A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy and Safety of Pemigatinib in Participants With Previously Treated Locally Advanced/Metastatic or Surgically Unresectable Solid Tumors Harboring Activating FGFR Mutations or Translocations (FIGHT-208)
Phase: PHASE2
Conditions: Advanced or Metastatic Solid Tumors, FGFR Mutations, FGFR Translocations
Sponsor: Incyte Corporation

Incyte Corporation 
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Protocol INCB 54828-MA-TA-208 Am 1 
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Clinical Study Protocol 
INCB 54828-MA-TA-208 / NCT04003623
A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the 
Efficacy and Safety of Pemigatinib in Participants With Previously 
Treated Locally Advanced/Metastatic or Surgically Unresectable Solid 
Tumors Harboring Activating FGFR Mutations or Translocations 
(FIGHT-208) 
Product: 
Pemigatinib (INCB054828) 
IND Number: 
124,358 
Phase of Study: 
2 
Sponsor: 
Incyte Corporation 
1801 Augustine Cut-Off 
Wilmington, DE 19803 
Original Protocol (Version 0): 
21 MAY 2019 
Amendment (Version) 1: 
14 JUN 2019 
This study will be performed in accordance with ethical principles that have their origin in the Declaration of 
Helsinki and conducted in adherence to the study Protocol, applicable Good Clinical Practices, and applicable laws 
and country-specific regulations in which the study is being conducted. 
The information in this document is confidential.  No part of this information may be duplicated, referenced, or 
transmitted in any form or by any means (electronic, mechanical, photocopy, recording, or otherwise) without prior 
written consent. 
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INVESTIGATOR'S AGREEMENT 
I have read the INCB 54828-MA-TA-208 Protocol Amendment 1 (Version 1 dated 
14 JUN 2019) and agree to conduct the study as outlined.  I agree to maintain the confidentiality 
of all information received or developed in connection with this Protocol. 
 
 
 
 
 
(Printed Name of Investigator) 
 
 
 
 
 
 
 
 
(Signature of Investigator) 
 
(Date) 
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TABLE OF CONTENTS 
LIST OF ABBREVIATIONS ..........................................................................................................8 
1. 
PROTOCOL SUMMARY ..........................................................................................10 
2. 
INTRODUCTION ......................................................................................................15 
2.1. 
Background .................................................................................................................15 
2.1.1. 
Fibroblast Growth Factor Receptor Inhibitor in Oncology ........................................15 
2.1.2. 
Solid Tumor Malignancies With Activating FGFR Mutations and 
Translocations .............................................................................................................16 
2.2. 
Study Rationale ...........................................................................................................17 
2.2.1. 
Scientific Rationale for Study Design ........................................................................17 
2.2.2. 
Justification for Dose and Regimen ............................................................................17 
2.3. 
Benefit/Risk Assessment of Pemigatinib....................................................................18 
2.3.1. 
Study INCB 54828-101 ..............................................................................................19 
3. 
OBJECTIVES AND ENDPOINTS ............................................................................22 
4. 
STUDY DESIGN .......................................................................................................23 
4.1. 
Overall Design ............................................................................................................23 
4.2. 
Overall Study Duration ...............................................................................................23 
4.3. 
Study Termination ......................................................................................................24 
5. 
STUDY POPULATION .............................................................................................24 
5.1. 
Inclusion Criteria ........................................................................................................24 
5.2. 
Exclusion Criteria .......................................................................................................25 
5.3. 
Lifestyle Considerations .............................................................................................28 
5.4. 
Screen Failures ............................................................................................................28 
5.5. 
Replacement of Participants .......................................................................................28 
6. 
STUDY TREATMENT ..............................................................................................29 
6.1. 
Study Treatment Administered ...................................................................................29 
6.2. 
Preparation, Handling, and Accountability ................................................................29 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding .......................................30 
6.4. 
Study Treatment Compliance .....................................................................................30 
6.5. 
Dose Modifications .....................................................................................................30 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study 
Drug ............................................................................................................................30 
6.5.2. 
Management of Hyperphosphatemia ..........................................................................31 
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6.5.3. 
Up-Titration ................................................................................................................32 
6.5.4. 
Criteria for Permanent Discontinuation of Study Drug ..............................................33 
6.6. 
Concomitant Medications and Procedures .................................................................33 
6.6.1. 
Restricted Medications and Procedures ......................................................................33 
6.6.2. 
Prohibited Medications and Procedures .....................................................................34 
7. 
DISCONTINUATION OF STUDY TREATMENT AND PARTICIPANT 
DISCONTINUATION/WITHDRAWAL ..................................................................34 
7.1. 
Discontinuation of Study Treatment ...........................................................................34 
7.1.1. 
Reasons for Discontinuation .......................................................................................34 
7.1.2. 
Discontinuation Procedures ........................................................................................35 
7.2. 
Participant Withdrawal From the Study .....................................................................35 
7.3. 
Lost to Follow-Up.......................................................................................................36 
8. 
STUDY ASSESSMENTS AND PROCEDURES ......................................................37 
8.1. 
Administrative and General Procedures .....................................................................37 
8.1.1. 
Informed Consent Process ..........................................................................................37 
8.1.2. 
Screening Procedures ..................................................................................................38 
8.1.3. 
Interactive Response Technology Procedure ..............................................................38 
8.1.4. 
Demography and Medical History ..............................................................................38 
8.1.4.1. 
Demographics and General Medical History .............................................................38 
8.1.4.2. 
Disease Characteristics and Treatment History ..........................................................39 
8.2. 
Efficacy Assessments .................................................................................................39 
8.2.1. 
Tumor Imaging ...........................................................................................................39 
8.2.2. 
ECOG Performance Status .........................................................................................39 
8.2.3. 
Medical Resource Utilization and Health Economics ................................................40 
 
40 
8.3. 
Safety Assessments .....................................................................................................40 
8.3.1. 
Adverse Events ...........................................................................................................40 
8.3.2. 
Physical Examinations ................................................................................................40 
8.3.3. 
Vital Signs ..................................................................................................................41 
8.3.4. 
Electrocardiograms .....................................................................................................41 
8.3.5. 
Comprehensive Eye Examination...............................................................................41 
8.3.6. 
Laboratory Assessments .............................................................................................42 
8.3.6.1. 
Pregnancy Testing ......................................................................................................44 
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8.3.6.2. 
Serology ......................................................................................................................44 
8.4. 
Pharmacokinetic Assessments ....................................................................................44 
8.5. 
Pharmacodynamic and Translational Assessments ....................................................44 
8.5.1. 
Tumor for Genomics Testing for FGFR Genetic Alterations and Gene 
Expression ...................................................................................................................44 
8.5.2. 
Blood for Mutational and Other Correlative Analysis ...............................................45 
8.5.3. 
Tissue Biopsies ...........................................................................................................45 
8.6. 
Unscheduled Visits .....................................................................................................45 
8.7. 
End of Treatment ........................................................................................................45 
8.8. 
Follow-Up ...................................................................................................................46 
8.8.1. 
Safety Follow-Up ........................................................................................................46 
8.8.2. 
Post-Treatment Disease Follow-Up ............................................................................46 
8.8.3. 
Survival Follow-Up ....................................................................................................46 
9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING ......................47 
9.1. 
Definition of Adverse Event .......................................................................................47 
9.2. 
Definition of Serious Adverse Event ..........................................................................48 
9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse Events .........49 
9.4. 
Reporting of Serious Adverse Events .........................................................................51 
9.5. 
Emergency Unblinding of Treatment Assignment .....................................................52 
9.6. 
Pregnancy ...................................................................................................................52 
9.7. 
Warnings and Precautions ..........................................................................................53 
9.8. 
Product Complaints ....................................................................................................53 
10. 
STATISTICS ..............................................................................................................54 
10.1. 
Sample Size Determination ........................................................................................54 
10.2. 
Populations for Analysis .............................................................................................56 
10.3. 
Level of Significance ..................................................................................................56 
10.4. 
Statistical Analyses .....................................................................................................56 
10.4.1. 
Primary Analysis ........................................................................................................56 
10.4.2. 
Secondary Efficacy Analysis ......................................................................................56 
10.4.3. 
Safety Analyses ..........................................................................................................57 
 
57 
10.5. 
Interim Analysis ..........................................................................................................57 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS ..................................................................................................58 
11.1. 
Investigator Responsibilities .......................................................................................58 
11.2. 
Data Management .......................................................................................................59 
11.3. 
Data Privacy and Confidentiality of Study Records ...................................................60 
11.4. 
Financial Disclosure ...................................................................................................61 
11.5. 
Publication Policy .......................................................................................................61 
11.6. 
Study and Site Closure................................................................................................61 
12. 
REFERENCES ...........................................................................................................63 
APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS ...............................................................................65 
APPENDIX B. INSTRUCTION TO PARTICIPANTS FOR HANDLING STUDY 
DRUG (PEMIGATINIB) ...........................................................................................66 
APPENDIX C. FGFR MUTATIONS AND TRANSLOCATIONS ..........................................67 
APPENDIX D. CYP3A4 INHIBITORS AND INDUCERS ......................................................69 
APPENDIX E. RANO RESPONSE CRITERIA ........................................................................72 
APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES ............................73 
 
LIST OF TABLES 
Table 1: 
Objectives and Endpoints ...........................................................................................10 
Table 2: 
Key Study Design Elements .......................................................................................11 
Table 3: 
Schedule of Activities .................................................................................................13 
Table 4: 
Schedule of Laboratory Assessments .........................................................................14 
Table 5: 
Tumors With Frequency > 1% for FGFR1-3 Mutations and Rearrangements 
in TCGA .....................................................................................................................16 
Table 6: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 10% of 
Participants on Pemigatinib Monotherapy in Study INCB 54828-101 (Parts 1 
and 2 Combined) in Decreasing Order of Frequency .................................................21 
Table 7: 
Objectives and Endpoints ...........................................................................................22 
Table 8: 
Exclusionary Laboratory Values ................................................................................26 
Table 9: 
Study Treatment Information .....................................................................................29 
Table 10: Guidelines for Interruption and Restarting of Study Drug .........................................31 
Table 11: Recommended Approach for Hyperphosphatemia Management ...............................32 
Table 12: ECOG Performance Status .........................................................................................39 
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Table 13: Required Laboratory Analytes ....................................................................................43 
Table 14: P(p<0.15|n/N,alpha=1.7625,beta=9.9875) ..................................................................55 
Table 15: P(p>0.3|n/N,alpha=1.7625,beta=9.9875) ....................................................................55 
Table 16: Populations for Analysis .............................................................................................56 
 
LIST OF FIGURES 
Figure 1: 
Study Design Schema .................................................................................................12 
Figure 2: 
Comparison of Steady State Exposures for Pemigatinib 13.5 mg QD 
Between Subjects With Nonhyperphosphatemia and Hyperphosphatemia ................18 
 
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LIST OF ABBREVIATIONS 
Abbreviations and 
Special Terms 
Definition 
AE 
adverse event 
ALT 
alanine aminotransferase 
AST 
aspartate aminotransferase 
 
 
CFR 
Code of Federal Regulations 
CNS 
central nervous system 
CR 
complete response 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
cytochrome P450 
DCR 
disease control rate 
DOR 
duration of response 
ECG 
electrocardiogram 
ECOG 
Eastern Cooperative Oncology Group  
eCRF 
electronic case report form 
EDC 
electronic data capture 
EOT 
end of treatment 
 
 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
FGFR1-3 
fibroblast growth factor receptors 1, 2, or 3 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCV 
hepatitis C virus 
HIPAA 
Health Insurance Portability and Accountability Act of 1996 
IB 
Investigator's Brochure 
ICF 
informed consent form 
ICH 
International Council on Harmonisation of Technical Requirements for 
Registration of Pharmaceuticals for Human Use 
IEC 
independent ethics committee 
IRB 
institutional review board 
IRT 
interactive response technology  
MedDRA 
Medical Dictionary for Regulatory Activities  
MRI 
magnetic resonance imaging 
NCI 
National Cancer Institute 
ORR 
objective response rate 
OS 
overall survival 
PD 
progressive disease 
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Abbreviations and 
Special Terms 
Definition 
PFS 
progression-free survival 
PR 
partial response 
PTH 
parathyroid hormone 
QD 
once daily 
 
 
RANO 
Response Assessment in Neuro-Oncology 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SD 
stable disease 
SoA 
schedule of activities 
SOP 
standard operating procedure 
TEAE 
treatment-emergent adverse event, AEs reported for the first time or worsening of 
a pre-existing event after first dose of study treatment 
ULN 
upper limit of normal 
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1. 
PROTOCOL SUMMARY 
Protocol Title:  A Phase 2, Open-Label, Single-Arm, Multicenter Study to Evaluate the Efficacy 
and Safety of Pemigatinib in Participants With Previously Treated Locally Advanced/Metastatic 
or Surgically Unresectable Solid Tumors Harboring Activating FGFR Mutations or 
Translocations (FIGHT-208) 
Protocol Number:  INCB 54828-MA-TA-208 
Objectives and Endpoints: 
Table 1 presents the objectives and endpoints. 
Table 1: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine the efficacy of pemigatinib in 
participants with locally advanced/metastatic or 
surgically unresectable solid tumor malignancies 
with an activating FGFR mutation or translocation 
• ORR:  defined as the proportion of participants in 
each cohort who achieve a CR or PR based on 
RECIST v1.1 
Secondary 
• To determine other clinical efficacy 
measurements of pemigatinib in participants 
with locally advanced/metastatic or surgically 
unresectable solid tumor malignancies with an 
activating FGFR mutation and/or translocation  
• To determine the safety and tolerability of 
pemigatinib 
• PFS:  defined as the time from first dose until PD 
(per RECIST v1.1 or RANO) or death 
(whichever is first) in each cohort 
• DOR:  defined as the time from the date of first 
assessment of CR or PR until the date of the first 
PD (per RECIST v1.1 or RANO) or death 
(whichever is first) in each cohort 
• DCR:  defined as the proportion of participants 
who achieved best overall response of CR, PR, or 
SD per RECIST v1.1 or RANO 
• OS:  defined as the time from first dose of study 
drug to death of any cause in each cohort 
• Safety and tolerability:  Occurrence of TEAEs 
and treatment-related AEs according to NCI 
CTCAE v5.0, physical exam changes, vital sign 
changes, laboratory evaluations, and ECG values 
in each cohort 
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Overall Design: 
Table 2 presents the key study design elements.  Further study details are presented after the 
table. 
Table 2: 
Key Study Design Elements 
Study Phase 
Phase 2 
Clinical Indication 
Solid tumor malignancy 
Population 
Male and female participants at least 18 years of age who have 
a solid tumor malignancy with an activating FGFR mutation or 
translocation who have progressed on prior therapies and have 
no available standard treatment options 
Number of Participants 
Approximately 50 participants will be enrolled 
Study Design 
Single-arm, open-label, multicenter 
Estimated Duration of Study 
Participation 
Up to 35 days for screening, continuous treatment in 
consecutive 21-day cycles as long as participants are receiving 
benefit and have not met any criteria for study withdrawal, and 
30 (+5) days for follow-up after the last dose of study drug.  It 
is estimated that an individual will participate for 
approximately 6 months 
Treatment Groups and Duration: 
This is an open-label, monotherapy study of pemigatinib in participants with advanced/metastatic 
or surgically unresectable solid tumor malignancies harboring an activating mutation or 
translocation.  This study consists of 2 cohorts, Cohort A will enroll participants with FGFR 
translocations, fusions, and rearrangements, and Cohort B will enroll participants with FGFR 
mutations. 
Participants will receive pemigatinib 13.5 mg QD continuously (each cycle consisting of 
3 weeks) as long as they are receiving benefit and have not met any criteria for study withdrawal.  
Participants with local laboratory data documenting a gain-of-function FGFR1, FGFR2, or 
FGFR3 mutations or gene rearrangements identified in a CLIA-certified laboratory are eligible.  
This study excludes participants with bladder cancer and cholangiocarcinoma.  Confirmatory 
testing through the central genomics laboratory (Tempus, Chicago, IL) will be performed for all 
participants; however, results from the central genomics laboratory are not required before 
enrollment.  Participants will be assigned to 1 of the following cohorts (see Appendix C for list 
of alterations): 
• Cohort A:  FGFR1-3 in-frame fusions or FGFR2 intron 17 rearrangements 
• Cohort B:  Known/predicted activating point mutations in FGFGR1-3 (excluding 
kinase domain) 
Note that there is no difference in the treatment regimen between the cohorts. 
The sponsor may choose to cap enrollment of any one tumor type and/or FGFR alteration for 
lack of response based on predefined futility boundaries. 
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A fresh biopsy at baseline (or archival tissue that was collected within 12 months from date of 
screening) will be required for enrollment for participants whose tumors were not previously 
profiled at the reference lab.  Additional biopsies on-treatment and/or at time of progression 
though not mandatory are encouraged for safely accessible lesions.  Treatment will start on 
Day 1.  Participants will undergo regular safety assessments during treatment as well as regular 
efficacy assessments. 
Figure 1: 
Study Design Schema 
Advanced/metastatic/non-resectable solid tumor malignancy
 FGF/FGFR status
Cohort A:  FGFR 1-3 
translocations or FGFR2 
intron 17 rearrangements
Treatment (21-day cycle; 
continuous dosing)
Disease Assessment 
every 3 cycles
PD
SD, PR, CR
D/C tx; safety 
and survival 
follow up
Continue tx; 
assess per 
protocol
Cohort B: known/predicted activating point 
mutations in FGFR1-3 (excluding kinase domain) 
Screen
Discontinue
Pass
SF
CR= Complete Response 
D/C = discontinue
FGFR = fibroblast growth factor receptor
PD= progressive disease 
PR= partial response
SD = Stable Disease 
SF= screen failure
tx = treatment
 
Adherence to the study design requirements, including those specified in the SoA, is essential 
and required for study conduct. 
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Table 3: 
Schedule of Activities 
Visit Day (Range) 
Screening 
Treatment 
EOT 
Follow-Up 
Survival 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycles 2+ 
Safety 
Disease 
Day 1 
Day 8 
(± 3 d) 
Day 15 
(± 3 d) 
Day 1 
(± 3 d) 
(EOT + 
30-35 d) 
Every 9 Weeks 
(± 7 d) 
Every 
12 Weeks 
Administrative procedures 
Informed consent 
X 
 
 
 
 
 
 
 
 
Section 8.1.1 
Contact IRT 
X 
X 
 
 
X 
X 
 
 
 
 
Inclusion/exclusion criteria 
X 
 
 
 
 
 
 
 
 
 
Prior treatments, procedures, 
surgery for disease 
X 
 
 
 
 
 
 
 
 
 
General and disease medical 
history 
X 
 
 
 
 
 
 
 
 
 
Prior/concomitant medications 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Dispense/administer pemigatinib 
 
X 
 
 
X* 
 
 
 
 
*Assess for up-titration. 
Collect study drug and review 
diary cards 
 
 
X 
X 
X 
X 
 
 
 
Study drug collected only at 
Cycles 2+ and EOT. 
Safety assessments 
Slit lamp, visual acuity, 
fundoscopy with digital imaging 
(eye) 
X 
 
 
 
X* 
X 
 
 
 
*Once every 3 cycles starting at 
Cycle 3. 
Optical coherence tomography 
X* 
 
 
 
X* 
X* 
 
 
 
*Only if clinically indicated. 
AE assessments 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Physical examination 
X 
X 
X 
X 
X 
X 
X 
 
