A Phase 0 Study of Infigratinib in Recurrent High-Grade Glioma Participants Scheduled for Resection to Evaluate Central Nervous System (CNS) Penetration With PK Triggered Expansion Cohort
Phase: EARLY_PHASE1
Conditions: Glioma, Glioblastoma, GBM
Sponsor: Nader Sanai



A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
         
Protocol 2020-08 
 
Initial Version – v1.0 27Mar2020 
 
 
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Revision Date: v3.0 10Sep2020 
 
Protocol Signature Page – Participating Sites 
 
Protocol No.: 2020-08  
 
I have read this protocol and agree to conduct the protocol in accordance with Good Clinical 
Practices (ICH-GCP), the applicable ethical principles, the Statement of Investigator (Form FDA 
1572), Institutional Review Board regulations, and all national, state and local laws and/or 
requirements of the pertinent regulatory requirements. 
 
Principal Investigator 
 
 
Printed Name 
 
 
Signature 
 
Date 
 
 
 

A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
Protocol 2020-08 
Initial Version – v1.0 27Mar2020 
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Revision Date: v3.0 10Sep2020 
TABLE OF CONTENTS 
STATEMENT OF COMPLIANCE ...................................................................................................................... 1 
1 
PROTOCOL SUMMARY ....................................................................................................................... 2 
1.1 
Synopsis ................................................................................................................................... 2 
1.2 
Schedule of Activities (SoA) ..................................................................................................... 8 
2 
INTRODUCTION ............................................................................................................................... 11 
2.1 
Study Rationale ...................................................................................................................... 11 
2.1.1 
Rationale and Purpose ......................................................................................... 11 
2.2 
Background ............................................................................................................................ 12 
2.2.1 
Infigratinib Nonclinical Studies ............................................................................ 12 
2.2.2 
Infigratinib Clinical Studies .................................................................................. 12 
2.3 
Risk/Benefit Assessment........................................................................................................ 13 
2.3.1 
Known Potential Risks .......................................................................................... 13 
2.3.2 
Known Potential Benefits .................................................................................... 13 
2.3.3 
Assessment of Potential Risks and Benefits ........................................................ 14 
3 
OBJECTIVES AND ENDPOINTS .......................................................................................................... 15 
4 
STUDY DESIGN ................................................................................................................................. 16 
4.1 
Overall Design ........................................................................................................................ 16 
4.1.1 
Phase 0 Design ..................................................................................................... 16 
4.1.2 
Expansion Cohort Design ..................................................................................... 16 
4.2 
Scientific Rationale for Study Design ..................................................................................... 16 
4.3 
Justification for Dose ............................................................................................................. 16 
4.3.1 
Dose Rationale for infigratinib ............................................................................. 16 
4.1 
End of Study Definition .......................................................................................................... 17 
5 
STUDY POPULATION ........................................................................................................................ 18 
5.1 
Inclusion Criteria .................................................................................................................... 18 
5.2 
Exclusion Criteria ................................................................................................................... 19 
5.3 
Lifestyle Considerations ......................................................................................................... 20 
5.3.1 
General Guidance for Women of Childbearing Potential and/or Use of 
Contraceptive Methods 
21 
5.4 
Screen Failures ....................................................................................................................... 21 
5.5 
Strategies for Recruitment and Retention............................................................................. 21 
5.5.1 
Participant Recruitment ....................................................................................... 22 
5.5.2 
Pre-screening Activities ....................................................................................... 22 
5.5.3 
Confidentiality Participant Information and Confidentiality ............................... 23 
6 
STUDY INTERVENTION ..................................................................................................................... 24 
6.1 
Study Intervention(s) Administration .................................................................................... 24 
6.1.1 
Study Intervention Description ............................................................................ 24 
6.1.2 
Dosing and Administration .................................................................................. 24 
6.1.3 
Dose Modifications .............................................................................................. 25 
6.2 
Preparation/Handling/Storage/Accountability ..................................................................... 35 
6.2.1 
Acquisition and accountability ............................................................................. 35 
6.2.2 
Formulation, Appearance, Packaging, and Labeling ............................................ 35 
6.2.3 
Product Storage and Stability .............................................................................. 35 
6.2.4 
Disposal and Destruction ..................................................................................... 35 
6.3 
Study Intervention Compliance ............................................................................................. 35 
6.4 
Concomitant Therapy ............................................................................................................ 35 

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STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION / WITHDRAWAL
 
42 
7.1 
Discontinuation of Study Intervention .................................................................................. 42 
7.2 
Participant Discontinuation/Withdrawal from the Study ..................................................... 42 
7.3 
Lost to Follow-Up ................................................................................................................... 42 
8 
STUDY ASSESSMENTS AND PROCEDURES ....................................................................................... 44 
8.1 
Efficacy Assessments ............................................................................................................. 44 
8.1.1 
Pharmacokinetic (PK) Measurements ................................................................. 44 
8.1.2 
Pharmacodynamic (PD) Measurements .............................................................. 44 
8.1.3 
Neuroradiology .................................................................................................... 46 
8.1.4 
Response Assessment in neuro-oncology criteria (RANO) .................................. 46 
8.2 
Safety and Other Assessments .............................................................................................. 47 
8.2.1 
Demographics ...................................................................................................... 47 
8.2.2 
Medical History .................................................................................................... 47 
8.2.3 
Physical examination ........................................................................................... 47 
8.2.4 
Abbreviated Physical and Neurological Examination .......................................... 48 
8.2.5 
Ophthalmic Examination ..................................................................................... 48 
8.2.6 
Performance status .............................................................................................. 48 
8.2.7 
Vital signs ............................................................................................................. 48 
8.2.8 
Height and weight ................................................................................................ 48 
8.2.9 
Electrocardiogram (ECG) ...................................................................................... 48 
8.2.10 
Echocardiogram (ECHO) or Multigated Acquisition (MUGA) .............................. 49 
8.2.11 
Craniotomy .......................................................................................................... 49 
8.2.12 
Laboratory evaluations ........................................................................................ 49 
8.2.13 
Patient Derived Xenografts (PDX) ........................................................................ 50 
8.2.14 
Adverse Events ..................................................................................................... 50 
8.3 
Adverse Events and Serious Adverse Events ......................................................................... 50 
8.3.1 
Definition of Adverse Events (AE) ........................................................................ 51 
8.3.2 
Definition of Serious Adverse Events (SAE) ......................................................... 51 
8.3.3 
Classification of an Adverse Event ....................................................................... 52 
8.3.4 
Time Period and Frequency for Event Assessment and Follow-Up ..................... 53 
8.3.5 
Adverse Event Reporting ..................................................................................... 54 
8.3.6 
Serious Adverse Event Reporting......................................................................... 54 
8.3.7 
Reporting Events to Participants ......................................................................... 55 
8.3.8 
Events of Special Interest ..................................................................................... 55 
8.3.9 
Reporting of Pregnancy ....................................................................................... 55 
8.4 
Unanticipated Problems ........................................................................................................ 55 
8.4.1 
Definition of Unanticipated Problems (UP) ......................................................... 55 
8.4.2 
Unanticipated Problem Reporting ....................................................................... 55 
8.4.3 
Reporting Unanticipated Problems to Participants ............................................. 56 
9 
STATISTICAL CONSIDERATIONS ....................................................................................................... 57 
9.1 
Statistical Hypotheses ............................................................................................................ 57 
9.2 
Sample Size Determination.................................................................................................... 57 
9.3 
Populations for Analyses ....................................................................................................... 57 
9.4 
Statistical Analyses................................................................................................................. 57 
9.4.1 
Analysis of the Primary Efficacy Endpoint(s) ....................................................... 57 
9.4.2 
Analysis of the Secondary Endpoint(s) ................................................................ 58 
9.4.3 
Baseline Descriptive Statistics ............................................................................. 58 

A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
         
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9.4.4 
Planned Interim Analyses .................................................................................... 58 
9.4.5 
Data Handling Rules ............................................................................................. 58 
9.4.6 
Exploratory Analyses ............................................................................................ 59 
10 
SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS ...................................... 60 
10.1 
Regulatory, Ethical, and Study Oversight Considerations ..................................................... 60 
10.1.1 
Informed Consent Process ................................................................................... 60 
10.1.2 
Study Discontinuation and Closure ...................................................................... 60 
10.1.3 
Confidentiality and Privacy .................................................................................. 61 
10.1.4 
Future Use of Stored Specimens and Data .......................................................... 61 
10.1.5 
Key Roles and Study Governance ........................................................................ 62 
10.1.6 
Safety Oversight ................................................................................................... 62 
10.1.7 
Clinical Monitoring ............................................................................................... 63 
10.1.8 
Quality Assurance and Quality Control ................................................................ 63 
10.1.9 
Data Handling and Record Keeping ..................................................................... 63 
10.1.10 
Protocol Deviations .............................................................................................. 64 
10.1.11 
Publication and Data Sharing Policy .................................................................... 64 
10.1.12 
Conflict of Interest Policy ..................................................................................... 64 
10.2 
Abbreviations ......................................................................................................................... 66 
10.3 
Protocol Amendment History ................................................................................................ 68 
11 
REFERENCES..................................................................................................................................... 70 
12 
APPENDICES ..................................................................................................................................... 71 
12.1 
Performance Status Criteria .................................................................................................. 71 
 
List of Tables 
Table 1 Study Interventions ........................................................................................................................ 24 
Table 2 Phase 0 Dose Schedule ................................................................................................................... 24 
Table 3 Dose adjustments for infigratinib-related toxicity ......................................................................... 25 
Table 4 Toxicity Follow-up Evaluation ........................................................................................................ 32 
Table 5 infigratinib dose reductions ........................................................................................................... 33 
Table 6 Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality.................................. 34 
Table 7 Drugs to be used with caution while on study ............................................................................... 37 
Table 8 List of prohibited medications and substances while on study ..................................................... 39 
Table 9 Clinical laboratory parameters collection plan .............................................................................. 49 

A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
         
Protocol 2020-08 
 
Initial Version – v1.0 27Mar2020 
 
 
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Revision Date: v3.0 10Sep2020 
 
STATEMENT OF COMPLIANCE 
The trial will be conducted in accordance with International Conference on Harmonisation Good Clinical 
Practice (ICH GCP), applicable United States (US) Code of Federal Regulations (CFR), and the IBTC 
contractual terms. The Principal Investigator will assure that no deviation from, or changes to the protocol 
will take place without prior agreement from the Investigational New Drug (IND) sponsor and documented 
approval from the Institutional Review Board (IRB), except where necessary to eliminate an immediate 
hazard(s) to the trial participants. All personnel involved in the conduct of this study have completed 
Human Subjects Protection and ICH GCP Training. 
The protocol, informed consent form(s), recruitment materials, and all participant materials will be 
submitted to the IRB for review and approval.  Approval of both the protocol and the consent form must 
be obtained before any participant is enrolled.  Any amendment to the protocol will require review and 
approval by the IRB before the changes are implemented to the study.  All changes to the consent form 
will be IRB approved; a determination will be made regarding whether a new consent needs to be 
obtained from participants who provided consent, using a previously approved consent form. 

A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
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PROTOCOL SUMMARY 
1.1 
SYNOPSIS 
Title: 
A Phase 0 Study of infigratinib in Recurrent High-Grade Glioma (HGG) 
Participants Scheduled for Resection to Evaluate Central Nervous System (CNS) 
Penetration with PK triggered expansion cohort 
Study Description: 
This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20 
participants with recurrent high-grade glioma with FGFR1 K656E or FGFR3 
K650E mutation or FGFR3-TACC3 translocation which are scheduled for 
resection. In the lead-in cohort, a total of 20 participants will be enrolled into 
the proposed phase 0 clinical trial. Participants will be administered infigratinib 
prior to surgical resection of their tumor.  
Phase 0: 
The Phase 0 study will include treatment of recurrent high-grade glioma 
participants with 125 mg of infigratinib 7 days prior to surgical resection. 
To assess the PK and PD endpoints listed, blood, CSF and brain tumor tissue will 
be collected intraoperatively on Day 7 (enhancing and non-enhancing tumor 
tissue will be collected and analyzed separately). Additionally, blood samples 
will be obtained on Day 7 at pre-dosing (trough level), 0.5, 1, 2, 4, 6, 8, and 24 
hours post dose. (Note: 24 h blood sample on Day 8).  
Expansion Cohort: 
Participants with tumors demonstrating PK-response will continue treatment 
with the same dose continuously for 21 days in 28-day cycles after surgery. A 
positive PK response will be unbound concentrations of infigratinib reaching 5-
fold higher than cell-free biochemical IC50 within the non-enhancing region of 
the tumor. PD biomarkers will be included for exploratory analyses. Participants 
in the expansion cohort will return to the clinic to monitor safety per the 
schedule of events until treatment is ended and will be contacted 
approximately every 3 months by letter or phone for collection of survival data. 
The start of follow up for long-term survival begins following completion of the 
Day 30 safety follow up call.  
Participants will be treated until unacceptable toxicity is observed, or until 
disease progression as assessed by radiographic or clinical metrics.  
Primary 
Objectives/Endpoint
s 
1.
Phase 0: To measure the
pharmacokinetic (PK) effects of
infigratinib in recurrent high-grade
glioma participants.
1.
Phase 0: Total and Unbound
infigratinib concentration in
enhancing and non-enhancing
tumor tissue (8hr), plasma (0-
24H) and CSF (8hr) will be
determined.
2.
Expansion Cohort: Examine
progression-free survival in
recurrent high-grade glioma
2.
Expansion Cohort: 6-month
progression-free survival (PFS6)

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participants with demonstrated PK 
effects 
rate measured from time of 
surgery to date of recurrence  
Secondary 
Objectives/Endpoint
s 
1. Phase 0: PD Analysis 
1. Phase 0: percentage of pERK+, 
MIB-1+ and Cleaved Caspase 3+ 
cells from the surgical tissue 
will be quantified and 
compared to baseline 
archival/biopsy tissue. 
2. Expansion cohort: To monitor safety 
and tolerability of study drug in 
participants with recurrent high-
grade glioma. 
2. Expansion cohort: Safety and 
tolerability: 
a. Drug-related toxicity 
b. Number of Adverse Events 
through study completion, 
assessed up to 60 months 
c. Treatment-emergent 
adverse events (TEAEs) 
d. Deaths 
e. Clinical laboratory 
abnormalities per CTCAE 
(Version 5.0) 
Exploratory 
Objectives/Endpoint
s 
1. Phase 0: Describe systemic PK 
1. Phase 0: Systemic plasma PK 
profile parameters (Tmax, Cmax, 
t1/2, AUC0-24h) for total and 
unbound levels will be 
determined for infigratinib. 
2. Expansion Cohort: Examine Overall 
Survival (OS) in recurrent high-grade 
glioma participants with 
demonstrated PK effects 
2. Expansion Cohort Efficacy: 
a. Median Overall Survival 
(OS) from time of surgery 
to date of death from any 
cause 
Study Population: 
Participants undergoing resection for a recurrent high-grade glioma. Each 
participant must meet all the following inclusion criteria and none of the 
exclusion criteria to be eligible for study entry: 
Inclusion Criteria: 
1. Prior resection of histologically diagnosed high-grade gliomas (III and 
IV) defined as participants who have progressed on or following 
standard (Stupp regimen) therapy, which included maximal surgical 
resection, temozolomide, and fractionated radiotherapy. 
2. Recurrence must be confirmed by diagnostic biopsy with local 
pathology review or contrast-enhanced MRI.  
3. Have measurable disease preoperatively, defined as at least 1 contrast-
enhancing lesion, with 2 perpendicular measurements of at least 1 cm, 
as per RANO criteria. 

