [BQL]) 
analyte concentration
AUC∞
AUC from time 0 to infinite time
λz
apparent terminal elimination rate constant, estimated by linear regression 
using the terminal log-linear phase of the log-transformed concentration 
versus time curve
t1/2term
apparent terminal elimination half-life
CL/F
total apparent clearance
Ratio Cmax, 
metabolite /parent
ratio of individual Cmax values between metabolite and parent 
Ratio AUClast, 
metabolite/ parent
ratio of individual AUClast values between metabolite and parent 
Ratio AUC∞, 
metabolite/ parent
ratio of individual AUC∞values between metabolite and parent 
Ratio Cmax, 
test/reference
ratio of individual Cmax values between test and reference treatment
Ratio AUClast, 
test/reference
ratio of individual AUClast values between test and reference treatment
Ratio AUC∞, 
test/reference
ratio of individual AUC∞values between test and reference treatment

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1.
INTRODUCTION 
1.1.
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 (NSCLC), 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 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 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. The
observed median time to maximum concentration (tmax) 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.
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.
 
 
The most frequently reported treatment-emergent adverse events 
(TEAEs) were hyperphosphatemia (65%), dry mouth (46%), asthenia (45%), stomatitis (39%), 
constipation (37%), and decreased appetite (34%). 
In Study BLC2001 (n=210, based on the primary analysis), the antitumor effect of erdafitinib was 
further demonstrated in subjects with relapsed/refractory advanced urothelial cancer with defined 
FGFR mutations and gene fusions. 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 
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of response was 5.4 months. The most frequently reported adverse events were hyperphosphatemia 
(76%), stomatitis (56%), diarrhea (47%), and dry mouth (45%). The follow-up efficacy analysis 
(cut-off date of 09 August 2019) was consistent with the primary analysis, ie, the time-to-event 
outcomes such as median DOR (5.98 months), median PFS (5.52 months) and median overall 
survival (11.30 months) indicate that the efficacy outcomes overall were robust.
For the most comprehensive nonclinical and clinical information regarding erdafitinib, refer to the 
latest version of the Erdafitinib Investigator’s Brochure.
1.2.
Substudy Rationale
The purpose of this DDI substudy is to evaluate the potential inhibition or induction effects of 
erdafitinib on the CYP3A-mediated metabolism of the probe drug midazolam and the potential 
inhibition effect on the OCT2-mediated transport of the probe drug metformin as discussed in the 
following section. 
The DDI substudy expands the population to patients with advanced or metastatic solid tumors 
who have exhausted standard-of-care options. As described in the introduction above, these 
patients have a dismal prognosis and a high unmet medical need for new therapies. The rationale 
for the use of erdafitinib as treatment for patients with metastatic urothelial carcinoma provided in 
the Main Protocol (Section 3.1.1) provides support, along with data from early evaluation of 
erdafitinib as treatment for advanced solid tumors discussed in this section, for the expansion of 
the DDI substudy population to those with advanced solid tumors. 
 
 
 
 
 
 
 
 
 
Erdafitinib is a treatment for cancer patients, a population that frequently requires concomitant 
medications. Time-dependent inhibition of CYP3A-mediated metabolism by erdafitinib can lead
to a decreased rate of elimination of concomitantly administered drugs resulting in an increased 
systemic exposure and possible toxicity. Also, induction of CYP3A-mediated metabolism by 
erdafitinib can lead to an increased rate of elimination of concomitantly administered drugs 
resulting in a decreased systemic exposure and possible loss of efficacy. An increased systemic 
exposure is also possible if in vivo inhibition of OCT2-mediated drug transport by erdafitinib is 
significant. Currently, there is no existing data on the in vivo effect of erdafitinib on CYP3A 
enzyme and OCT2 transporter.
The rationale for the use of erdafitinib in FGFR-eligible subjects with metastatic or surgically 
unresectable urothelial cancer (one of the tumor types in the DDI substudy), as well as background 
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detail for the earlier Phase 2 dose selection of erdafitinib, is provided in the Main Protocol 
(Section 3).  
1.3.
Study Purpose 
As previously mentioned, the purpose of this DDI substudy is to evaluate the potential inhibition 
or induction effects of erdafitinib on the CYP3A-mediated metabolism of the probe drug 
midazolam and the potential inhibition effect on the OCT2-mediated transport of the probe drug 
metformin. In addition, this substudy will ensure characterization of the maximal erdafitinib-
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To ensure characterization of the maximal erdafitinib-mediated effect of CYP3A and OCT2, the 
DDI test will be conducted after erdafitinib reaches steady-state. Due to the potential tolerability 
issue of administering multiple doses of erdafitinib to healthy subjects, the study will be conducted 
in FGFR-eligible subjects, who will be administered single doses of midazolam and metformin 
before initiating continuous daily dosing of erdafitinib. Once erdafitinib reaches steady-state after 
approximately 2 weeks, subjects will receive an additional single dose of midazolam and 
metformin concomitantly with erdafitinib.
In order to more efficiently characterize the potential for in vivo drug interactions in cancer 
subjects, midazolam and metformin will be administered as single doses to the same group of 
subjects. Considering the non-overlapping metabolism and disposition pathway of midazolam and 
metformin, there is no theoretical basis for an interaction between these 2 drugs. To avoid the 
chance of an unexpected interaction, midazolam and metformin will be dosed on 2 consecutive 
days. Compared with the administration of individual probe drugs in separate studies, 
administration of multiple probe drugs in the same group of subjects offers the advantage of 
reduced study complexity and duration, an important consideration when having to conduct the 
DDI substudy in cancer subjects with genetic alterations.
Overview of Probe Drugs
Midazolam
Midazolam is a short-acting benzodiazepine commonly used as an anxiolytic and 
sedative/hypnotic before procedures. Midazolam is commercially available as solution for oral 
administration. Time to onset of effect is most frequently reported as 10 to 20 minutes.  Midazolam 
is extensively metabolized by CYP3A to 1’-hydroxymidazolam in the liver and intestine and is 
widely used as a sensitive CYP3A probe drug for evaluating the effect of an inhibitor or inducer 
on CYP3A activity in vivo. Following a single oral dose, peak midazolam concentrations are 
achieved at 0.5 to 1 hour. The Cmax values are reported to average 10 and 24 ng/mL following a 
single oral dose of 2 and 5 mg, respectively. The elimination half-life values of midazolam have 
been reported to range from 2.1 to 3.7 hours. The extent of plasma protein binding of midazolam 
is moderately high and concentration-independent. In adults, midazolam is approximately 97% 
bound to plasma protein, principally to albumin. Midazolam is a Biopharmaceutics Classification 
System Class 1 Drug with high solubility and high permeability. Comparable bioavailability and 
oral absorption are expected for the different formulations of this drug. For more detailed 
information, refer to the package insert for oral midazolam (as available on the local market).
Metformin
Metformin is a biguanide antihyperglycemic agent that improves glycemic control by decreasing 
hepatic glucose production, decreasing glucose absorption, and increasing insulin-mediated 
glucose uptake. Metformin is commercially available as tablet for oral administration. Metformin
is transported by the organic cation transporters OCT1 and OCT2. The uptake of metformin in the 
liver, which is the primary target of metformin, is mediated primarily by OCT1. Studies in healthy 
volunteers suggest that human multidrug and toxin extrusion 1 (MATE1) and MATE2-K also 
contribute to the renal excretion of metformin.