 
Height at screening only. 
Vital signs/body weight 
X 
X 
X 
X 
X 
X 
X 
 
 
Weight on Day 1 of each cycle. 
12-lead ECG 
X 
X 
 
 
X 
X 
X 
 
 
 
Efficacy assessments 
CT or MRI 
X 
 
 
 
X* 
X** 
 
X 
 
*Once every 3 cycles starting at 
the end of Cycle 3. 
Participants achieving PR or CR 
will have a confirmatory CT or 
MRI ≥ 4 weeks (per 
RECIST v1.1). 
**Perform at EOT if not done 
within 1 month prior to EOT. 
ECOG 
X 
X 
 
 
X 
X 
X 
 
 
 
Survival 
 
 
 
 
 
 
 
 
X 
 
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Table 4: 
Schedule of Laboratory Assessments 
Procedure 
Screening 
Treatment 
EOT 
Follow-Up 
Survival 
Notes 
Days 
-35 to -1 
Cycle 1 
Cycles 2+ 
Safety 
Disease 
Day 1 
Day 8 
(± 3 d) 
Day 15 
(± 3 d) 
Day 1 
(± 3 d) 
(EOT + 
30-35 d) 
Every 9 Weeks 
(± 7 d) 
Every 
12 Weeks 
Clinical laboratory assessments 
Blood chemistries 
X 
X* 
X 
X 
X** 
X 
X 
 
 
*May be performed within 
3 days of first dose (cannot be 
same as screening results). 
**Hyperphosphatemia in 
Cycle 1 requires Day 8 testing 
of serum phosphate in Cycle 2+. 
Hematology 
X 
X* 
 
 
X 
X 
 
 
 
*May be performed within 
3 days of first dose (cannot be 
same as screening results). 
Endocrine (PTH only) 
X 
 
 
 
X* 
X 
 
 
 
*Every 3 cycles on Day 1 
starting with Cycle 3. 
HBV/HCV testing 
X 
 
 
 
 
 
 
 
 
 
Urinalysis 
X 
 
 
 
 
X 
 
 
 
 
Pregnancy testing  
X* 
X 
 
 
X 
X* 
 
 
 
*Serum 
Genomic testing 
Tumor tissue sampling 
X* 
 
 
 
X** 
X*** 
 
 
 
*Mandatory tissue at baseline; 
archival tissue allowed if less 
than 12 months from date of 
screening. 
**Optional on-treatment 
biopsies (preferably Cycle 2 
between Days 7-14). 
***Optional biopsy at time of 
progression. 
Blood or Saliva 
X 
 
 
 
 
 
 
 
 
Tumor/normal matched sample. 
Note:  Screening laboratory assessments must be performed within 14 days of Cycle 1 Day 1.  If performed more than 14 days before Cycle 1 Day 1, then the tests must be 
repeated and eligibility confirmed before study drug administration on Cycle 1 Day 1. 
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2. 
INTRODUCTION 
2.1. 
Background 
Pemigatinib is an inhibitor of the FGFR family of receptor tyrosine kinases that is proposed for 
the treatment of solid tumor malignancies with an activating FGFR mutation or translocation.  
Aberrant signaling through FGFR resulting from gene mutations or chromosomal translocations 
has been demonstrated in multiple types of human cancers.  Fibroblast growth factor receptor 
signaling contributes to the development of malignancies by promoting tumor cell proliferation, 
survival, migration, and angiogenesis.  Incyte is proposing to study pemigatinib for the treatment 
of solid tumor malignancies harboring an activating FGFR mutation or translocation. 
2.1.1. 
Fibroblast Growth Factor Receptor Inhibitor in Oncology 
The mammalian FGFR family is composed of 4 highly conserved receptors (FGFR1, FGFR2, 
FGFR3, and FGFR4) that have an extracellular ligand-binding domain, a single transmembrane 
domain, and an intracellular tyrosine kinase domain.  Eighteen FGF ligands, divided into 
canonical and hormonal FGFs, bind to FGFRs, leading to receptor dimerization, activation of the 
kinase domain, and transphosphorylation of the receptors (Eswarakumar et al 2005).  Subsequent 
signal transduction occurs through phosphorylation of substrate proteins, such as FGFR substrate 
2, which leads to activation of the RAS-mitogen–activated protein kinase and phosphoinositide 
3-kinase–protein kinase B pathways and of the phospholipase Cγ that activates the protein kinase 
C pathway.  In some cellular contexts, signal transducer and activator of transcription proteins 
are also activated by FGFRs.  Signaling through the FGF-FGFR pathway is tightly controlled 
through feedback regulation.  Mitogen-activated protein kinase phosphatases and Sprouty 
proteins are upregulated upon FGFR stimulation and antagonize FGF-dependent activation of 
extracellular signal-regulated kinases.  In many cases FGFR pathway activation promotes cell 
proliferation, survival, and migration; however, cellular context plays an important role, and in 
certain tissues, FGFR signaling results in growth arrest and cellular differentiation (Dailey 
et al 2005). 
In adults, FGF-FGFR signaling is involved in angiogenesis during wound healing.  The 
hormonal FGF ligands contribute to regulation of metabolic pathways involving lipid, glucose, 
phosphate, and vitamin D (Itoh 2010).  Genetic defects in the FGF-23 signaling pathway lead to 
disordered phosphate metabolism:  loss of function mutations in FGF-23 or its signaling results 
in retention of phosphate and tissue mineralizing, while gain of function mutations in the 
FGF-23 pathway manifests as hypophosphatemic Rickets syndrome (Farrow and White 2010). 
Strong genetic and functional evidence support that dysregulation of FGFR can lead to the 
establishment and progression of cancer.  Genetic alterations in FGFR1, FGFR2, and FGFR3 
have been described in many tumor types (Knights and Cook 2010, Turner and Grose 2010).  
These include activating mutations, translocations, and gene amplification resulting in 
ligand-independent constitutive activation of the receptors or aberrant ligand-dependent 
signaling through FGFRs. 
A substantial body of evidence supports that a genetically activated FGFR pathway sensitizes 
FGFR-altered cancer cells to knockdown or inhibition of these receptors (Kunii et al 2008, 
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Lamont et al 2011, Nakamura et al 2015, Qing et al 2009, Sia et al 2015, Weiss et al 2010).  A 
large screen of more than 500 tumor cell lines with a selective FGFR inhibitor demonstrated that 
only a small percentage (5.9%) of all cells are sensitive to FGFR inhibition, and growth-
suppressed cell lines were highly enriched for FGFR alterations (Guagnano et al 2012).  These 
results demonstrate that FGFR inhibitors are active in a targeted manner against cancers with 
activated FGFR pathway.  An implication of these data is that selection based on molecular-, 
genetic-, or protein-based diagnostic tests for specific FGFR alterations in tumors may be 
important for identifying patients most likely to benefit from an FGFR inhibitor. 
2.1.2. 
Solid Tumor Malignancies With Activating FGFR Mutations and 
Translocations 
Activation of the FGFR pathway by mutation or rearrangement is well recognized as an 
oncogenic event in cancer.  A recent survey of 4853 solid tumors identified FGFR1-3 mutations 
or rearrangements in 2.25% of all tumors tested (Helsten et al 2016).  Analysis of 
FGFR1-3 mutations and rearrangements in the NCI Genomic Data Commons Data Portal (2019), 
demonstrate that FGFR alterations are not restricted to 1 tumor type but rather broadly 
distributed across a diverse range of tumors (see Table 5).  Importantly, preclinical and clinical 
data support the use of FGFR inhibitors in FGFR altered cell lines and tumors derived from a 
variety of cancer types, including bladder cancer, cholangiocarcinoma, endometrial cancer, 
glioma, and squamous lung cancer (Porta et al 2017). 
Table 5: 
Tumors With Frequency > 1% for FGFR1-3 Mutations and Rearrangements 
in TCGA 
Tumor Type 
FGFR1 
FGFR2 
FGFR3 
Total 
(%) 
Mutation 
(%) 
Fusion 
(%) 
Mutation 
(%) 
Fusion 
(%) 
Mutation 
(%) 
Fusion 
(%) 
Urothelial carcinoma 
0 
0 
0.75 
0 
12.64 
3.15 
16.54 
Cholangiocarcinoma 
0 
0 
0 
13.9 
0 
0 
13.9 
Endometrial carcinoma 
0 
0 
9.68 
0.18 
0 
0 
9.86 
Glioblastoma multiforme 
0.48 
0 
0 
0 
0.48 
8.62 
9.58 
Lung squamous cell carcinoma 
0.21 
0.2 
1.45 
0.2 
1.45 
1.4 
4.91 
Cervical carcinoma 
0 
0 
0.51 
0 
0 
1.97 
2.48 
Renal papillary cell carcinoma 
0 
0 
0 
0 
1.41 
0.68 
2.09 
Rectal adenocarcinoma 
0 
0 
2.01 
0 
0 
0 
2.01 
Head and neck squamous cell carcinoma 
0 
0 
0 
0 
1.14 
0.76 
1.9 
Low grade glioma 
0.19 
0 
0 
0 
0 
1.71 
1.9 
Uterine carcinosarcoma 
0 
0 
1.75 
0 
0 
0 
1.75 
Esophageal adenocarcinoma 
0 
0.54 
0 
0 
0 
1.08 
1.62 
Stomach adenocarcinoma 
0.25 
0 
0.5 
0.48 
0.25 
0 
1.48 
Prostate adenocarcinoma 
0 
0 
0 
1.2 
0 
0.2 
1.4 
Breast (invasive) carcinoma 
0 
0.36 
0. 6 
0.36 
0 
0 
1.32 
Adrenocortical carcinoma 
0 
0 
1.1 
0 
0 
0 
1.1 
Pheochromocytoma and paraganglioma 
1.09 
0 
0 
0 
0 
0 
1.09 
Colorectal adenocarcinoma 
0.27 
0 
0.54 
0 
0.27 
0 
1.08 
Skin cutaneous melanoma 
0.21 
0 
0.84 
0 
0 
0 
1.05 
Based on these observations, an FGFR inhibitor may be active across a variety of tumor types 
with activating point mutations and gene fusions of FGFR1-3. 
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2.2. 
Study Rationale 
Pemigatinib is a potent selective inhibitor of FGFR1-3.  This compound is proposed for the 
treatment of participants with advanced/metastatic or surgically unresectable solid tumor 
malignancies harboring activating FGFR mutations or translocations. 
2.2.1. 
Scientific Rationale for Study Design 
The planned study will evaluate the efficacy and safety of pemigatinib as treatment in 
participants with advanced/metastatic or unresectable solid tumor malignancies with an 
activating FGFR mutation or translocation.  Preliminary data from the ongoing Phase 1/2 study 
(INCB 54828-101) in second-line or greater treatment in all tumor types have shown interesting 
efficacy signals (ORR, PFS) and tolerable safety in participants with FGFR alterations. 
The proposed study design is a single arm, open-label study of pemigatinib.  Individual 
investigators will evaluate tumor responses to support the primary and secondary endpoints. 
2.2.2. 
Justification for Dose and Regimen 
Pemigatinib will be administered at 13.5 mg QD, continuously, during a cycle.  Each cycle is 
3 weeks.  This dose and dosing schedule was selected based on emerging clinical and safety data 
from the INCB 54828-101 study, where the continuous dosing regimen has been tested in 8 and 
16 participants at 9 mg and 13.5 mg QD continuous administration, respectively.  In Study 
INCB 54828-101, the emerging safety data demonstrated that tolerability of the continuous 
dosing regimen of pemigatinib was comparable to that of intermittent dosing. 
The hypothesis with a targeted therapy is that continued inhibition of the aberrant receptor may 
increase the potential for benefit from the treatment.  Therefore, administering pemigatinib 
continuously will allow that consistent inhibition of the aberrant FGFR receptor in this 
population.  Continuous dosing would still allow for dose holds for safety reasons with criteria 
and procedures for dose interruptions and adjustments clearly outlined in the Protocol. 
Hyperphosphatemia is an expected on-target pharmacological effect of FGFR inhibition.  The 
incidence of hyperphosphatemia, defined as any postbaseline phosphate level exceeding 
5.5 mg/dL, has been observed in the majority of participants treated with pemigatinib (refer to 
the IB for complete data).  Some participants do not achieve hyperphosphatemia, and it is 
estimated that pharmacological concentration of pemigatinib in these participants is lower 
(see Figure 2).  Therefore, up-titration of pemigatinib will be used to increase the exposure of 
pemigatinib in participants who do not achieve hyperphosphatemia when treated with 
13.5 mg QD.  The goal is to increase the serum concentration of pemigatinib.  
 
 
 