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4. Sufficient archival or biopsy tissue available to confirm eligibility. 
5. Archival or biopsy tissue must demonstrate: FGFR1 K656E or FGFR3 
K650E mutation or FGFR3-TACC3 translocation from NGS sequencing or 
IHC and RT-PCR. 
6. Ability to understand and the willingness to sign a written informed 
consent document (personally or by the legally authorized 
representative, if applicable).  
7. Has voluntarily agreed to participate by giving written informed consent 
(personally or via legally authorized representative(s), and assent if 
applicable). Written informed consent for the protocol must be 
obtained prior to any screening procedures. If consent cannot be 
expressed in writing, it must be formally documented and witnessed, 
ideally via an independent trusted witness. 
8. Willingness and ability to comply with scheduled visits, treatment plans, 
laboratory tests and other procedures. 
9. Age ≥18 at time of consent. 
10. Have a performance status (PS) of ≤2 on the Eastern Cooperative 
Oncology (Group (ECOG) scale (Oken et al. 1982). 
11. Ability to swallow oral medications. 
12. Has adequate bone marrow and organ function as defined by the 
following laboratory values (as assessed by the local laboratory for 
eligibility): 
Adequate bone marrow function: 
absolute neutrophil 
count 
≥1,000/mcL 
Platelets (at time of 
surgery) 
≥100,000/mcL 
hemoglobin 
≥8.0 g/dL 
Participants 
may 
receive 
erythrocyte 
transfusions to achieve this hemoglobin 
level at the discretion of the investigator.   
Adequate hepatic and renal function: 
total bilirubin 
≤1.5 X ULN. 
Participants with Gilbert’s syndrome with a 
total bilirubin ≤2.0 times ULN and direct 
bilirubin within normal limits are permitted. 
AST(SGOT) 
≤3 X institutional ULN 
ALT(SGPT) 
≤3 X institutional ULN 
Calculated or 
measured creatinine 
clearance 
≥45 mL/min 
Other Lab Values: 
 
Amylase or lipase 
≤2 X institutional ULN 

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calcium or 
phosphorus, or 
calcium-phosphorus 
product 
≤55 mg2/dL2 
a. Inorganic phosphorus within normal 
limits 
b. Total corrected serum calcium within 
normal limits 
13. Confirmed negative serum pregnancy test (β-hCG) before starting study 
treatment or participant  is no longer of childbearing potential due to 
surgical, chemical, or natural menopause. 
14. For females of reproductive potential: use of highly effective 
contraception for at least 1 month prior to screening and agreement to 
use such a method during study participation and for an additional 3 
months after the end of treatment administration.  
15. For males of reproductive potential: use of condoms or other methods 
to ensure effective contraception with partner and for an additional 1 
month after the end of treatment administration. A condom is required 
to be used also by vasectomized men as well as during intercourse with 
a male partner to prevent delivery of the drug via seminal fluid. 
16. Agreement to adhere to Lifestyle Considerations (see Section 5.3) 
throughout study duration. 
17. Participants who received chemotherapy must have recovered 
(Common Terminology Criteria for Adverse Events [CTCAE] Grade ≤1) 
from the acute effects of chemotherapy except for residual alopecia or 
Grade 2 peripheral neuropathy prior to Day 1.   A washout period of at 
least 21 days is required between last chemotherapy dose and Day 1 
(provided the patient did not receive radiotherapy). 
18. Participants who received radiotherapy must have completed and fully 
recovered from the acute effects of radiotherapy. A washout period of 
at least 14 days is required between end of radiotherapy and Day 1. 
Exclusion Criteria: 
1.  Have a history of liver transplant. 
2. Have impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of oral infigratinib (e.g., ulcerative 
diseases, uncontrolled nausea, vomiting, diarrhea, malabsorption 
syndrome, small bowel resection). 
3. Known active systemic bacterial infection (requiring intravenous [IV] 
antibiotics at time of initiating study treatment), fungal infection, or 
detectable viral infection (such as known human immunodeficiency 
virus positivity or with known active hepatitis B or C [for example, 
hepatitis B surface antigen positive].  Screening is not required for 
enrollment. 
4. Have a history and/or current evidence of extensive tissue calcification 
including, but not limited to, the soft tissue, kidneys, intestine, 
myocardium, vascular system, and lung with the exception of calcified 
lymph nodes, minor pulmonary parenchymal calcifications, and 
asymptomatic coronary calcification.  
5. Have current evidence of corneal or retinal disorder/keratopathy 
including, but not limited to, bullous/band keratopathy, inflammation 

A Phase 0 Study of Infigratinib in Recurrent Glioblastoma Patients 
         
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or 
ulceration, 
keratoconjunctivitis 
confirmed 
by 
ophthalmic 
examination. Subjects with asymptomatic ophthalmic conditions 
assessed by the investigator to pose minimal risk for study participation 
may be enrolled in the study. 
6. Have current evidence of endocrine alterations of calcium/phosphate 
homeostasis, e.g., parathyroid disorders, history of parathyroidectomy, 
tumor lysis, tumoral calcinosis etc.  
7. Have had a recent (≤3 months prior to first dose of study drug) transient 
ischemic attack or stroke. 
8. CTCAE (v5.0) Grade ≥2 hearing loss. 
9. CTCAE (v5.0) Grade ≥2 neuropathy. 
10. Have clinically significant cardiac disease including any of the following: 
a. Known congestive heart failure requiring treatment (New York 
Heart Association Grade ≥2), LVEF <50% or local lower limit of 
normal as determined by MUGA scan or echocardiogram 
(ECHO), or uncontrolled hypertension (refer to the European 
Society of Cardiology and European Society of Hypertension 
guidelines [Williams et al 2018]).  
b. Presence of Common Terminology Criteria for Adverse Events 
(CTCAE) v5.0 Grade ≥2 ventricular arrhythmias, atrial 
fibrillation, bradycardia, or conduction abnormality. 
c. Unstable angina pectoris or acute myocardial infarction ≤3 
months prior to first dose of study drug. 
d. QTcF >470 msec (males and females). Note: If the QTcF is >470 
msec in the first ECG, a total of 3 ECGs separated by at least 5 
minutes should be performed. If the average of these 3 
consecutive results for QTcF is ≤470 msec, the participant 
meets eligibility in this regard. 
e. Known history of congenital long QT syndrome. 
11. Has serious and/or uncontrolled preexisting medical condition(s) that, 
in the judgment of the investigator, would preclude participation in this 
study (for example, interstitial lung disease, severe dyspnea at rest or 
requiring oxygen therapy, severe renal impairment [e.g. estimated 
creatinine clearance <30ml/min], history of major surgical resection 
involving the stomach or small bowel,  or preexisting Crohn’s disease or 
ulcerative colitis or a preexisting chronic condition resulting in baseline 
Grade 2 or higher diarrhea). 
12. Prior therapy with any mitogen-activated protein kinase (MEK) or FGFR 
inhibitor. Prior therapy is defined as a therapeutic dosing, as 
determined by the Investigator.  
13. Are currently receiving or are planning to receive during participation in 
this study, treatment with agents that are known strong inducers or 
inhibitors of CYP3A4 and medications which increase serum 
phosphorus and/or calcium concentration. Participants are not 
permitted to receive enzyme-inducing anti-epileptic drugs, including 
carbamazepine, phenytoin, phenobarbital, and primidone.  

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14. Current use of coumarin-derived anticoagulant for treatment, 
prophylaxis or otherwise. Therapy with heparin, low molecular weight 
heparin (LMWH) or fondaparinux is allowed.  
15. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-
lowering agents, infigratinib, or their excipients. 
16. Treatment with another investigational drug or other intervention 
within 30 days prior to enrollment or within 5 half-lives of the 
investigational product, whichever is longer. 
17. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges or products 
containing juice of these fruits within 7 days prior to first dose of study 
drug. 
18. Have used medications known to prolong the QT interval and/or are 
associated with a risk of Torsades de Pointes (TdP) 7 days prior to first 
dose of study drug. 
19. Have used amiodarone within 90 days prior to first dose of study drug 
Phase: 
0 
Description of 
Sites/Facilities 
Enrolling 
Participants: 
Up to 3 U.S. Sites will enroll participants for this study  
Description of Study 
Intervention: 
Phase 0: 125 mg of infigratinib administered orally for 7 days prior to surgical 
resection.  
Expansion Cohort: 125 mg of infigratinib administered orally for 21 days of a 28-
day treatment cycles. 
Study Duration: 
Approximately 30 months 
Participant 
Duration: 
Phase 0: up to approximately 2 months (screening window of 28 days through 
Day 30 phone call follow up).  
Expansion Cohort: infigratinib will be taken by the participant as long as the drug 
is tolerated and the investigator believes the participant may be obtaining 
benefit. Treatment will be taken by the participant until confirmed progression 
or end of treatment.  
All participants will be followed for survival.  
Statistical 
Considerations 
The trial is a phase 0 trial and therefore no formal statistics is planned. 
Historically, the Ivy Center operates on 400 recurrent high-grade glioma 
patients per year.  If 5% of the patients carrying FGFR3 fusion or FGFR1/3 
mutations, we expect 20 patients to be eligible for study each year.  Assuming 
50% patient capture, we envision 10 patients per year to be enrolled in the trial. 
The duration of the trial is therefore designed to be 24 months with an 
additional 6 months for clinical follow-up of participants enrolled into expansion 
cohort (estimated at 50% of the Phase 0 cohort) 
 

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2 
 
INTRODUCTION 
2.1 
STUDY RATIONALE  
2.1.1 RATIONALE AND PURPOSE 
Primary brain tumors are among the top 10 causes of cancer-related deaths in the United States, 
accounting for approximately 1.4% of all cancers and 2.4% of all cancer-related deaths.  About 14 per 
100,000 people in the United States are diagnosed with a primary brain tumor each year, and 6 to 8 per 
100,000 are diagnosed with a WHO grade III or IV primary brain tumor.  Glioblastoma multiforme (GBM, 
WHO Grade IV gliomas) is the most frequently reported malignant brain tumor histology (29.6%) in the 
National Cancer Database. The prognosis for patients who develop WHO Grade III or IV gliomas is bleak, 
with average survival after diagnosis ranging from 12-16 months.  Although conventional treatment with 
surgery, irradiation, and temozolomide postpones tumor progression and extends patients survival, these 
tumors universally recur and unrelentingly result in patient death.  Therefore, new targeted agents are 
urgently needed for high-grade glioma patients. 
Phase 0 trials identify promising new drugs by ‘humanizing’ preclinical studies. An array of design 
variations exists under the Phase 0 umbrella to address a range of possible study objectives.  These include 
studies to (1) determine whether a mechanism of action (MOA) defined in nonclinical models is achievable 
in humans; (2) refine a biomarker assay using human tumor tissue; (3) develop a novel imaging probe and 
evaluate its distribution, binding characteristics, and target effects in humans; (4) evaluate the human 
pharmacodynamics (PD) and/or pharmacokinetics (PK) of 2 or more analogs to select the most promising 
candidate for further development; (5) determine a dose-range and sequence of administration of a 
biomodulator for use in combination with established chemotherapy; and (6) provide human PK-PD 
relationship data for an agent before Phase 1 testing. For CNS oncology studies, PK analysis refers to 
measurement of study drug concentration in brain tumor tissue and PD analysis refers to quantification 
of a molecular/cellular target influenced by the study drug. 
For brain tumor patients, Phase 0 clinical trials are challenging, not only due to trial logistics, but also 
because of the dampening effect the non-therapeutic nature of such studies has on patient accrual. A 
Phase 0 + Expansion trial adapts the Phase 0 strategy to brain tumor patients but incorporates a PK- and 
PD-dependent trigger that graduates Phase 0 patients into an exploratory Expansion study arm. In doing 
so, this tactic is compelling to potential brain tumor patients by providing them with the confidence that, 
if selected for treatment, there is biological evidence suggesting their tumor can respond. For these 
patients graduating to the Expansion Arm, they (and their providers) are motivated by the biological 
rationale connecting the experimental therapy to their individual cases. Anecdotally, our institutional 
experience with both Phase 0 and Phase 0 + Expansion Arm studies speaks to this advantage and, since 
transitioning to the latter model in 2016, patient accrual has increased from 14% to 35%.  While the Phase 
2 component is typically exploratory, it can be randomized, as well. 
Less than 1% of all published clinical trials for brain tumors contain both PK and PD endpoints evaluating 
tissue effects following initial drug exposure. Fewer studies, however, examine tissue from these same 
patients following extended periods of drug treatment, even though 19% of all high-grade glioma patients, 
for example, undergo 3 or more tumor resections. Using the Phase 0/2 study paradigm, patients with 
planned re-resections for tumor recurrence following therapeutic dosing of the experimental agent(s) 
provide a critical opportunity for longitudinal tissue analysis. Within this population, enhancing and 
nonenhancing tumor tissue from fast- vs. slow-recurring tumors can be compared to identify the roles of 

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on-target and off-target pathways in tumor escape. To control for interindividual variations in CNS drug 
penetration, putative resistance mechanisms can also be examined in matched tissue specimens from 
initial, second (Phase 0), and third (Expansion Arm) resections.  Beyond characterizing resistance 
mechanisms, planned identification of tissue biomarker signatures associated with susceptibility to 
experimental agents can inform future clinical trial designs. For patients completing the Phase 0 
component of the study with evidence of adequate tumor penetration (i.e., a ‘positive’ PK endpoint), 
variations in observed PD effects provide an opportunity to distinguish biological responders (i.e., patients 
with positive PK and PD endpoints) from non-responders (i.e., patients with a positive PK endpoint and 
negative PD endpoints). Using a variety of molecular and genetic techniques, a menu of tumor biomarker 
combinations predictive of pharmacodynamic sensitivity to the study drug(s) can be formulated for 
prospective interrogation. Taken together, these longitudinal studies of human brain tumors exposed to 
experimental therapies can provide actionable evidence for future strategies. 
Thus, the Phase 0 clinical trial mechanism originally proposed by the FDA was conceived with the general 
drug development community in mind. Brain tumor drug development, however, poses unique study 
limitations due to the absence of predictive animal models, the significant risks of tumor acquisition, the 
unsuitability of microdosing, the challenge of the BBB, and the potentially confounding effects of 
neurosurgical anesthesia. Adapting the Phase 0 trial paradigm for neuro-oncology patients is an effective 
avenue to obtain direct evidence of drug delivery and target modulation. Specific modifications included 
in this proposal are: (1) abandoning microdosing in favor of a higher-dose regimen, (2) using archival or 
biopsy tissue as a pretreatment control specimen, (3) incorporating CSF into PK and PD analyses, and (4) 
adding a Phase 2 component for patients with demonstrable PK and PD responses. 
Chromosomal translocations that fuse in-frame members of the FGFR (fibroblast growth factor receptor) 
and TACC (transforming acidic coiled-coil containing proteins) gene  families (the FGFR-TACC gene fusions) 
were first described in 2012 in human GBMs (Singh, et al. 2012)and later in several other cancer types. 
The finding that a subset of GBMs harbor oncogenic fusions of FGFR-TACC has raised hope that inhibition 
of FGFR with FGFR kinase inhibitors could be a valuable therapeutic option for this subgroup of deadly 
brain cancer (Lasorella, et al. 2017). From epidemiological estimates based on published literature and 
other publicly available sources such as cBioPortal datasets, FGFR3-TACC3 rearrangements were present 
in 2.4% of GBM. In addition, gain-of-function mutations in FGFR1 and FGFR3 were present around 0.5% 
of GBM cases. Together, there are ~ 3-4 % of GBMs suitable for FGFR kinase inhibitor treatment. 
Infigratinib phosphate (formerly BGJ398, also known as BBP-831, hereafter referred to as infigratinib) is 
an orally bioavailable, potent, selective ATP-competitive inhibitor of fibroblast growth factor receptor 
(FGFR) 1-3.
 
. (QED 2019) 
2.2 
BACKGROUND  
2.2.1 INFIGRATINIB NONCLINICAL STUDIES 
See the infigratinib IB for additional nonclinical information (QED 2019) 
2.2.2 INFIGRATINIB CLINICAL STUDIES 
See the infigratinib IB for additional clinical information (QED 2019) 

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2.3 
RISK/BENEFIT ASSESSMENT   
2.3.1 KNOWN POTENTIAL RISKS 
2.3.1.1 INFIGRATINIB  
 
 
 
 
 
 
 
 
 
 
 
 
. 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
More information about the known and expected risks, serious adverse events (SAEs) and reasonably 
anticipated AEs of infigratinib are found in the IB (QED 2019). 
2.3.2 KNOWN POTENTIAL BENEFITS  
More information about the known and expected benefits of infigratinib are found in the IB (QED 2019). 