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Metformin is excreted unchanged in the urine and does not undergo hepatic metabolism (no 
metabolites have been identified in humans) nor biliary excretion. Following oral administration, 
approximately 90% of the absorbed drug is eliminated via the renal route within the first 24 hours, 
with a plasma elimination half-life of approximately 6.2 hours.
1.5.
Background
In the US, 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. The label also notes that patients are selected for therapy based on an 
FDA-approved companion diagnostic, ie, the QIAGEN therascreen® FGFR RGQ RT PCR Kit 
that was also approved by the Agency on 12 April 2019. Detailed information regarding 
erdafitinib, as well as the role of FGFR and FGFR alterations in solid tumors is provided in this 
section
1.6.
Dose Selection Rationale for Probe Drugs
Midazolam
Oral doses used for midazolam in DDI studies in human subjects range from 2 to 10 mg. A 2 mg 
oral dose of midazolam given in combination with ketoconazole, a strong CYP3A inhibitor, has 
been reported to be safe and tolerated in healthy subjects, despite increases in midazolam AUC 
and Cmax of approximately 16- and 5-fold, respectively. 
 
 
 
 
 
 
 
 
 
 
Metformin
Oral doses used for metformin in DDI studies in human subjects range from 250 to 2,000 mg. In 
a DDI study, co-administration of a 1,000 mg single oral dose of metformin with vandetanib in 
subjects wild-type for OCT2 has been reported to be safe and tolerated in healthy subjects, with a 
74% increase in AUCinf and a 50% increase in Cmax. This magnitude of increase in metformin 
systemic exposure is consistent with the reported impact on metformin exposure known 
prototypical OCT2 inhibitors (such as cimetidine). 
 
 
 
 
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Upon meeting the eligibility criteria and enrollment, subjects will receive pretreatment with single 
doses of midazolam (Day -2) and metformin (Day -1). Treatment with 8 mg erdafitinib daily begins 
on Day 1, while single doses of midazolam (Day 13) and metformin (Day 14) will be administered 
after erdafitinib has reached steady state. Pharmacokinetic samples are collected around the times 
of the first (Days -2, -1, and 1) and second (Day 13, 14, and 15) administration of probe drugs. 
The conduct of the DDI Treatment Phase including the collection of PK samples is discussed 
further in Section 9.2.
Upon completion of the DDI Treatment Phase on Day 15, erdafitinib treatment will continue until 
disease progression, or until any of the other conditions listed in Section 10.2 are met such as 
unacceptable toxicity and refusal of further treatment. On Day 15, erdafitinib may be uptitrated to 
9 mg erdafitinib daily based on Day 14 serum phosphate levels as described in Section 6. Safety 
assessments will be based on medical review of adverse event reports and the results of vital sign 
measurements, ECGs, physical examinations, clinical laboratory tests, and ophthalmologic 
examinations conducted as described in the Time and Events Schedule. Further detail regarding 
safety evaluations is provided in Section 9.3). Radiological assessments are done for the purpose 
of identification of disease progression (Section 9.5).
 
 
 
Guidance for study conduct for ongoing subjects in the event of a national disaster is provided in 
Attachment 11.
The DDI portion of this study will be reported separately from the Main Study, as well as the safety 
data and biomarker data for subjects who are enrolled under the DDI substudy.
Following approval of Protocol Amendment 9, once the end of study data collection timepoint has 
been achieved, subjects who continue to benefit from study treatment, as determined by their 
investigator, may continue to receive access to study treatment as described in DDI Section 9.1.5.
4.
SUBJECT POPULATION
The inclusion and exclusion criteria for subjects enrolled in the DDI substudy are provided in the 
following 2 subsections. If there is a question about the eligibility criteria below, the investigator 
should consult with the appropriate sponsor representative before enrolling a subject in the study.
(Do NOT use the inclusion and exclusion criteria in the main study.) 
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4.1.
Inclusion Criterion for the DDI Substudy
Potential subjects must meet all of the inclusion criteria to be eligible to participate in the study:
1.
18 years of age or older.
2.
Criterion modified per Amendment 8
2.1 Histologic demonstration of an unresectable, locally advanced, or metastatic solid 
tumor malignancy.
3.
Criterion modified per Amendment 8
3.1 Subject must have had documented disease progression after having received at least
one prior line of systemic therapy in the advanced, unresectable, or metastatic setting. 
Subject does not have standard of care options that have shown meaningful clinical 
benefit for the relevant underlying histology and line of therapy or the subject is unable 
to tolerate the therapy. Documented progression of disease is defined as any progression 
that requires a change in treatment, prior to full study screening.
4.
Criterion modified per Amendment 8
4.1 Subjects with target FGFR mutations (The List of Target FGFR Mutations is 
provided in DDI Table 31) or * FGFR gene fusions are eligible for enrollment in the 
substudy, as determined by local** screening.
* FGFR gene fusions: 

Have a report suggesting the presence of an intact FGFR kinase domain
o
FGFR fusion with a 3-prime partner (FGFR gene is listed first, 
eg, FGFR-GENE or FGFR3-TACC3):

The FGFR portion of the fusion must involve exon 17 or greater (≥17)
o
FGFR fusion with a 5-prime partner (Partner gene is listed first and FGFR gene 
is second, eg, GENE-FGFR or KLK2-FGFR2):

The FGFR portion of the fusion must involve less than or equal to exon 11 
(≤11)

Have a named FGFR fusion partner gene (rearrangements, eg, FGFR-FGFR, are 
not eligible)
FGFR gene identifiers, canonical transcript identifiers, and kinase domain positions are 
provided below for reference.
Gene
Ensembl ID
RefSeqID
mRNA
Kinase 
Domain AA 
Positionⱡ
Kinase 
Domain 
Exonsⱡ
FGFR1
ENST00000447712
NM_023110.3
478 → 754
Exons 11-17
FGFR2
ENST00000358487
NM_000141.5
481 → 757
Exons 11-17
FGFR3
ENST00000440486 
NM_000142.4
478 → 754
Exons 11-17
FGFR4
ENST00000292408
NM_002011.5
467 → 743
Exons 11-17
Pfam= Protein Families (database)

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ⱡKinase domains defined by Pfam annotations from NCBI Entrez Gene. Exons of the RefSeq 
transcript are inclusive of the kinase domain. Exon boundaries defining the kinase domain are 
equivalent to NM_015850.
**Locally performed or commercial testing results from tissue or blood with NGS tests, 
direct digital counting methods, or the Qiagen therascreen® FGFR RT-PCR test 
performed in Clinical Laboratory Improvement Amendments (CLIA)-certified or 
regional equivalent laboratories.
Mutations in this study are defined as protein-coding single nucleotide variant (SNV) 
and insertions or deletions (indels).
5.
ECOG performance status score 0, 1, or 2 (Attachment 1). 
6.
Criterion modified per Amendment 8
6.1 Adequate bone marrow, liver, and renal function as described below:

Bone marrow function (without the support of cytokines and/or erythropoiesis-
stimulating agent [ESA] in preceding 2 weeks):
-
Absolute neutrophil count (ANC) ≥1000/mm3
-
Platelet count >75,000/mm3
-
Hemoglobin ≥8.0 g/dL (without transfusion or demonstrate stability, ie, no 
significant decline in hemoglobin, for 2 weeks after transfusion).