 
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Any participant who does not reach the target serum phosphate level of > 5.5 mg/dL at any time 
during Cycle 1, and who is compliant with taking study drug and does not experience an ongoing 
Grade 2 or higher treatment-related AEs, will increase the daily dose to 18 mg starting at Cycle 2 
Day 1. 
Dose modifications for tolerability issues are noted in Section 6.5. 
2.3. 
Benefit/Risk Assessment of Pemigatinib 
Targeted therapies with a manageable safety profile that can provide a durable response or 
significant disease control in a molecularly defined population would provide a meaningful 
clinical benefit. 
The comprehensive safety data that are included in the IB (v5) utilized a data cut of 
25 NOV 2018.  As of the cutoff date, a total of 562 participants (78 healthy participants and 
484 participants with advanced malignancies) were enrolled in ongoing clinical studies and 
received at least 1 dose of pemigatinib.  Based on preliminary unaudited data from these ongoing 
studies the most frequently occurring TEAEs (ie, incidence > 20%) were (in descending order of 
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frequency) hyperphosphatemia, diarrhea, alopecia, fatigue, dry mouth, stomatitis, constipation, 
dysgeusia, nausea, decreased appetite, and anemia.  Additional details are provided in the 
following section. 
2.3.1. 
Study INCB 54828-101 
Of the 150 participants with advanced malignancies who have been enrolled in Study 
INCB 54828-101 as of the data cutoff date, 43 participants have been administered pemigatinib 
in Part 1(monotherapy dose escalation), 63 participants in Part 2 (monotherapy dose expansion), 
and 44 participants in Part 3 (pemigatinib combined with gemcitabine and cisplatin 
[8 participants], docetaxel [7 participants], pembrolizumab [23 participants], and trastuzumab 
[6 participants]). 
Dose limiting toxicities informed dose escalation procedures during Part 1 of the study.  Among 
participants in Part 1, 28 received pemigatinib at doses of 1 to 20 mg QD on a 
2-weeks-on/1-week-off therapy schedule (ie, interval dose regimen), and 15 participants received 
pemigatinib at doses of 9, 13.5, or 20 mg QD on a continuous schedule (ie, continuous dose 
regimen).  There were no DLTs for the monotherapy dose regimens, and the monotherapy MTD 
was not reached.  The recommended Part 2 dose for pemigatinib was determined to be 13.5 mg 
based on PD and clinical effect, and the recommended Phase 2 dose regimens for pemigatinib 
based on safety and pharmacokinetic data and preliminary signals of clinical benefit were 
13.5 mg QD following the interval schedule and 13.5 mg QD following the continuous schedule. 
Overall 105 participants (99.1%) who received pemigatinib monotherapy (all doses and dose 
regimens combined) in Study INCB 54828-101 had TEAEs.  Treatment-emergent AEs occurring 
in ≥ 10% of participants who received pemigatinib monotherapy (Parts 1 and 2 combined) are 
presented by dose and dose regimen and overall in Table 6.  Consistent with the expected 
pharmacological effect of FGFR inhibition on serum phosphate levels, the most frequently 
occurring TEAE was hyperphosphatemia (74 participants [69.8%]; serum phosphate 
> 5.5 mg/dL).  Other frequent TEAEs (> 30%) included fatigue in 43 participants (40.6%), dry 
mouth in 39 participants (36.8%), and alopecia in 35 participants (33.0%).  Comparison of the 
most frequently occurring TEAEs for the continuous and interval dose regimens suggests higher 
incidences of hyperphosphatemia (76.7% vs 67.1%), stomatitis (46.7% vs 22.4%), dry mouth 
(43.3% vs 34.2%), diarrhea (43.3% vs 22.4%), constipation (40.0% vs 25.0%), alopecia 
(40.0% vs 30.3%), and nausea (33.3% vs 22.4%) with continuous dosing.  Other TEAEs that 
occurred more frequently with continuous dosing included dry eye, pain in extremity, 
hypercalcemia, onycholysis, and paronychia. 
Forty-five participants (42.5%) who received pemigatinib monotherapy had at least 1 SAE; the 
overall incidence of SAEs for the continuous dose regimen (56.7%) was higher than was seen for 
the interval dose regimen (36.8%).  Pneumonia in 7 participants (6.6%) was the most frequently 
occurring SAE.  Other SAEs occurring in more than 1 participant included back pain and disease 
progression in 4 participants (3.8%) each; abdominal pain, dehydration, fatigue, hyponatremia, 
and acute renal failure in 3 participants (2.8%) each; and blood bilirubin increased, 
cerebrovascular accident, constipation, hypotension, pain in extremity, pleural effusion, and 
pyrexia in 2 participants (1.9%) each.  Within the eye disorders, a single participant had an SAE 
of ocular hyperemia (Grade 2), which was considered unrelated to pemigatinib by the 
investigator.  
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A total of 11 participants (10.4%), 7 participants (9.2%) on an interval dose regimen and 
4 participants (13.3%) on a continuous dose regimen, had SAEs with a fatal outcome:  disease 
progression in 4 participants (3.8%) and pneumonia, malignant neoplasm progression (ie, disease 
progression), cerebrovascular accident, intracranial hemorrhage, multiorgan failure, esophageal 
varices hemorrhage, pneumonia, respiratory failure, and acute respiratory failure secondary to 
acute anemia (verbatim term) in 1 participant (0.9%) each.  None of these fatal events were 
assessed as related to pemigatinib by the investigator. 
Eleven participants (10.4%) discontinued pemigatinib monotherapy due to TEAEs; pneumonia 
in 3 participants (2.8%) and dehydration and small intestinal obstruction in 2 participants (1.9%) 
each were the only TEAEs leading to discontinuation of pemigatinib that occurred in more than 
1 participant. 
More detailed information about the known and expected benefits and risks (clinical safety and 
nonclinical toxicology) and reasonably expected AEs of pemigatinib are provided in the IB. 
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Table 6: 
Summary of Treatment-Emergent Adverse Events Occurring in ≥ 10% of Participants on Pemigatinib 
Monotherapy in Study INCB 54828-101 (Parts 1 and 2 Combined) in Decreasing Order of Frequency 
MedDRA Preferred Term, n (%) 
Pemigatinib Interval Dose Regimena 
Pemigatinib Continuous Dose Regimenb 
Total 
(N = 106) 
1/2/4 mg 
(N = 3) 
6 mg 
(N = 4) 
9 mg 
(N = 13) 
13.5 mg 
(N = 50) 
20 mg 
(N = 6) 
Subtotal 
(N = 76) 
9 mg 
(N = 8) 
13.5 mg 
(N = 16) 
20 mg 
(N = 6) 
Subtotal 
(N = 30) 
Hyperphosphataemia 
0 
1 (25.0) 
8 (61.5) 
38 (76.0) 
4 (66.7) 
51 (67.1) 
4 (50.0) 
14 (87.5) 
5 (83.3) 
23 (76.7) 
74 (69.8) 
Fatigue 
1 (33.3) 
1 (25.0) 
7 (53.8) 
19 (38.0) 
2 (33.3) 
30 (39.5) 
5 (62.5) 
5 (31.3) 
3 (50.0) 
13 (43.3) 
43 (40.6) 
Dry mouth 
0 
1 (25.0) 
6 (46.2) 
17 (34.0) 
2 (33.3) 
26 (34.2) 
2 (25.0) 
7 (43.8) 
4 (66.7) 
13 (43.3) 
39 (36.8) 
Alopecia 
0 
0 
7 (53.8) 
15 (30.0) 
1 (16.7) 
23 (30.3) 
2 (25.0) 
7 (43.8) 
3 (50.0) 
12 (40.0) 
35 (33.0) 
Constipation 
0 
0 
3 (23.1) 
14 (28.0) 
2 (33.3) 
19 (25.0) 
3 (37.5) 
5 (31.3) 
4 (66.7) 
12 (40.0) 
31 (29.2) 
Stomatitis 
0 
0 
3 (23.1) 
11 (22.0) 
3 (50.0) 
17 (22.4) 
4 (50.0) 
7 (43.8) 
3 (50.0) 
14 (46.7) 
31 (29.2) 
Diarrhoea 
0 
1 (25.0) 
2 (15.4) 
12 (24.0) 
2 (33.3) 
17 (22.4) 
1 (12.5) 
8 (50.0) 
4 (66.7) 
13 (43.3) 
30 (28.3) 
Nausea 
1 (33.3) 
1 (25.0) 
5 (38.5) 
8 (16.0) 
2 (33.3) 
17 (22.4) 
2 (25.0) 
7 (43.8) 
1 (16.7) 
10 (33.3) 
27 (25.5) 
Decreased appetite 
0 
2 (50.0) 
2 (15.4) 
12 (24.0) 
1 (16.7) 
17 (22.4) 
0 
4 (25.0) 
2 (33.3) 
6 (20.0) 
23 (21.7) 
Dysgeusia 
1 (33.3) 
0 
5 (38.5) 
8 (16.0) 
2 (33.3) 
16 (21.1) 
1 (12.5) 
3 (18.8) 
3 (50.0) 
7 (23.3) 
23 (21.7) 
Anaemia 
1 (33.3) 
0 
3 (23.1) 
10 (20.0) 
2 (33.3) 
16 (21.1) 
3 (37.5) 
2 (12.5) 
1 (16.7) 
6 (20.0) 
22 (20.8) 
Abdominal pain 
0 
0 
3 (23.1) 
11 (22.0) 
1 (16.7) 
15 (19.7) 
1 (12.5) 
4 (25.0) 
1 (16.7) 
6 (20.0) 
21 (19.8) 
Vomiting 
1 (33.3) 
0 
4 (30.8) 
8 (16.0) 
1 (16.7) 
14 (18.4) 
1 (12.5) 
2 (12.5) 
2 (33.3) 
5 (16.7) 
19 (17.9) 
Aspartate aminotransferase increased 
1 (33.3) 
0 
4 (30.8) 
7 (14.0) 
0 
12 (15.8) 
2 (25.0) 
4 (25.0) 
0 
6 (20.0) 
18 (17.0) 
Hypophosphataemia 
0 
0 
2 (15.4) 
10 (20.0) 
1 (16.7) 
13 (17.1) 
0 
4 (25.0) 
1 (16.7) 
5 (16.7) 
18 (17.0) 
Dehydration 
1 (33.3) 
1 (25.0) 
0 
7 (14.0) 
1 (16.7) 
10 (13.2) 
2 (25.0) 
2 (12.5) 
1 (16.7) 
5 (16.7) 
15 (14.2) 
Dry eye 
0 
0 
1 (7.7) 
7 (14.0) 
1 (16.7) 
9 (11.8) 
0 
5 (31.3) 
1 (16.7) 
6 (20.0) 
15 (14.2) 
Pain in extremity 
0 
1 (25.0) 
3 (23.1) 
3 (6.0) 
1 (16.7) 
8 (10.5) 
1 (12.5) 
5 (31.3) 
1 (16.7) 
7 (23.3) 
15 (14.2) 
Alanine aminotransferase increased 
1 (33.3) 
0 
4 (30.8) 
4 (8.0) 
0 
9 (11.8) 
2 (25.0) 
3 (18.8) 
0 
5 (16.7) 
14 (13.2) 
Cough 
1 (33.3) 
0 
1 (7.7) 
6 (12.0) 
2 (33.3) 
10 (13.2) 
1 (12.5) 
3 (18.8) 
0 
4 (13.3) 
14 (13.2) 
Vision blurred 
1 (33.3) 
1 (25.0) 
2 (15.4) 
4 (8.0) 
2 (33.3) 
10 (13.2) 
0 
3 (18.8) 
1 (16.7) 
4 (13.3) 
14 (13.2) 
Weight decreased 
2 (66.7) 
0 
2 (15.4) 
5 (10.0) 
2 (33.3) 
11 (14.5) 
1 (12.5) 
0 
2 (33.3) 
3 (10.0) 
14 (13.2) 
Blood alkaline phosphatase increased 
1 (33.3) 
0 
3 (23.1) 
6 (12.0) 
0 
10 (13.2) 
2 (25.0) 
1 (6.3) 
0 
3 (10.0) 
13 (12.3) 
Hypercalcaemia 
1 (33.3) 
0 
1 (7.7) 
5 (10.0) 
0 
7 (9.2) 
2 (25.0) 
3 (18.8) 
1 (16.7) 
6 (20.0) 
13 (12.3) 
Back pain 
1 (33.3) 
0 
4 (30.8) 
4 (8.0) 
0 
9 (11.8) 
1 (12.5) 
2 (12.5) 
0 
3 (10.0) 
12 (11.3) 
Onycholysis 
0 
0 
1 (7.7) 
5 (10.0) 
0 
6 (7.9) 
1 (12.5) 
5 (31.3) 
0 
6 (20.0) 
12 (11.3) 
Paronychia 
0 
0 
1 (7.7) 
2 (4.0) 
2 (33.3) 
5 (6.6) 
1 (12.5) 
4 (25.0) 
2 (33.3) 
7 (23.3) 
12 (11.3) 
Arthralgia 
0 
1 (25.0) 
3 (23.1) 
2 (4.0) 
2 (33.3) 
8 (10.5) 
0 
2 (12.5) 
1 (16.7) 
3 (10.0) 
11 (10.4) 
Hyponatraemia 
0 
0 
1 (7.7) 
5 (10.0) 
1 (16.7) 
7 (9.2) 
0 
3 (18.8) 
1 (16.7) 
4 (13.3) 
11 (10.4) 
Nail discolouration 
0 
0 
2 (15.4) 
5 (10.0) 
0 
7 (9.2) 
1 (12.5) 
2 (12.5) 
1 (16.7) 
4 (13.3) 
11 (10.4) 
Note:  Participants were counted once under each MedDRA preferred term.  Adverse events are ordered by the descending frequency in the total column. 
Note:  Treatment-emergent AEs are any AEs either reported for the first time or worsening of a pre-existing event after first dose of study drug. 
a Pemigatinib was administered QD on a 2-weeks-on/1-week-off therapy schedule. 
b Pemigatinib was administered QD. 
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3. 
OBJECTIVES AND ENDPOINTS 
Table 7 presents the objectives and endpoints. 
Table 7: 
Objectives and Endpoints 
Objectives 
Endpoints 
Primary 
To determine the efficacy of pemigatinib in 
participants with locally advanced/metastatic or 
surgically unresectable solid tumor malignancies 
with an activating FGFR mutation or translocation 
• ORR:  defined as the proportion of participants in 
each cohort who achieve a CR or PR based on 
RECIST v1.1 
Secondary 
• To determine other clinical efficacy 
measurements of pemigatinib in participants 
with locally advanced/metastatic or surgically 
unresectable solid tumor malignancies with an 
activating FGFR mutation and/or translocation 
• To determine the safety and tolerability of 
pemigatinib 
• PFS:  defined as the time from first dose until PD 
(per RECIST v1.1 or RANO) or death 
(whichever is first) in each cohort 
• DOR:  defined as the time from the date of first 
assessment of CR or PR until the date of the first 
PD (per RECIST v1.1 or RANO) or death 
(whichever is first) in each cohort 
• DCR:  defined as the proportion of participants 
who achieved best overall response of CR, PR, or 
SD per RECIST v1.1 or RANO 
• OS:  defined as the time from first dose of study 
drug to death of any cause in each cohort 
• Safety and tolerability:  Occurrence of TEAEs 
and treatment-related AEs according to NCI 
CTCAE v5.0, physical exam changes, vital sign 
changes, laboratory evaluations, and ECG values 
in each cohort 
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4. 
STUDY DESIGN 
4.1. 
Overall Design 
This is an open-label, monotherapy study of pemigatinib in participants with advanced/metastatic 
or surgically unresectable solid tumor malignancies harboring an activating FGFR mutation or 
translocation.  This study consists of 2 cohorts; Cohort A will enroll participants with FGFR 
translocations, fusions, and rearrangements, and Cohort B will enroll participants with FGFR 
mutations.  This study will enroll approximately 50 participants.  Participants will receive 
pemigatinib 13.5 mg QD continuously as long as they are receiving benefit and have not met any 
criteria for study withdrawal.  Participants with local laboratory data documenting a 
gain-of-function FGFR1, FGFR2, or FGFR3 mutation gene rearrangement, or other mutation 
identified in a CLIA-certified laboratory are eligible.  Confirmatory testing through the central 
genomics laboratory (Tempus, Chicago, IL) will be performed for all participants; however, 
results from the central genomics laboratory are not required before enrollment.  Centralized 
genomic testing results will allow participants to be assigned to 1 of the following cohorts 
(see Appendix C for list of alterations): 
• Cohort A:  FGFR1-3 in-frame fusions or FGFR2 intron 17 rearrangements 
• Cohort B:  Known/predicted activating point mutations in FGFR1-3 (excluding kinase 
domain) 
Note that there is no difference in the treatment regimen between the cohorts. 
The sponsor may choose to cap enrollment of any one tumor type and/or FGFR alteration in 
order to allow representation of multiple tumor types and avoid analysis being influenced by any 
1 tumor type or due to lack of response in 1 or more tumor subtypes. 
A fresh biopsy at baseline (or archival tissue that was collected less than 12 months from date of 
screening) will be mandatory for participants whose tumors were not previously profiled at the 
reference lab.  On-treatment and end of study biopsies are encouraged for participants with 
safely accessible lesions.  Treatment will start on Day 1.  Participants will undergo regular safety 
assessments during treatment as well as regular efficacy assessments.  Participants will be 
allowed to continue administration in 21-day cycles until documented disease progression or 
unacceptable toxicity is reported. 
4.2. 
Overall Study Duration 
The study begins when the first participant signs the ICF.  The end of the study is defined as the 
date of the last visit of the last participant in the study. 
Once the study has reached the target enrollment, if there are approximately ≤ 3 participants on 
study for more than 6 months, a database lock of the study may occur to allow the analysis of the 
study data.  Any remaining participants may continue to receive study treatment and be seen by 
the investigator per Protocol.  The investigator will be expected to monitor for and report any 
SAEs, AEs of special interest, and pregnancies, as detailed in Section 9.  The remaining 
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participants are considered to be on study until a discontinuation criterion is met and written 
notification is provided to the sponsor. 
4.3. 
Study Termination 
The investigator retains the right to terminate study participation at any time, according to the 
terms specified in the study contract.  The investigator is to notify the IRB/IEC in writing of the 
study's completion or early termination, send a copy of the notification to the sponsor or 
sponsor's designee, and retain 1 copy for the site study regulatory file. 
The sponsor may terminate the study electively, if required by regulatory decision.  If the study 
is terminated prematurely, the sponsor will notify the investigators, the IRBs and IECs, and 
regulatory bodies of the decision and reason for termination of the study. 
5. 
STUDY POPULATION 
Deviations from eligibility criteria are not allowed because they can potentially jeopardize the 
scientific integrity of the study, regulatory acceptability, and/or participant safety.  Therefore, 
adherence to the criteria as specified in the Protocol is essential.  Prospective approval of 
Protocol deviations to recruitment and enrollment criteria, also known as Protocol waivers or 
exemptions, are not permitted. 
5.1. 
Inclusion Criteria 
Participants are eligible to be included in the study only if all of the following criteria apply: 
1. Ability of the participant (or parent, guardian, or legally authorized representative) to 
comprehend and willingness to sign the ICF. 
2. Age 18 years or older, inclusive at the time of signing the informed consent. 
3. Histologically or cytologically confirmed solid tumor malignancy that is advanced or 
metastatic (Stage IIIB or IV per the American Joint Committee on Cancer, Cancer 
Staging Manual, 6th Edition) or is surgically unresectable.  
4. Radiographically measurable disease (per RECIST v1.1 or RANO for primary brain 
tumors).  Tumor lesions located in a previously irradiated area or in an area subjected to 
other loco-regional therapy are considered measureable if progression has been clearly 
demonstrated in the lesion.  
5. Documentation of an FGFR1-3 gene mutation or translocation (see Section 8.4 and 
Appendix C). 
6. Objective disease progression after at least 1 prior therapy, and there is no further 
approved therapy available that is likely to provide clinical benefit.  Participants who are 
intolerant to or decline the approved therapy are eligible only if they have no therapy 
available that is likely to provide clinical benefit. 
7. ECOG performance status 0 to 2. 
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8. Baseline archival tumor specimen (if less than 12 months from date of screening) 
available or willingness to undergo a pretreatment tumor biopsy to obtain the specimen.  
Must be a tumor block or approximately 15 unstained slides from biopsy or resection of 
primary tumor or metastasis. 
9. Not eligible or able to participate in any other Incyte Sponsored Clinical Trial. 
10. Willingness to avoid pregnancy or fathering children based on the criteria below. 
a. Men must agree to take appropriate precautions to avoid fathering children (with at 
least 99% certainty) from screening through 90 days after the last dose of study drug 
and must refrain from donating sperm during this period.  Permitted methods that are 
at least 99% effective in preventing pregnancy (see Appendix A) should be 
communicated to the participants and their understanding confirmed. 
b. Women of childbearing potential must have a negative serum pregnancy test at 
screening and before the first dose on Day 1 and must agree to take appropriate 
precautions to avoid pregnancy (with at least 99% certainty) from screening through 
safety follow-up.  Permitted methods that are at least 99% effective in preventing 
pregnancy (see Appendix A) should be communicated to the participants and their 
understanding confirmed. 
c. Women of nonchildbearing potential (ie, surgically sterile with a hysterectomy and/or 
bilateral oophorectomy OR ≥ 12 months of amenorrhea) are eligible. 
5.2. 
Exclusion Criteria 
Participants are excluded from the study if any of the following criteria apply: 
1. Participants with advanced/metastatic bladder cancer or advanced/metastatic 
cholangiocarcinoma. 
2. Participants with primary brain tumor may not be enrolled if they have received prior 
bevacizumab. 
3. Prior receipt of a selective FGFR inhibitor. 
4. Receipt of anticancer medications or investigational drugs for any indication or reason 
within 28 days before the first dose of pemigatinib.  Participants must have recovered 
(≤ Grade 1 as per CTCAE v5.0) from AEs from previously administered therapies 
(excluding alopecia). 
5. Concurrent anticancer therapy (eg, chemotherapy, radiation therapy, surgery, 
immunotherapy, biologic therapy, hormonal therapy, investigational therapy, or tumor 
embolization). 
6. The participant cannot be a candidate for potentially curative surgery. 
7. Current evidence of clinically significant corneal (including but not limited to 
bullous/band keratopathy, corneal abrasion, inflammation/ulceration, and 
keratoconjunctivitis) or retinal disorder (including but not limited to macular/retinal 
degeneration, diabetic retinopathy, retinal detachment) as confirmed by ophthalmologic 
examination. 
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8. Radiation therapy administered within 2 weeks of enrollment or first dose of study drug.  
Participants must have recovered from all radiation-related toxicities, not require 
corticosteroids, and not have had radiation pneumonitis.  Evidence of fibrosis within a 
radiation field from prior radiotherapy is permitted with medical monitor approval.  A 
1-week washout is permitted for palliative radiation to non-CNS disease with medical 
monitor approval. 
9. Untreated brain or CNS metastases or brain or CNS metastases that have progressed 
(eg, evidence of new or enlarging brain metastasis or new neurological symptoms 
attributable to brain or CNS metastases).  Participants with previously treated and 
clinically stable brain or CNS metastases are eligible if there is no evidence of 
progression for at least 4 weeks after CNS-directed treatment as ascertained by clinical 
examination and brain imaging (MRI or CT scan) during the screening period and they 
are on a stable or decreasing dose of corticosteroids for at least 1 week. 
10. Known additional malignancy that is progressing or requires active treatment.  
Exceptions include basal cell carcinoma of the skin, squamous cell carcinoma of the skin, 
or in situ cervical cancer that has undergone potentially curative therapy. 
11. Participants with laboratory values at screening defined in Table 8. 
Table 8: 
Exclusionary Laboratory Values 
Laboratory Parameter 
Exclusion Criterion 
Hematology 
a 
Platelets 
≤ 75 × 109/L (transfusion allowed with 2-week washout period) 
b 
Hemoglobin 
≤ 9.0 g/L (transfusion allowed within 2-week washout period) 
c 
Absolute neutrophil count 
≤ 1.5 × 109/L 
Hepatic 
d 
ALT 
≥ 3 × ULN 
e 
AST 
≥ 3 × ULN (5 × ULN for liver mets) 
f 
Total bilirubin 
≥ 1.5 × ULN (2.5 × ULN if Gilbert's syndrome or liver mets) 
g 
Alkaline phosphatase 
≥ 3 × ULN 
Renal 
h 
Serum creatinine clearance 
≤ 30 mL/minute based on Cockcroft-Gault formula 
Chemistry 
i 
Serum phosphate 
> ULN 
j 
Serum calcium 
Outside of normal range or serum albumin-corrected calcium 
outside of the normal range when serum albumin is outside of 
the normal range 
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12. History of calcium and phosphate hemostasis disorder or systemic mineral imbalance 
with ectopic calcification of soft tissues (exception:  commonly observed calcifications in 
soft tissues such as the skin, kidney tendon or vessels due to injury, disease, or aging in 
the absence of systemic mineral imbalance). 
13. Gastrointestinal condition/disorder that may raise gastric and/or small intestinal pH that 
could interfere with absorption, metabolism, or excretion of pemigatinib.  
14. Inability to swallow and retain oral medication. 
15. Clinically significant or uncontrolled cardiac disease including unstable angina, acute 
myocardial infarction within 6 months from Day 1 of study drug administration, 
New York Heart Association Class III or IV congestive heart failure, and uncontrolled 
arrhythmia (participants with a pacemaker or with atrial fibrillation and well-controlled 
heart rate are allowed). 
16. History or presence of an abnormal ECG that, in the investigator's opinion, is clinically 
meaningful.  A screening QTcF interval > 480 milliseconds is excluded.  For participants 
with an intraventricular conduction delay (QRS interval ≥ 120 milliseconds), the JTc 
interval may be used in place of the QTc with sponsor approval.  The JTc must be 
≤ 340 milliseconds if JTc is used in place of the QTc. 
17. Active chronic or current infectious disease requiring systemic antibiotic, antifungal, or 
antiviral treatment within 2 weeks before enrollment (participants with asymptomatic 
chronic infections on prophylactic treatment are allowed). 
18. Evidence of active HBV or HCV infection (defined as participants with elevated 
transaminases or cirrhosis.  Participants with chronic HBV/HCV infection with no 
cirrhosis and no elevated transaminases are allowed). 
19. Known HIV infection. 
20. Current use of prohibited medication as described in Section 6.6.2. 
21. Use of any potent CYP3A4 inhibitors or inducers or moderate CYP3A4 inducers within 
14 days or 5 half-lives (whichever is longer) before the first dose of study drug. 
22. Known hypersensitivity or severe reaction to pemigatinib or excipients of pemigatinib 
(refer to the IB). 
23. Inability or unlikeliness of the participant to comply with the dose schedule and study 
evaluations, in the opinion of the investigator. 
24. Inadequate recovery from toxicity and/or complications from a major surgery before 
starting therapy. 
25. Women who are pregnant or breastfeeding. 
26. Any condition that would, in the investigator's judgment, interfere with full participation 
in the study, including administration of study drug/treatment and attending required 
study visits; pose a significant risk to the participant; or interfere with interpretation of 
study data. 
27. History of hypovitaminosis D requiring supraphysiologic doses (eg, 50,000 IU/week) to 
replenish the deficiency.  Vitamin D supplements are allowed. 
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5.3. 
Lifestyle Considerations 
Based on the preliminary results from food-effect cohort in Study INCB 54828-101, no 
significant food effect was observed.  Pemigatinib may be administered with or without food. 
Refrain from consumption of red wine, Seville oranges, grapefruit or grapefruit juice (pomelos, 
exotic citrus fruits, grapefruit hybrids, or fruit juices) for 7 days before the start of study 
treatment until after the final dose, as this can influence the metabolism of the study drug. 
5.4. 
Screen Failures 
Screen failures are defined as participants who consent to participate in the clinical study but are 
not subsequently entered in the study.  Individuals who do not meet the criteria for participation 
in this study (screen failure) may be rescreened no more than 1 time. 
Tests with results that fail eligibility requirements may be repeated once during screening if the 
investigator believes the result to be in error.  Additionally, a participant who fails screening may 
repeat the screening process 1 time if the investigator believes that there has been a change in 
eligibility status.  Participants who rescreen must reconsent and be assigned a new participant 
number. 
5.5. 
Replacement of Participants 
No participants will be replaced at any time during this study. 
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6. 
STUDY TREATMENT 
6.1. 
Study Treatment Administered 
Table 9 presents the study treatment information.  Starting dose for all participants is 
13.5 mg QD. 
Table 9: 
Study Treatment Information 
Study treatment name: 
Pemigatinib 
Dosage formulation: 
Tablet 
Unit dose strengths/dosage levels: 
4.5 mg tablet/4.5 mg, 9 mg, 13.5 mg, and 18 mg 
Route of administration:  
Oral 
Administration instructions: 
1-4 tablet(s) taken every morning (unless otherwise directed) 
Packaging and labeling: 