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2.3.3 ASSESSMENT OF POTENTIAL RISKS AND BENEFITS  
The preliminary efficacy signals observed in oncology clinical trials, combined with the emerging safety 
profile of infigratinib, warrant continued development of this compound for the treatment of solid tumors 
with genetic alterations of the FGFR pathway. 
 
(QED 2019). 

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4 
STUDY DESIGN  
4.1 
OVERALL DESIGN 
This trial is an open-label, multicenter, Phase 0 trial that will enroll up to 20 participants with recurrent 
high-grade glioma (HGG) with FGFR1 K656E or FGFR3 K650E mutation or FGFR3-TACC3 translocation 
which are schedule for resection. In the lead-in cohort, a total of 20 HGG participants will be enrolled into 
the proposed phase 0 clinical trial. Participants will be administered infigratinib prior to surgical resection 
of their tumor.  
4.1.1 PHASE 0 DESIGN 
The Phase 0 study will include treatment of recurrent high-grade glioma participants with 125 mg of 
infigratinib days 1- 7 prior to surgical resection. On Day 7, participants will receive infigratinib dose 7 to 9 
hours prior to craniotomy for tumor resection. 
To assess the PK endpoints listed above, blood, CSF and brain tumor tissue will be collected 
intraoperatively (enhancing and non-enhancing tumor tissue will be collected and analyzed separately). 
Additionally, blood samples will be obtained on Day 7 at pre-dosing (trough level), 0.5, 1, 2, 4, 6, 8, and 24 
hours post dose. (Note: 24 h sample is the blood sample on Day 8).  
A positive PK response in Phase 0 will be unbound concentrations of infigratinib reaching 5-fold higher 
than their respective cell-free biochemical IC50 values within the non-enhancing region of the tumor.   
Phase 0 participants who do not proceed to the Expansion Cohort will be contacted every 3 months by 
letter or phone for collection of survival data. 
4.1.2 EXPANSION COHORT DESIGN 
Participants with tumors demonstrating PK-response in Phase 0 will continue treatment with the same 
dose continuously for 21 days in 28d cycles after surgery. This will constitute the Expansion Cohort 
component of the study. PD biomarkers will be included for exploratory analyses. Expansion Cohort 
participants will be contacted every 3 months by letter or phone for collection of survival data.  
Participants will be treated until unacceptable toxicity is observed, or until disease progression as assessed 
by RANO criteria. 
4.2 
SCIENTIFIC RATIONALE FOR STUDY DESIGN 
The applicability of a Phase 0 study is most ideal in the situation of a targeted molecule, where there is 
availability of a validated biomarker for a well-understood target and evidence for linear drug kinetics.  
The Phase 0 trial will examine a novel therapy, infigratinib, in FGFR altered glioma patients which meets 
both these criteria.   
4.3 
JUSTIFICATION FOR DOSE 
4.3.1 DOSE RATIONALE FOR INFIGRATINIB 
 
 
 

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4.1 
END OF STUDY DEFINITION 
A participant is considered to have completed the study if he or she has completed Phase 0 of the study 
including the Phone Follow Up visit shown in the Schedule of Activities (SoA), Section 1.2. All participants 
will be followed for survival. Participants will be followed until death for up to 5 years following the last 
dose administration. 
The end of the study is defined as completion of the last visit or procedure shown in the SoA in the trial 
by the last participant enrolled across all sites.  

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5 
STUDY POPULATION 
5.1 
INCLUSION CRITERIA 
In order to be eligible to participate in this study, an individual must meet all of the following criteria: 
1. Prior resection of histologically diagnosed high-grade gliomas (III and IV) defined as participants 
who have progressed on or following standard (Stupp regimen) therapy, which included maximal 
surgical resection, temozolomide, and fractionated radiotherapy. 
2. Recurrence must be confirmed by diagnostic biopsy with local pathology review or contrast-
enhanced MRI.  
3. Have measurable disease preoperatively, defined as at least 1 contrast-enhancing lesion, with 2 
perpendicular measurements of at least 1 cm, as per RANO criteria. 
4. Sufficient archival/biopsy tissue available to confirm eligibility. 
5. Archival or biopsy tissue must demonstrate: FGFR1 K656E or FGFR3 K650E mutation or FGFR3-
TACC3 translocation from NGS sequencing or IHC and RT-PCR. 
6. Ability to understand and the willingness to sign a written informed consent document (personally 
or by the legally authorized representative, if applicable).  
7. Has voluntarily agreed to participate by giving written informed consent (personally or via legally 
authorized representative(s), and assent if applicable). Written informed consent for the protocol 
must be obtained prior to any screening procedures. If consent cannot be expressed in writing, it 
must be formally documented and witnessed, ideally via an independent trusted witness. 
8. Willingness and ability to comply with scheduled visits, treatment plans, laboratory tests and 
other procedures. 
9. Age ≥18 at time of consent 
10. Have a performance status (PS) of ≤2 on the Eastern Cooperative Oncology (Group (ECOG) scale 
(Oken et al. 1982) 
11. Ability to swallow oral medications. 
12. Has adequate bone marrow and organ function as defined by the following laboratory values (as 
assessed by the local laboratory for eligibility): 
Adequate bone marrow function: 
absolute neutrophil count 
≥1,000/mcL 
Platelets (at time of surgery) 
≥100,000/mcL 
hemoglobin 
≥8.0 g/dL 
Participants may receive erythrocyte transfusions to achieve this 
hemoglobin level at the discretion of the investigator.   
Adequate hepatic and renal function: 
total bilirubin 
≤1.5 X ULN. 
Participants with Gilbert’s syndrome with a total bilirubin ≤2.0 
times ULN and direct bilirubin within normal limits are permitted. 
AST(SGOT) 
≤3 X institutional ULN 
ALT(SGPT) 
≤3 X institutional ULN 
Calculated or measured 
creatinine clearance 
≥45 mL/min 

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Other Lab Values: 
 
Amylase or lipase 
≤2 X institutional ULN 
calcium or phosphorus, or 
calcium-phosphorus product 
<55 mg2/dL2 
a. Inorganic phosphorus within normal limits 
b. Total corrected serum calcium within normal limits 
13. Confirmed negative serum pregnancy test (β-hCG) before starting study treatment or participant  
is no longer of childbearing potential due to surgical, chemical, or natural menopause. 
14. For females of reproductive potential: use of highly effective contraception for at least 1 month 
prior to screening and agreement to use such a method during study participation and for an 
additional 3 months after the end of treatment administration.  
15. For males of reproductive potential: use of condoms or other methods to ensure effective 
contraception with partner and for an additional 1 month after the end of treatment 
administration. A condom is required to be used also by vasectomized men as well as during 
intercourse with a male partner to prevent delivery of the drug via seminal fluid. 
16. Agreement to adhere to Lifestyle Considerations (see Section 5.3) throughout study duration. 
17. Participants who received chemotherapy must have recovered (Common Terminology Criteria for 
Adverse Events [CTCAE] Grade ≤1) from the acute effects of chemotherapy except for residual 
alopecia or Grade 2 peripheral neuropathy prior to Day 1.   A washout period of at least 21 days 
is required between last chemotherapy dose and Day 1 (provided the patient did not receive 
radiotherapy). 
18. Participants who received radiotherapy must have completed and fully recovered from the acute 
effects of radiotherapy. A washout period of at least 14 days is required between end of 
radiotherapy and Day 1. 
5.2 
EXCLUSION CRITERIA 
An individual who meets any of the following criteria will be excluded from participation in this study: 
1. Have a history of liver transplant. 
2. Have impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral infigratinib (e.g., ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection). 
3. Known active systemic bacterial infection (requiring intravenous [IV] antibiotics at time of 
initiating study treatment), fungal infection, or detectable viral infection (such as known human 
immunodeficiency virus positivity or with known active hepatitis B or C [for example, hepatitis B 
surface antigen positive].  Screening is not required for enrollment. 
4. Have a history and/or current evidence of extensive tissue calcification including, but not limited 
to, the soft tissue, kidneys, intestine, myocardium, vascular system, and lung with the exception 
of calcified lymph nodes, minor pulmonary parenchymal calcifications, and asymptomatic 
coronary calcification.  
5. Have current evidence of corneal or retinal disorder/keratopathy including, but not limited to, 
bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis confirmed by 
ophthalmic examination. Subjects with asymptomatic ophthalmic conditions assessed by the 
investigator to pose minimal risk for study participation may be enrolled in the study. 
6. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, e.g., 
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis etc. 
7. Have had a recent (≤3 months prior to first dose of study drug) transient ischemic attack or stroke.  

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8. CTCAE (v5.0) Grade ≥2 hearing loss. 
9. CTCAE (v5.0) Grade ≥2 neuropathy. 
10. Have clinically significant cardiac disease including any of the following: 
a. Known congestive heart failure requiring treatment (New York Heart Association Grade 
≥2), LVEF <50% or local lower limit of normal as determined by MUGA scan or 
echocardiogram (ECHO), or uncontrolled hypertension (refer to the European Society of 
Cardiology and European Society of Hypertension guidelines [Williams et al 2018]).  
b. Presence of Common Terminology Criteria for Adverse Events (CTCAE) v5.0 Grade ≥2 
ventricular arrhythmias, atrial fibrillation, bradycardia, or conduction abnormality. 
c. Unstable angina pectoris or acute myocardial infarction ≤3 months prior to first dose of 
study drug. 
d. QTcF >470 msec (males and females). Note: If the QTcF is >470 msec in the first ECG, a 
total of 3 ECGs separated by at least 5 minutes should be performed. If the average of 
these 3 consecutive results for QTcF is ≤470 msec, the participant meets eligibility in this 
regard. 
e. Known history of congenital long QT syndrome. 
11. Has serious and/or uncontrolled preexisting medical condition(s) that, in the judgment of the 
investigator, would preclude participation in this study (for example, interstitial lung disease, 
severe dyspnea at rest or requiring oxygen therapy, severe renal impairment [e.g. estimated 
creatinine clearance <30ml/min], history of major surgical resection involving the stomach or 
small bowel,  or preexisting Crohn’s disease or ulcerative colitis or a preexisting chronic condition 
resulting in baseline Grade 2 or higher diarrhea). 
12. Prior therapy with any mitogen-activated protein kinase (MEK) or FGFR inhibitor. Prior therapy is 
defined as a therapeutic dosing, as determined by the Investigator.  
13. Are currently receiving or are planning to receive during participation in this study, treatment with 
agents that are known strong inducers or inhibitors of CYP3A4 and medications which increase 
serum phosphorus and/or calcium concentration. Participants are not permitted to receive 
enzyme-inducing anti-epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and 
primidone.  
14. Current use of coumarin-derived anticoagulant for treatment, prophylaxis or otherwise. Therapy 
with heparin, low molecular weight heparin (LMWH) or fondaparinux is allowed.  
15. Have any known hypersensitivity to gemcitabine, cisplatin, calcium-lowering agents, infigratinib, 
or their excipients. 
16. Treatment with another investigational drug or other intervention within 30 days prior to 
enrollment or within 5 half-lives of the investigational product, whichever is longer. 
17. Have consumed grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star fruits, 
pomelos, Seville oranges or products containing juice of these fruits within 7 days prior to first 
dose of study drug. 
18. Have used medications known to prolong the QT interval and/or are associated with a risk of 
Torsades de Pointes (TdP) 7 days prior to first dose of study drug. 
19. Have used amiodarone within 90 days prior to first dose of study drug. 
 
5.3 
LIFESTYLE CONSIDERATIONS 
During the Phase 0 portion study, participants are asked to: 
• 
No herbal or dietary supplements known as strong inhibitors or inducers of CYP3A4 are permitted. 

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• 
Refrain from consumption of red wine, grapefruit, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges or products containing juice of these fruits 
from 7 days before the start of study treatment until after the final dose during Phase 0 (Lilja 
2000). 
• 
Abstain from caffeine- or xanthine-containing products (e.g., coffee, tea, cola drinks, and 
chocolate) for 24 hours before Day 1 until after collection of the final pharmacokinetic (PK) and/or 
pharmacodynamic sample in Phase 0. 
• 
Abstain from alcohol for 24 hours before the start of Day 1 until after collection of the final PK 
and/or pharmacodynamic sample in Phase 0.  
• 
Abstain from strenuous exercise for 24 hours before each blood collection for clinical laboratory 
tests. Participants may participate in light recreational activities during studies (e.g., watching 
television, reading).  
5.3.1 GENERAL GUIDANCE FOR WOMEN OF CHILDBEARING POTENTIAL AND/OR USE OF 
CONTRACEPTIVE METHODS   
Infigratinib could cause fetal harm and developmental abnormalities. Advise participants of the potential 
risk to the fetus and to use effective contraception while on infigratinib and for at least 3 months following 
the last dose. (QED 2019) 
• 
A female of childbearing potential must have a negative serum pregnancy test within 28 days of the 
first dose of infigratinib and agree to use a highly effective contraception method for at least 1 month 
prior to treatment and for 3 months following the last dose of infigratinib.  
• 
Contraceptive methods may include an intrauterine device [IUD] or barrier method. If condoms are 
used as a barrier method, a spermicidal agent should be added as a double barrier protection. 
• 
Use of condoms or other methods to ensure effective contraception with partner and for an additional 
3 months after the end of treatment administration. A condom is required to be used also by 
vasectomized men as well as during intercourse with a male partner to prevent delivery of the drug 
via seminal fluid. 
• 
Cases of pregnancy that occur during maternal exposures to infigratinib should be reported. If a 
patient or spouse/partner is determined to be pregnant following infigratinib initiation, she must 
discontinue treatment immediately. Data on fetal outcome and breast-feeding are to be collected for 
regulatory reporting and drug safety evaluation. 
5.4 
SCREEN FAILURES 
Screen failures are defined as participants who consent to participate in the clinical trial but are not 
subsequently entered in the study and receive study intervention. A minimal set of screen failure 
information is required and includes demography, screen failure details, eligibility criteria, and any serious 
adverse event (SAE). 
Individuals who do not meet the criteria for participation in this trial (screen failure) may have certain 
assessments repeated (e.g. laboratory results, ECG, vital signs, etc.) based on the investigator’s judgment. 
Rescreened participants should be assigned the same participant number as for the initial screening. 
5.5 
STRATEGIES FOR RECRUITMENT AND RETENTION 

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5.5.1 PARTICIPANT RECRUITMENT 
Participants may be identified in the following ways: 
• 
submission of information into a Second Opinion Program Portal; 
• 
a call into the IBTC Phase 0 navigator or other research staff in regard to the study; 
• 
as an existing patient at Barrow Brain and Spine (BBS) and/or Investigator Institution and has been 
identified as a possible study participant at a clinic visit or is reviewed at Tumor Board and 
recommended to be screened for an IBTC trial; 
• 
other recruitment strategies identified. 
5.5.1.1 SECOND OPINION PROGRAM PORTAL 
Second Opinion Programs are standard practice and potential participants may submit to the portal in 
order to consult with the neurosurgeons and obtain their opinion on the potential participant’s diagnosis 
or proposed treatment. Potential participants who submit information to the IBTC Second Opinion Portal 
also receive a consent form to be included in the Subject Recruitment Database.  
5.5.1.2 EXISTING PATIENT(S) 
Potential participants may be identified in the course of the participant’s medical record review and the 
neurosurgeon may recommend consideration for the trial. At that time, the Phase 0 navigator or other 
research staff may contact the potential participant via phone, email or letter. Study specific phone 
scripts, email or letters may be developed for each study and submitted to the IRB for review and approval 
prior to use. 
5.5.1.3 CALLS WITH RESEARCH STAFF 
Potential participants may find information regarding the clinical trials via media advertisements or word-
of-mouth and call the Phase 0 Navigator or another research team member. The research team will utilize 
the IRB-approved phone script to guide the conversation. If there is follow-up contact via mail or email, 
an IRB-approved template should be utilized. 
5.5.2 PRE-SCREENING ACTIVITIES 
Pre-screening activities may be utilized to assess potential participants for inclusion in studies prior to 
obtaining consent if the procedures are performed as part of the practice of medicine and which would 
be done whether or not study entry was contemplated (FDA 1998).  
5.5.2.1 INFORMATION GATHERED DURING PRE-SCREENING 
Information not available through a medical record review may be obtained during a pre-screening 
discussion with the potential participant either in person or via the telephone prior to informed consent. 
The pre-screening questions in the IRB-approved script will be suitable and appropriate to address specific 
inclusion/exclusion criteria and other study specific details to ascertain the participant’s ability to 
participate in the trial. The discussion may not strictly adhere to the script; however, the script and/or 
consent form will provide a guide for the discussion. The information obtained will be limited to the 
minimum necessary to determine screening eligibility. 