Liver function:
-
Total bilirubin ≤1.5 x institutional upper limit of normal (ULN), unless know to 
have Gilbert’s disease, OR direct bilirubin ≤ULN for subjects with total bilirubin 
levels >1.5xULN.
-
Alanine aminotransferase (ALT) and aspartate aminotransferase (AST) ≤2.5 x 
institutional ULN or ≤5x institutional ULN for subjects with liver metastases 
(ALT and AST both ≤1.5xULN and alkaline phosphatase ≤2.5xULN).
-
Albumin ≥2.0 g/dL

Renal function: Creatinine clearance ≥60 mL/min either directly measured via 
24-hour urine collection or calculated using Cockcroft-Gault. (Attachment 2) 
7.
Criterion modified per Amendment 8
7.1 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:

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
user-independent 
methods: 
implantable 
progestogen-only 
hormone 
contraception associated with inhibition of ovulation; intrauterine device; 
intrauterine hormone-releasing system; tubal closure (eg, bilateral tubal 
occlusion, bilateral tubal ligation; 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

advised on egg preservation prior to entering the study
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 of study drug

not planning to father a child during the study or within 3 months after the last 
dose of study drug

advised on sperm banking prior to entering the study
8.
Negative pregnancy test (urine or serum beta human chorionic gonadotropin [β-hCG]) 
at Screening (ie, screening test within 7 days before treatment) for women of child-
bearing potential who are sexually active.
9.
Subject (or his/her legally acceptable representative) must sign the informed consent 
documents indicating that they understand the purpose of procedures required for the 
DDI substudy and continuation of treatment until disease progression and are willing to 
participate in the study.

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DDI Table 31:
List of Target Fibroblast Growth Factor Receptor (FGFR) Mutations  
Gene
Variant
Gene
Variant
Gene
Variant
Gene
Variant
FGFR1
K656E
FGFR2
C390YS
FGFR3
M528I
FGFR4
Y367C
FGFR1
R189C
FGFR2
E565G
FGFR3
K650T
FGFR1
S125L
FGFR2
E565Q
FGFR3
S371G
FGFR1
P150S
FGFR2
S252L
FGFR3
K650N
FGFR2
C382F
FGFR3
G380E
FGFR2
P253L
FGFR3
E627D
FGFR2
R251Q
FGFR3
Y373N
FGFR2
A389T
FGFR3
Y373H
FGFR2
S252P
FGFR3
D641N
FGFR2
R210Q
FGFR3
S249Y
FGFR2
S252T
FGFR3
A391V
FGFR2
R203H
FGFR3
S249F
FGFR2
S252A
FGFR3
S371R
FGFR2
S351C
FGFR3
R248H
FGFR2
Y340C
FGFR3
G370S
FGFR2
G338R
FGFR3
R669Q
FGFR2
S354C
FGFR3
P250R
FGFR2
L617F
FGFR3
Y278C
FGFR2
W290R
FGFR3
L324V
FGFR2
L550F
FGFR3
S84L
FGFR2
M535I
FGFR3
R750C
FGFR2
Y308C
FGFR3
S433C
FGFR2
E777*
FGFR3
K650Q
FGFR2
K641R
FGFR3
S371C
FGFR2
T370R
FGFR3
S249C
FGFR2
W72C
FGFR3
G370C
FGFR2
K526E
FGFR3
R248C
FGFR2
D304N
FGFR3
Y373C
FGFR2
K659M
FGFR2
S267P
FGFR2
E731K
FGFR2
M537I
FGFR2
F276C
FGFR2
I547V
FGFR2
E565A
FGFR2
V395D
FGFR2
W290C
FGFR2
R678G
FGFR2
E777K
FGFR2
C382R
FGFR2
S372C
FGFR2
A315T
FGFR2
D101Y
FGFR2
Y375C
FGFR2
E219K
FGFR2
L770*
FGFR2
L770V
FGFR2
K659N
Note: Numbering may differ depending on which reference sequence was used.

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4.2.
Exclusion Criterion for the DDI Substudy
Potential subjects who meet any of the following criteria will be excluded from participation in 
the study:
1.
Treatment with any other investigational agent in another clinical study within 30 days 
prior to randomization.
2.
Persistent phosphate level >ULN during screening (within 14 days of treatment and 
prior to Cycle 1 Day 1) despite medical management.
3.
History of uncontrolled cardiovascular disease including:
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 (Main Protocol, 
Attachment 3), cerebrovascular accident, or transient ischemic attack.
a.
QTc prolongation as confirmed by ECG assessment at screening (Fridericia; QTc 
>480 milliseconds).
b. Pulmonary embolism or other venous thromboembolism within the preceding 
2 months
4.
Any reason that in the view of investigator would substantially impair the ability of the 
subject to comply with study procedures and increase the risk to the subject.
5.
Females who are pregnant, breast-feeding, or planning to become pregnant within 
3 months after the last dose of study drug and males who plan to father a child while 
enrolled in this study or within 5 months after the last dose of study drug.
6.
Not recovered from reversible toxicity of prior anticancer therapy (except toxicities 
which are not clinically significant such as alopecia, skin discoloration, or Grade 1 
neuropathy).
7.
Impaired wound healing capacity defined as skin/decubitus ulcers, chronic leg ulcers, 
known gastric ulcers, or unhealed incisions.
8.
Major surgery within 4 weeks before enrollment.
9.
Known human immunodeficiency virus (HIV) infection, or active hepatitis B or C 
infection (subjects with history of hepatitis C infection but negative hepatitis C virus 
polymerase chain reaction (PCR) test and subjects with hepatitis B with positive 
hepatitis B surface antibody are allowed.) For known active AIDS (human 
immunodeficiency virus (HIV) infection), unless the subject has been on a stable anti-
retroviral therapy regimen for the last 6 months or more, has had no opportunistic 
infections in the last 6 months, and has CD4 count >350.
10.
Known allergies, hypersensitivity, or intolerance to erdafitinib or its excipients (see 
current version of the Investigator’s Brochure).
11.
Current central serous retinopathy (CSR) or retinal pigment epithelial detachment of 
any grade.