Pemigatinib will be provided in bottles; each bottle will be labeled 
as required per country requirement. 
Storage: 
Room temperature (15-30°C) 
6.2. 
Preparation, Handling, and Accountability 
The investigator or designee must confirm appropriate temperature conditions have been 
maintained during transit for all study treatments received and any discrepancies are reported and 
resolved before use of the study treatment.  
Only participants enrolled in the study may receive study treatment, and only authorized site 
staff may supply or administer study treatment.  All study treatment must be stored in a secure, 
environmentally controlled, and monitored (manual or automated) area in accordance with the 
labeled storage conditions with access limited to the investigator and authorized site staff.  
The investigator (or designee) is responsible for study treatment accountability, reconciliation, 
and record maintenance (ie, receipt, reconciliation, and final disposition records).  Inventory and 
accountability records must be maintained and readily available for inspection by the study 
monitor and are open to inspection at any time by any applicable regulatory authorities.  The 
investigator or designee must maintain records that document: 
• Delivery of study drug to the study site. 
• Inventory of study drug at the site. 
• Participant use of the study drug including pill counts from each supply dispensed. 
• Return of study drug to the investigator or designee by participants. 
The investigational product must be used only in accordance with the Protocol.  Tablets are not 
to be crushed, dissolved, or broken.  The investigator will also maintain records adequately 
documenting that the participants were provided the specified study drug.  These records should 
include dates, quantities, and any available batch or serial numbers or unique code numbers 
assigned to the investigational product and study participants. 
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Completed accountability records will be archived by the site.  The investigator or designee will 
be expected to collect and retain all used, unused, and partially used containers of study drug 
until verified by the study monitor (unless otherwise agreed to by the sponsor).  At the 
conclusion of the study, the investigator or designee will oversee shipment of any remaining 
study drug back to the sponsor or its designee for destruction according to institutional standard 
operating procedures.  If local procedures mandate on-site destruction of investigational supply, 
the site should (where local procedures allow) maintain the investigational supply until the study 
monitor inspects the accountability records in order to evaluate compliance and accuracy of 
accountability by the investigative site.  At sites where the study drug is destroyed before 
monitor inspection, the monitors rely on documentation of destruction per the site SOP. 
Instructions for participants regarding the handling of the study drug are in Appendix B. 
6.3. 
Measures to Minimize Bias:  Randomization and Blinding 
Not applicable.  This is an open-label, non-randomized study. 
6.4. 
Study Treatment Compliance 
Compliance with all study-related treatments and assessments should be emphasized to the 
participant by the site personnel and appropriate steps should be taken to optimize compliance 
during the study. 
Compliance with pemigatinib will be calculated by the sponsor based on the drug accountability 
documented by the site staff and monitored by the sponsor/designee (tablet counts).  Participants 
will be instructed to bring all study drugs with them to the study visits in order for site personnel 
to conduct tablet counts to assess study drug accountability.  The drug accountability 
documentation will be used by the sponsor to calculate treatment compliance. 
6.5. 
Dose Modifications 
Individual decision regarding dose modifications of pemigatinib should be made using clinical 
judgement and in consultation with the sponsor's medical monitor, taking into account 
relatedness of the AE to the study treatment and the participant's underlying condition.  Adverse 
events that have a clear alternative explanation or transient (≤ 72 hours) abnormal laboratory 
values without associated clinically significant signs or symptoms, may be exempt from 
dose-reduction rules. 
6.5.1. 
Criteria and Procedures for Dose Interruptions and Adjustments of Study Drug 
Safety concerns should be discussed with the sponsor immediately upon occurrence or awareness 
to determine if the participant should continue or discontinue study treatment. 
Treatment with pemigatinib may be delayed up to 2 weeks (14 days) to allow for resolution of 
toxicity.  Participants may resume treatment if no medical condition or other circumstance exists 
that, in the opinion of the investigator, would make the participant unsuitable for further 
participation in the study.  The treating investigator should contact the sponsor to discuss the 
case of any participant whose treatment has been delayed for more than 14 days before restarting 
treatment with pemigatinib.  Refer to Table 10 for guidelines. 
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Table 10: 
Guidelines for Interruption and Restarting of Study Drug 
ADVERSE EVENT 
ACTION TAKEN 
Chemistry 
• AST and/or ALT is > 5.0 × ULN. 
Note: In participants with liver 
metastasis-related elevations at baseline, 
contact sponsor to discuss clinical 
management and possible dose reductions. 
Step 1:  Interrupt pemigatinib up to 2 weeks (14 days) until 
the toxicity has resolved to ≤ Grade 1 except by approval of 
the medical monitor. 
Step 2:  Restart pemigatinib at same dose.  If assessed as 
related to pemigatinib, restart pemigatinib at next lower 
dose; monitor as clinically indicated. 
Other toxicities 
• Any Grade 1 or Grade 2 toxicity. 
Continue pemigatinib treatment and treat the toxicity; 
monitor as clinically indicated. 
• Any Grade 3 toxicity, if clinically 
significant and not manageable by 
supportive care. 
Step 1:  Interrupt pemigatinib up to 2 weeks (14 days), until 
toxicity resolves to ≤ Grade 1. 
Step 2:  Restart pemigatinib at same dose.  If assessed as 
related to pemigatinib, restart pemigatinib at next lower 
dose; monitor as clinically indicated. 
• Any recurrent Grade 3 toxicity after 
2 dose reductions. 
Discontinue pemigatinib administration and follow-up per 
Protocol (exceptions require approval of sponsor). 
• Any other Grade 4 toxicity. 
Discontinue pemigatinib administration and follow-up per 
Protocol. 
The sponsor recommends a maximum of 2 level dose reductions:  participants treated at 13.5 mg 
can decrease to 9 mg, and if additional dose reduction is required, participants can decrease to 
4.5 mg.  Dose reductions below 4.5 mg are not allowed.  The frequency of dosing (ie, QD) as 
well as the schedule (ie, continuous dosing) remain the same. 
For participants who are up-titrated from 13.5 mg to 18 mg, a maximum of 2 dose level 
reductions is also recommended.  The 18-mg dose can be decreased to 13.5 mg, and if additional 
dose reduction is required, participants can decrease to 9 mg.  Dose reductions below 9 mg are 
not allowed. 
6.5.2. 
Management of Hyperphosphatemia 
Hyperphosphatemia is an expected on-target pharmacologic effect of FGFR inhibition.  
Hyperphosphatemia should be managed with diet modifications, phosphate binders and diuretics, 
or a dose reduction per the recommendations in Table 11. 
The use of diet modifications alone include food exchanges from high-phosphate foods to 
low-phosphate foods and can be implemented once serum phosphate levels are above the ULN 
but do not exceed 7.0 mg/dL.  Diet modification should continue with the inclusion of phosphate 
binders once serum phosphate levels exceed 7.0 mg/dL.  An example of a phosphate binder is 
sevelamer HCl (eg, Renegel®, Renvela®).  Administration of phosphate binders should be 
3 times per day (eg, with each meal) to reduce absorption of phosphate.  Doses and frequency of 
doses should be based on the participant's tolerance for the binder and the control of serum 
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phosphate.  If binders are used to manage hyperphosphatemia during treatment, it is 
recommended to stop binders at the same time pemigatinib is stopped to reduce risk of 
hypophosphatemia. 
For grading of hyperphosphatemia, please note that CTCAE v5.0 now has a category for 
hyperphosphatemia. 
Table 11: 
Recommended Approach for Hyperphosphatemia Management 
Serum Phosphate 
Level 
Supportive Care 
Guidance for 
Interruption/Discontinuation 
of Pemigatinib 
Guidance for 
Restarting 
Pemigatinib 
> 5.5 mg/dL and 
≤ 7 mg/dL 
Initiate a low-phosphate diet  
No action. 
Not applicable. 
> 7 mg/dL and 
≤ 10 mg/dL  
Initiate/continue a low-phosphate 
diet and initiate phosphate binding 
therapy.  Monitor serum 
phosphate approximately twice a 
week and adjust the dose of 
binders as needed; continue to 
monitor serum phosphate at least 
twice a week until return to 
≤ 7 mg/dL. 
If serum phosphate level 
continues to be > 7 mg/dL and 
≤ 10 mg/dL with concomitant 
phosphate-binding therapy for 
2 weeks, or if there is 
recurrence of serum phosphate 
level in this range, interrupt 
pemigatinib for up to 2 weeks  
Restart at the same 
dose when serum 
phosphate is 
< 7 mg/dL.  If serum 
phosphate level 
recurs at > 7 mg/dL, 
restart pemigatinib 
with dose reduction. 
> 10 mg/dL 
Continue to maintain a 
low-phosphate diet, adjust 
phosphate-binding therapy, and 
start/continue phosphaturic agent.  
Continue to monitor serum 
phosphate approximately twice a 
week until return to ≤ 7 mg/dL. 
If serum phosphate level is 
> 10 mg/dL for 1 week 
following phosphate-binding 
therapy and low-phosphate diet, 
interrupt pemigatinib.  If there 
is recurrence of serum 
phosphate level in this range 
following 2 dose reductions, 
permanently discontinue 
pemigatinib. 
Restart pemigatinib at 
reduced dose with 
phosphate binders 
when serum 
phosphate is 
< 7 mg/dL. 
6.5.3. 
Up-Titration 
Any participant who does not reach the target serum phosphate level of > 5.5 mg/dL at any time 
during Cycle 1, are compliant with taking study drug and do not experience an ongoing Grade 2 
or higher treatment-related AEs will increase the daily dose to 18 mg starting from Cycle 2 
Day 1. 
Participants who are titrated up to 18 mg QD will begin the next cycle at the new dose level and 
must agree to all Cycle 1 assessments.  Up-titration may occur no earlier than Cycle 2 Day 1 so 
that subjects are observed for phosphate level and AEs for at least 1 cycle. 
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6.5.4. 
Criteria for Permanent Discontinuation of Study Drug 
The occurrence of unacceptable toxicity not caused by the underlying disease will require that 
the study drug be permanently discontinued.  Unacceptable toxicity is defined as follows: 
• Occurrence of an AE that is related to study drug that, in the judgment of the 
investigator or the sponsor's medical monitor, compromises the participant's ability to 
continue study-specific procedures or is considered to not be in the participant's best 
interest.  
• An AE requiring more than 2 dose reductions. 
• Persistent AE requiring a delay of therapy for more than 2 weeks (14 days) unless a 
greater delay has been approved by the sponsor. 
• Increase in QT/QTc to > 500 milliseconds or to > 60 milliseconds over baseline.  In 
case of a QTc > 500 milliseconds, the participant must be hospitalized and continuous 
ECG monitoring must be set up until the measure of the QTc interval decreases below 
500 milliseconds and is acceptable in the opinion of the local cardiologist.  
See Section 7 for discontinuation procedures. 
6.6. 
Concomitant Medications and Procedures 
All concomitant medications and treatments (including over-the-counter or prescription 
medicines, vitamins, vaccines, and/or herbal supplements) must be recorded in the eCRF.  Any 
prior medication received up to 35 days before the first dose of study treatment and 30 to 35 days 
after the last dose of study treatment, or until the participant begins a new anticancer therapy, 
whichever occurs first, will be recorded in the eCRF.  Any addition, deletion, or change in the 
dose of these medications will also be recorded.  Concomitant medications administered after 
30-35 days after the last dose of study treatment should be recorded for SAEs as defined in 
Section 9.2.  Concomitant treatments/procedures that are required to manage a participant's 
medical condition during the study will also be recorded in the eCRF.  The medical monitor 
should be contacted if there are any questions regarding concomitant or prior therapy. 
6.6.1. 
Restricted Medications and Procedures 
Pemigatinib is predominantly metabolized by CYP3A4.  There is an expected 50% increase in 
exposure in participants who concomitantly use CYP3A4 moderate inhibitors.  However, as 
doses above the recommended Phase 2 dose of 13.5 mg QD have been tested (20 mg QD is 
tolerable), there is a sufficient safety margin.  Therefore, the use of moderate CYP3A4 inhibitors 
is not prohibited but should involve careful monitoring, especially in relation to safety, while 
moderate CYP3A4 inducers and potent CYP3A4 inhibitors and inducers are prohibited 
(see Appendix D). 
Careful monitoring is required when pemigatinib is concomitantly administered with organic 
cation transporter 2 substrates such as dofetilide and metformin. 
Calcium-based phosphate binding medications should not be used due to a concern for soft tissue 
mineralization. 
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6.6.2. 
Prohibited Medications and Procedures 
The following medications and measures are prohibited: 
• The concomitant administration of potent CYP3A4 inhibitors and inducers and 
moderate CYP3A4 inducers (see Appendix D).  Based on the low overall 
bioavailability of topical ketoconazole, there are no restrictions on topical 
ketoconazole.  
• Any concomitant use of a selective FGFR inhibitor (other than pemigatinib). 
• Investigational study drug for any indication. 
• Use of any anticancer medications other than the study medications being tested in 
this Protocol. 
7. 
DISCONTINUATION OF STUDY TREATMENT AND 
PARTICIPANT DISCONTINUATION/WITHDRAWAL 
7.1. 
Discontinuation of Study Treatment 
7.1.1. 
Reasons for Discontinuation 
Participants must be discontinued from study treatment for the following reasons.  Please note 
that if a participant discontinues study treatment for reasons other than disease progression or 
withdraw of consent, the participant should be followed until disease progression is documented. 
• The participant becomes pregnant. 
• Consent is withdrawn. 
Note:  Consent withdrawn means that the participant has explicitly indicated that they 
do not want to be followed any longer; in this case no further data, except data in 
public domain, may be solicited from or collected on the participant.  Participants 
may choose to discontinue study treatment and remain in the study to be followed for 
progression and survival. 
• Further participation would be injurious to the participant's health or well-being, in 
the investigator's medical judgment.  
• Unacceptable toxicity as noted in Section 6.5.4. 
• The study is terminated by the sponsor. 
• The study is terminated by the local health authority, IRB, or IEC. 
• Disease progression has been reported by radiology review. 
• Other antineoplastic treatment is initiated, not including palliative radiation. 
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A participant may be discontinued from study treatment as follows: 
• If, during the course of the study, a participant is found not to have met eligibility 
criteria, the medical monitor, in collaboration with the investigator, will determine 
whether the participant should be withdrawn from study treatment. 
• If a participant is noncompliant with study procedures or study drug/treatment 
administration in the investigator's opinion, the sponsor should be consulted for 
instruction on handling the participant. 
7.1.2. 
Discontinuation Procedures 
In the event that the decision is made to permanently discontinue the study treatment, the EOT 
visit should be conducted.  Reasonable efforts should be made to have the participant return for a 
follow-up visit.  These visits are described in Table 3 and Table 4.  The last date of the last dose 
of study drug and the reason for discontinuation of study treatment will be recorded in the eCRF. 
If a participant is discontinued from study treatment: 
• The study monitor or sponsor must be notified. 
• The reason(s) for withdrawal must be documented in the participant's medical record 
and the primary reason for withdrawal must be included in the eCRF. 
• The EOT visit should be performed. 
• The date of the EOT visit should be recorded in the IRT. 
• Participants must be followed for safety until the time of the follow-up visit or until 
study drug–related toxicities resolve, return to baseline, or are deemed irreversible, 
whichever is longest. 
If the participant discontinues study treatment and actively withdraws consent for collection of 
follow-up data (safety follow-up or disease assessment), then no additional data collection 
should occur; however, participants will have the option of withdrawing consent for study 
treatment but continuing in the follow-up period of the study for safety/efficacy assessments and 
survival follow-up. 
7.2. 
Participant Withdrawal From the Study 
A participant may withdraw from the study at any time at his/her own request, or may be 
withdrawn at any time at the discretion of the investigator for safety, behavioral, compliance, or 
administrative reasons. 
If the participant withdraws consent for disclosure of future information, the sponsor may retain 
and continue to use any data collected before such a withdrawal of consent. 
If a participant withdraws from the study, he/she may request destruction of any samples taken 
and not tested, and the investigator must document this in the site study records. 
See Table 3 and Table 4 for data to be collected at the time of study discontinuation and 
follow-up and for any further evaluations that need to be completed. 
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7.3. 
Lost to Follow-Up 
A participant will be considered lost to follow-up if he/she repeatedly fails to return for 
scheduled visits and is unable to be contacted by the study site. 
The following actions must be taken if a participant fails to return to the clinic for a required 
study visit: 
• The site must attempt to contact the participant and reschedule the missed visit as 
soon as possible and counsel the participant on the importance of maintaining the 
assigned visit schedule and ascertain whether or not the participant wishes to and/or 
should continue in the study.  
• Before a participant is deemed lost to follow-up, the investigator or designee must 
make every effort to regain contact with the participant (where possible, 3 telephone 
calls and, if necessary, a certified letter to the participant's last known mailing address 
or local equivalent methods).  These contact attempts should be documented in the 
participant's medical record. 
• Should the participant continue to be unreachable, he/she will be considered to have 
withdrawn from the study. 
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8. 
STUDY ASSESSMENTS AND PROCEDURES 
8.1. 
Administrative and General Procedures 
8.1.1. 
Informed Consent Process 
• The investigator or his/her representative will explain the nature of the study to the 
participant or his/her legally authorized representative and answer all questions 
regarding the study. 
− Informed consent must be obtained before any study-related procedures are 
conducted, unless otherwise specified by the Protocol. 
− Informed consent must be obtained using the IRB/IEC-approved version in a 
language that is native and understandable to the participant.  A template will be 
provided by the sponsor or its designee.  The sponsor or its designee must review 
and acknowledge the site-specific changes to the ICF template.  The ICF must 
include a statement that the sponsor or its designee and regulatory authorities have 
direct access to participant records. 
− The ICF must contain all required elements and describe the nature, scope, and 
possible consequences of the study in a form understandable to the study 
participant. 
• Participants must be informed that their participation is voluntary.  Participants or 
their legally authorized representative will be required to sign a statement of informed 
consent that meets the applicable requirements and regulations for the country in 
which the study is being conducted as well as the IRB/IEC or study center. 
• The participant must be informed that his/her personal study-related data will be used 
by the sponsor in accordance with local data protection laws.  The level of disclosure 
must also be explained to the participant. 
• The participant must be informed that his/her medical records may be examined by 
Clinical Quality Assurance auditors or other authorized personnel appointed by the 
sponsor, by appropriate IRB/IEC members, and by inspectors from regulatory 
authorities. 
• The medical record must include a statement that written informed consent was 
obtained before the participant was enrolled in the study and the date the written 
consent was obtained.  The authorized person obtaining the informed consent must 
also sign the ICF. 
• Participants must provide consent to the most current version of the ICF(s) during 
their participation in the study. 
• A copy of the ICF(s) must be provided to the participant or the participant's legally 
authorized representative. 
• Participants who are rescreened are required to sign a new ICF. 
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8.1.2. 
Screening Procedures 
Screening is the interval between signing the ICF and the day the participant is enrolled in the 
study (Cycle 1 Day 1).  Screening may not exceed 35 days.  Assessments that are required to 
demonstrate eligibility may be performed over the course of 1 or more days during the screening 
process. 
Procedures conducted as part of the participant's routine clinical management (eg, blood count, 
imaging study) and obtained before signing of informed consent may be used for screening or 
baseline purposes provided the procedure meets the Protocol-defined criteria and has been 
performed in the timeframe of the study (ie, within 35 days of Cycle 1 Day 1).  For participants 
who are enrolled in the study, information associated with eligibility requirements must be 
entered into the appropriate eCRF pages. 
Results from the screening visit evaluations will be reviewed to confirm eligibility before 
enrollment or the administration of study drug.  Tests with results that fail eligibility 
requirements may be repeated once during screening if the investigator believes the results to be 
in error.  For screening assessments that are repeated, the most recent available result before 
treatment begins will be used to determine eligibility.  Treatment should start as soon as possible 
but within 3 days after the date of enrollment. 
See Sections 5.4 and 5.5 for information regarding screen failures and replacement of 
participants, respectively. 
8.1.3. 
Interactive Response Technology Procedure 
Each participant will be identified in the study by a participant ID number, which is a 
combination of the site ID and participant number.  Site staff should contact the IRT to obtain the 
participant ID number during screening.  Upon determining that the participant is eligible for 
study entry, the IRT will be contacted to obtain the treatment assignment.  Additionally, the IRT 
will be contacted as indicated in Table 3 to update the study drug supply.  Additional details are 
provided in the IRT Manual. 
8.1.4. 
Demography and Medical History 
8.1.4.1. 
Demographics and General Medical History 
Demographic data and general medical history will be collected at screening by the investigator 
or qualified designee and will include year of birth/age, race, ethnicity, medical and surgical 
history, and current illnesses.  Medical history will include relevant medical or surgical treatment 
within the last 10 years that are considered to be clinically significant by the investigator. 
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8.1.4.2. 
Disease Characteristics and Treatment History 
A disease-targeted medical and treatment history will be collected at screening.  Details 
regarding the participant's malignancy under study, including date of diagnosis, initial and 
current cancer stage, tumor histology, and relevant disease characteristics, and prior treatments, 
including systemic treatments, radiation, and surgical procedures, will be recorded. 
8.2. 
Efficacy Assessments 
8.2.1. 
Tumor Imaging 
Objective assessment of tumor status is required using RECIST v1.1 (Eisenhauer et al 2009) and 
RANO (Wen et al 2010) for patients with primary brain tumors to determine responses and will 
be logged into the eCRF.  The recommended method for measuring and following tumor burden 
will be CT scan to include the thorax, abdomen, and pelvis; the neck can be included if needed.  
Alternative modalities (eg, MRI) may be substituted for a CT scan at the discretion of the 
investigator, provided that the same modality is used throughout the study and that the 
methodology is consistent with RECIST v1.1 or RANO. 
The schedule for efficacy assessments will be at screening (this will be considered the baseline 
scan), every 9 weeks (every 3 cycles), and then at EOT (if applicable).  Imaging should continue 
in 9-week intervals regardless of delays in cycle starts.  For participants showing a response, a 
confirmatory scan may be performed a minimum of 4 weeks (per RECIST v1.1 and RANO) 
from the previous scan.  For participants showing a progression based on radiologic review, 
treatment should be discontinued. 
For participants who discontinue treatment for reasons other than disease progression, every 
effort should be made to continue monitoring their disease status by radiographic imaging until 
1) start of new anticancer therapy, 2) documented disease progression, 3) death, or 4) end of 
study, whichever occurs first. 
8.2.2. 
ECOG Performance Status 
ECOG performance status (see Table 12) will be assessed at the visits specified in Table 3. 
Table 12: 
ECOG Performance Status 
Grade 
Performance Status 
0 
Fully active, able to carry on all predisease 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 self-care but unable to carry out any work activities.  Up and 
about more than 50% of waking hours. 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours. 
4 
Completely disabled.  Cannot carry on any self-care.  Totally confined to bed or chair. 
5 
Dead. 
Source:  Oken et al 1982. 
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8.2.3. 
Medical Resource Utilization and Health Economics 
Medical Resource Utilization and Health Economics parameters are not evaluated in this study. 
 