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The following activities will not be considered acceptable pre-screening activities (if not part of the 
standard clinical visit) and will not be completed until the participant has signed the consent form.  
• 
Staff asking participants to wash-out from medications or fast prior laboratory testing; 
• 
Staff obtaining complete medical histories, physical exams, laboratory testing and other screening 
assessments.  
5.5.3 CONFIDENTIALITY PARTICIPANT INFORMATION AND CONFIDENTIALITY 
Potential participants may provide private information and medical records from non-covered entities. A 
separate authorization to release and review medical records will be obtained from the participant to 
allow the institution to request the information from a non-covered entity to determine eligibility.   
The institution will not retain identifying information about potential participants that: 
 are not existing patients and; 
 have not provided verbal consent to be recorded in an IRB-approved participant recruitment 
database and; 
 are pre-screened for a study but do not enroll.  
For these participants, any pre-screening documents with identifying information gathered prior to 
obtaining consent and prior to enrollment may also be retained in research files but must have segments 
containing identifiable information blacked out as soon as it is determined the individual will not be 
enrolled, or adhere to institutional guidelines and policies.  

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If a participant receiving the 75-mg dose of infigratinib requires further dose reduction, infigratinib should 
be discontinued.  Based on the judgment of the investigator, if a participant is receiving clinical benefit 
from study therapy and requires further dose reduction than what is outlined in the table above, the 
investigator must discuss with the IBTC Safety Officer prior to further dose reduction. 
Dose omissions are allowed within a cycle.  If a participant requires omission of more than 25% of doses 
during a cycle for tolerability, then treatment may continue if the investigator determines the participant 
is receiving clinical benefit. 
To ensure patient safety the investigator should collect specific recommended clinical information and 
follow-up laboratory tests as shown below in Table 6.  
Details for hepatic monitoring depend upon the severity and persistence of observed laboratory test 
abnormalities. If a study patient experiences elevated ALT 5×ULN and elevated TBL 2×ULN, or ALT 8×ULN, 
liver tests, including ALT, AST, TBL, direct bilirubin, gamma-glutamyl transferase (GGT), and creatine 
phosphokinase (CPK), should be repeated within 3 to 5 days to confirm the abnormality and to determine 
if it is increasing or decreasing.  If the abnormality persists or worsens, clinical and laboratory monitoring 
should be initiated by the investigator, based on the hepatic monitoring tests below. 
Table 6 Hepatic Monitoring Tests for a Hepatic Treatment Emergent Abnormality 
Hepatic Hematology 
Haptoglobin 
Hemoglobin 
 
Hematocrit 
Hepatic Coagulation 
RBC 
Prothrombin Time 
WBC 
Prothrombin Time, INR 
Neutrophils, segmented and bands 
 
Lymphocytes 
Hepatic Serologiesa 
Monocytes 
Hepatitis A antibody, total 
Eosinophils 
Hepatitis A antibody, IgM 
Basophils 
Hepatitis B surface antigen 
Platelets 
Hepatitis B surface antibody 
 
Hepatitis B Core antibody 
Hepatic Chemistry 
Hepatitis C antibody 
Total bilirubin (TBL) 
Hepatitis E antibody, IgG 
Direct bilirubin 
Hepatitis E antibody, IgM 
Alkaline phosphatase 
 
ALT 
Anti-nuclear antibody 
AST 
Anti-actin antibody 
GGT 
CPK  
Anti-smooth muscle antibody 

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Abbreviations:  ALT = alanine aminotransferase; AST = aspartate aminotransferase; CPK = creatine 
phosphokinase; GGT = gamma-glutamyl transferase; Ig = immunoglobulin; INR = international normalized 
ratio; RBC = red blood cells; WBC = white blood cells. 
a 
Reflex/confirmation dependent on regulatory requirements and/or testing availability. 
6.2 
PREPARATION/HANDLING/STORAGE/ACCOUNTABILITY 
6.2.1 ACQUISITION AND ACCOUNTABILITY 
Infigratinib will be provided by QED to IBTC and will be labeled according to regulatory requirements.  QED 
will distribute to the investigative sites. 
6.2.2 FORMULATION, APPEARANCE, PACKAGING, AND LABELING 
QED will perform the labeling and the final packaging of these study medications under good 
manufacturing practice (GMP) conditions.   
6.2.3 PRODUCT STORAGE AND STABILITY 
Infigratinib will be supplied as 100-mg and 25-mg capsules for oral consumption.  Infigratinib hard gelatin 
capsules are packaged in white HDPE (high-density polyethylene) bottles with aluminum induction seal 
and child-resistant screw cap closure. Please refer to clinical labels for current shelf-life, in-use period and 
storage conditions for infigratinib hard gelatin capsules. 
Investigators should instruct participants to store the capsules at home in the original container and to 
keep out of the reach of children.  Capsules should not be opened, crushed, or dissolved. 
6.2.4 DISPOSAL AND DESTRUCTION 
The study drug supply can be destroyed at the institution or third party, as appropriate, if permitted by 
local regulations, policies and authorized by IBTC. 
6.3 
STUDY INTERVENTION COMPLIANCE 
Participant compliance with study medication will be assessed at each visit.  Compliance will be assessed 
by direct questioning, review of the dosing diary and counting returned capsules.  In the Expansion Cohort, 
plasma levels will be measured for the first 2 cycles on days 1, 8, and 15.  Deviations from the prescribed 
dosage regimen should be recorded in the CRF.  A participant dosing diary will be used to capture dose 
information for infigratinib for in clinic and at home dosing.    
The participant must take ≥80% of the intended doses in each cycle to be deemed compliant with study 
drug administration.  Similarly, a participant may be considered noncompliant if he or she is judged by the 
investigator to have intentionally or repeatedly taken more than the prescribed amount of drug(s).  
Potential discontinuation of a participant due to study drug noncompliance will be discussed between the 
investigator and IBTC before the final determination is made to discontinue the participant. 
6.4 
CONCOMITANT THERAPY 

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For this protocol, a prescription medication is defined as a medication that can be prescribed only by a 
properly authorized/licensed clinician. Medications to be reported in the Case Report Form (CRF) are 
concomitant prescription medications, over-the-counter medications and supplements. 
No other chemotherapy, radiotherapy immunotherapy, cancer related hormone therapy, or experimental 
drugs, or herbal supplements intended to treat cancer will be permitted while the participants are on this 
study.  An exception will be made for the following circumstances: 
• 
prostate cancer participants continuing GnRH agonist therapy or breast cancer participants 
continuing antiestrogen therapy (for example, an aromatase inhibitor).   
• 
palliative radiotherapy of ≤14 calendar days in Cycles 2 and beyond following discussion and 
approved in writing by the IBTC (e.g., for a solitary skeletal metastasis), as long as the participant 
has not developed another reason for study discontinuation 
• 
in select cases, after discussion and approved in writing by IBTC, local therapies (such as radiation 
treatment to control isolated areas of CNS progression) may be permissible after cycle 1 provided 
study drug(s) are held on the days of local therapy. 
In addition, any disease progression requiring other forms of specific antitumor therapy will also 
necessitate early discontinuation from the study.  Replacement hormone therapy initiated before study 
entry will be allowed.  
For the craniotomy in Phase 0, anesthesia may use medications that would otherwise be prohibited when 
deemed clinically necessary, but if possible, should be avoided. 
Investigational agents used to improve surgical resection, craniotomy, wound healing, or recovery are 
allowed. 
All concomitant medication and concurrent therapies administered within 30 days of study entry will be 
documented at Screening and during the study.  Dose, route, unit frequency of administration, and 
indication for administration and dates of medication will be captured. 
6.4.1.1 PERMITTED CONCOMITANT THERAPY REQUIRING CAUTION AND/OR ACTION  
Details for specific medications which require action and/or caution while on study in participants taking 
infigratinib are provided in Table 7. The rationale for these medications is provided below. 
Infigratinib is characterized by pH-dependent solubility, and therefore, medicinal products that alter the 
pH of the upper GI tract may alter the solubility of infigratinib, and limit bioavailability. These agents 
include, but are not limited to, proton pump inhibitors (e.g., omeprazole), H2-antagonists (e.g., ranitidine) 
and antacids. If possible, proton pump inhibitors should be avoided due to their long PD effect and 
replaced with H2-antagonists or antacids. Study drug should be taken ≥2 hours before or 10 hours after 
dosing with a gastric protection agent. 
Infigratinib is a substrate of CYP3A4. Therefore, moderate inhibitors and inducers should be used with 
caution if an alternative is not available. If anticoagulation is required, heparin and/or low-molecular-
weight heparins or direct thrombin inhibitors and/or Factor Xa inhibitors that are not metabolized by 
CYP3A4 (e.g., dabigatran, edoxaban) are preferred. If unavoidable, anticoagulants that are CYP3A4 
substrates and have a narrow therapeutic index (e.g., warfarin sodium or any other coumadin-derivative 
anticoagulants or certain direct thrombin inhibitors [e.g., argatroban] or Factor Xa inhibitors [eg, 
rivaroxaban]) should be used with caution. 

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Infigratinib was shown in vitro to inhibit the drug transporter breast cancer resistance protein (BCRP), 
with an IC50 of 210 nM. While the clinical relevance of this inhibition is unknown, drugs transported by 
BCRP should be used with caution. 
Anti-emetics are recommended as clinically appropriate at the first sign of nausea and vomiting or as 
prophylaxis to prevent emesis, along with supportive care according to clinical practice guidelines. 
It is recommended to avoid using drugs that are known to cause QT prolongation. Note that some anti-
emetics have a known risk for Torsade de Pointes, and therefore need to be used with caution. See Table 
7 for list of drugs that need to be used with caution. Aprepitant (brand name: Emend) is both a sensitive 
substrate and a moderate CYP3A4 inhibitor and should be used with caution if an alternative is not 
available.  
 
 
 
 
 
 
Table 7 Drugs to be used with caution while on study 
Category 
Drug Names 
CYP3A substrates with narrow 
therapeutic index 
alfentanil, 
cyclosporine, 
diergotamine, 
dihydroergotamine, 
ergotamine, fentanyl, sirolimus, tacrolimus, terfenadine, warfarin 
sodium or any other coumadin-derivative anticoagulants, direct 
thrombin inhibitors (eg, argatroban), and Factor Xa inhibitors (eg, 
rivaroxaban) 
Moderate inhibitors of CYP3A4 
amprenavir, aprepitant, atazanavir, cannabinoids, casopitant, 
cimetidine, ciprofloxacin, darunavir, diltiazem, fosamprenavir, 
imatinib, metronidazole, Schisandra sphenanthera, sertraline, 
suboxone, tofisopam, verapamil, zafirlukast 
Moderate inducers of CYP3A4 
bosentan, cotrimoxazole, efavirenz, etravirine, ethosuximide, 
genistein, metyrapone, mexiletine, modafinil, nafcillin, talviraline, 
tipranavir 
Medications which alter the pH of 
the GI tract a,b 
antacids, H2antagonists (eg, ranitidine), proton-pump inhibitors (eg, 
omeprazole) 
Medications that have possible 
risk of TdP/QT prolongation 
alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, eribulin, famotidine, felbamate, fingolimod, foscarnet, 
fosphenytoin, gatifloxacin, gemifloxacin, granisertron, iloperidone, 
indapamide, isradipine, lapatinib, lithium, moexipril, nicardipine, 
nilotinib, octreotide, ofloxacin, oxytocin, paliperidone, pasireotide, 
quetiapine, ranolazine, risperidone, roxithromycin, sertindole, 
sunitinib, tamoxifen, tizanidine, vardenafil, venlafaxine, ziprasidone 
Medications 
that 
have 
conditional 
risk 
of 
TdP/QT 
prolongation 
amitriptyline, amisulpride, ciprofloxacin, clomipramine, desipramine, 
diphenhydramine, doxepin, fluoxetine, galantamine, imipramine, 
nortriptyline, paroxetine, protriptyline, sertraline, solifenacin, 
trazodone, trimethoprim-sulfa, trimipramine 

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Category 
Drug Names 
BCRP substrates 
atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin, 
sulfasalazine, topotecan 
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome p; FDA, Food and Drug 
Administration; GI, gastrointestinal; TdP, Torsades de Pointes 
a Infigratinib should be dosed at least 2 hours before or 10 hours after dosing with a gastric protection 
agent.  
b If possible, proton pump inhibitors should be avoided due to their long pharmacodynamic effect and 
replaced with H2 antagonists or antacids. 
Sources: FDA Guidance for Industry, 2017; Flockhart 2007; drugbank.ca. 
6.4.1.1.1 CORTICOSTEROIDS 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce CYP3A 
enzymes, thereby increasing the risk of reducing drug exposure to sub-therapeutic levels. In addition 
infigratinib is an in vitro inhibitor of CYP3A4 and has the potential to increase the systemic exposure of 
corticosteroids that are metabolized by CYP3A4.  
Systemic corticosteroid treatment can be used with caution. If possible, the participant should be on a 
stable dose for at least 2 weeks prior to study entry.  
6.4.1.2 PROHIBITED CONCOMITANT THERAPY 
A concomitant medication is considered prohibited if it appears on any of the prohibited medication lists 
for any clinical pharmacology property of the drug (eg, CYP, BCRP). 
Details for specific medications prohibited while on study are provided in Table 8. The rationale for the 
restricted medications is provided below. 
Other investigational therapies must not be used while the participant is on the study. Anticancer therapy 
(chemotherapy, biologic or radiation therapy, and surgery) other than the study drug must not be given 
to participants while the participant is on study drug. If such agents are required, then the participant 
must be discontinued from study drug. The only exception is palliative localized radiation therapy for bone 
metastases with approval by QED Therapeutics’ medical monitor.  
Strong inhibitors of CYP3A4 such as the ones listed in Table 8 are prohibited because infigratinib is a likely 
substrate of this isoenzyme.  
Strong inducers of CYP3A4 are prohibited because their usage may decrease the exposure of infigratinib. 
Therefore, agents such as those listed in Table 8 are prohibited. Please note that the list may not be 
exhaustive. 
Subjects must also avoid the consumption of grapefruits, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges or juice within 7 days prior to the first dose of 
infigratinib and throughout the treatment period due to a potential CYP3A4 interaction with study drug. 
Medications that increase the serum levels of phosphorus and/or calcium are prohibited.  
 