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12.
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
13.
Medications known to induce or inhibit CYP3A or CYP2C9, or inhibit OCT2 must be 
discontinued or substituted 1 week prior to the first intake of the probe drugs, or must 
be temporarily interrupted during the course of the DDI substudy (see tables in DDI 
Section 8).
14.
Known allergies, hypersensitivity, or intolerance to any of the probe drugs or excipients.
15.
Use of midazolam and metformin from 2 weeks before the first intake of probe drugs 
(for DDI purpose on Day -2 or Day -1), and until the last PK sample is collected on 
Study Day 15 (last 24-hour PK sampling).
16.
Known contraindication to the use of metformin and/or midazolam, based on the local 
prescribing information.
17.
Criterion modified per Amendment 8
The known* presence of FGFR gatekeeper and resistance alterations. Mutations in the 
following positions: FGFR1 V561; FGFR2 V564; FGFR3 V555; FGFR4 V550; 
FGFR1 N546; FGFR2 N549; FGFR3 N540; and FGFR4 N535.
*Observation of a gatekeeper/resistance alteration in the local or central report. If the 
local test does not screen for all four FGFRs, eg FGFR4, the local report remains 
evaluable for molecular screening.
Subjects with known germ-line mutations will not be eligible.
18.
Criterion modified per Amendment 8
For NSCLC subjects only - pathogenic somatic mutations in EGFR* or BRAF V600E, 
or any gene fusions in the following genes: ALK, ROS1, or NTRK.
*Assessment of these genes may be performed per institutional standard and do not 
have to be assessed via NGS.
Subjects will be allowed to be rescreened only once for eligibility (both molecular and 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, 
availability of a different tumor tissue for FGFR testing, molecular test internal quality control 
failure).

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5.
TREATMENT ALLOCATION AND BLINDING
As this is an open-label study, blinding procedures are not applicable.  
6.
DOSAGE AND ADMINISTRATION 
6.1.
Administration of Study Drug
The Time and Events Schedule (DDI Table 28) provides detailed dosing information for 
administration of erdafitinib, midazolam, and metformin. Midazolam and metformin will only be 
administered at the study site during the DDI portion of the substudy. Erdafitinib will be 
administered on an outpatient basis, except at Cycle 1 on Days 1, 13, 14, and 15. 
During the LTE Phase, dispensation of erdafitinib will occur every 1 to 6 months in accordance 
with local practice. Subjects will be supplied with 1 to 6 months of erdafitinib at each visit. 
Subjects can be withdrawn if an alternative access to erdafitinib is available, or marketing 
authorization is obtained in accordance with local regulations.
Midazolam 2.5 mg will be administrated orally as a syrup, solution, or suspension dosage form
(including pre-filled oral syringes). Metformin will be administered orally as a single tablet of 
1,000-mg strength. Erdafitinib 8 mg will be administered orally once daily, with the possibility of 
up-titration to 9 mg once daily based on Day 14 serum phosphate levels as described further in this 
section). 
Instructions regarding the administration of erdafitinib, midazolam, and metformin are outlined 
below: 

Study drug administration should be at approximately the same time in the morning from 
Day -2 to Day 14. Subjects should not take erdafitinib on the morning of study visits 
designated for PK sampling until the appropriate time during the site visit. Specifically, 
subjects will be contacted by telephone and reminded NOT to take their morning dose of 
erdafitinib at home but rather will be instructed to bring erdafitinib to the study site. 

Day -2 and Day -1: midazolam (Day -2) and metformin (Day -1) will be administered orally 
after an overnight fast of at least 8 hours. Subjects will continue to fast from food and drink 
(except water) for another 4 hours after dosing. The study drugs are to be taken with 
approximately 240 mL (8 ounces) of water. The tablets should be swallowed intact and 
subjects should not attempt to dissolve them in water, tablets must not be broken or chewed. 
Subjects should avoid consuming grapefruit or Seville oranges due to CYP450 3A4/5 
inhibition.

Erdafitinib self-administered at home (Cycle 1: Day 2 to Day 12, Day 16, and daily thereafter) 
may be taken with or without food during the morning hours. Erdafitinib administration will 
take place at the site on Cycle 1 Days 1, 13, 14, and 15. 

Cycle 1 Day 13 and Day 14: erdafitinib (daily), midazolam (Cycle 1 Day 13), metformin 
(Cycle 1 Day 14) will be administered orally after an overnight fast of at least 8 hours, one 
after the other, ie, first erdafitinib and then midazolam (Cycle 1 Day 13) and metformin 
(Cycle 1 Day 14) within 2 minutes with a glass of water. Subjects will continue to fast from 
food and drink (except water) for another 4 hours after dosing.

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
In the case of severe sedation by oral midazolam, the benzodiazepine antagonist flumazenil 
may be used via intravenous route per local standard of care.
Erdafitinib treatment will continue until disease progression, or until any of the other conditions 
listed in Section 10.2 are met such as unacceptable toxicity and refusal of further treatment. 
If a dose is missed, then it can be taken up to 6 hours after the scheduled time; the subject may 
return to the normal schedule the following day. If more than 6 hours have passed since the missed 
dose, the dose should be skipped and the subject should continue treatment at the scheduled time 
the following day. If vomiting occurred with drug administration, no replacement dose will be 
taken and any such event that occurs up to 4 hours following dose administration must be recorded 
on the electronic case report form (eCRF).  
The study drug will be dispensed at the first visit of each cycle. All study drug doses dispensed 
must be captured in the source documents, and the eCRF. 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 re-issued in this 
study or outside the study (follow study drug accountability guidelines in the Site Investigational 
Product Manual). During the LTE Phase, the study drug dispensation will be performed at the 
investigator’s discretion.
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.
6.2.
Dose Uptitration Guidelines
See Main Protocol Section 6.2.
6.3.
Dose Modifications and Dose Delays (Management of Toxicities)
Guidance for dose modification and management of toxicities including eye, skin/nail, dry 
mouth/mucositis, liver, and phosphate toxicity are found in the Main Protocol (Section 6.3).
7.
TREATMENT COMPLIANCE
See Main Protocol Section 7.
8.
PROHIBITIONS AND RESTRICTIONS
During the DDI portion of the substudy, potential subjects must be willing and able to adhere to 
the following prohibitions and restrictions during the course of the DDI substudy to be eligible for 
participation:

Subjects should discontinue prohibited medications listed in DDI Table 32 and DDI Table 33. 

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
Subjects should not consume grapefruit, grapefruit juice, or Seville oranges (or products 
containing grapefruit or Seville oranges) from 72 hours before the first intake of the probe 
drugs (Study Day -2 onwards) until after the last PK sample is collected on Study Day 15
(Cycle 1 Day 15). This restriction is also in place after completion of the 14-day DDI 
Treatment Phase during continued treatment with erdafitinib.

Subjects may not consume food or beverages containing alcohol on Day -3 to Day 1, and on 
Day 12 to Day 15. Alcohol intake should not be more than 1 drink per day on a daily basis on 
Days -5, -4, -3, and on Days 10, 11 and 12. Note that 1 drink is equivalent to 5 ounces of wine, 
12 ounces of beer, or 1 ounce of hard liquor.