 
 
8.3. 
Safety Assessments 
See Section 6.5 for guidelines regarding the management of relevant laboratory or other safety 
assessment abnormalities. 
8.3.1. 
Adverse Events 
Adverse events will be monitored from the time the participant signs the ICF until at least 
30-35 days after the last dose of study drug or until the start of new anticancer therapy, 
whichever occurs first.  Adverse events that begin or worsen after informed consent should be 
recorded on the Adverse Events Form in the eCRF regardless of the assumption of a causal 
relationship with the study drug.  Conditions that were already present at the time of informed 
consent should be recorded on the Medical History Form in the eCRF.  Adverse events 
(including laboratory abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible rather than by individual underlying signs and symptoms. 
Adverse events will be reported by the participant (or, when appropriate, by a caregiver, 
surrogate, or the participant's legally authorized representative).  The investigator and any 
qualified designees are responsible for detecting, documenting, and recording events that meet 
the definition of an AE or SAE and remain responsible for following-up on AEs that are serious, 
considered related to the study treatment/procedures, or that caused the participant to discontinue 
study drug.  Care will be taken not to introduce bias when detecting AEs and/or SAEs.  
Open-ended and nonleading verbal questioning of the participant, such as "How are you 
feeling?" is the preferred method to inquire about AE occurrences.  Adverse events may also be 
detected when they are volunteered by the participant during the screening process or between 
visits, or through physical examinations, laboratory tests, or other assessments.  The definition, 
reporting, and recording requirements for AEs are described in Section 9. 
All SAEs will be recorded and reported to the sponsor or designee within 24 hours.  The 
investigator will submit any updated SAE data to the sponsor within 24 hours of it being 
available. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
8.3.2. 
Physical Examinations 
A medically qualified individual, such as a licensed physician, physician's assistant, or an 
advanced registered nurse practitioner, must perform physical examinations as local law permits.  
Abnormalities identified after the first dose of study treatment constitute an AE if they are 
considered clinically meaningful, induce clinical signs or symptoms, require concomitant 
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therapy, or require changes in study drug.  Investigators should pay special attention to clinical 
signs related to previous serious illnesses. 
At the screening visit, a comprehensive physical examination should be conducted.  The 
comprehensive physical examination will include height and body weight, and assessment(s) of 
the following organ or body systems:  skin; head, eyes, ears, nose, and throat; thyroid; lungs; 
cardiovascular system; abdomen (liver, spleen); extremities; and lymph nodes; as well as a brief 
neurological examination. 
During the study, participants will be assessed by the investigator or medically qualified 
designee per institutional standard of care.  These assessments should be an evaluation as 
indicated by participant symptoms, AEs, or other findings and documented on the Adverse 
Events eCRF. 
8.3.3. 
Vital Signs 
Vital sign measurements (to be taken before blood collection for laboratory tests), include blood 
pressure, pulse, respiratory rate, and body temperature.  Blood pressure and pulse will be taken 
with the participant in the recumbent, semirecumbent, or sitting position after approximately 
5 minutes of rest.  Weight will be assessed on Day 1 of each study cycle.  Abnormal vital sign 
results identified after the first dose of study treatment constitute an AE if they are considered 
clinically meaningful, induce clinical signs or symptoms, require concomitant therapy, or require 
changes in study drug. 
8.3.4. 
Electrocardiograms 
Single 12-lead ECGs will be obtained as outlined in the SoA (see Table 3) using an ECG 
machine that automatically calculates the heart rate and measures PR, QRS, QT, and 
QTc intervals.  All 12-lead ECGs will be performed with the participant in a recumbent or 
semirecumbent position after approximately 5 minutes of rest. 
The 12-lead ECGs will be interpreted by the investigator at the site to be used for immediate 
participant management.  Additional 12-lead ECGs may be performed as clinically indicated to 
manage participant safety.  The decision to include or exclude a participant or withdraw a 
participant from the study treatment based on an ECG flagged as "Abnormal, Clinically 
Significant" is the responsibility of the investigator, in consultation with the sponsor's medical 
monitor, as appropriate.  Clinically notable abnormalities that are considered clinically 
significant in the judgment of the investigator are to be reported as AEs.  In the event that a 
single QTc is > 480 milliseconds at screening, the participant may enroll if the average QTc for 
the 3 ECGs is ≤ 480 milliseconds or with approval from the medical monitor.  For participants 
with an intraventricular conduction delay (QRS interval > 120 milliseconds) at screening, the 
JTc interval may be used in place of the QTc with medical monitor approval.  The JTc must be 
≤ 340 milliseconds if JTc is used in place of the QTc.  In addition, the JTc interval should be 
used for all subsequent assessments. 
8.3.5. 
Comprehensive Eye Examination 
A comprehensive eye examination should be performed by a qualified ophthalmologist at 
screening, once every 3 cycles (± 7 days, starting at Cycle 3), at EOT, and as clinically indicated.  
The eye examination should include a visual acuity test, slit-lamp examination, and funduscopy 
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with digital imaging.  Additional assessments (eg, optical coherence tomography) should be 
performed if clinically relevant retinal findings are observed on ophthalmologic exams and in 
participants with reported visual AEs or change in visual acuity, if the events or changes are 
suspected to be of retinal origin.  Every effort should be made to ensure that all subsequent 
examinations are performed by the same ophthalmologist. 
8.3.6. 
Laboratory Assessments 
See Table 13 for the list of clinical laboratory tests to be performed and see Table 4 for the 
timing and frequency.  The local laboratory will perform all clinical laboratory assessments for 
safety (ie, blood chemistries, hematology assessments, coagulation tests, endocrine function, and 
urinalysis), and a central laboratory will be used to study the translational samples at the end of 
the study. 
Serum phosphate testing is required on a more frequent basis if a participant develops 
hyperphosphatemia during Cycle 1 and/or is up-titrated (see Table 4).  Parathyroid hormone 
(endocrine) testing is required at baseline and Day 1 of every third cycle (starting with Cycle 3) 
as parathyroid hormone plays a role in calcium and phosphate hemostasis (Khundmiri 
et al 2016). 
Additional testing may be required by the sponsor based on emerging safety data.  All 
Protocol-required laboratory assessments must be conducted in accordance with the Laboratory 
Manual and the SoA (see Table 4).  Information regarding collection, processing, and shipping 
of laboratory assessments is provided in the Laboratory Manual. 
Clinically significant abnormal laboratory findings are those which are not associated with the 
underlying disease, unless judged by the investigator to be more severe than expected for the 
participant's condition.  All laboratory tests with values considered clinically significantly 
abnormal during participation in the study or within 30-35 days after the last dose of study 
treatment should be repeated until the values return to normal or baseline or are no longer 
considered clinically significant by the investigator or medical monitor.  
Screening laboratory assessments must be performed within 14 days of Cycle 1 Day 1.  If 
performed more than 14 days before Cycle 1 Day 1, then the tests must be repeated and 
eligibility confirmed before study drug administration on Cycle 1 Day 1.  Laboratory samples 
collected on study Day 1 must be performed before study treatment administration.  After 
Cycle 1, predose laboratory procedures can be conducted up to 72 hours before study treatment 
administration (within the 3-day study window), and results should be reviewed by the 
investigator or qualified designee and found to be acceptable before a new cycle of treatment is 
initiated. 
See Section 9.1 for information regarding laboratory abnormalities that should be recorded as an 
AE in the eCRF.  Additionally, if laboratory values from laboratory assessments performed at the 
institution's local laboratory require a change in participant management (eg, require treatment), 
or are considered clinically significant by the investigator (eg, SAE or AE or dose modification; 
see Section 9.2), then the result(s) of the specific laboratory assessment(s) must be recorded in 
the eCRF. 
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Table 13: 
Required Laboratory Analytes 
Blood Chemistries 
Hematology 
Urinalysis With 
Microscopic Examination 
Serology 
Coagulation 
Albumin 
Alkaline phosphatase 
ALT 
AST 
Amylase 
Bicarbonate or CO2 
Blood urea nitrogen or urea 
Calcium 
Chloride 
Creatinine 
Glucose 
Lactate dehydrogenase 
Lipase 
Magnesium 
Phosphate 
Potassium 
Sodium 
Total bilirubin 
Direct bilirubin (if total bilirubin is 
elevated above ULN) 
Total protein 
Uric acid 
Vitamin D (25-hydroxyvitamin D 
and 1,25-dihidrosyvitamin D) 
Complete blood count, 
including: 
• Hemoglobin 
• Hematocrit 
• Platelet count 
• Red blood cell count 
• White blood cell count 
 
Differential count, including: 
• Basophils 
• Eosinophils 
• Lymphocytes 
• Monocytes 
• Neutrophils 
 
Absolute values must be 
provided for: 
• WBC differential 
laboratory results 
Color and appearance 
pH and specific gravity 
Bilirubin 
Glucose 
Ketones 
Leukocytes 
Nitrite 
Occult blood 
Protein 
Hepatitis B surface antigen 
Hepatitis B surface antibody 
Hepatitis B core antibody 
HCV antibody 
NOTE:  If any of the above 
are positive, HBV-DNA, 
HCV-RNA to assess risk of 
reactivation 
PT 
PTT or aPTT 
INR 
Endocrine Function 
Pregnancy Testing 
PTH 
Female participants of 
childbearing potential 
only require a serum test 
at screening and EOT and 
a urine pregnancy test 
before the first dose on 
Cycle 1 Day 1 and then 
on Day 1 of every cycle.  
Pregnancy tests (serum or 
urine) should be repeated 
if required by local 
regulations. 
aPTT = activated partial thromboplastin time; INR = international normalized ratio; PT = prothrombin time; PTT = partial thromboplastin time 
Note:  Additional tests may be required, as agreed upon by the investigator and sponsor, based on emerging safety data. 
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8.3.6.1. 
Pregnancy Testing 
A serum pregnancy test will be required for all women of childbearing potential during screening 
and at the EOT visit; participants going into hospice are not required to provide EOT pregnancy 
test.  Urine pregnancy tests will be performed locally on Day 1 of each cycle, as outlined in 
Table 4, as medically indicated (eg, in case of loss of menstrual cycle, when pregnancy is 
suspected), or per country-specific requirement (note that country-required urine pregnancy 
testing will be outlined and communicated to investigational sites under separate cover).  If a 
urine pregnancy test is positive, the results should be confirmed with a serum pregnancy test. 
If the serum pregnancy test is negative after a urine test was positive, the investigator will assess 
the potential benefit/risk to the participant and determine whether it is in the participant's best 
interest to resume study drug and continue participation in the study. 
If a pregnancy is confirmed by a serum pregnancy test, see Section 9.5 for reporting 
requirements. 
8.3.6.2. 
Serology 
Hepatitis screening assessments will be performed at the screening visit to assess infection and 
viral status; required analytes are shown in Table 13.  Generally, hepatitis tests should be 
performed early in the screening process due to the length of time needed to obtain the results.  
Additional tests may be performed if clinically indicated. 
8.4. 
Pharmacokinetic Assessments 
Pharmacokinetic parameters are not evaluated in this study. 
8.5. 
Pharmacodynamic and Translational Assessments 
Pharmacodynamic parameters are not evaluated in this study. 
8.5.1. 
Tumor for Genomics Testing for FGFR Genetic Alterations and Gene 
Expression 
All potential participants must be evaluated for FGFR mutations and rearrangements before 
enrollment.  Participants with local lab data documenting an FGFR1, FGFR2, or FGFR3 
mutation or translocation (in-frame fusion regardless of fusion partner) are eligible.  
Confirmatory testing through the central genomics laboratory will be performed on all 
participants (not required when tissue already profiled at the reference lab); results from the 
central laboratory are not required prior to enrollment.  Details for sample collection, processing, 
and shipping will be provided in the Laboratory Manual. 
Appendix C contains a list of the most common recurrent activating FGFR mutations (excluding 
the kinase domain) that have been previously described, are present in somatic mutation 
databases, and/or are homologous to activating mutations present in another FGFR.  Appendix C 
is not all-inclusive, as extremely rare or novel activating alterations may not be present in the list. 
 
 
  
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8.5.2. 
Blood for Mutational and Other Correlative Analysis 
 
 
 Analysis of tumor mutational status will be 
conducted by the sponsor or its designee, and other assays relevant to the objectives of the study 
may be performed based upon emerging data.  Details for sample collection, processing, and 
shipping will be provided in the Laboratory Manual.  The correlative analyses may include 
assessment of markers of immune and inflammation status, including cytokines and soluble 
receptors, as well as examination of markers associated with tumor metabolism.  Other assays 
relevant to the objectives of the study may be performed based upon emerging data.  
 