 

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prolong the QT/QTc interval or induce TdP (risk of TdP/QT prolongation) are prohibited. List of these 
medications is given in Table 8. Please note that the list might not be comprehensive. 
Table 8 List of prohibited medications and substances while on study 
Category 
Drug Names 
Strong inhibitors of CYP3A4 
clarithromycin, conivaptan, fluconazole, fluvoxamine, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, 
nefazodone, nelfinavir, norfloxacin, posaconazole, ritonavir, 
saquinavir, telithromycin, voriconazole 
grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, star 
fruits, pomelos, Seville oranges or products containing juice of these 
fruits   
Strong inducers of CYP3A4 
avasimibe, carbamazepine, nevirapine, phenobarbital, phenytoin, 
pioglitazone, primidone, rifabutin, rifampin, St. John's wort, 
troglitazone 
Medications which increase serum 
phosphorus and/or calcium 
calcium, parathyroid hormone, phosphate, vitamin D (including 
multivitamins containing vitamin D) 
Medications 
with 
established 
potential for QT prolongation or 
TdP 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US 
market), azithromycin, bepridil (off US market), chloroquine, 
chlorpromazine, 
cisapride 
(off 
US 
market), 
citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone (not 
on 
US 
market), 
dronedarone, 
droperidol, 
erythromycin, 
escitalopram, flecainide, halofantrine, haloperidol, ibutilide, 
levofloxacin, levomethadyl (off US market), mesoridazine (off US 
market), methadone, moxifloxacin, ondansetron, pentamidine, 
pimozide, probucol (off US market), procainamide (oral off US 
market), quinidine, sevoflurane, sotalol, sparfloxacin (off US 
market), sulpiride (not on US market), terfenadine (off US market), 
thioridazine, vandetanib 
Abbreviations: CYP, cytochrome p; TdP, Torsades de Pointes; US, United States 
6.4.1.3 SUPPORTIVE CARE 
Participants should receive full supportive care.  Participants are instructed to maintain adequate oral 
hydration at home, in order to prevent dehydration secondary to vomiting and diarrhea.  During visits, 
participants should be evaluated for signs and symptoms of dehydration and, if necessary, intravenous 
hydration should be implemented at the discretion of the investigator.   
6.4.1.3.1 SUPPORTIVE MANAGEMENT FOR DIARRHEA 
Participants should receive instructions on the management of diarrhea.  In the event of diarrhea (Section 
6.1.3), supportive measures should be initiated as early as possible.  These include the following: 
• 
At the first sign of loose stools, the participant should initiate anti-diarrheal therapy (for example, 
loperamide) and notify the investigator/site for further instructions and appropriate follow-up. 

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• 
Participants should also be encouraged to drink fluids (for example, 8 to 10 glasses of clear liquids 
per day). 
• 
Site personnel should assess response within 24 hours. 
• 
If diarrhea does not resolve with anti-diarrheal therapy within 48 hours to either baseline or Grade 
1, the participant should be seen at the investigational site for further evaluation and 
management per institutional guidelines. 
• 
Refer to 6.1.3 for additional information for diarrhea management and dose modification. 
In severe cases of diarrhea, the measurement of neutrophil counts and body temperature and proactive 
management of diarrhea with antidiarrheal agents should be considered. 
If diarrhea is severe (requiring IV rehydration) and/or associated with fever or severe neutropenia, broad-
spectrum antibiotics such as fluoroquinolones must be prescribed. 
Participants with severe diarrhea or any grade of diarrhea associated with severe nausea or vomiting 
should be carefully monitored and given intravenous fluid (IV hydration) and electrolyte replacement. 
When therapy with antidiarrheal agents does not control diarrhea to tolerable levels, study treatment 
should be temporarily interrupted, dose reduced, or permanently discontinued per 6.1.3. 
6.4.1.3.2 SUPPORTIVE MANAGEMENT RECOMMENDATIONS FOR NAUSEA AND VOMITING 
Recommended antiemetic treatment should follow current guidelines for high/moderate emetic risk 
agents, such as consensus-based guidelines from the National Comprehensive Cancer Network but is left 
to investigator’s discretion based on participant characteristics and local medical practices. Note: 
ondansetron is listed as a prohibited medication but may be used at the investigator’s discretion.  
Current recommendation for antiemetic treatment consists of a 5-HT3 receptor antagonist and should be 
given prior to starting study drug (continue daily, choose 1): 
• 
Ondansetron 8-16 mg (total dose) PO daily 
• 
Dolasetron 100 mg PO daily, as needed 
Breakthrough treatment can be given by adding 1 agent from a different drug class to the current regimen 
(i.e., olanzapine 5-10 mg PO daily, dexamethasone 12 mg PO/IV daily). 
In Phase 0, ondansetron IV may be administered as per routine care or institutional guidelines.  
In the event that the investigator believes concomitant antiemetic medication is not necessary in cycles 
2+, the antiemetic regimen may be discontinued. 
6.4.1.3.3 SUPPORTIVE MANAGEMENT RECOMMENDATIONS FOR HYPERPHOSPHATEMIA 
Increases in phosphate, a pharmacodynamic effect of infigratinib, can affect the homeostasis of serum 
phosphorus and serum calcium. As such, within the first week of infigratinib treatment (Expansion Phase), 
serum phosphorus and calcium levels should be monitored and checked. Manage as clinically indicated 
with a low phosphate diet, dose modifications/interruption, and phosphate binders. Prophylactic use of 
a phosphate-binding agent is allowed on days of infigratinib administration per institutional guidelines. 
Per investigator’s discretion, if there is no ongoing hyperphosphatemia during the week with no 
infigratinib treatment, use of the phosphate binder should be paused. If necessary, infigratinib dosing may 
be interrupted to allow for normalization of serum levels of phosphorus and calcium and then resumed 
at a lower dose. Also see Table 4 for toxicity follow-up evaluation. 

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Mild to moderate elevations in serum creatinine have occurred in association with hyperphosphatemia. 
Subjects should be carefully monitored for electrolyte changes and early signs of renal insufficiency; 
dosing should be withheld until serum creatinine returns to baseline, Grade 1, or better. Additionally, SAEs 
of renal failure, nephropathy, and acute kidney injury have been reported. In the event of acute, severe 
hyperphosphatemia and clinical evidence of emerging calciphylaxis, additional phosphorus-lowering 
strategies, including hemodialysis, should be considered. (QED 2019) 
6.4.1.3.4 SUPPORTIVE MANAGEMENT RECOMMENDATIONS FOR HEMATOPOIETIC GROWTH 
FACTORS 
Prophylactic use of recombinant hematopoietic growth factors may be used per the investigator’s 
discretion and institutional guidelines. 
6.4.1.3.5 SUPPORTIVE MANAGEMENT RECOMMENDATIONS FOR OCULAR DISORDER 
Infigratinib very commonly causes dry eye and blurred vision; other commonly reported ocular events 
include conjunctivitis, increased lacrimation, punctate keratitis, and visual impairments. CSC/RPED have 
also been reported. Subjects should receive dry eye prophylaxis with ocular demulcents as needed. 
Ophthalmological examinations (performed by an ophthalmologist) should be done at baseline/screening, 
phase 0 follow-up, every 3-4 months thereafter, and at any time as per physician discretion for visual 
symptoms. Withhold infigratinib if central serous chorioretinopathy (CSC)/ retinal pigment epithelial 
detachment (RPED) occurs and permanently discontinue if it does not resolve after 14 days or if it is Grade 
4 in severity. Also discontinue infigratinib for other Grade 4 ocular disorders and for Grade ≥1 retinal vein 
occlusion. (QED 2019) 
6.4.1.3.6 SUPPORTIVE MANAGEMENT RECOMMENDATIONS FOR STOMATITIS, PALMAR-
PLANTAR ERYTHRODYSAESTHESIA SYNDROME, AND NAIL TOXICITY 
Stomatitis (35%), palmar-plantar erythrodysaesthesia syndrome (12%), and nail toxicity (eg, nail disorder 
[11%], nail discoloration [7%], and paronychia [4%]) are very commonly reported with infigratinib use. 
Management of these types of events should be considered, and treatment should follow institutional 
guidelines where applicable. (QED 2019) 
 

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7 
STUDY INTERVENTION DISCONTINUATION AND PARTICIPANT DISCONTINUATION / 
WITHDRAWAL 
7.1 
DISCONTINUATION OF STUDY INTERVENTION 
Discontinuation from treatment does not mean discontinuation from the study, and remaining study 
procedures should be completed as indicated by the study protocol.  If a clinically significant finding is 
identified (including, but not limited to changes from baseline) after enrollment, the investigator or 
qualified designee will determine if any change in participant management is needed. Any new clinically 
relevant finding will be reported as an adverse event (AE). 
The data to be collected at the time of study intervention discontinuation will include the end-of-study 
(EOS) procedures as shown in Section 1.2.  
7.2 
PARTICIPANT DISCONTINUATION/WITHDRAWAL FROM THE STUDY 
Participants are free to withdraw from participation in the study at any time upon request. 
An investigator may discontinue or withdraw a participant from the study for the following reasons: 
• 
Pregnancy 
• 
Significant study intervention non-compliance  
• 
If any clinical adverse event (AE), laboratory abnormality, or other medical condition or situation 
occurs such that continued participation in the study would not be in the best interest of the 
participant 
• 
Disease progression which requires discontinuation of the study intervention 
• 
If the participant meets an exclusion criterion (either newly developed or not previously 
recognized) that precludes further study participation 
• 
Participant unable to receive study intervention for >28 days 
• 
Participant has had 2 dose reductions and experiences an AE that would cause a third dose 
reduction.   
The reason for participant discontinuation or withdrawal from the study will be recorded on the Case 
Report Form (CRF). Participants who sign the informed consent form and but do not receive the study 
intervention may be replaced.  Participants who sign the informed consent form, and receive the study 
intervention, and subsequently withdraw, or are withdrawn or discontinued from the study, may be 
replaced. 
7.3 
LOST TO FOLLOW-UP 
A participant will be considered lost to follow-up if he or she fails to return for the Expansion Cohort for 4 
scheduled visits and is unable to be contacted by the study site staff.  
The following actions may be taken if a participant fails to return to the clinic for a required study visit: 
• 
The site will attempt to contact the participant and reschedule the missed visit within ~1 day of 
the missed visit and counsel the participant on the importance of maintaining the assigned visit 
schedule and ascertain if the participant wishes to and/or should continue in the study. 
• 
Before a participant is deemed lost to follow-up, the investigator or designee will make every 
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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 or study file.  
• 
Should the participant continue to be unreachable, he or she will be considered to have 
withdrawn from the study with a primary reason of lost to follow-up. 

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8 
STUDY ASSESSMENTS AND PROCEDURES 
8.1 
EFFICACY ASSESSMENTS  
8.1.1 PHARMACOKINETIC (PK) MEASUREMENTS 
The total and unbound concentrations of infigratinib in plasma, CSF, and tumor tissues (including contrast-
enhancing and non-enhancing regions) will be determined by a validated LC-MS/MS method.  All analyses 
will be performed at the Ivy Brain Tumor Center.  
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, packaging 
and shipment.  
8.1.1.1 PK BLOOD SAMPLES COLLECTION 
Participants will donate approximately a total of fifteen 4mL blood samples (approximately 60mL of blood) 
as noted in Section 1.2. If intravenous vein (IV) blood collection is utilized, the approximate total volume 
of blood will be 120mL of blood. Venipuncture may cause some pain, bleeding or bruising where the 
needle entered the participant’s body. Some participants may have an intravenous (IV) catheter placed 
or a midline catheter for blood collection, as determined needed by the investigator. Placing an IV may 
cause some pain, and bleeding or bruising at the spot where the needle entered the participant’s body. 
There may also be a risk of irritation of the vein (phlebitis), infection, blood clot, leakage or infiltration 
and/or nerve or tendon injury during insertion. Care will be taken to avoid these problems. The longer an 
IV catheter is left in place, the more common it is for redness or infection to develop. This information will 
be included in the participant informed consent and discussed with the participant as needed 
8.1.1.2 PK CSF SAMPLE COLLECTION 
Approximately 1 mL of CSF from the resection cavity will be collected. Lumbar punctures are not 
considered necessary for CSF collection.  
8.1.1.3 PK TUMOR SAMPLES COLLECTION 
Approximately 200mg of contrast-enhancing and 200mg of non-enhancing tumor tissue samples will be 
collected. 
8.1.2 PHARMACODYNAMIC (PD) MEASUREMENTS 
See the Ivy Brain Tumor Center Laboratory Manual for additional details regarding collection, processing, 
packaging and shipment. 
8.1.2.1 HISTORICAL/ARCHIVAL TISSUE SAMPLE COLLECTION 
Archival or biopsy tissue testing to confirm eligibility may be conducted under this protocol or may also 
be conducted under the 2020-09 Data Tissue Screening Protocol, which received IRB approval on 
06April2020. This protocol will collect available blood or tumor tissue from a previous or planned surgery 
in order to complete genetic and other tests to determine if the tumors indicate a match to one of the 
open clinical trial protocols, including Ivy 2020-08. If the tumor is a match to this study, the participant 
will be consented for participation into Ivy 2020-08. 

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The archival tissue or biopsy tissue obtained through the Data and Tissue Screening Protocol will be stored 
at the Ivy Brain Tumor Center and used for the PD/Biomarker evaluation as noted in the Ivy 2020-08 
Protocol. 
If tissue testing is not conducted under the 2020-09 Data Tissue Screening Protocol, pretreatment archival 
tissue samples from a prior resection or biopsy tissue from either the current or prior recurrence will be 
requested to evaluate for PD and biomarkers to determine study eligibility after obtaining informed 
consent. Archival/biopsy tissue will be requested from pathology lab.  
Request will be for approximately 3-10-micron sections of archival tissue FFPE blocks which contain > 3 
mm x 3 mm portions of viable tumor, on 20 unstained slides, a representative H & E slide from this tissue, 
and 12 scrolls of 20-micron thickness of the pathology core tissue for (2 scrolls per 2 ml tube), if there is 
adequate tissue available.  In the event when biopsy tissue is available, FFPE block of the needle biopsy 
and fresh-frozen tumor core biopsy will be requested. FFPE block will be processed to obtain 3-10 micron 
sections of 20 unstained slides and one H & E slide. The frozen tissue will be used for NGS analysis. 
Adjustments to the request may be made based on the available tissue. If adjustments are necessary, the 
decision should be made in conjunction with the nursing team, pathology lab and research lab.   
8.1.2.2 INTRAOPERATIVE TISSUE SAMPLE COLLECTION 
Post-treatment surgical tissue should be placed in formalin until taken to hospital histology lab where it 
will be prepared as a FFPE block (see Ivy Brain Tumor Center Laboratory Manual for tissue fixation 
protocol) and then made into approximately 3-10-micron sections of 20 unstained slides plus one H & E 
slide and 12 scrolls of 20-micron thickness of the pathology core tissue for (2 scrolls per 2 ml tube), if there 
is adequate tissue available.  
The H&E slide will be examined by neuropathologist to confirm the presence of >20% of viable tumor in 
the resected tissue before proceeding with PD analysis. 
In addition, one tumor sample (dimensions, 0.5 cm3) will be collected from participants and divided into 
two equal portions.  
8.1.2.3 PD EVALUATION IN TUMOR TISSUE 
Identification of a positive PD effect (as defined by a significantly >30% decrease in the percentage of 
phospho-ERK+ cells) will be based upon comparative analysis of archival, biopsy (if available) and post-
treatment tumor tissue. Immunohistochemistry (IHC) analysis will be used to identify the % positive cells 
of pERK, cleaved caspase 3 and MIB-1 (ki67) in archival versus infigratinib treated high-grade glioma tissue 
samples. The staining and biomarker positive cells will be quantified using Aperio Brightfield Toolbox 
Software available at Ivy Brain Tumor Center Pharmacodynamics and Pharmacokinetics Core at Barrow 
Neurological Institute. Optionally, western blotting will be performed for pERK, cleaved caspase 3 and 
MIB-1 on frozen treated tumor tissue and analyzed using the LiCOR Odyssey Imaging system. For 
comparison, treatment naïve tumor tissue with similar pathology from the Biobank will be used. The 
normalized average staining and/or luminescence for banked treatment naïve tumor will be used as a 
baseline to determine the pharmacodynamics of FGFR inhibition in the treated tumor tissues. 
8.1.2.4 BIOMARKER EVALUATION IN TUMOR TISSUE 
To assess other biomarker changes in the treated tumor tissue, mRNA and/or protein from FFPE slides 
from pre- and post-treatment samples will be extracted and be analyzed by nanostring nCounter analysis 
system for their cancer panel examination or RNAseq analysis. This cancer panel includes key components 