Subjects should not use midazolam and metformin from 2 weeks before the first intake of 
probe drugs and until after the last PK sample is collected on Study Day 15 (Cycle 1 Day 15), 
as it will interfere with the DDI evaluation.
Moderate to strong CYP3A4 inducers and inhibitors (DDI Table 32) and moderate CYP2C9 
inducers and inhibitors and OCT2 inhibitors (DDI Table 33) are prohibited one week before the 
start of dosing (on Day -2) until the end of the DDI Treatment Phase (Cycle 1 Day 15).
After completion of the DDI portion of the study, subjects will follow the instruction regarding 
concomitant therapy in the Main Protocol (Section 8). 

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DDI Table 32:
Prohibited Concomitant Medications: Moderate to Strong CYP3A4 Inducers and Inhibitors
Moderate to Strong CYP3A4 Inducers
Moderate CYP3A4 Inducers: 50% to 80% decrease in area under the curve (AUC)
Bosentan
Efavirenz
Etravirine
Modafinil
Nafcillin
Lersivirine
Talviraline
Tipranavir
Lopinavir
Strong CYP3A Inducers: ≥80% decrease in AUC.
Avasimibe
Carbamazepine
Barbiturates eg, phenobarbital
Phenytoin
Rifabutin
Rifampin
St. John’s wort
Mitotane
Enzalutamide
Apalutamide
Moderate to Strong CYP3A Inhibitors
Moderate CYP3A4 Inhibitors
Netupitant
Darunavir
Atazanavir/ritonavir
Darunavir/ritonavir
Amprenavir
Diltiazem
Atazanavir
Verapamil
Grapefruit juice
Imatinib
Aprepitant
Crizotinib
Casopitant
Tofisopam
Cimetidine
Lomitapide
Nilotinib
Strong CYP3A4 Inhibitors: ≥5-fold increase in AUC or >80% decrease in CL
Boceprevir
Conivaptan
Clarithromycin
Indinavir
Lopinavir
Itraconazole
Mibefradil
Ketoconazole
Nefazodone
Ritonavir
Posaconazole
Nelfinavir
Saquinavir
Erythromycin
Telaprevir
Troleandomycin
Telithromycin
Fluconazole
Voriconazole

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DDI Table 33:
Prohibited Concomitant Medications: Moderate CYP2C9 Inducers and Inhibitors and 
OCT2 Inhibitors and Substrates
Moderate CYP2C9 Inhibitors and Inducers
Moderate CYP2C9 Inhibitors
Fluconazole
Amiodarone
Miconazole
Piperine
Oxandrolone
Ataciguat
Tienilic acid
Azapropazone
Bucolome
Sulfaphenazole
Benzbromarone
Moderate CYP2C9 Inducers
Carbamazepine
Rifampin
Enzalutamide
Aprepitant
OCT2 Inhibitors
Abacavir
Gefitinib
Amantadine
Imatinib
Amitriptyline
Irinotecan
Amsacrine
Nilotinib
Bosutinib
Ondansetron
Cimetidine
Pentamidine
Clopidogrel
Phenoxybenzamine
Clonidine
Prazosin
Dasatinib
Propafenone
Doxazosin
Quetiapine
Erlotinib
Quinidine
Rabeprazole
Verapamil
Repaglinide
Zidovudine
Sunitinib
OCT2 Substrates (Transporters) 
6-beta-hydroxycortisol
Oxyplatin
Amantadine
Oxybutynin
Carboplatin
Phenformin
Cisplatin
Picoplatin
Histamine
Pramsorafenib
Lamivudine
Tropisetron
Linagliptin
Trospium
Metformin
Varenicline
Umeclidinium
University of Washington’s Drug Interaction Database: 
http://www fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabeling/ucm09
3664 htm#4 
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.

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9.
STUDY EVALUATIONS
9.1.
Study Procedures  
The Time and Events Schedule in the DDI substudy summarizes the frequency and timing of 
efficacy, safety, pharmacokinetic, and biomarker assessments for this study. See DDI Table 29 for 
the Time and Events Schedule for LTE phase.
For subjects who will have the optional fresh tissue biopsy at baseline (done after the most recent 
progression prior to enrollment), every effort should be made to conduct another biopsy at C1D15 
and disease progression.  
The total blood volume is (approximately 44 mL at screening, 316 mL for Cycles 1 to 3, 24 mL 
for each subsequent cycle [except for Cycle 5 that is approximately 44 mL], and 37 mL at the end 
of treatment visit) is considered within the normal range allowed for this subject population over 
this time frame. For adult subjects, the amount of blood collected is less than the American Red 
Cross standard blood donation of 500 mL over 60 daysa and is aligned with World Health 
Organization blood donation guidelines.b
9.1.1.
Molecular and DDI Substudy Screening
Subjects considered for this substudy will undergo assessment of molecular eligibility after 
consent is obtained using the molecular eligibility informed consent form (ICF). 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. 
Subjects must meet appropriate molecular eligibility criteria, as determined by available test results 
(from tissue or blood) using next-generation sequencing (NGS), direct digital counting methods, 
or the Qiagen Therascreen® FGFR RGQ RT-PCR kit. After meeting molecular eligibility, potential 
subjects will provide consent using the DDI Substudy ICF and will be assessed using the Inclusion 
and Exclusion Criteria in Section 4.
Archival tumor tissue for concordance testing of FGFR alterations from local testing will be sent 
to the central laboratory for alterations detected by the Qiagen Therascreen® FGFR RGQ RT-PCR 
kit if available.
                                                
a
American Red Cross. Available at: http://www.redcrossblood.org/learn-about-blood/blood-facts-and-statistics. 
Accessed 29 March 2019.
b    World Health Organization. Blood donor selection. Guidelines on assessing donor suitability for blood donation. 
https://www.who.int/bloodsafety/publications/bts_guideline1/en/ Accessed 13 May 2019.