  
Details for sample collection, processing, and shipping will be provided in the Laboratory 
Manual. 
Blood or saliva will be collected at baseline for the purpose of tumor/normal matched sampling 
and assessment of germline versus somatic mutation status. 
8.5.3. 
Tissue Biopsies  
Tumor biopsies will be collected as specified below: 
• Screening:  Mandatory tumor tissue will be collected during screening.  A fresh 
biopsy at screening is preferred; however, formalin-fixed paraffin embedded tissue is 
acceptable as long as the sample has been collected less than 12 months from date of 
screening (not required for participants who have already had tumor sequenced at the 
reference laboratory). 
Note:  Fresh tumor biopsies should be taken from nontarget lesions when possible. 
• Optional on-treatment:  An on-treatment biopsy may be collected during Cycle 2, 
between Day 7 and Day 14, but is allowed to be performed at any cycle; the 
on-treatment biopsy should be performed on a study drug administration day, 
preferably between Day 7 and Day 14. 
Note:  On-treatment biopsies should be taken from the same site as the screening 
biopsy whenever possible. 
• Optional end of treatment:  An EOT/at the time of progression biopsy is requested 
but not required from all participants.  If EOT occurs less than 6 weeks after the 
on-treatment biopsy was performed, an EOT biopsy should not be performed. 
8.6. 
Unscheduled Visits 
Unscheduled visits may occur as clinically indicated.  They can be used for visits that occur 
outside of visit windows and should be noted in the eCRF as an unscheduled visit. 
8.7. 
End of Treatment 
When the participant permanently discontinues study drug, whether the participant is terminating 
the study early or the participant has completed the study, the EOT visit should be conducted.  If 
the EOT visit coincides with a regular study visit, the EOT evaluations will supersede those of 
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that scheduled visit, and the data should be entered in the EOT visit in the eCRF.  The participant 
should be encouraged to return for the follow-up visit. 
8.8. 
Follow-Up 
8.8.1. 
Safety Follow-Up 
The safety follow-up period is the interval between the EOT visit and the scheduled follow-up 
visit, which should occur 30 to 35 days after the EOT visit (or after the last dose of study 
treatment if the EOT visit was not performed).  Adverse events and SAEs must be reported up 
until 1) at least 30 days after the last dose of study drug, the date of the follow-up visit, or the 
start of a new anticancer therapy or 2) until toxicities resolve, return to baseline, or are deemed 
irreversible, whichever is longer.  Reasonable efforts should be made to have the participant 
return for the follow-up visit and report any AEs that may occur during this period.  If the 
participant cannot return to the site for the safety follow-up visit (eg, lives far away), the 
participant should be contacted by telephone for assessment of AEs and SAEs.  Sites should 
document this contact in the source. 
If a participant is scheduled to begin a new anticancer therapy before the end of the 30- to 35-day 
safety follow-up period, the safety follow-up visit should be performed before new anticancer 
therapy is started.  Once new anticancer therapy has been initiated, the participant will move into 
the survival follow-up period. 
8.8.2. 
Post-Treatment Disease Follow-Up 
Participants who discontinue study treatment for a reason other than disease progression will 
move into the disease status follow-up period and should be assessed every 9 weeks ± 7 days by 
radiologic imaging to monitor disease status.  Every effort should be made to collect information 
regarding disease status until: 
• The start of new anticancer therapy:  the start of the new treatment should be 
captured, but the participant should continue to have disease assessments until 
progressive disease. 
• Disease progression (confirmed by a local radiologist). 
• Death. 
• The end of the study. 
8.8.3. 
Survival Follow-Up 
Once a participant has received the last dose of study treatment, confirmed disease progression, 
or starts a new anticancer therapy, the participant moves into the survival follow-up period and 
should be contacted by telephone, email, or visit at least every 12 weeks to assess for survival 
status until death, withdrawal of consent, or the end of the study, whichever occurs first. 
For participants having entered the survival follow-up period of the study, the site will use 
continuing participant records to supply data on subsequent treatment regimens, tumor 
assessments (if discontinued treatment for a reason other than progression), and OS in the eCRF.  
For participants who do not intend to return to the study investigator for their ongoing care, 
follow-up should be maintained by phone contact, patient records, and public records/databases 
approximately every 12 weeks. 
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9. 
ADVERSE EVENTS:  DEFINITIONS AND PROCEDURES FOR 
RECORDING, EVALUATING, FOLLOW-UP, AND REPORTING 
9.1. 
Definition of Adverse Event 
Adverse Event Definition 
• An AE is any untoward medical occurrence associated with the use of a drug in humans, whether or not 
considered drug-related. 
• An AE can therefore be any unfavorable and unintended sign (including an abnormal laboratory 
finding), symptom, or disease (new or exacerbated) temporally associated with the use of study 
treatment. 
Events Meeting the Adverse Event Definition  
• Any safety assessments (eg, ECG, vital signs measurements), including those that worsen from 
baseline, considered clinically significant in the medical and scientific judgment of the investigator 
(ie, not related to progression of underlying disease). 
• Abnormal laboratory test results constitute an AE if they are considered clinically meaningful, induce 
clinical signs or symptoms, require concomitant therapy, or require changes in study drug.  Whenever 
possible, a diagnosis (eg, anemia, thrombocytopenia) should be recorded in the eCRF rather than the 
abnormal lab result (eg, low hemoglobin, platelet count decreased). 
• Exacerbation of a chronic or intermittent pre-existing condition including either an increase in 
frequency and/or intensity of the condition. 
• New conditions detected or diagnosed after study treatment administration even though they may have 
been present before the start of the study. 
• Signs, symptoms, or the clinical sequelae of a suspected drug-drug interaction. 
• Signs, symptoms, or the clinical sequelae of a suspected overdose of either study treatment or a 
concomitant medication.  Overdose per se will not be reported as an AE/SAE unless it is an intentional 
overdose taken with possible suicidal/self-harming intent.  Such overdoses should be reported 
regardless of sequelae. 
Events NOT Meeting the Adverse Event Definition 
• Any clinically significant abnormal laboratory findings or other abnormal safety assessments that are 
associated with the underlying disease, unless judged by the investigator to be more severe than 
expected for the participant's condition. 
• The disease/disorder being studied or expected progression, signs, or symptoms of the disease/disorder 
being studied, unless more severe than expected for the participant's condition or considered to be 
treatment-related by the investigator. 
• Efficacy endpoints as outlined in Section 3 will not be reported as AE/SAEs, specifically, any event 
that is related to disease progression of the cancer under study.  Unblinded aggregated efficacy endpoint 
events and safety data will be monitored to ensure the safety of the participants in the study.  Any 
suspected endpoint that upon review is not progression of the cancer under study will be forwarded to 
Incyte Pharmacovigilance as a SAE within 24 hours of determination that the event is not progression 
of the cancer under study. 
• Medical or surgical procedure (eg, endoscopy, appendectomy):  the condition that leads to the 
procedure is the AE if it occurred after signing informed consent.  If present before entering the study, 
the condition should be captured as medical history.  
• Situations in which an untoward medical occurrence did not occur (social and/or convenience 
admission to a hospital). 
• Anticipated day-to-day fluctuations of pre-existing disease(s) or condition(s) present or detected at the 
start of the study that do not worsen. 
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9.2. 
Definition of Serious Adverse Event 
If an event is not an AE per definition above, then it cannot be an SAE even if serious conditions 
are met (eg, hospitalization for signs/symptoms of the disease under study, death due to 
progression of disease). 
A Serious Adverse Event is defined as any untoward medical occurrence that, at any dose: 
a. Results in death 
b. Is life-threatening 
The term 'life-threatening' in the definition of 'serious' refers to an adverse drug experience that places the 
participant, in the opinion of the initial reporter, at immediate risk of death from the adverse experience as 
it occurred.  This does not include an adverse drug experience that, had it occurred in a more severe form, 
might have caused death. 
c.  Requires inpatient hospitalization or prolongation of existing hospitalization 
In general, hospitalization signifies that the participant has been detained (usually involving at least an 
overnight stay) at the hospital or emergency ward for observation and/or treatment that would not have 
been appropriate in the physician's office or outpatient setting.  Complications that occur during 
hospitalization are AEs.  If a complication prolongs hospitalization or fulfills any other serious criteria, 
the event is serious.  When in doubt as to whether "hospitalization" occurred or was necessary, the AE 
should be considered serious. 
Hospitalization for elective treatment of a pre-existing condition that did not worsen from baseline is not 
considered an AE. 
d. Results in persistent or significant disability/incapacity 
• The term disability means a substantial disruption of a person's ability to conduct normal life functions. 
• This definition is not intended to include experiences of relatively minor medical significance, such as 
uncomplicated headache, nausea, vomiting, diarrhea, influenza, and accidental trauma (eg, sprained 
ankle), that may interfere with or prevent everyday life functions but do not constitute a substantial 
disruption. 
e.  Is a congenital anomaly/birth defect 
f. Other situations (Important Medical Event) 
An event that may not result in death, be immediately life-threatening, or require hospitalization, but may 
be considered serious when, based on appropriate medical judgment, the event may jeopardize the 
participant and may require medical or surgical intervention to prevent one of the outcomes listed in the 
above definition.  Examples of such events include invasive or malignant cancers (excluding the 
disease[s] under study in oncology protocols), intensive treatment in an emergency department or at home 
for allergic bronchospasm, blood dyscrasias, or convulsions that do not result in hospitalization, or 
development of drug dependency or drug abuse. 
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9.3. 
Recording and Follow-Up of Adverse Events and/or Serious Adverse 
Events 
Adverse Event and Serious Adverse Event Recording 
• An AE/SAE that begins or worsens after informed consent is signed should be recorded on the Adverse 
Event Form in the eCRF.  Conditions that were present at the time informed consent was given should 
be recorded on the Medical History Form in the eCRF. 
• When an AE/SAE occurs, it is the responsibility of the investigator to review all documentation 
(eg, hospital progress notes, laboratory reports, and diagnostics reports) related to the event. 
• The investigator (or delegate) will then record all relevant AE/SAE information in the eCRF. 
• It is not acceptable for the investigator to send photocopies of the participant's medical records in lieu 
of completing the AE eCRF page. 
• There may be instances when copies of medical records for certain cases are requested.  In this case, all 
participant identifiers, with the exception of the participant number, will be redacted on the copies of 
the medical records before submission. 
• The investigator will attempt to establish a diagnosis of the event based on signs, symptoms, and/or 
other clinical information.  Whenever possible, the diagnosis (not the individual signs/symptoms) will 
be documented as the AE/SAE.  When a clear diagnosis cannot be identified, each sign or symptom 
should be reported as a separate AE/SAE. 
To the extent possible, each AE/SAE should be evaluated to determine: 
• The severity grade (CTCAE Grade 1 to 5).  See below for further instructions on the assessment of 
intensity.  
• Whether there is at least a reasonable possibility that the AE is related to the study drug:  suspected 
(yes) or not suspected (no).  See below for further instructions on the assessment of causality. 
• The start and end dates, unless unresolved at final follow-up. 
• The action taken with regard to study drug as a result of the AE/SAE(s). 
• The event outcome (eg, not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown). 
• The seriousness, as per the SAE definition provided in Section 9.2. 
• The action taken with regard to the event.  Note:  If an AE is treated with a concomitant medication or 
nondrug therapy, this action should be recorded on Adverse Event Form and the treatment should be 
specified on the appropriate eCRF (eg, Prior/Concomitant Medications, Procedures and Non-Drug 
Therapy). 
Assessment of Intensity 
The severity of AEs will be assessed using CTCAE v5.0 Grades 1 through 5.  If an event is not classified 
by CTCAE, the severity of the AE will be graded according to the scale below to estimate the grade of 
severity: 
The investigator will make an assessment of intensity for each AE and SAE reported during the study and 
assign it to 1 of the following categories: 
• Grade 1:  Mild; asymptomatic or mild symptoms; clinical or diagnostic observations only; treatment 
not indicated. 
• Grade 2:  Moderate; minimal, local, or noninvasive treatment indicated; limiting age appropriate 
activities of daily living. 
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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. 
• Grade 4:  Life-threatening consequences; urgent treatment indicated. 
• Grade 5:  Fatal. 
Assessment of Causality 
• The investigator is obligated to assess the relationship between study treatment and each occurrence of 
each AE/SAE.  If reference therapy is used in combination with an Incyte study drug or multiple Incyte 
study drugs are used, the relationship to each study drug must be assessed (ie, for the Incyte product(s) 
and for the other product(s) that is used in combination with the Incyte product).  If appropriate, the 
relationship to the combination may be assessed as well. 
• A "reasonable possibility" of a relationship conveys that there are facts, evidence, and/or arguments to 
suggest a causal relationship, rather than that a relationship cannot be ruled out. 
• The investigator will use clinical judgment to determine the relationship. 
• The investigator will also consult the RSI in the IB and/or Product Information, for marketed products, 
in his/her assessment. 
• Alternative causes, such as underlying disease(s), concomitant therapy, and other risk factors, as well as 
the temporal relationship of the event to study treatment administration, will be considered and 
investigated. 
• For each AE/SAE, the investigator must document in the medical notes that he/she has reviewed the 
AE/SAE and has provided an assessment of causality. 
• With regard to assessing causality of SAEs: 
− There may be situations in which an SAE has occurred and the investigator has minimal information 
to include in the initial report.  However, the causality assessment is one of the criteria used when 
determining regulatory reporting requirements.  Therefore, it is very important that the 
investigator always make an assessment of causality for every event before the initial 
transmission of the SAE. 
− The investigator may change his/her opinion of causality in light of follow-up information and send a 
follow-up SAE report with the updated causality assessment. 
Follow-Up of Adverse Events and Serious Adverse Events 
• The investigator is obligated to perform or arrange for the conduct of supplemental measurements 
and/or evaluations as medically indicated or as requested by the sponsor to elucidate the nature and/or 
causality of the AE or SAE as fully as possible.  This may include additional laboratory tests or 
investigations, histopathological examinations, or consultation with other health care professionals. 
• New or updated information will be recorded in the originally completed eCRF. 
• Any updated SAE data will be submitted to the sponsor (or designee) within 24 hours of receipt of the 
information. 
• Once an AE is detected, it should be followed until it has resolved or until it is judged to be permanent; 
assessment should be made at each visit (or more frequently if necessary) of any changes in severity, 
the suspected relationship to the study drug, the interventions required to treat the event, and the 
outcome. 
• When the severity of an AE changes over time for a reporting period (eg, between visits), each change 
in severity will be reported as a separate AE until the event resolves. 
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9.4. 
Reporting of Serious Adverse Events 
Regardless of suspected causality (eg, relationship to study drug or study procedure[s]), all SAEs 
occurring after the participant has signed the ICF through 30-35 days after the last dose of study 
treatment or until the participant starts a new anticancer therapy, whichever occurs earlier) must 
be reported to the sponsor (or designee) within 24 hours of learning of its occurrence, unless 
otherwise specified by the Protocol.  The investigator will submit any updated SAE data to the 
sponsor (or designee) within 24 hours of it being available. 
Investigators are not obligated to actively seek AE or SAE information after conclusion of the 
study participation.  However, if the investigator learns of any SAE, including a death, at any 
time after a participant has been discharged from the study, and he/she considers the event to be 
reasonably related to the study treatment or study participation, the investigator must notify the 
sponsor (or designee) within 24 hours of becoming aware of the event. 
After the initial AE/SAE report, the investigator is required to proactively follow each participant 
at subsequent visits/contacts.  All SAEs will be followed until resolution, stabilization, the event 
is otherwise explained, or the participant is lost to follow-up (as defined in Section 7.3). 
Prompt notification by the investigator to the sponsor of a SAE is essential so that legal 
obligations and ethical responsibilities towards the safety of participants and the safety of a study 
treatment under clinical investigation are met. 
If the SAE is not documented in the IB for the study drug (new occurrence) and is thought to be 
related to the sponsor's study drug, the sponsor or its designee may urgently require further 
information from the investigator for reporting to health authorities.  The sponsor or its designee 
may need to issue an Investigator Notification to inform all investigators involved in any study 
with the same drug that this SAE has been reported.  Suspected Unexpected Serious Adverse 
Reactions will be collected and reported to the competent authorities and relevant ethics 
committees in accordance with Directive 2001/20/EC, or as per national regulatory requirements 
in participating countries. 
The sponsor has a legal responsibility to notify both the local regulatory authority and other 
regulatory agencies about the safety of a study treatment under clinical investigation.  The 
sponsor will comply with country-specific regulatory requirements relating to safety reporting to 
the regulatory authority, IRB/IEC, and investigators. 
Investigator safety reports must be prepared for suspected unexpected adverse reactions 
according to local regulatory requirements and sponsor policy and forwarded to investigators as 
necessary. 
An investigator who receives an investigator safety report describing a SAE or other specific 
safety information (eg, summary or listing of SAEs) from the sponsor will review and then file it 
along with the Investigator's Brochure and will notify the IRB/IEC, if appropriate according to 
local requirements. 
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Serious Adverse Event Reporting 
• Information about all SAEs is collected and recorded on the Adverse Event Form in the eCRF. 
• The investigator must also complete the Incyte Serious Adverse Event Report Form, in English.  Refer 
to the Incyte Reference Guide for Completing the Serious Adverse Event Report Form. 
• Facsimile or email transmission of the Serious Adverse Event Report Form is the preferred method to 
transmit this information to the PhV/designee (eg, C3i/Telerx).  The original copy of the Serious 
Adverse Event Report Form and the confirmation sheet must be kept at the study site. 
• Follow-up information is recorded on an amended or new Serious Adverse Event Report Form, with an 
indication that it is follow-up to the previously reported SAE and the date of the original report.  The 
follow-up report should include information that was not provided on the previous Serious Adverse 
Event Report Form, such as the outcome of the event (eg, resolved or ongoing), treatment provided, 
action taken with study drug because of the SAE (eg, dose reduced, interrupted, or discontinued), or 
participant disposition (eg, continued or withdrew from study participation).  Each recurrence, 
complication, or progression of the original event should be reported as follow-up to that event, 
regardless of when it occurs. 
• In rare circumstances and in the absence of facsimile or computer equipment, notification by telephone 
is acceptable with a copy of the Incyte Serious Adverse Event Report Form sent by overnight mail or 
courier service.  Initial notification via telephone does not replace the need for the investigator to 
complete and sign the Serious Adverse Event Report Form within the designated reporting time frames. 
9.5. 
Emergency Unblinding of Treatment Assignment 
Not applicable. 
9.6. 
Pregnancy 
Pregnancy, in and of itself, is not regarded as an AE unless there is suspicion that study drug may 
have interfered with the effectiveness of a contraceptive medication or method.  When a 
pregnancy has been confirmed in a participant during maternal or paternal exposure to study 
drug, the following procedures should be followed in order to ensure safety: 
• The study drug must be interrupted immediately (female participants only; see 
Section 6.5.1 for the maximum permitted duration of study drug interruption).  
• If the female participant is no longer pregnant and meets the treatment continuation 
criteria within 28 days of the scheduled start of a cycle (or your maximum allowable 
time off study drug), study treatment may be resumed after approval has been 
received from the sponsor medical monitor. 
• The investigator must complete and submit the Incyte Clinical Trial Pregnancy Form 
to the sponsor or its designee within 24 hours of learning of the pregnancy. 
Data on fetal outcome are collected for regulatory reporting and drug safety evaluation.  
Follow-up should be conducted for each pregnancy to determine outcome, including spontaneous 
or voluntary termination, details of the birth, and the presence or absence of any birth defects, 
congenital abnormalities, or maternal and/or newborn complications, by following until the first 
well-baby visit.  Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported 
by the investigator to the sponsor or its designee.  Pregnancy follow-up information should be 
recorded on the same form and should include an assessment of the possible causal relationship 
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to the sponsor's study drug to any pregnancy outcome, as well as follow-up to the first well-baby 
visit or the duration specified in local regulations, whichever is later.  Refer to the Incyte 
Reference Guide for Completing the Clinical Trial Pregnancy Form. 
Any SAE occurring during pregnancy of a study participant must be recorded on the 
Serious Adverse Event Report Form and submitted to the sponsor or designee. 
Abnormal pregnancy outcomes (eg, spontaneous abortion, fetal death, stillbirth, congenital 
anomalies, or ectopic pregnancy) are considered SAEs (if occurring in the study participant) and 
must be reported as described in Section 9.4.  If an abnormal pregnancy outcome is reported in a 
study participant's partner, the event should be reported to the sponsor on the Clinical Trial 
Pregnancy Form. 
9.7. 
Warnings and Precautions 
Special warnings or precautions for the study drug, derived from safety information collected by 
the sponsor or its designee, are presented in the IB.  Additional safety information collected 
between IB updates will be communicated in the form of Investigator Notifications.  Any 
important new safety information should be discussed with the participant during the study, as 
necessary.  If new significant risks are identified, they will be added to the ICF. 
9.8. 
Product Complaints 
The sponsor collects product complaints on study drugs and drug delivery systems used in 
clinical studies in order to ensure the safety of study participants, monitor quality, and facilitate 
process and product improvements. 
All product complaints associated with material packaged, labeled, and released by the sponsor 
or its designee will be reported to the sponsor.  All product complaints associated with other 
study material will be reported directly to the respective manufacturer. 
The investigator or his/her designee is responsible for reporting a complete description of the 
product complaint via email or other written communication to the sponsor contact or respective 
manufacturer as noted in the packaging information.  Any AE associated with a product 
complaint should be recorded as described in Section 9.3. 
If the investigator is asked to return the product for investigation, he/she will return a copy of the 
product complaint communication with the product. 
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10. 
STATISTICS 
10.1. 
Sample Size Determination 
Overall, the study plans to enroll approximately 50 participants.  Assuming ORR is 30%, 
50 participants will provide at least 80% power to test the null hypothesis of ORR ≤ 15% using a 
normal-approximate z test at 1-sided significance level of 0.05. 
When a tumor subtype j within each cohort reaches 10 participants (or more), a statistical 
evaluation for ORR (pj) within the subtype will be conducted.  The tumor subtype j may be 
discontinued from further enrollment if the posterior probability P(pj < 0.15|nj, Nj,α, β) > 0.3 
where nj is the number of responders in jth subtype, Nj is the number of participants with jth 
tumor subtype, α and β are parameters of the prior distribution and are set to be α = 1.7625 and 
β = 9.9875 (Beta distribution with mean = 0.15, variance = 0.01).  Tumor subtypes with at least 
10 patients and P(pj < 0.15|nj, Nj,α, β) ≤ 0.3 may continue to enroll participants.  Any tumor 
subtype j with at least 10 participants and P(pj > 0.30|nj, Nj,α, β) > 0.5 may enroll up to 
30 additional participants as an expansion cohort of the tumor subtype.  These participants will 
not be counted towards the 50 participants planned for the study.  At the end of the study, 
P(pj < 0.15|nj, Nj,α, β) and P(pj > 0. 30|nj, Nj,α, β) will be evaluated for all tumor subtypes within 
each cohort (see Table 14 and Table 15).  A cohort of at least 25 participants will provide 
> 0.8 probability of observing 6 responders if underlying response rate is 0.3.  The initial 
calculation of these posterior probabilities of each tumor subtype will begin when 10 participants 
have completed the assessment for primary response. 
These rules based on posterior probabilities are provided as guidance for recruiting participants 
and discontinuing recruitment due to lack of response.  The decision to continue recruiting to a 
tumor subtype or discontinue recruitment will be made based on the degree of responses 
observed (eg, number of CRs), other relevant clinical parameters, and medical assessments. 
In addition to the aforementioned process, other methods including but not limited to hierarchical 
Bayesian models may be used to decide if a tumor subtype in each cohort will discontinue 
enrollment or continue to enroll subjects. 
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Table 14: 
P(p<0.15|n/N,alpha=1.7625,beta=9.9875) 
Number of 
Responders 
Number of Participants 
N = 4 
N = 5 
N = 6 
N = 7 
N = 8 
N = 9 
N = 10 
0 
0.7384 
0.7693 
0.7969 
0.8215 
0.8433 
0.8626 
0.8797 
1 
0.4501 
0.4933 
0.5347 
0.5740 
0.6112 
0.6460 
0.6785 
2 
0.2108 
0.2467 
0.2837 
0.3213 
0.3592 
0.3970 
0.4344 
3 
0.0763 
0.0965 
0.1190 
0.1437 
0.1703 
0.1987 
0.2284 
4 
0.0215 
0.0297 
0.0397 
0.0516 
0.0654 
0.0812 
0.0988 
5 
 