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in the oncogenic signaling pathways, cell cycle pathway, apoptosis pathways and immune cell profiling. 
This would allow comparison with surgical tissue with archival and/or biopsy tissue. Any promising targets 
will be confirmed with quantitative RT-PCR. 
In addition, gliomas can be sub-classified by IHC or RNA sequencing as mesenchymal, proneural, or 
classical signatures based on the sequencing analysis and comparison to the TCGA database.   
8.1.2.5 PD BLOOD COLLECTION 
Participants will donate approximately a total of 4mL of blood as noted in Section 1.2. If intravenous vein 
(IV) blood collection is utilized, the approximate total volume of blood will be 8mL of blood. Plasma will 
be shipped to the IBTC for further testing. 
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, packaging 
and shipment. 
8.1.2.6 PD/BIOMARKER EVALUATION IN BLOOD SAMPLES 
Pre-treatment blood sample will be collected for biomarker evaluation and baseline analysis. The tests 
include genetic sequencing to obtain status of the germline mutations, liquid biopsy for tumor DNA or 
tumor secreted extra-cellular vesicles to identify biomarkers that will help predict drug efficacy. 
8.1.3 NEURORADIOLOGY 
Brain MRI scans (with and without contrast) will be performed per the Schedule of Activities.  
8.1.4 RESPONSE ASSESSMENT IN NEURO-ONCOLOGY CRITERIA (RANO) 
In Phase 0, RANO criteria will be used to confirm recurrence for eligibility criteria. In Expansion Phase, only 
those participants who have received at least one cycle of therapy and obtained an MRI in Expansion 
Phase will be considered evaluable. The Expansion Phase baseline MRI will be the first MRI taken post-
operatively. Subsequent MRIs will be compared to the Expansion Phase baseline. 
MRI scans will be evaluated using the criteria for response assessment incorporating MRI and clinical 
factors (Chukwueke 2018). 
8.1.4.1 EXPANSION COHORT EVALUATION OF TARGET LESIONS 
Complete Response (CR) 
Requires all of the following: complete disappearance of all enhancing measurable and nonmeasurable 
disease sustained for at least 4 weeks; no new lesions; stable or improved nonenhancing (T2/FLAIR) 
lesions; participants must be off corticosteroids (or on physiologic replacement doses only); and stable or 
improved clinically. Note: Participants with nonmeasurable disease only cannot have achieved CR; the 
best response possible is SD.  
Partial Response (PR) 
Requires all of the following: ≥50% decrease compared with baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks; no 
progression of nonmeasurable disease; no new lesions; stable or improved nonenhancing (T2/FLAIR) 

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lesions on same or lower dose of corticosteroids compared with baseline scan; the corticosteroid dose at 
the time of scan evaluation.  
Stable Disease (SD) 
Requires all of the following: Does not qualify for CR, PR or progression; stable nonenhancing (T2/FLAIR) 
lesions on the same or lower dose of corticosteroids compared with baseline scan. In the event that the 
corticosteroid dose was increased for new symptoms and signs without confirmation of disease 
progression on neuroimaging, and subsequent follow-up imaging shows that this increase in 
corticosteroids was required because of disease progression, the last scan considered to show SD will be 
the scan obtained when the corticosteroid dose was equivalent to the baseline dose. 
Progressive Disease (PD) 
Defined by any of the following: ≥25% increase in the sum of the products of perpendicular diameters of 
enhancing lesions compared with the smallest tumor measurement obtained either at baseline (if no 
decrease) or best response on stable or increasing doses of corticosteroids†; significant increase in 
T2/FLAIR nonenhancing lesion on stable or increasing doses of corticosteroids compared with baseline 
scan or best response after initiation of therapy† not caused by comorbid events (e.g., radiation therapy, 
demyelination, ischemic injury, infection, seizures, postoperative changes or other treatment effects); any 
new lesion; clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication adverse effects, complications of therapy, cerebrovascular events, infection, etc.) or 
changes in corticosteroid dose; failure to return for evaluation as a result of death or deteriorating 
condition; or clear progression of nonmeasurable disease. 
8.1.4.2 EXPANSION COHORT EVALUATION OF NON-TARGET LESIONS 
Complete Response (CR) 
Disappearance of all non-target lesions and normalization of tumor marker level.  All lymph nodes must 
be non-pathological in size (< 10 mm short axis). 
Incomplete Response/Stable Disease (SD) 
Persistence of one or more non-target lesion(s) and/or maintenance of tumor marker level above the 
normal limits. 
Progressive Disease (PD) 
Appearance of one or more new lesions and/or unequivocal progression of existing non-target lesions. 
8.2 
SAFETY AND OTHER ASSESSMENTS 
8.2.1 DEMOGRAPHICS 
Demographic information (date of birth, gender, race) will be recorded at Screening. 
8.2.2 MEDICAL HISTORY 
Relevant medical history, including history of current disease, other pertinent history, and information 
regarding underlying diseases will be recorded at Screening. 
8.2.3 PHYSICAL EXAMINATION 

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Physical examinations will include an examination as per standard of care and if available, will be obtained 
through the review of existing data in the medical record. The exam may include a review of general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, lymph nodes, 
extremities, and a neurologic evaluation. The physical exam should be completed by appropriately 
licensed personnel as per institutional guidelines or as delegated by the Investigator. 
8.2.4 ABBREVIATED PHYSICAL AND NEUROLOGICAL EXAMINATION   
An abbreviated physical and neurological exam will note any new findings or changes from baseline and 
should be completed by appropriately licensed personnel as per institutional guidelines or as delegated 
by the Investigator. May be obtained through the review of existing data in the medical record. 
8.2.5 OPHTHALMIC EXAMINATION 
Ophthalmic examination will be assessed as per the assessment schedule (Section 1.2) and with any new 
onset of visual disturbance by an ophthalmologist and should include: visual acuity testing (including 
corrected distance acuity), slit lamp examination of the anterior eye segment, intraocular pressure (IOP), 
retinal OCT and dilated fundoscopy. Additional examinations such as specular microscopy and corneal 
pachymetry will be performed as clinically indicated. In addition, ophthalmic exams should be done as 
clinically indicated. 
8.2.6 PERFORMANCE STATUS 
ECOG performance status will be assessed as per the assessment schedule (Section 1.2). More frequent 
examinations may be performed at the investigator’s discretion, if medically indicated. (Appendix 12.1). 
ECOG should be completed by physician, nurse or other appropriately licensed personnel as delegated by 
the Investigator. 
8.2.7 VITAL SIGNS 
Vital signs include body temperature, blood pressure, pulse, and respiration rate measurements and if 
available, may be obtained through the review of existing data in the medical record. If not available, the 
assessment should be completed per the Schedule of Activities. Blood pressure (systolic and diastolic) and 
pulse should be measured after the participant has been sitting for five minutes. 
8.2.8 HEIGHT AND WEIGHT 
Height in centimeters (cm) and body weight (to the nearest 0.1 kilogram [kg] in indoor clothing, but 
without shoes) will be measured. Height will be measured at screening only.  May be obtained through 
the review of existing data in the medical record. 
8.2.9 ELECTROCARDIOGRAM (ECG) 
A standard 12-lead ECG will be obtained at Screening and Phase 0 Day 1 pre-dose. The single ECG that is 
obtain as routine care at the pre-surgical assessment will be collected. Additional single ECGs will be 
obtained as noted in the Schedule of Activities. 
All ECGs should be obtained after the participant has rested in a supine position for at least 5 minutes on 
a machine that automatically calculates heart rate and determines intervals for PR, QRS, QC and QTc using 
the Fridericia formula.  

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8.2.12.2 CLINICAL CHEMISTRY 
Blood chemistry assessments of the parameters listed in Table 9 will be tested as per the Schedule of 
Activities. 
8.2.12.3 COAGULATION 
International normalized ration (INR), prothrombin time (PT) and active partial thromboplastin time 
(aPPT) or Quick Test will be measured as listed in Table 9 and per the Schedule of Activities. 
8.2.12.4 URINALYSIS 
Dipstick measurements will be performed as per Table 9  and according to the schedule of events. Any 
significant findings on dipstick will be followed up with microscopic evaluation as per Schedule of 
Activities. 
8.2.12.5 PREGNANCY AND ASSESSMENTS OF FERTILITY 
Women who are determined to be of childbearing potential before the study will be tested. When non-
childbearing potential status is determined during the study, pregnancy testing will not be completed. 
Women are considered post-menopausal if they have had 12 months of natural (spontaneous) 
amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of vasomotor symptoms), 
and otherwise not of child bearing potential if they have had surgical bilateral oophorectomy (with or 
without hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, only 
when the reproductive status of the woman has been confirmed by follow up hormone level assessment 
is she considered not of childbearing potential. 
If a positive pregnancy test is performed in between study visits, the participants must immediately notify 
the investigator. 
8.2.13 PATIENT DERIVED XENOGRAFTS (PDX) 
Participant-related tissue, cells and fluids from outpatient and inpatient sources will be collected by St. 
Joseph’s Hospital and Medical Center (SJHMC); tissue will be processed and stored by the IBTC team 
according to standard collection, processing, and storage procedures and with Institution Biosafety 
Committee (IBC) approval. The IBTC team will prepare all tissue samples according to approved protocols 
and/or standard procedures (also called Working Instructions, WIs) for storage, development into cell 
lines, creation of patient-derived xenografts (PDXs) and/or preparation for histochemistry, as needed. 
Only SJHMC will be asked to collect tissue and provide to the IBTC.  
See the Ivy Brain Tumor Center Laboratory Manual for details regarding collection, processing, packaging 
and shipment. 
8.2.14 ADVERSE EVENTS 
Information regarding occurrence of adverse events will be captured throughout the study. Duration 
(start and stop dates and times), severity/grade, outcome, treatment and relation to study drug will be 
recorded on the CRF. See Section 8.3 for additional information. 
8.3 
ADVERSE EVENTS AND SERIOUS ADVERSE EVENTS 

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8.3.1 DEFINITION OF ADVERSE EVENTS (AE) 
Adverse event means any untoward medical occurrence associated with the use of an intervention in 
humans, whether or not considered intervention-related (21 CFR 312.32 (a)). Adverse Events that are will 
be captured following first administration of study drug. 
AEs include: 
• 
Any deleterious change from the participant’s baseline status, including an increase in the severity 
or frequency of a pre-existing abnormality or disorder; 
• 
Concurrent illnesses; 
• 
Injury or accidents; 
• 
Subjective symptoms considered unfavorable by the reporter; 
• 
Clinically significant physical examination, laboratory, imaging, or physiological testing 
abnormalities (abnormalities requiring treatment or a change in medication are AEs) 
• 
Overdose 
AEs do not include: 
• 
Laboratory or test abnormalities that are not considered clinically significant 
• 
Incidental findings on imaging that are not considered clinically significant 
• 
Conditions for which a procedure was planned prior to signing the informed consent (e.g., elective 
knee replacement) 
• 
Conditions present at baseline which have not worsened 
• 
Hospitalization solely to complete procedures, or for social reasons such as respite care 
• 
Cosmetic procedures 
• 
Pregnancy without complications (see Section 8.3.9) 
• 
Abnormal vital sign values that are not considered clinically significant; or, do not require medical 
intervention; or, interruption/change to study treatment; or, not accompanied by clinical 
symptoms. 
• 
Events that are clearly consistent with the expected patter of progression of the underlying 
disease (may be based on RANO or symptomatic deterioration).  
• 
Events that are clearly related to surgical complications experienced as a result of the craniotomy 
and not related to study participation or the test article(s) should not be recorded as AEs. If there 
is any indication that the event may be related to study participation or the test article, the event 
should be recorded as an adverse event. 
Cancer progression and cancer-related death are a study endpoint and will not be reported as an AE. 
8.3.2 DEFINITION OF SERIOUS ADVERSE EVENTS (SAE)  
An adverse event (AE) or suspected adverse reaction is considered "serious" if, in the view of either the 
investigator or sponsor, it results in any of the following outcomes:  
• 
death,  
• 
a life-threatening adverse event,  
• 
inpatient hospitalization or prolongation of existing hospitalization,  
• 
a persistent or significant incapacity or substantial disruption of the ability to conduct normal life 
functions, or a congenital anomaly/birth defect.  
• 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered serious when, based upon appropriate medical judgment, they 
may jeopardize the participant and may require medical or surgical intervention to prevent one 
of the outcomes listed in this definition. Examples of such medical events include allergic 

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bronchospasm requiring intensive treatment in an emergency room or at home, blood dyscrasias 
or convulsions that do not result in inpatient hospitalization, or the development of drug 
dependency or drug abuse. 
The following hospitalizations are not considered to be SAEs: 
• 
Routine treatment or monitoring of the studied indication, not associated with any deterioration 
in condition 
• 
Elective or pre-planned treatment for a pre-existing condition that is unrelated to the indication 
under study and has not worsened since signing the informed consent 
• 
Social reasons and respite care in the absence of any deterioration in the participant’s general 
condition 
• 
Hospitalization due solely to progression of the underlying cancer 
• 
Events that are clearly related to surgical complications experienced as a result of the craniotomy 
and not related to study participation or the test article(s) should not be recorded as AEs. If there 
is any indication that the event may be related to study participation or the test article, the event 
should be recorded as an adverse event. 
For any of the above, any associated AEs or complications should be reported as an SAE if the AE prolongs 
hospitalization or otherwise meet the criteria for an SAE. 
8.3.3 CLASSIFICATION OF AN ADVERSE EVENT 
8.3.3.1 SEVERITY OF EVENT 
The severity of an AE should be defined according to the National Cancer Institute (NCI) Common Toxicity 
Criteria Adverse Events (CTCAE) Version 5.0. AEs that are not described in the NCI CTCAE should be 
evaluated using the following guidelines: 
• 
1 = Mild AE: Awareness of symptom, but easily tolerated; usually transient requiring no special 
treatment; does not interfere with usual status or activities 
• 
2 = Moderate AE: May be ameliorated by simple therapeutic measures; may interfere with usual 
activities 
• 
3 = Severe AE: Incapacitating, inability to perform usual activities 
• 
4 = Life threatening consequences; urgent intervention indicated 
• 
5 = Fatal AE  
8.3.3.2 RELATIONSHIP TO STUDY INTERVENTION 
All adverse events (AEs) must have their relationship to study intervention assessed by the clinician who 
examines and evaluates the participant based on temporal relationship and his/her clinical judgment. The 
degree of certainty about causality will be graded using the categories below. In a clinical trial, the study 
product must always be suspect.  
• 
Definitely Related – There is clear evidence to suggest a causal relationship, and other possible 
contributing factors can be ruled out. The clinical event, including an abnormal laboratory test 
result, occurs in a plausible time relationship to study intervention administration and cannot be 
explained by concurrent disease or other drugs or chemicals. 
• 
Probably Related – There is evidence to suggest a causal relationship, and the influence of other 
factors is unlikely. The clinical event, including an abnormal laboratory test result, occurs within a 

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reasonable time after administration of the study intervention, is unlikely to be attributed to 
concurrent disease or other drugs or chemicals, and follows a clinically reasonable response on 
withdrawal. 
• 
Potentially Related – There is some evidence to suggest a causal relationship (e.g., the event 
occurred within a reasonable time after administration of the trial medication). However, other 
factors may have contributed to the event (e.g., the participant’s clinical condition, other 
concomitant events). Although an AE may rate only as “possibly related” soon after discovery, it 
can be flagged as requiring more information and later be upgraded to “probably related” or 
“definitely related”, as appropriate. 
• 
Unlikely to be related – A clinical event, including an abnormal laboratory test result, whose 
temporal relationship to study intervention administration makes a causal relationship 
improbable (e.g., the event did not occur within a reasonable time after administration of the 
study intervention) and in which other drugs or chemicals or underlying disease provides plausible 
explanations (e.g., the participant’s clinical condition, other concomitant treatments). 
• 
Not Related – The AE is completely independent of study intervention administration, and/or 
evidence exists that the event is definitely related to another etiology.  
8.3.3.3 EXPECTEDNESS  
The Safety Officer will be responsible for determining whether an adverse event (AE) is expected or 
unexpected.  An AE will be considered unexpected if the nature, severity, or frequency of the event is not 
consistent with the risk information previously described for the study intervention. 
8.3.4 TIME PERIOD AND FREQUENCY FOR EVENT ASSESSMENT AND FOLLOW-UP 
The occurrence of an adverse event (AE) or serious adverse event (SAE) may come to the attention of 
study personnel during study visits and interviews of a study participant presenting for medical care, or 
upon review by a study monitor. 
All AEs including local and systemic reactions will be captured on the appropriate case report form (CRF). 
Information to be collected includes event description, time of onset, clinician’s assessment of severity, 
relationship to study product (assessed only by those with the training and authority to make a diagnosis), 
and time of resolution/stabilization of the event. All AEs occurring while on study must be documented 
appropriately regardless of relationship. All AEs will be followed to adequate resolution. 
Any medical condition that is present at the time that the participant is screened will be considered as 
baseline and not reported as an AE. However, if the study participant’s condition deteriorates at any time 
during the study, it will be recorded as an AE.  
Changes in the severity of an AE will be documented to allow an assessment of the duration of the event 
at each level of severity to be performed. AEs characterized as intermittent require documentation of 
onset and duration of each episode. 
The Investigator will record adverse events from the time of treatment until 7 days after the last day of 
study participation (for non-serious AEs). All serious adverse events will be recorded with start dates 
occurring any time after informed consent is obtained until 30 days (for SAEs) after the last day of study 
participation.  At each study visit, the investigator will inquire about the occurrence of AE/SAEs since the 
last visit.  Events will be followed for outcome information until resolution or stabilization. 