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9.1.2.
Pretreatment with Probe Drugs
Qualified subjects will be pretreated with the probe drugs on 2 consecutive days (midazolam
2.5 mg on Day -2 and metformin 1,000 mg on Day -1) before administration of erdafitinib under 
fasting conditions (ie, no food should be eaten at least 8 hr before dosing and 4 hr after dosing).
A full PK profile will be collected before dosing and over 24 hours after dosing with midazolam 
and metformin in order to obtain baseline PK data for these probe drugs.
9.1.3.
Treatment Phase (DDI Treatment Phase Through Day 15)
The DDI Treatment Phase begins after the 24-hour PK sample for metformin (administered on 
Day -1) is collected on Cycle 1 Day 1. During this phase, erdafitinib 8 mg will be taken once daily 
beginning on Day 1. This first dose will be administered at the study site in the morning after the 
24-hour PK sample for metformin is collected. From Days 2 to 12, erdafitinib will be self-
administered at home with or without food at approximately the same time each day in the 
morning. Subjects will record the date and time of each erdafitinib dose on Days 2 to 12 on a diary 
card. Compliance with the erdafitinib assigned dose and dose administration time will be 
confirmed by study personnel during study visits (ie, via subject diaries). If a subject cannot read 
or write for any reason, it is acceptable for the subject to have diary card information completed 
by an independent witness.
During the DDI Treatment Phase, midazolam and metformin are administered again on Day 13 
and Day 14, respectively. On Day 13, subjects will NOT take their morning dose of erdafitinib at 
home but will bring erdafitinib to the study site. Study personnel must contact the subject the day 
before Day 12 by telephone to remind the subject of this requirement. A predose PK sample for 
midazolam will be collected before administration of a single oral dose of 8 mg erdafitinib
followed by a single oral dose of 2.5 mg midazolam (taken within 2 minutes of each other with a 
glass of water) under fasting conditions. A full PK profile for midazolam will then be collected 
over the following 24 hours.
On Day 14, subjects will NOT take their morning dose of erdafitinib at home but will bring 
erdafitinib to the study site. Study personnel must remind the subject of this requirement while in 
the clinic on Day 13 or by telephone. A predose PK sample taken for erdafitinib and a 24-hour 
postdose PK sample for midazolam will be collected before administration of a single oral dose of 
8 mg erdafitinib followed by a single oral dose of 1,000 mg metformin (taken within 2 minutes of 
each other with a glass of water) under fasting conditions. A full PK profile for metformin will 
then be collected over the following 24 hours. 
On Day 15, subjects will NOT take their morning dose of erdafitinib at home but will bring 
erdafitinib to the study site. Study personnel must inform the subject of this requirement while in 
the clinic on Day 14 or by telephone. The 24-hour postdose PK sample for metformin will be 
collected prior to the erdafitinib dose on Day 15.
The full PK profile of midazolam and metformin on Day 13 and Day 14, respectively, in the 
presence of erdafitinib at steady-state, will be compared with the baseline full PK profiles (prior 
to erdafitinib dosing) to assess the extent of effects of erdafitinib daily dosing on CYP3A and 

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OCT2 activities. A detailed overview of the dosing regimen for erdafitinib and the probe drugs, 
and the PK sampling timepoints for erdafitinib and the probe drugs are provided in the Time and 
Events Schedule in the DDI Substudy.
9.1.4.
Continued Treatment with Erdafitinib 
Upon completion of the DDI Treatment Phase, erdafitinib will be continued until disease 
progression or unacceptable toxicity, or until another condition for treatment discontinuation is 
met (Section 10.2). A treatment cycle with erdafitinib will consist of 4 weeks (28 days).
Radiological assessments will be conducted every 3 months for the first 6 months and thereafter 
per standard of care for assessment of response (and disease progression) by the investigator.
9.1.5.
Long-Term Extension Phase
Following approval of Protocol Amendment 9, once the end of study data collection timepoint has 
been achieved, subjects who continue to benefit from study treatment, as determined by their 
investigator, may continue to receive access to study treatment on this study, in the LTE Phase or 
any other post-trial access program, when permitted by local regulations. Provision of erdafitinib 
through the study may continue until the subject can commercially access study treatment within 
the local healthcare system, until the investigator decides it is in the best interest of the subject that 
study treatment be discontinued, or until 2 years after local marketing authorization is obtained for 
the studied indication, whichever comes first.
There are no protocol-required assessments during the LTE Phase; radiological and safety 
assessments including laboratory assessments will be performed based on the investigator’s 
discretion (DDI Table 29). Data for subjects in the LTE Phase will not be added to the clinical 
database. All SAEs and associated concomitant therapies will be reported through the Company 
Safety Repository.
9.2.
Pharmacokinetic Evaluations 
9.2.1.
Pharmacokinetic Evaluations
Serial venous blood samples (2 mL/time point/analyte) will be collected for measurement of 
plasma concentrations of midazolam and its metabolite, 1-OH-midazolam, and metformin, at 
timepoints specified in DDI Table 28 and processed, handled, and identified according to the 
Laboratory Manual. An indwelling intravenous cannula may be used for blood sample collection. 
If a mandarin (obturator) is used, blood loss due to discard is not expected.
The exact dates and times of dosing, and exact dates and times of blood sampling must be recorded 
on the laboratory requisition form and appropriate eCRF in the clinical database. If vomiting of 
probe drugs (midazolam, metformin) or study drug (erdafitinib) occurs within 4 hours of dosing, 
the time of vomiting should also be recorded on the eCRF.
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9.2.2.
Analytical Procedures
Midazolam and metformin plasma samples will be analyzed to determine the concentrations of 
midazolam, and 1-OH-midazolam, and metformin, using validated, specific, and sensitive Liquid 
Chromatography-Tandem Mass Spectrometry methods by, or under the supervision of, the 
sponsor’s Bioanalytical Laboratory Department of Bioanalysis.
If required, some plasma samples may be analyzed to document the presence of circulating 
metabolites using a qualified research method.
9.2.3.
Pharmacokinetic Parameters
Pharmacokinetic analysis will be the responsibility of the sponsor in accordance with the current 
Clinical Pharmacokinetics Guideline. Additional PK parameters and details of the PK analysis, 
including data handling rules and software used to perform PK analysis will be provided in the 
Clinical Pharmacology Analysis Plan. Based on the individual plasma concentration-time data 
based on sampling schedule per DDI Table 28 (not including erdafitinib timepoints), using the 
actual sampling times, the following PK parameters will be derived:

Erdafitinib:

Predose concentration of erdafitinib on Cycle 1 Day 14

Midazolam and its metabolite 1-OH-midazolam, and metformin:

Cmax, tmax, AUClast, AUC∞, λz, t1/2term

CL/F (only for parent compounds midazolam and metformin)

Ratio Cmax, metabolite/parent, Ratio AUClast, metabolite/parent, Ratio AUC∞, metabolite/parent
(metabolite/parent = 1-OH-midazolam/midazolam) – for midazolam only

Ratio Cmax, test/reference, Ratio AUClast, test/reference, Ratio AUC∞, test/reference
(test/reference = probe drug in presence of erdafitinib/probe drug alone)
9.2.4.
Sample Collection and Handling
The actual dates and times of PK sample collection must be recorded on the laboratory requisition 
form and appropriate eCRF in the clinical database. If blood samples are collected via an 
indwelling cannula, an appropriate amount (1 mL) of serosanguineous fluid slightly greater than 
the dead space volume of the lock will be removed from the cannula and discarded before each 
blood sample is taken. After blood sample collection, the cannula will be flushed with 0.9% sodium 
chloride, US Pharmacopeia (or equivalent), and charged with a volume equal to the dead space 
volume of the lock. If a mandarin (obturator) is used, blood loss due to discard is not expected.
Refer to DDI Table 28 for the timing and frequency of all sample collections. Instructions for the 
collection, handling, storage, and shipment of samples are found in the Laboratory Manual. 
Collection, handling, storage, and shipment of samples must be under the specified, and where 
applicable, controlled temperature conditions as indicated in the Laboratory Manual.