0.0073 
0.0106 
0.0150 
0.0205 
0.0272 
0.0353 
6 
 
 
0.0023 
0.0035 
0.0053 
0.0075 
0.0105 
7 
 
 
 
0.0007 
0.0011 
0.0017 
0.0026 
8 
 
 
 
 
0.0002 
0.0003 
0.0005 
9 
 
 
 
 
 
0.0001 
0.0001 
10 
 
 
 
 
 
 
0.0000 
Table 15: 
P(p>0.3|n/N,alpha=1.7625,beta=9.9875) 
Number of 
Responders 
Number of Participants 
N = 4 
N = 5 
N = 6 
N = 7 
N = 8 
N = 9 
N = 10 
0 
0.0258 
0.0188 
0.0137 
0.0100 
0.0073 
0.0053 
0.0038 
1 
0.1044 
0.0808 
0.0622 
0.0477 
0.0364 
0.0276 
0.0209 
2 
0.2627 
0.2152 
0.1749 
0.1411 
0.1131 
0.0901 
0.0713 
3 
0.4790 
0.4141 
0.3544 
0.3006 
0.2527 
0.2108 
0.1746 
4 
0.6928 
0.6286 
0.5643 
0.5013 
0.4411 
0.3846 
0.3325 
5 
 
0.8040 
0.7514 
0.6952 
0.6371 
0.5783 
0.5202 
6 
 
 
0.8816 
0.8426 
0.7984 
0.7500 
0.6985 
7 
 
 
 
0.9319 
0.9051 
0.8731 
0.8362 
8 
 
 
 
 
0.9625 
0.9453 
0.9236 
9 
 
 
 
 
 
0.9801 
0.9696 
10 
 
 
 
 
 
 
0.9898 
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10.2. 
Populations for Analysis 
Populations for analysis are shown in Table 16. 
Table 16: 
Populations for Analysis 
Population 
Description 
Efficacy evaluable 
The efficacy evaluable population includes all enrolled participants who received at 
least 1 dose of study drug. 
The efficacy evaluable population will be used for the summary of demographics, 
baseline characteristics, participant disposition, and analyses of all efficacy data. 
Safety 
The safety population includes all enrolled participants who received at least 1 dose 
of study drug.  All safety analyses will be conducted using the safety population. 
Per protocol 
The per protocol population includes all efficacy evaluable population participants 
who are sufficiently compliant with the protocol. 
10.3. 
Level of Significance 
The overall level of significance is 1-sided 0.05. 
10.4. 
Statistical Analyses 
10.4.1. 
Primary Analysis 
The primary endpoint of the study is ORR.  Objective response rate is defined as the proportion 
of participants who achieved a CR or a PR based on RECIST v1.1 or RANO, as assessed by 
local radiological review.  This analysis will be based on the efficacy evaluation population.  
Participants who do not have sufficient baseline or on-study response assessment information to 
be adequately assessed for response status will be included in the denominators in the calculation 
of ORR.  The 90% CI for the ORR will be estimated using the Clopper-Pearson method.  The 
p-value from the exact binomial test will be provided. 
The ORR will also be analyzed based on the per protocol population as a sensitivity analysis. 
10.4.2. 
Secondary Efficacy Analysis 
Secondary efficacy analysis will be conducted for the efficacy evaluable population. 
Progression-free survival is defined as the time from date of first dose of study drug to the date 
of progressive disease or death, whichever is first.  Progressive disease is evaluated based 
RECIST v1.1, or RANO, by the local radiographic review.  Participants who are alive without 
progression before analysis cutoff date will be censored.  Censoring for PFS will follow FDA 
guidance.  Progression-free survival data will be analyzed by the Kaplan-Meier method. 
For objective responders, DOR is defined as the time from the date a participant first achieves 
CR or PR based on RECIST v1.1 or RANO until the date of first documented disease 
progression based on RECIST v1.1 or RANO or death.  Participants who are alive without 
progression before analysis cutoff date will be censored.  Censoring of DOR will follow the 
same algorithm as the censoring of PFS.  Duration of response data will be analyzed by the 
Kaplan-Meier method. 
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Disease control rate, defined as the proportion of participants who achieved best overall response 
of CR, PR, or SD per RECIST v1.1 or RANO, and its exact 90% CI will be calculated in each 
cohort. 
Overall survival is defined as the time from date of first dose of study drug to death due to any 
cause.  Participants without death observed at the time of the analysis will be censored at last 
date known to be alive.  Overall survival will be analyzed by the Kaplan-Meier method. 
10.4.3. 
Safety Analyses 
Safety analyses will be conducted for the safety population.  Adverse events will be coded by the 
MedDRA dictionary, and TEAEs (ie, AEs reported for the first time or worsening of a 
pre-existing event after first dose of study drug/treatment) will be tabulated by preferred term 
and system organ class for all events, related events, and events of Grade 3 or higher.  
Quantitative safety variables and their changes from baseline (eg, laboratory, vital signs) will be 
summarized with descriptive statistics.  Clinically notable abnormal values will be flagged and 
tabulated based on predefined criteria. 
The clinical laboratory data will be analyzed using summary statistics; no formal treatment group 
comparisons are planned.  In addition, distributions of key laboratory parameters may be plotted 
over time; these values will also be classified into CTCAE toxicity grades, and tabulated.  
Descriptive statistics and mean change from baseline will be determined for vital signs at each 
assessment time.  Vital sign results will be reviewed for clinically notable abnormalities. 
Descriptive statistics and mean change from baseline will be determined for each ECG parameter 
at each assessment time.  Electrocardiogram results will be reviewed for clinically notable 
abnormalities according to predefined criteria (see Section 8.3.4).  Participants exhibiting 
clinically notable ECG abnormalities will be listed. 
Measures of exposure of study drug will be summarized by means of summary statistics. 
 
 
 
 
10.5. 
Interim Analysis 
No formal interim analysis is planned.  However, each tumor subtype within each cohort will be 
assessed when 10 or more participants are enrolled. 
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11. 
SUPPORTING DOCUMENTATION AND OPERATIONAL 
CONSIDERATIONS 
11.1. 
Investigator Responsibilities 
• The Protocol, Protocol amendments, ICF, IB, and other relevant documents 
(eg, advertisements) must be submitted to an IRB/IEC by the investigator and 
reviewed and approved by the IRB/IEC before the study is initiated. 
• The investigator is responsible for ensuring that the safety reports provided by the 
sponsor are reviewed and processed in accordance with regulatory requirements, the 
policies and procedures established by the IRB/IEC, and institutional requirements. 
• Any amendments to the Protocol will require IRB/IEC approval before 
implementation of changes made to the study design, except for changes necessary to 
eliminate an immediate hazard to study participants. 
• The investigator will be responsible for the following: 
− Providing written summaries of the status of the study to the IRB/IEC annually or 
more frequently in accordance with the requirements, policies, and procedures 
established by the IRB/IEC. 
− Notifying the IRB/IEC of SAEs or other significant safety findings as required by 
IRB/IEC procedures. 
− Providing oversight of the conduct of the study at the site and adherence to GCP, 
IRB/IEC requirements, institutional requirements, and applicable laws and 
country-specific regulations. 
• Adhering to the Protocol as described in this document and agreeing that changes to 
the Protocol procedures, with the exception of medical emergencies, must be 
discussed and approved, first, by the sponsor or its designee and, second, by the 
IRB/IEC.  Each investigator is responsible for enrolling participants who have met 
the specified eligibility criteria.  
• Retaining records in accordance with all local, national, and regulatory laws, but for a 
minimum period of at least 2 years after the last marketing application approval in an 
ICH region and until there are no pending or contemplated marketing applications in 
an ICH region, or if not approved, 2 years after the termination of the test article for 
investigation to ensure the availability of study documentation should it become 
necessary for the sponsor or a regulatory authority to review. 
− The investigator must not destroy any records associated with the study without 
receiving approval from the sponsor.  The investigator must notify the sponsor or 
its designee in the event of accidental loss or destruction of any study records.  If 
the investigator leaves the institution where the study was conducted, the sponsor 
or its designee must be contacted to arrange alternative record storage options. 
− All eCRF data entered by the site (including audit trail), as well as computer 
hardware and software (for accessing the data), will be maintained or made 
available at the site in compliance with applicable record retention regulations.  
The sponsor will retain the original eCRF data and audit trail.  
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11.2. 
Data Management 
Data management will be performed in a validated EDC system.  The investigator will be 
provided with access to an EDC system so that an eCRF can be completed for each participant. 
The site will be provided eCRF completion guidelines for instructions on data entry in the eCRF.  
The study monitor will reference the Monitoring Plan in order to ensure that each issue identified 
is appropriately documented, reported, and resolved in a timely manner in accordance with the 
plan's requirements.  Other data outside the EDC system required in the study conduct of the 
protocol such as documents or results transmitted to the sponsor via a central laboratory or 
specialized technical vendors, and as designated by the sponsor, will have their own data flow 
management plans, or study charters, 
, as applicable. 
The sponsor (or designee) will be responsible for: 
• Managing the integrity of the data and the quality of the conduct of the study, such as  
ensuring that study monitors perform ongoing source data verification to confirm that 
data entered into the eCRF by authorized site personnel are accurate, complete, and 
verifiable from source documents; that the safety and rights of participants are being 
protected; and that the study is being conducted in accordance with the currently 
approved protocol and any other study agreements, ICH GCP, and all applicable 
regulatory requirements. 
• Managing and reconciling the data generated, and/or collected including documents 
and results such as laboratory or imaging data analyzed centrally by a designated 
vendor of the sponsor. 
The investigator will be responsible for: 
• Recording, or ensuring the recording of, all relevant data relating to the study in the 
eCRF. 
• Delivering, or ensuring the delivery of, all other results, documents, data, know-how, 
or formulas relating to the study to the sponsor or designee electronically and/or 
centrally (e.g., laboratory data, imaging data, 
 photographs, diary 
data), or as otherwise specified in the Protocol.   
• Verifying that data entries are accurate and correct by physically or electronically 
signing the eCRF. 
• Maintaining accurate documentation (source data) that supports the information 
entered in the eCRF, or sent to a central vendor designated by the sponsor, or as 
described in other study and data flow manuals. 
− Source documents provide evidence for the existence of the participant and 
substantiate the integrity of the data collected.  Source documents are filed at 
the investigator's site. 
− Data entered in the eCRF that are transcribed from source documents must be 
consistent with the source documents or the discrepancies must be explained.  
The investigator may need to request previous medical records or transfer 
records, depending on the study.  Also, current applicable medical records 
must be available. 
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• May have responsibility for sending participants’ data, either as unique samples, or 
copies, or photographs, to be evaluated centrally or analyzed centrally, or both, by a 
qualified vendor designated by the sponsor.  
• Permitting study-related monitoring, sponsor audits, IRB/IEC review, and regulatory 
inspections by providing direct access to source data and other relevant clinical study 
documents. 
− Monitoring:  Qualified representatives of the sponsor or its designee, study 
monitors, will monitor the study according to a predetermined plan.  The 
investigator must allow the study monitors to review any study materials and 
participant records at each monitoring visit. 
− Auditing:  Qualified representatives of the sponsor or its designee may audit the 
clinical study site and study data to evaluate compliance with the Protocol, 
applicable local clinical study regulations, and overall study conduct.  The 
investigator must allow the auditors to review original source records and study 
documentation for all participants. 
− Regulatory inspection:  Regulatory authorities may conduct an inspection of the 
study and the site at any time during the development of an investigational 
product.  The investigator and staff are expected to cooperate with the inspectors 
and allow access to all source documents supporting the eCRFs and other study 
related documents.  The investigator must immediately notify the sponsor when 
contacted by any regulatory authority for the purposes of conducting an 
inspection. 
11.3. 
Data Privacy and Confidentiality of Study Records 
The investigator and the sponsor or its designee must adhere to applicable data privacy laws and 
regulations.  The investigator and the sponsor or its designee are responsible for ensuring that 
sensitive personal information is handled in accordance with local data protection laws 
(including but not limited to HIPAA and GDPR) as applicable.  Appropriate consent for 
collection, use and disclosure and/or transfer (if applicable) of personal information must be 
obtained in accordance with local data protection laws. 
Participant names will not be supplied to the sponsor or its designee.  Only the participant 
number will be recorded in the eCRF; if the participant's name appears on any other document 
(eg, laboratory report), it must be obliterated on the copy of the document to be supplied to the 
sponsor or its designee.  Study findings stored on a computer will be stored in accordance with 
local data protection laws. 
Records and documents, including signed ICFs, pertaining to the conduct of this study must be 
retained by the investigator for 5 years after study completion unless local regulations or 
institutional policies require a longer retention period.  No records may be destroyed during the 
retention period without the written approval of the sponsor.  No records may be transferred to 
another location or party without written notification to the sponsor. 
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11.4. 
Financial Disclosure 
Before study initiation, all clinical investigators participating in clinical studies subject to 
FDA Regulation Title 21 CFR Part 54 – Financial Disclosure by Clinical Investigators 
(ie, "covered studies") are required to submit a completed Clinical Investigator Financial 
Disclosure form that sufficiently details any financial interests and arrangements that apply.  For 
the purpose of this regulation, "clinical investigator" is defined as any investigator or 
subinvestigator who is directly involved in the treatment or evaluation of research participants, 
including the spouse and each dependent child of the clinical investigator or subinvestigator.  
These requirements apply to both US and foreign clinical investigators conducting covered 
clinical studies. 
Any new clinical investigators added to the covered clinical study during its conduct must also 
submit a completed Investigator Financial Disclosure Form.  During a covered clinical study, 
any changes to the financial information previously reported by a clinical investigator must be 
reported to the sponsor or its designee.  At the conclusion of the covered clinical study, the 
clinical investigators will be reminded of their obligations.  In the event that the clinical 
investigator is not reminded, they nevertheless will remain obligated to report to the sponsor or 
its designee any changes to the financial information previously reported, as well as any changes 
in their financial information for a period of 1 year after completion of the covered clinical study. 
11.5. 
Publication Policy 
By signing the study Protocol, the investigator and his/her institution agree that the results of the 
study may be used by the sponsor, Incyte Corporation (Incyte), for the purposes of national and 
international registration, publication, and information for medical and pharmaceutical 
professionals.  Study results will be published in accordance with applicable local and national 
regulations.  If necessary, the authorities will be notified of the investigator's name, address, 
qualifications, and extent of involvement.  The terms regarding the publication of study results 
are contained in the agreement signed with the sponsor or its designee.  A signed agreement will 
be retained by the sponsor or its designee. 
The results of this study may be published or presented at scientific meetings.  If this is foreseen, 
the investigator agrees to submit all manuscripts or abstracts to the sponsor before submission.  
This allows the sponsor to protect proprietary information and to provide comments. 
The sponsor will comply with the requirements for publication of study results.  In accordance 
with standard editorial and ethical practice, the sponsor will generally support publication of 
multicenter studies only in their entirety and not as individual site data.  In this case, a 
coordinating investigator will be designated by mutual agreement. 
Authorship will be determined in line with International Committee of Medical Journal Editors 
authorship requirements. 
11.6. 
Study and Site Closure 
The sponsor designee 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. 
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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 
IRB/IEC or local health authorities, the sponsor's procedures, or GCP guidelines.  
• Inadequate recruitment of participants by the investigator.  
• Discontinuation of further study treatment development.  
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12. 
REFERENCES 
American Joint Committee on Cancer. AJCC Cancer Staging Manual. 6th ed. New York, NY: 
Springer; 2002. 
Clinical Trial Facilitation Group. Recommendations related to contraception and pregnancy 
testing in clinical trials. 2014. http://www. hma. eu/fileadmin/dateien/ 
Human_Medicines/01-About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_ 
Contraception. pdf. Accessed May 6, 2019. 
Dailey L, Ambrosetti D, Mansukhani A, Basilico C. Mechanisms underlying differential 
responses to FGF signaling. Cytokine Growth Factor Rev 2005;16:233-247. 
Eisenhauer EA, Therasse P, Bogaerts J, et al. New response evaluation criteria in solid tumors: 
revised RECIST guideline (version 1.1). Eur J Cancer 2009;45:228-247. 
Eswarakumar VP, Lax I, Schlessinger J. Cellular signaling by fibroblast growth factor receptors. 
Cytokine Growth Factor Rev 2005;16:139-149. 
 