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8.3.5 ADVERSE EVENT REPORTING  
The site investigator or designee will record adverse events. Investigator or designee should use correct 
medical terminology/concepts when recording AEs on the Adverse Event CRF. Avoid colloquialisms and 
abbreviations. 
Only one AE term should be recorded in the event field on the Adverse Event CRF. 
For all AEs, a diagnosis (if known) should be recorded on the Adverse Event eCRF rather than individual 
signs and symptoms. However, if a constellation of signs and/or symptoms cannot be medically 
characterized as a single diagnosis or syndrome at the time of reporting, each individual event should be 
recorded on the Adverse Event CRF. If a diagnosis is subsequently established, all previously reported AEs 
based on signs and symptoms should be nullified and replaced by one AE report based on the single 
diagnosis, with a starting date that corresponds to the starting date of the first symptom of the eventual 
diagnosis. 
8.3.5.1 PERSISTENT/RECURRENT AE 
A persistent AE is one that extends continuously, without resolution, between participant evaluation time 
points. Such events should only be recorded once on the Adverse Event CRF. The initial severity of the 
event should be recorded, and the severity should be updated to reflect the most extreme severity any 
time the event worsens. If the event becomes serious, the Adverse Event CRF should be updated to reflect 
this. 
A recurrent AE is one that resolves between participant evaluation time points and subsequently recurs. 
Each recurrence of an AE should be recorded separately on the Adverse Event CRF. 
8.3.6 SERIOUS ADVERSE EVENT REPORTING  
The site investigator or designee will report to IBTC-CC, any serious adverse event (SAE), whether or not 
considered study intervention related, including those listed in the protocol or investigator brochure and 
must include an assessment of whether there is a reasonable possibility that the study intervention caused 
the event. Study endpoints that are serious adverse events (e.g., all-cause mortality) must be reported in 
accordance with the protocol unless there is evidence suggesting a causal relationship between the study 
intervention and the event (e.g., death from anaphylaxis). In that case, the investigator must immediately 
report the event to the IBTC-CC. Cancer progression and cancer-related death are a study endpoint and 
will not be reported as an AE. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report Form; all 
applicable sections of the form must be completed in order to provide a clinically thorough report. The 
investigator must assess and record the relationship of each SAE to each specific study treatment (if there 
is more than one study treatment), complete the SAE Report Form, and send the completed, signed form 
safety@ivybraintumorcenter.org within 24 hours of determining the adverse event as serious. 
The original copy of the SAE Report Form must be kept at the study site. 
All SAEs will be followed until satisfactory resolution or until the site investigator deems the event to be 
chronic or the participant is stable. Other supporting documentation of the event may be requested by 
the IBTC-CC and should be provided as soon as possible. 
IBTC-CC will be responsible for notifying the Food and Drug Administration (FDA) of any unexpected fatal 
or life-threatening suspected adverse reaction as soon as possible, but in no case later than 7 calendar 
days after IBTC-CC's initial receipt of the information.  In addition, IBTC-CC must notify FDA and all 

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participating investigators in an Investigational New Drug (IND) safety report of potential serious risks, 
from clinical trials or any other source, as soon as possible, but in no case later than 15 calendar days after 
the IBTC-CC determines that the information qualifies for reporting. 
8.3.7 REPORTING EVENTS TO PARTICIPANTS  
Adverse events affecting a study participant on an individual level will be reported to that participant by 
the primary investigator as soon as they are known. Events affecting other study participants will be 
reported by the principal investigator to study participant(s) if the information may impact the decision 
to participate in the trial. Modification of the informed consents will be implemented if there are newly 
recognized risks. Previously enrolled participants will be reconsented as per required by IRB and 
institutional guidelines. 
8.3.8 EVENTS OF SPECIAL INTEREST  
AESIs for infigratinib have not yet been defined in the Investigator’s Brochure. 
8.3.9 REPORTING OF PREGNANCY  
Pregnancy is not considered an adverse event unless it is a spontaneous abortion. Each pregnancy 
occurring while the participant is on study treatment must be reported to IBTC-CC within 24 hours of 
learning of its occurrence. Participants who become pregnant during the trial must be withdrawn. The 
pregnancy will be followed up from the estimated date of delivery plus 3 months 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. 
Women of childbearing potential should be advised to use highly effective contraception methods while 
they are receiving study treatment and up to 3 months after treatment has been stopped. 
8.4 
UNANTICIPATED PROBLEMS 
8.4.1 DEFINITION OF UNANTICIPATED PROBLEMS (UP) 
The Office for Human Research Protections (OHRP) considers unanticipated problems involving risks to 
participants or others to include, in general, any incident, experience, or outcome that meets all of the 
following criteria: 
• 
Unexpected in terms of nature, severity, or frequency given (a) the research procedures that are 
described in the protocol-related documents, such as the Institutional Review Board (IRB)-
approved research protocol and informed consent document; and (b) the characteristics of the 
participant population being studied; 
• 
Related or possibly related to participation in the research (“possibly related” means there is a 
reasonable possibility that the incident, experience, or outcome may have been caused by the 
procedures involved in the research); and 
• 
Suggests that the research places participants or others at a greater risk of harm (including 
physical, psychological, economic, or social harm) than was previously known or recognized. 
8.4.2 UNANTICIPATED PROBLEM REPORTING  
The investigator will report unanticipated problems (UPs) to the reviewing Institutional Review Board 
(IRB) and to the IBTC-CC. The UP report will include the following information: 

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• 
Protocol identifying information: protocol title and number, PI’s name, and the IRB project 
number; 
• 
A detailed description of the event, incident, experience, or outcome;  
• 
An explanation of the basis for determining that the event, incident, experience, or outcome 
represents an UP;  
• 
A description of any changes to the protocol or other corrective actions that have been taken or 
are proposed in response to the UP. 
To satisfy the requirement for prompt reporting, UPs will be reported using the following timeline:   
• 
UPs that are serious adverse events (SAEs) will be reported to the IRB and to the IBTC-CC within 
7 days of the investigator becoming aware of the event.  
• 
Any other UP will be reported to the IRB and to the IBTC-CC within 14 days of the investigator 
becoming aware of the problem.  
• 
All UPs should be reported to appropriate institutional officials (as required by an institution’s 
written reporting procedures), the supporting agency head (or designee), and the Office for 
Human Research Protections (OHRP) within approximately 1 month of the IRB’s receipt of the 
report of the problem from the investigator. 
8.4.3 REPORTING UNANTICIPATED PROBLEMS TO PARTICIPANTS  
Unanticipated problems affecting the study or study participants will be reported to participants by the 
primary investigator as soon as they are known. Modification of the informed consents will be 
implemented if there are newly recognized risks. Previously enrolled participants will be reconsented as 
per required by IRB and institutional guidelines.  

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9 
STATISTICAL CONSIDERATIONS  
9.1 
STATISTICAL HYPOTHESES 
The phase 0 study will be conducted as an open-label, multi-institution study (up to 3 sites) with 20 
patients in the phase 0 component and progression-free-survival (PFS) determination in the expansion 
cohort. The clinical trial will be considered an exploratory study to study the PK and PD effect of infigratinib 
from intra-operative tumor tissue and no formal statistical comparison or hypotheses will be carried out. 
Thus, the outcome will be summarized with descriptive statistics (N, median, mean, standard deviation, 
minimum, maximum and the 80% of confidence interval [CI] for the mean). The 80% confidence level is 
appropriate for a phase 0 study with small sample size. 
If, after the study has begun, changes are made to primary and/or key secondary hypotheses, or the 
statistical methods related to those hypotheses, then the protocol will be amended.  Changes to 
exploratory or other non-confirmatory analyses made after the protocol has been finalized, along with an 
explanation as to when and why they occurred, will be listed in results for the study.  Post hoc exploratory 
analyses will be clearly identified.  No separate Statistical Analysis Plan (SAP) will be issued for this study. 
9.2 
SAMPLE SIZE DETERMINATION 
Historically, the Ivy Center operates on 400 recurrent high-grade glioma patients per year.  If 5% of the 
patients carrying FGFR3 fusion or FGFR1/3 mutations, we expect 20 patients to be eligible for study each 
year.  Assuming 50% patient capture, we envision 10 patients per year to be enrolled in the trial. The 
duration of the trial is therefore designed to be 24 months with an additional 6 months for clinical follow-
up of participants enrolled into expansion cohort (estimated at 50% of the Phase 0 cohort). 
9.3 
POPULATIONS FOR ANALYSES 
• 
Safety Analysis Dataset: participants who took at least one dose of study intervention 
• 
PK Analysis Dataset: All participants who undergo surgery and are assessed for the PK endpoint 
in Phase 0 
• 
Efficacy Analysis Dataset: The subset of participants who meet the PK criteria in Phase 0 and begin 
at least one day of treatment on Expansion Cohort.   
• 
PD Analysis Dataset:  All participants with evaluable PD data assessable for the PD secondary 
endpoints 
9.4 
STATISTICAL ANALYSES 
9.4.1 ANALYSIS OF THE PRIMARY EFFICACY ENDPOINT(S) 
Phase 0 endpoint PK Analysis:   
A positive PK response will be unbound concentrations of infigratinib (along with its active metabolites) 
reaching 5-fold higher than their respective cell-free biochemical IC50 values within the non-enhancing 
region of the tumor.  
Expansion cohort endpoint: For the primary endpoint of PFS rate at 6 months: 
• 
Progression-free survival (PFS) is defined as the number of days from the date of surgery to the 
first documentation of progression or death due to any cause. Participants who remain alive 
without progression will be censored for PFS at the date of their last tumor assessment.  

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Participants removed from study treatment due to symptomatic deterioration will be considered 
as having progression for the purposes of the primary endpoint.   
• 
Disease progression is defined per RANO criteria for high-grade glioma patients.  
9.4.2 ANALYSIS OF THE SECONDARY ENDPOINT(S) 
PD Analysis: To compare pharmacodynamics biomarkers, paired archival, biopsy (if available) and surgical 
tissue will be examined. Once the percentage of individual biomarker positive cells was quantified, a 
paired t test will be used to compare log-transformed percent positive cells between archival, biopsy (if 
available) and surgical tissue at a 2-sided 5% level. 
 
Safety Analyses:   All adverse events will be tabulated according to the highest grade observed per 
patient for each event or category.  Tabulations (n and %) will be produced for each of the following 
categories:  Clinical laboratory abnormalities will be coded per CTCAE (Version 5.0) 
 
a. All treatment-emergent Adverse Events  
b. Treatment related Adverse Events (defined as those definitely, probably, or potentially 
related to treatment)  
c. Serious Adverse Events 
9.4.3 BASELINE DESCRIPTIVE STATISTICS 
Baseline characteristics, including demographics and laboratory measurements, will be summarized using 
descriptive statistics. Mean, Median, Minimum and Maximum values will be reported for continuous 
values such as age and laboratory values, and N and % will be reported for categorical values such as sex 
and performance status. 
9.4.4 PLANNED INTERIM ANALYSES  
No planned interim analysis will be carried out. 
9.4.5 DATA HANDLING RULES 
Conversions from Days to Years, Months or Weeks 
Years = # of days / 365.25 
Months = # of days / 30.4375 (i.e. 365.25/12)  
Weeks = # of days / 7 
Values based on the above computations will be rounded to tenths. 
 
Computation of Duration 
Duration for time variables based on two dates, e.g., Start Date and End Date, will be calculated as (End 
Date – Start Date + 1) (in days) unless otherwise specified. 
 
Missing normal ranges for laboratory parameters 
When either the lower limit of normal, the upper limit of normal or both are missing or are not machine 
readable, a standardized reference range will be used.  
 
Non-Numeric Laboratory Results and Calculation of Normal Ranges 

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Laboratory values including symbols (“<” or “>”, for example) will not be used in summary analyses.   These 
values will be reflected in listings of the data. When there are potential conflicts between local lab normal 
ranges and ranges used in CTC grading, CTC normal ranges will be used. 
 
Missing outcome data 
Missing efficacy data and partial dates related to clinical outcomes will not be imputed. 
9.4.6 EXPLORATORY ANALYSES 
Systemic plasma PK profile parameters (Tmax, Cmax, t1/2, AUC0-24h) for total and unbound levels will be 
determined for infigratinib. Plasma pharmacokinetic parameters of total and unbound drugs will be 
estimated from individual plasma concentration–time profiles using the noncompartmental analysis with 
Phoenix WinNonlin software (Certara USA, Inc.). Kinetic parameters, including the maximum plasma 
concentration (Cmax), time to reach Cmax (Tmax), area under the curve during one dosing interval (AUCτ), 
drug elimination half-life (t1/2), will be calculated by modeling group mean data at each time point. 
Overall Survival:  the distributions of survival outcomes (OS) will be summarized using Kaplan-Meier 
Curves, and their median times and associated 95% confidence intervals will be estimated using Kaplan-
Meier estimates. Overall survival is defined as the number of days from the date of surgery to the date 
of death due to any cause. Participants alive at the time of analysis will be censored at the date of last 
contact. 
 