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9.2.5.
Criteria for PK Evaluability  
At least 15 subjects will be enrolled in this DDI substudy. Due to the potential for subjects not to 
meet the PK evaluability criteria or other criteria relevant to PK (ie, co-medication exclusion 
criteria), additional subjects may be enrolled to ensure that the required number of PK-evaluable 
subjects is met.
The minimum criteria for PK evaluability are as follows:

Subjects took planned dose (2.5 mg) of midazolam on Day -2 and Day 13. Two interpretable 
PK profiles were obtained following the administration of midazolam and midazolam plus 
erdafitinib at a dose of 8 mg.

Subjects took planned dose (1,000 mg) of metformin on Day -1 and on Day 14. Two 
interpretable PK profiles were obtained following the administration of metformin and
metformin plus erdafitinib at a dose of 8 mg.

Subjects did not vomit within 4 hours after receiving either dose of the probe drugs
(midazolam, metformin) and no reported vomiting with erdafitinib dosing while at home for 
5 consecutive doses before co-administration of the probe drugs on Day 13 and Day 14. 

Subjects received the next 5 consecutive doses of erdafitinib at a dose of 8 mg prior to 
co-administration of the probe drugs on Day 13 and Day 14.

Additionally, the DDI PK data for a specific subject may be considered non-evaluable as per 
scientific judgment by the sponsor even if the above criteria are fulfilled. For such a case, the 
reason will be documented.
The final assessment of PK evaluability will be determined by the sponsor based on the available 
PK data and other relevant data. The DDI Treatment Phase will be completed after the collection 
of the 24-hour metformin PK sample on Day 15.
9.3.
Safety Evaluations
There are no protocol-required assessments during the LTE Phase; safety assessments including 
laboratory assessments will be performed based on the investigator’s discretion (DDI Table 29). 
Data for subjects in the LTE Phase will not be added to the clinical database. All SAEs and 
associated concomitant therapies will be reported through the Company Safety Repository.
9.3.1.
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 Time and Events Schedule for the DDI Substudy. 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 
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9.3.2.
Vital Signs
Vital signs will be assessed per the Time and Events Schedule in the DDI Substudy. Blood pressure 
(systolic and diastolic), heart rate, and temperature will be assessed. The investigator must review 
vital signs results and record any clinically relevant changes occurring during the study in the 
adverse event section of the eCRF.
9.3.3.
Electrocardiograms
Twelve-lead electrocardiograms will be performed as specified in the Time and Events Schedule 
for the DDI Substudy. Additional ECGs may be performed as clinically indicated. During 
treatment, 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 
and calibrated per institutional standard. The following intervals should be measured: PR, QRS, 
QT, 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).
9.3.4.
Clinical Safety Laboratory Assessments
Blood samples for serum chemistry and hematology will be collected for all subjects as indicated 
in the Time and Events Schedule for the DDI substudy. 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 of the eCRF. 
Laboratory test results completed on Day -3 should be reviewed prior to enrollment (except PTH), 
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
-hemoglobin
-platelet count
-white blood cell count
-absolute neutrophil count 
Comprehensive Metabolic Panel
-alanine aminotransferase (ALT)
-calcium
-aspartate aminotransferase (AST)
- potassium
-total bilirubin
- albumin
-creatinine
-sodium
-magnesium
- bicarbonate (if feasible)
- alkaline phosphatase

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Parathyroid Hormone
Phosphate
9.3.5.
Ophthalmologic Examination
All subjects should have an ophthalmologic examination performed at Screening by an 
ophthalmologist, which should include assessment of 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 
physician or nurse at Screening. A follow-up examination should be performed as clinically 
necessary based on the findings of the Amsler grid tests and clinical assessment, or at regular 
intervals as deemed necessary by the screening ophthalmologist.
When central serous retinopathy (CSR)/retinal pigment epithelial detachment (RPED) 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 (RVO). In subjects with suspected retinal pathology such as CSR or RVO, a 
consultation with a retina specialist should be considered.
All images of the OCT scans for enrolled subjects must be stored in the subject’s records.
Amsler Grid Testing
Amsler grid (Attachment 5) testing will be administered to all subjects at Screening and during the 
treatment phase according to the Time and Events Schedule for the DDI substudy. 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 exam within 7 days. However, if the subject has an abnormal Amsler grid test and 
otherwise normal ophthalmologic exam at baseline (during Screening), then 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.
9.3.6.
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 Time and Events Schedule for the DDI substudy. 
Pregnancy tests will be performed to establish the absence of pregnancy at any time during the 
subject's participation in the study.
9.3.7.
ECOG Performance Status
Eastern Cooperative Oncology Group performance status grade will be determined as part of 
screening evaluations. The scoring information is provided in Main Protocol, Attachment 1.

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9.5.
Radiologic Assessment for Identification of Disease Progression
Radiologic assessments will be performed according to the Time and Events Schedule for the DDI 
Substudy for the purpose of determining disease progression. More frequent radiological 
assessments are allowed, if clinically indicated/desirable. If symptomatic deterioration (on the 
basis of global deterioration of health status) occurs without documentation of radiographic 
progression, the clinical findings used to make this determination must be specified in the eCRF 
and documented in the source documents. During the DDI Substudy, assessment of responses for 
solid tumors will be performed according to standard of care per the principal investigator’s 
judgement.
During the LTE Phase, please refer to the Time and Events Schedule (DDI Table 29).
10.
SUBJECT COMPLETION/WITHDRAWAL FOR THE DDI SUBSTUDY
10.1.
Completion
A subject will be considered to have completed the DDI portion after completing the assessments 
on Cycle 2 Day 1.
For subjects who continue to derive benefit from study treatment following the end of study data 
collection timepoint, please refer to LTE Phase Section 9.1.5.
10.2.
Discontinuation of Study Treatment 
A subject's study treatment will be discontinued for any of the following reasons:

Concurrent medical conditions or unmanageable disease-related events for which the 
investigator believes that it is in the best interest of the subject to stop treatment

The subject becomes pregnant

Disease progression

Unacceptable toxicity (Exception: If a subject has been deriving benefit from treatment, and 
the investigator can demonstrate that re-introduction of study drug is in the best interest of the 
subject considering the terminal nature of the disease, the drug may be re-introduced at a lower 
dose and/or intensity if the medical monitor is in agreement with this assessment. With 
appropriate re-consenting, the subject can be retreated with a 1- or 2-dose level reduction as 
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appropriate, along with appropriate clinical follow-up as designated by the investigator (please 
see Main Protocol Section 16.2.3 for details.)