Farrow EG, White KE. Recent advances in renal phosphate handling. Nat Rev Nephrol 
2010;6:207-217. 
Guagnano V, Kauffmann A, Wöhrle S, et al. FGFR genetic alterations predict for sensitivity to 
NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov 2012;2:1118-1133. 
Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR Landscape in 
cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res 
2016;22:259-267. 
Itoh N. Hormone-like (endocrine) Fgfs: their evolutionary history and roles in development, 
metabolism, and disease. Cell Tissue Res 2010;342:1-11. 
Khundmiri SJ, Murray RD, Lederer E. PTH and vitamin D. Compr Physiol 2016;6:561-601. 
Knights V, Cook SJ. De-regulated FGF receptors as therapeutic targets in cancer. Pharmacol 
Ther 2010;125:105-117. 
Kunii K, Davis L, Gorenstein J, et al. FGFR2-amplified gastric cancer cell lines require FGFR2 
and Erbb3 signaling for growth and survival. Cancer Res 2008;68:2340-2348. 
Lamont FR, Tomlinson DC, Cooper PA, Shnyder SD, Chester JD, Knowles MA. Small molecule 
FGF receptor inhibitors block FGFR-dependent urothelial carcinoma growth in vitro and in vivo. 
Br J Cancer 2011;104:75-82. 
Nakamura H, Arai Y, Totoki Y, et al. Genomic spectra of biliary tract cancer. Nat Genet 
2015;47:1003-1010. 
National Cancer Institute (NCI). Common Terminology Criteria for Adverse Events (CTCAE) 
Version 5.0. 2017. http://evs. nci. nih. gov/ftp1/CTCAE/CTCAE_5.0_QuickReference_5x7.pdf. 
Accessed May 6, 2019. 
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National Cancer Institute. Genomic Data Commons Data Portal. 2019. 
https://portal.gdc.cancer.gov. Accessed May 3, 2019. 
Oken MM, Creech RH, Tormey DC, et al. Toxicity and response criteria of the Eastern 
Cooperative Oncology Group. Am J Clin Oncol 1982;5:649-655. 
Pemigatinib Investigator's Brochure. Wilmington, DE: Incyte Corporation.  
Porta R, Borea R, Coelho A, et al. FGFR a promising druggable target in cancer: molecular 
biology and new drugs. Crit Rev Oncol Hematol 2017;113:256-267. 
Qing J, Du X, Chen Y, et al. Antibody-based targeting of FGFR3 in bladder carcinoma and 
t(4;14)-positive multiple myeloma in mice. J Clin Invest 2009;119:1216-1229. 
Sia D, Losic B, Moeini A, et al. Massive parallel sequencing uncovers actionable FGFR2-
PPHLN1 fusion and ARAF mutations in intrahepatic cholangiocarcinoma. Nat Commun 
2015;22:6087. 
Turner N, Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev 
Cancer 2010;10:116-129. 
Weiss J, Sos ML, Seidel D, et al. Frequent and focal FGFR1 amplification associates with 
therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl Med 
2010;2:62ra93. 
Wen PY, Macdonald DR, Reardon DA, et al. Updated response assessment criteria for high-
grade gliomas: Response Assessment in Neuro-Oncology Working Group. J Clin Oncol 
2010;28:1963-1972. 
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APPENDIX A. INFORMATION REGARDING EFFECTIVENESS OF 
CONTRACEPTIVE METHODS 
For male participants in the study: 
Male participants should use a condom from screening through 90 days after the end of systemic 
exposure.  If the male participant has a partner that is of child-bearing potential, the partner should also 
use contraception through 90 days after the end of relevant systemic exposure.  In addition, male 
participants must refrain from donating sperm from screening through 90 days after the end of relevant 
systemic exposure.  Males who have had a vasectomy qualify as having met the requirement for a 
highly effective birth control method. 
For female participants in the study: 
The following methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods: 
• Combined (estrogen and progestogen containing) hormonal contraception associated with 
inhibition of ovulation
a 
− oral 
− intravaginal 
− transdermal 
• Progestogen-only hormonal contraception associated with inhibition of ovulationa 
− oral 
− injectable 
− implantable
b 
• Intrauterine deviceb 
• Intrauterine hormone-releasing systemb 
• Bilateral tubal occlusionb 
• Vasectomized partnerbc 
• Sexual abstinence
d 
Acceptable birth control methods that result in a failure rate of more than 1% per year include: 
• Progestogen-only oral hormonal contraception, where inhibition of ovulation is not the primary 
mode of action 
• Male or female condom with or without spermicide
e 
• Cap, diaphragm, or sponge with spermicidee 
• Tubal ligation 
a Hormonal contraception may be susceptible to interaction with the investigational medicinal product, which may 
reduce the efficacy of the contraception method.  
b Contraception methods that in the context of this guidance are considered to have low user dependency.  
c Vasectomized partner is a highly effective method of avoiding pregnancy provided that partner is the sole sexual 
partner of the woman of childbearing potential study participant and that the vasectomized partner has received 
medical assessment of the surgical success.  
d In the context of this guidance, sexual abstinence is considered a highly effective method only if defined as 
refraining from heterosexual intercourse during the entire period of risk associated with the study treatments.  The 
reliability of sexual abstinence needs to be evaluated in relation to the duration of the clinical study and the 
preferred and usual lifestyle of the participant.  
e A combination of male condom with either cap, diaphragm, or sponge with spermicide (double barrier methods) 
are also considered acceptable, but not highly effective, birth control methods.  
Source:  Clinical Trial Facilitation Group 2014.  
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APPENDIX B. INSTRUCTION TO PARTICIPANTS FOR HANDLING 
STUDY DRUG (PEMIGATINIB) 
The participant must be instructed in the handling of study drug as follows: 
• Store the study drug at room temperature. 
• Only remove the number of tablets needed at the time of administration. 
• Not to remove doses in advance of the next scheduled administration. 
• Make every effort to take doses on schedule. 
• Report any missed doses/lost tablets. 
• Not to crush, dissolve, or break tablets 
• To take study drug with a full glass of water. 
• If the participant vomits after taking study drug, the participant should not take 
another dose. 
• To keep study drug in a safe place and out of reach of children. 
• To bring all used and unused study drug bottles/kits to the site at each visit. 
• If a dose of pemigatinib is missed by more than 4 hours, that dose should be skipped 
and the next scheduled dose should be administered at the usual time). 
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APPENDIX C. FGFR MUTATIONS AND TRANSLOCATIONS 
Please follow instructions outlined in the Investigator Site Files for screening/enrolling 
participants.  For FGFR alterations not present on this list, the study sponsor must be consulted 
for enrollment. 
All in-frame fusions of FGFR1-3 or FGFR2 intron 17 rearrangements are allowed in Cohort A 
regardless of fusion partner. 
Table C1 lists the nonkinase domain mutations in FGFR1-3 allowed in Cohort B without prior 
consultation with the sponsor.  This list contains alterations considered oncogenic or likely 
oncogenic (excluding the kinase domain) based on known or previously described activating 
mutations, and/or are present in somatic mutation databases.  This list is not all-inclusive, as 
some rare mutations may not have met our inclusion cutoff criteria. 
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Table C1: Known/Presumed Activating Point Mutations of FGFR1-3 Allowed in Cohort B  
Gene 
Alteration 
Position 
Gene 
Alteration 
Position 
Gene 
Alteration 
Position 
FGFR1 
S24F 
24 
FGFR2 
S24F 
24 
FGFR3 
A99T 
99 
FGFR1 
G70R 
70 
FGFR2 
A97T 
97 
FGFR3 
S131L 
131 
FGFR1 
S125L 
125 
FGFR2 
R178C 
178 
FGFR3 
R175C 
175 
FGFR1 
T141R 
141 
FGFR2 
R203C 
203 
FGFR3 
R196C 
196 
FGFR1 
P150S 
150 
FGFR2 
R203H 
203 
FGFR3 
R200C 
200 
FGFR1 
R189C 
189 
FGFR2 
R210Q 
210 
FGFR3 
R248C 
248 
FGFR1 
S251F 
251 
FGFR2 
S252F 
252 
FGFR3 
S249C 
249 
FGFR1 
P252R 
252 
FGFR2 
S252L 
252 
FGFR3 
S249F 
249 
FGFR1 
P252T 
252 
FGFR2 
S252P 
252 
FGFR3 
S249Y 
249 
FGFR1 
G315E 
315 
FGFR2 
S252W 
252 
FGFR3 
D333N 
333 
FGFR1 
G315R 
315 
FGFR2 
P253F 
253 
FGFR3 
G342C 
342 
FGFR1 
Y372C 
372 
FGFR2 
P253L 
253 
FGFR3 
S351C 
351 
FGFR1 
Y374C 
374 
FGFR2 
P253R 
253 
FGFR3 
G370C 
370 
FGFR1 
C379R 
379 
FGFR2 
S267P 
267 
FGFR3 
S371C 
371 
FGFR1 
C381R 
381 
FGFR2 
W290C 
290 
FGFR3 
Y373C 
373 
FGFR1 
R445L 
445 
FGFR2 
G305R 
305 
FGFR3 
G375C 
375 
FGFR1 
R445Q 
445 
FGFR2 
G305W 
305 
FGFR3 
G380R 
380 
FGFR1 
R445W 
445 
FGFR2 
A315S 
315 
FGFR3 
A391E 
391 
FGFR1 
G818R 
818 
FGFR2 
A315T 
315 
FGFR3 
A391V 
391 
 
 
 
FGFR2 
D336G 
336 
FGFR3 
R399C 
399 
 
 
 
FGFR2 
D336N 
336 
 
 
 
 
 
 
FGFR2 
C342F 
342 
 
 
 
 
 
 
FGFR2 
C342G 
342 
 
 
 
 
 
 
FGFR2 
C342R 
342 
 
 
 
 
 
 
FGFR2 
C342S 
342 
 
 
 
 
 
 
FGFR2 
C342W 
342 
 
 
 
 
 
 
FGFR2 
C342Y 
342 
 
 
 
 
 
 
FGFR2 
S347C 
347 
 
 
 
 
 
 
FGFR2 
S351C 
351 
 
 
 
 
 
 
FGFR2 
S354C 
354 
 
 
 
 
 
 
FGFR2 
S372C 
372 
 
 
 
 
 
 
FGFR2 
Y375C 
375 
 
 
 
 
 
 
FGFR2 
C382F 
382 
 
 
 
 
 
 
FGFR2 
C382G 
382 
 
 
 
 
 
 
FGFR2 
C382R 
382 
 
 
 
 
 
 
FGFR2 
C382Y 
382 
 
 
 
 
 
 
FGFR2 
M391R 
391 
 
 
 
 
 
 
FGFR2 
V395D 
395 
 
 
 
 
 
 
FGFR2 
E777K 
777 
 
 
 
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APPENDIX D. CYP3A4 INHIBITORS AND INDUCERS 
CYP3A4 Inducers 
Inducers 
Therapeutic class 
Potent CYP3A Inducers 
Rifampin 
Antibiotics 
Mitotane 
Other Antineoplastics 
Avasimibe 
Other Antilipemics 
Rifapentine 
Antibiotics 
Apalutamide 
Antiandrogens 
Phenytoin 
Anticonvulsants 
Carbamazepine 
Anticonvulsants 
Enzalutamide 
Antiandrogens 
St John's Wort extract 
Herbal medications 
Lumacaftor 
Cystic fibrosis treatments 
Rifabutin 
Antibiotics 
Phenobarbital 
Anticonvulsants 
Moderate CYP3A Inducers 
Ritonavir and St. John's wort 
None 
Semagacestat 
Alzheimer's treatments 
Efavirenz 
NNRTIs 
Tipranavir and ritonavir 
Protease inhibitors 
Dabrafenib 
Kinase inhibitors 
Lesinurad 
Antigout and uricosuric agents 
Bosentan 
Endothelin receptor antagonists 
Genistein 
Food products 
Thioridazine 
Antipsychotics 
Nafcillin 
Antibiotics 
Talviraline 
NNRTIs 
Lopinavir 
Protease inhibitors 
Modafinil 
Psychostimulants 
Pf-06282999 
Myeloperoxidase inactivators 
Etravirine 
NNRTIs 
Lersivirine 
NNRTIs 
Telotristat ethyl 
Antidiarrheals 
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CYP3A4 Inhibitors 
Inhibitors 
Therapeutic class 
Potent CYP3A Inhibitors 
VIEKIRA PAK 
Antivirals 
Indinavir /RIT 
Protease inhibitors 
Tipranavir/RIT 
Protease inhibitors 
Ritonavir 
Protease inhibitors 
Cobicistat (GS-9350) 
None 
Ketoconazole 
Antifungals 
Indinavir 
Protease inhibitors 
Troleandomycin 
Antibiotics 
Telaprevir 
Antivirals 
Danoprevir/RIT 
Antivirals 
Elvitegravir/RIT 
Treatments of AIDS 
Saquinavir/RIT 
Protease inhibitors 
Lopinavir/RIT 
Protease inhibitors 
Itraconazole 
Antifungals 
Voriconazole 
Antifungals 
Mibefradil 
Calcium channel blockers 
LCL161 
Cancer treatments 
Clarithromycin 
Antibiotics 
Posaconazole 
Antifungals 
Telithromycin 
Antibiotics 
Grapefruit juice DS 
Food products 
Conivaptan 
Diuretics 
Nefazodone 
Antidepressants 
Nelfinavir 
Protease inhibitors 
Saquinavir 
Protease inhibitors 
Ribociclib 
Kinase inhibitors 
Idelalisib 
Kinase inhibitors 
Boceprevir 
Antivirals 
Inhibitor 
Therapeutic Class 
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Inhibitors 
Therapeutic class 
Moderate CYP3A Inhibitors 
Erythromycin 
Antibiotics 
Fluconazole 
Antifungals 
Atazanavir/RIT 
Protease inhibitors 
Darunavir 
Protease inhibitors 
Diltiazem 
Calcium channel blockers 
Darunavir/RIT 
Protease inhibitors 
Dronedarone 
Antiarrhythmics 
Crizotinib 
Kinase inhibitors 
Atazanavir 
Protease inhibitors 
Letermovir 
Antivirals 
GSK2647544 
Alzheimer's disease & dementia treatments 
Aprepitant 
Antiemetics 
Casopitant 
Antiemetics 
Amprenavir 
Protease inhibitors 
Faldaprevir 
Antivirals 
Imatinib 
Antineoplastic agents 
Verapamil 
Calcium channel blockers 
Netupitant 
Antiemetics 
Nilotinib 
Kinase inhibitors 
Grapefruit juice 
Food products 
Tofisopam 
Benzodiazepines 
Cyclosporine 
Immunosuppressants 
ACT-178882 
Renin inhibitors 
Ciprofloxacin 
Antibiotics 
Magnolia vine (Schisandra sphenanthera) 
Herbal medications 
Isavuconazole 
Antifungals 
Cimetidine 
H-2 receptor antagonists 
FK1706 
Central nervous system agents 
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APPENDIX E. RANO RESPONSE CRITERIA 
Criterion 
CR 
PR 
SD 
PD 
T1 Gadolinium enhancing disease 
None 
≥ 50% ↓ 
< 50% ↓ but < 25% ↑ 
≥ 25% ↑
a 
T2/FLAIR 
Stable or ↓ 
Stable or ↓ 
Stable or ↓ 
↑a 
New Lesion 
None 
None 
None 
Presenta 
Corticosteroids 
None 
Stable or ↓ 
Stable or ↓ 
NA
b 
Clinical Status 
Stable or ↑ 
Stable or ↑ 
Stable or ↑ 
↓a 
Requirement for response 
All 
All 
All 
Anya 
CR = complete response; FLAIR = fluid-attenuated inversion recovery; NA = not applicable; PD = progressive disease; 
PR = partial response; RANO = Response Assessment in Neuro-Oncology; SD = stable disease. 
Note:  Adapted from Wen et al 2010. 
a Progression occurs when this criterion is present. 
b Increase in corticosteroids alone will not be taken into account in determining progression in the absence of persistent clinical 
deterioration. 
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APPENDIX F. PROTOCOL AMENDMENT SUMMARY OF CHANGES 
Document 
Date 
Amendment (Version) 1: 
14 JUN 2019 
Amendment 1 (14 JUN 2019) 
Overall Rationale for the Amendment: 
The overall rationale for the amendment was to clarify sample collection and dose strength.  
Specifically, the collection of blood or saliva at baseline was added, and tumor tissue previously 
tested at the reference laboratory will not need to be resubmitted or retested for validation.  The 
dose strength to be used in this study will be 4.5 mg, though doses of 4.5, 9, 13.5, and 18 mg 
may be tested.  Additional items were added to this amendment and are listed below. 
1. Section 1, Protocol Summary (Table 3:  Schedule of Activities) 
Description of change:  A note was added to indicate that study drug will be collected 
only at Cycles 2+ and EOT. 
Rationale for change:  Study drug will not be collected on Day 8 or Day 15. 
2. Section 1, Protocol Summary; Section 4.1, Overall Design; Section 8.5.1, Tumor for 
Genomics Testing for FGFR Genetic Alterations and Gene Expression; 
Section 8.5.3, Tissue Biopsies 
Description of change:  Language was added to indicate that a biopsy at baseline is not 
mandatory for participants who had tumor tissue previously tested. 
Rationale for change:  Tumor tissue previously tested at the reference lab will not need 
to be resubmitted or retested for validation. 
3. Section 1, Protocol Summary (Table 4:  Schedule of Laboratory Assessments); 
Section 8.5.2, Blood for Mutational and Other Correlative Analysis 
Description of change:  Additional genomic testing (blood or saliva) was added. 
Rationale for change:  The laboratory will be performing this test at baseline for the 
purpose of tumor/normal matched sampling and assessment of mutation status. 
4. Section 6.1, Study Treatment Administered (Table 9:  Study Treatment 
Information) 
Description of change:  The dose strength/dosage levels and administration instructions 
were updated. 
Rationale for change:   Tablets will be 4.5 mg only. 
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5. Section 6.2, Preparation, Handling, and Accountability; Section 9.4, Reporting of 
Serious Adverse Events 
Description of change:  References to the Study Reference Manual were removed. 
Rationale for change:  A Study Reference Manual will not be provided. 
6. Incorporation of administrative changes.  Other minor, administrative changes have 
been incorporated throughout the Protocol and are noted in the redline version of the 
amendment. 
CONFIDENTIAL 

Signature Manifest
Document Number: IC-DEV-PROT-AMEND-0484
Revision: 0
Title: 54828-MA-TA-208 Protocol Amendment 1
All dates and times are in Eastern Standard Time.
APPROVAL: 54828-MA-TA-208 PR AM1
Approval and Release
Name/Signature
Title
Date
Meaning/Reason
14 Jun 2019, 01:50:48 PM
Approved
17 Jun 2019, 08:54:15 AM
Approved
17 Jun 2019, 09:25:22 AM
Approved
Quick Approval
Approve Now
Name/Signature
Title
Date
Meaning/Reason
21 Jun 2019, 11:08:43 AM
Approved