The subject refuses further treatment with the study drug

The sponsor terminates the study

Investigator decision approved by the sponsor
If a subject discontinues treatment, an End-of-Treatment visit should be conducted within 30 days 
of the subject’s last dose of study drug. Subjects who re-consent to LTE Phase will not be required 
to complete EoT visit. The primary reason for treatment discontinuation will be clearly 
documented in the subject’s medical record and recorded in the eCRF. Once a subject discontinues 
treatment with the study drug, the subject will not be permitted to be retreated.
10.3.
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
If a subject is lost to follow-up, every reasonable effort must be made by the study site personnel 
to contact the subject and determine the reason for discontinuation/withdrawal. The measures 
taken to follow-up must be documented.
When a subject withdraws before completing the study, the reason for withdrawal is to be 
documented in the eCRF and in the source document. Study drug assigned to the withdrawn subject
may not be assigned to another subject.
A subject may be replaced if the subject withdraws prior to study drug administration or prior to 
the first disease assessment for reasons other than toxicity or disease progression.
11.
STATISTICAL METHODS
Treated subjects in the DDI portion of the substudy who completed Cycle 2 Day 1 will be included 
in the analysis. Safety analyses will be based on the Safety Analysis Set, defined as all subjects 
who received at least 1 dose of study drug, and will be based on actual treatment received, unless 
otherwise specified. The same safety analysis methods described in the main study SAP will be 
used.
11.1.
Sample Size Determination
Approximately 22 subjects will be enrolled to account for a potential greater intra-subject 
variability for this DDI substudy that will be conducted in FGFR-eligible cancer patients. The 
sample size calculation is based on statistical estimation enabling the study to provide an estimate 
with reasonable precision on the magnitude of the interaction. If the number of subjects evaluable 
for PK in the DDI Treatment Phase up to Study Day 15 (Cycle 1 Day 15) drops below 15, 
additional subjects may be enrolled.

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Previous DDI studies with the same probe drugs conducted by the sponsor indicated that the 
intra-subject coefficient of variation (CV) for probe drugs ranged from 16% to 21% for Cmax and 
11% to 18% for AUC (DDI Table 34).
DDI Table 34:
Intra-subject Coefficient of Variation for the Probe Drugs and Their Metabolites From
Previous Drug-Drug Interaction Studies and Publications
JNJ Study Number
Compound
Intra-Subject CV
Cmax
AUC
54179060CLL1017
midazolam 2 mg
16% - 20%
17% - 18%
ESKETINTRD1010
midazolam 6 mg
17%
11%
28431754DIA1028 
metformin 2,000 mg
21%
17%
Intra-subject CV Range
16% - 21%
11% - 18%
  AUC=area under the curve; Cmax=maximum plasma concentration; CV= coefficient of variation 
Assuming an intra-subject CV of 21% among the probe drugs for AUC and Cmax, a sample size of 
15 subjects would be sufficient for the point estimate of the geometric mean ratio of AUC and 
Cmax of the probe drugs with and without erdafitinib, to fall within 88% and 114% of the true value 
with 90% confidence.
11.2.
Pharmacokinetic Analyses
Descriptive statistics will be provided for the plasma concentrations of erdafitinib, and for the 
probe drugs, metformin and midazolam (and its metabolite 1-OH-midazolam). Statistical analysis 
will be performed for the PK parameters of each of the following analytes:

The probe drugs: metformin and midazolam (and its metabolite 1-OH-midazolam).
The test / reference treatments are defined as follows:
Study Day 13 (midazolam [2.5 mg] + erdafitinib [8 mg] / Study Day -2 (midazolam 
[2.5 mg])
Study Day 14 (metformin [1,000 mg] + erdafitinib [8 mg] / Study Day -1 (metformin 
[1,000 mg])
The primary PK parameters of interest for statistical analysis are Cmax, AUClast, and AUC∞ of the 
parent compounds of the probe drugs. For each analyte, all subjects who have the primary PK 
parameters of interest from both prior to treatment and the DDI Treatment Phase will be included 
in the statistical analysis. 
Linear mixed effects models will be applied to log-transformed PK parameter data with treatment 
as fixed-effect and subject as random-effect. The least square means and intra-subject coefficients 
of variation will be derived from the model. The geometric mean ratios and the 90% confidence 
interval of the PK parameters of each drug probes with and without co-administration of erdafitinib 
will then be constructed through back-transformed results based on the model.

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12.
ADVERSE EVENT REPORTING
Instruction regarding adverse event reporting is provided in the Main Protocol (Section 12); 
however, attribution definitions (ie, assessment of causality) and the severity criteria have been 
updated for the DDI Substudy. 
During the LTE Phase, all SAEs and associated concomitant therapies will be reported through 
the Company Safety Repository.
Assessment of Causality
The causal relationship to study intervention 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 intervention administration and the 
adverse event.
Not Related
There is not a reasonable causal relationship between study intervention 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 (ADL).a
                                                
a
Instrumental ADL refers to preparing meals, shopping for groceries or clothes, using the telephone, managing 
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
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.a

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 participant (eg, laboratory abnormalities).
Any adverse event will be graded as per the above. Should an adverse event become fatal or have 
a fatal outcome, the original grade is not changed but “fatal” shall be reported as an outcome.
Only in the following cases a Grade 5 event is to be reported:

Death NOS:
only for deaths due to unknown reason (pending follow-up information; if 
further information becomes available this should be adapted as adequate)

Sudden death: a sudden (defined as instantaneous or within 1 hour of the onset of 
symptoms) cessation of life that cannot be attributed to a CTCAE term.
13.
PRODUCT QUALITY COMPLAINT HANDLING
See Main Protocol Section 13.
14.
STUDY DRUG INFORMATION
14.1.
Physical Description of Study Drug
The erdafitinib study drug supplied for this study is formulated as 3-, 4-, and 5-mg tablets for oral 
use. Refer to the Investigator’s Brochure for a list of excipients.
Description of the probe drugs is supplied in the Study Investigational Product Procedures Manual.
14.2.
Packaging
The study drug and probe drugs for oral use in this study will be packaged in child-resistant bottles.
14.3.
Labeling
Study drug and probe drug labels will contain information to meet the applicable regulatory 
requirements. No medication can be relabeled without prior approval from the sponsor.
                                                
a
Self-care ADL refers to bathing; dressing and undressing; feeding self; using the toilet; taking medications; and 
not bedridden.

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14.4.
Preparation, Handling, and Storage
Refer to the study pharmacy manual (Investigational Product Binder)/study Investigational 
Product Preparation Instructions and Investigational Product Procedures Manual for additional 
guidance on study drug and probe drug preparation, handling, and storage.
14.5.
Drug Accountability
See the Main Protocol (Section 14.5) for instruction regarding drug accountability. 
15.
STUDY-SPECIFIC MATERIALS
The investigator will be provided with the following supplies:

Protocol

Investigator’s Brochure

Electronic CRFs and electronic data capture (eDC) manual

Site Investigational Product Manual

Laboratory manual

Kits for PK, pharmacodynamics/biomarker, and tissue sample assessments  

Subject diary card and information booklet

Investigator binder to store all documents concerning the study. This is a confidential binder 
and only personnel involved in the study should have access to it.

Amsler Grid tests  
16.
ETHICAL ASPECTS
See Main Protocol Section 16.
17.
ADMINISTRATIVE REQUIREMENTS
See Main Protocol Section 17.