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10 SUPPORTING DOCUMENTATION AND OPERATIONAL CONSIDERATIONS 
10.1 REGULATORY, ETHICAL, AND STUDY OVERSIGHT CONSIDERATIONS 
10.1.1 INFORMED CONSENT PROCESS 
In obtaining and documenting informed consent, the investigator must comply with applicable regulatory 
requirements (e.g., 45 CFR Part 46, 21 CFR Part 50, 21 CFR Part 56) and should adhere to ICH GCP. Prior 
to the beginning of the trial, the investigator should have the IRB’s written approval for the protocol and 
the written informed consent form(s) and any other written information to be provided to the 
participants.  
10.1.1.1 CONSENT AND OTHER INFORMATIONAL DOCUMENTS PROVIDED TO PARTICIPANTS 
Consent forms describing in detail the study intervention, study procedures, and risks are given to the 
participant and written documentation of informed consent is required prior to starting 
intervention/administering study intervention.   
10.1.1.2 CONSENT PROCEDURES AND DOCUMENTATION 
Informed consent is a process that is initiated prior to the individual’s agreeing to participate in the study 
and continues throughout the individual’s study participation. Consent forms will be Institutional Review 
Board (IRB)-approved and the participant will be asked to read and review the document. The investigator 
will explain the research study to the participant and answer any questions that may arise. A verbal 
explanation will be provided in terms suited to the participant’s comprehension of the purposes, 
procedures, and potential risks of the study and of their rights as research participants.  Participants will 
have the opportunity to carefully review the written consent form and ask questions prior to signing. The 
participants should have the opportunity to discuss the study with their family or surrogates or think about 
it prior to agreeing to participate. The participant will sign the informed consent document prior to any 
procedures being done specifically for the study. Participants must be informed that participation is 
voluntary and that they may withdraw from the study at any time, without prejudice. A copy of the 
informed consent document will be given to the participants for their records. The informed consent 
process will be conducted and documented in the source document (including the date), and the form 
signed, before the participant undergoes any study-specific procedures. The rights and welfare of the 
participants will be protected by emphasizing to them that the quality of their medical care will not be 
adversely affected if they decline to participate in this study. 
10.1.2 STUDY DISCONTINUATION AND CLOSURE 
This study may be temporarily suspended or prematurely terminated if there is sufficient reasonable 
cause.  Written notification, documenting the reason for study suspension or termination, will be provided 
by the suspending or terminating party to study participants, investigator(s), funding agency, the 
Investigational New Drug (IND) sponsor and regulatory authorities.  If the study is prematurely terminated 
or suspended, the Principal Investigator (PI) will promptly inform study participants, the Institutional 
Review Board (IRB), and will provide the reason(s) for the termination or suspension.  Study participants 
will be contacted, as applicable, and be informed of changes to study visit schedule. 
 Circumstances that may warrant termination or suspension include, but are not limited to: 

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• 
Determination of unexpected, significant, or unacceptable risk to participants 
• 
Demonstration of efficacy that would warrant stopping    
• 
Insufficient compliance to protocol requirements 
• 
Data that are not sufficiently complete and/or evaluable 
• 
Determination that the primary endpoint has been met 
• 
Determination of futility 
Study may resume once concerns about safety, protocol compliance, and data quality are addressed, and 
satisfy the IND sponsor, IRB and/or Food and Drug Administration (FDA). 
10.1.3 CONFIDENTIALITY AND PRIVACY  
Participant confidentiality and privacy is strictly held in trust by the participating investigators, their staff, 
and the sponsor(s) and their interventions. This confidentiality is extended to cover testing of biological 
samples and genetic tests in addition to the clinical information relating to participants. Therefore, the 
study protocol, documentation, data, and all other information generated will be held in strict confidence. 
No information concerning the study or the data will be released to any unauthorized third party without 
prior written approval of the sponsor.  
All research activities will be conducted in as private a setting as possible. 
The study monitor, other authorized representatives of the sponsor, representatives of the Institutional 
Review Board (IRB), regulatory agencies or pharmaceutical company supplying study product may inspect 
all documents and records required to be maintained by the investigator, including but not limited to, 
medical records (office, clinic, or hospital) and pharmacy records for the participants in this study. The 
clinical study site will permit access to such records. 
The study participant’s contact information will be securely stored at each clinical site for internal use 
during the study. At the end of the study, all records will continue to be kept in a secure location for as 
long a period as dictated by the reviewing IRB, Institutional policies, or sponsor requirements. 
Study participant research data, which is for purposes of statistical analysis and scientific reporting, will 
be transmitted to and stored at the IBTC-CC. This will not include the participant’s contact or identifying 
information. Rather, individual participants and their research data will be identified by a unique study 
identification number. The study data entry and study management systems used by clinical sites and by 
IBTC-CC research staff will be secured and password protected. At the end of the study, all study databases 
will be de-identified and archived at the IBTC-CC. 
10.1.4 FUTURE USE OF STORED SPECIMENS AND DATA  
Data collected for this study will be analyzed and stored at the IBTC-CC. After the study is completed, the 
archived data will be transmitted to and stored at the Data Repository, for use by other researchers 
including those outside of the study. Permission to transmit data to the Data Repository will be included 
in the informed consent.  
With the participant’s approval and as approved by local Institutional Review Boards (IRBs), de-identified 
biological samples will be stored at the Ivy Brain Tumor Center Laboratory with the same goal as the 
sharing of data with the Data Repository. These samples could be used to research the causes of brain 
tumors, its complications and other conditions for which individuals with brain tumors are at increased 
risk, and to improve treatment. The Data Repository will also be provided with a code-link that will allow 

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DSMB will provide its input to the IBTC Coordinating Center and the Sponsor-Investigator and reported to 
the IRBs as applicable. 
10.1.7 CLINICAL MONITORING 
Clinical site monitoring is conducted to ensure that the rights and well-being of trial participants are 
protected, that the reported trial data are accurate, complete, and verifiable, and that the conduct of the 
trial is in compliance with the currently approved protocol/amendment(s), with International Conference 
on Harmonisation Good Clinical Practice (ICH GCP), and with applicable regulatory requirement(s).  
• 
Monitoring for this study will be performed by IBTC Coordinating Center.  
• 
Details of clinical site monitoring are documented in a Data and Safety Monitoring Plan (DSMP). 
The DSMP describes in detail who will conduct the monitoring, at what frequency monitoring will 
be done, at what level of detail monitoring will be performed, and the distribution of monitoring 
reports. 
10.1.8 QUALITY ASSURANCE AND QUALITY CONTROL 
Each clinical site will perform internal quality management of study conduct, data and biological specimen 
collection, documentation and completion.  
Quality control (QC) procedures will be implemented beginning with the data entry system and data QC 
checks that will be run on the database will be generated. Any missing data or data anomalies will be 
communicated to the site(s) for clarification/resolution. 
Following the Data and Safety Monitoring Plan, the monitors will verify that the clinical trial is conducted 
and data are generated and biological specimens are collected, documented (recorded), and reported in 
compliance with the protocol, International Conference on Harmonisation Good Clinical Practice (ICH 
GCP), and applicable regulatory requirements.  
The investigational site will provide direct access to all trial related sites, source data/documents, and 
reports for the purpose of monitoring and auditing by the sponsor, and inspection by local and regulatory 
authorities. 
10.1.9 DATA HANDLING AND RECORD KEEPING  
10.1.9.1 DATA COLLECTION AND MANAGEMENT RESPONSIBILITIES  
Data collection is the responsibility of the clinical trial staff at the site under the supervision of the site 
investigator. The investigator is responsible for ensuring the accuracy, completeness, legibility, and 
timeliness of the data reported. 
All source documents should be completed in a neat, legible manner to ensure accurate interpretation of 
data.   
Hardcopies of the study visit worksheets will be provided for use as source document worksheets for 
recording data for each participant enrolled in the study.  Data may also be available in the Electronic 
Health Record (EHR). Data recorded in the electronic case report form (eCRF) derived from source 
documents and the EHR should be consistent with the data recorded on the source documents and in the 
EHR.  
 

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Clinical data (including adverse events (AEs), concomitant medications, and expected adverse reactions 
data) and clinical laboratory data will be entered into REDCap Cloud, a 21 CFR Part 11-compliant electronic 
data capture system provided by the IBTC. The data system includes password protection and internal 
quality checks, such as automatic valid value and valid range alerts, to identify data that appear 
inconsistent, incomplete, or inaccurate. REDCap Cloud uses secure encryption technology to protect 
Internet data exchanges. All system modifications and data entries will be logged on a real-time audit trail. 
Clinical data will be entered directly from the source documents. 
10.1.9.2 STUDY RECORDS RETENTION  
Study documents should be retained for a minimum of 2 years after the last approval of a marketing 
application in an International Conference on Harminosation (ICH) region and until there are no pending 
or contemplated marketing applications in an ICH region or until at least 2 years have elapsed since the 
formal discontinuation of clinical development of the study intervention. These documents should be 
retained for a longer period, however, if required by local regulations. No records will be destroyed 
without the written consent of the sponsor, if applicable. It is the responsibility of the sponsor to inform 
the investigator when these documents no longer need to be retained. 
10.1.10 
PROTOCOL DEVIATIONS  
A protocol deviation is any noncompliance with the clinical trial protocol, International Conference on 
Harmonisation Good Clinical Practice (ICH GCP). The noncompliance may be either on the part of the 
participant, the investigator, or the study site staff. As a result of deviations, corrective actions may be 
developed by the site and implemented promptly.  
These practices are consistent with ICH GCP:  
• 
4.5 Compliance with Protocol, sections 4.5.1, 4.5.2, and 4.5.3  
• 
5.1 Quality Assurance and Quality Control, section 5.1.1  
• 
5.20 Noncompliance, sections 5.20.1, and 5.20.2.  
It is the responsibility of the site investigator to use continuous vigilance to identify and report deviations 
upon identification of the protocol deviation.  All deviations must be addressed in study source 
documents, reported to IBTC.  Protocol deviations must be sent to the reviewing Institutional Review 
Board (IRB) per the institutional and IRB policies. The site investigator is responsible for knowing and 
adhering to the reviewing IRB requirements.  
10.1.11 
PUBLICATION AND DATA SHARING POLICY 
This study will comply with the Clinical Trials Registration and Results Information Submission rule. As 
such, this trial will be registered at ClinicalTrials.gov, and results information from this trial will be 
submitted to ClinicalTrials.gov. In addition, every attempt will be made to publish results in peer-reviewed 
journals.   
10.1.12 
CONFLICT OF INTEREST POLICY 
The independence of this study from any actual or perceived influence, such as by the pharmaceutical 
industry, is critical.  Therefore, any actual conflict of interest of persons who have a role in the design, 
conduct, analysis, publication, or any aspect of this trial will be disclosed and managed. Furthermore, 
persons who have a perceived conflict of interest will be required to have such conflicts managed in a way 

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that is appropriate to their participation in the design and conduct of this trial.  The study leadership will 
establish a mechanism for the management of all reported dualities of interest. 

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10.2 ABBREVIATIONS 
AE 
adverse event 
ALP 
alkaline phosphatase 
ALT 
alanine aminotransferase 
ANC 
absolute neutrophil count 
AST 
aspartate aminotransferase 
ATC 
Anatomical Therapeutic Chemical (Classification System) 
AUC 
area under the curve 
BID 
twice daily 
BUN 
blood urea nitrogen 
CBC 
complete blood cell (count) 
CR 
complete response 
CRC 
Clinical Research Coordinator 
CRF 
case report form 
CSC 
central serous chorioretinopathy 
CSF 
cerebral spinal fluid 
CT 
computerized tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTMS 
Clinical Trial Management System 
DFS 
disease-free survival 
DLT 
dose limiting toxicity 
DSMC 
Data and Safety Monitoring Committee 
DSMP 
Data and Safety Monitoring Plan 
ECHO 
echocardiogram 
EGFR 
epidermal growth factor receptor 
FCBP 
female of childbearing potential 
FDA 
Food and Drug Administration 
FGFR 
fibroblast growth factor receptor 
GBM 
glioblastoma 
GCP 
Good Clinical Practice 
HBV 
hepatitis B virus 
HCT 
hematocrit 
HCV 
hepatitis C virus 
HGB 
hemoglobin 
HGG 
high-grade glioma 
HIV 
human immunodeficiency virus 
IBTC 
Ivy Brain Tumor Center 
ICH 
International Conference on Harmonization 
IND 
investigational new drug application 
IP 
investigational product 
IRB 
Institutional Review Board 
IV 
intravenous 
LAR 
legally authorized representative 
LDH 
lactate dehydrogenase 
LFT 
liver function test 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multigated acquisition 
NCI 
National Cancer Institute 
NHL 
non-Hodgkin’s lymphoma 
ORR 
overall response rate 

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OS 
overall survival 
PD 
disease progression 
PD 
Pharmacodynamic 
PFS 
progression free survival 
PK 
pharmacokinetic 
PO 
Per os (by mouth, orally) 
PR 
partial response 
PRC 
Protocol Review Committee (IBTC) 
QD 
once daily 
RBC 
red blood cell (count) 
RPED 
retinal pigment epithelial detachment 
SAE 
serious adverse event 
SD 
stable disease 
SD 
standard deviation 
SGOT 
serum glutamic oxaloacetic transaminase 
SGPT 
serum glutamic pyruvic transaminase 
ULN 
upper limit of normal 
WBC 
white blood cell (count) 
 
 
 
 

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10.3 PROTOCOL AMENDMENT HISTORY 
Version 
Date 
Description of Change  
Brief Rationale 
1.0 
27Mar2020 
Initial 
N/A 
2.0 
22Apr2020 
• 
Updated to clarify the 
description of IC50 and testing 
completed in the non-
enhancing tumor. 
• 
Updates to clarification for the 
indication under study,  
• 
Revised background in include 
a brief description of the known 
relevance with additional 
references added,  
• 
Required assessments revised 
(removed back) for the physical 
exam,  
• 
Ondansetron may be used per 
investigator discretion. 
• 
Typo corrections 
• 
Clarified per request by 
FDA. 
• 
Description of study 
population clarified for 
consistency. 
• 
Revised per request by 
FDA. 
• 
Clarification for Physical 
Exam assessments 
• 
Ondansetron is listed as a 
prohibited medication but 
may be necessary for 
clinical care.  
3.0 
10Sep2020 
• 
Updated to include use of 
biopsy 
tissue 
to 
confirm 
eligibility (includes update to 
SoA) 
• 
Phase 2 visit window allowance 
• 
Allowance 
for 
investigator 
discretion regarding pausing the 
use of a phosphate binder 
• 
Changes to allow trial eligibility 
to be determined under IBTC 
protocol 2020-09 
• 
Addition of radiographic images 
• 
Typo 
corrections 
and 
Administrative clarifications 
• 
Update allows flexibility in 
collecting 
tissue 
from 
either a previous surgery 
or the current recurrence 
in order to determine 
tissue eligibility and to 
complete analysis. 
• 
Allow some flexibility for 
visit schedules 
• 
Allowance for investigator 
discretion 
• 
Allowance for participants 
to be enrolled in 2020-09 
and test tissue across trials 
at IBTC 
• 
Additional data collection 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 

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11 REFERENCES  
Chukwueke, P., Wen, P.Y. Use of the Response Assessment in Neuro-Oncology (RANO) criteria in clinical 
trials and clinical practice. CNS Oncology. 2019; 8(1): CNS28. 
[FDA] CYP Enzymes Table. Drug Development and Drug Interactions: Table of Substrates, Inhibitors and 
Inducers page. Food and Drug Administration website. Available at: 
http://www.fda.gov/Drugs/DevelopmentApprovalProcess/DevelopmentResources/DrugInteractionsLabe
ling/ucm093664.htm#cypEnzymes.  
[FDA] Screening Tests Prior to Study Enrollment. January 1998. 
Lasorella, A., Sanson, M., Lavarone, A.  FGFR-TACC gene fusions in human glioma. Neuro-Oncology. 
2017;19(4):475-483. 
Lilja J, Kivisto, K, Neuvonen, P, Duration of effect of grapefruit juice on the pharmacokinetics of the CYP3A4 
substrate simvastatin, Clin Pharmacol & Ther. 2000;68(4):384-390. 
Novartis. November 2017. Investigator’s Brochure for BGJ398 (Infigratinib). 
Oken MM, Creech RH, Tormey DC, Horton J, Davis TE, McFadden ET, Carbone PP. Toxicity and response 
criteria of the eastern cooperative oncology group. Am J Clin Oncol. 1982;5:649-655. 
QED. November 2019. Investigator’s Brochure for Infigratinib phosphate. 
Singh D, Chan JM, Zoppoli P, et al. Transforming fusions of FGFR and TACC genes in human glioblastoma. 
Science. 2012;337(6099):1231–1235. 
Williams, et al. 2018 ESC/ESH Guidelines for the management of arterial hypertension. European Heart 
Journal. 2018;39:3021-3104 
 

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12 APPENDICES 
12.1 PERFORMANCE STATUS CRITERIA 
ECOG Performance Status Scale 
Grade 
Descriptions 
0 
Normal activity.  Fully active, able to carry on all pre-disease performance 
without restriction. 
1 
Symptoms, but ambulatory.  Restricted in physically strenuous activity, but 
ambulatory and able to carry out work of a light or sedentary nature (e.g., light 
housework, office work). 
2 
In bed <50% of the time.  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 
In bed >50% of the time.  Capable of only limited self-care, confined to bed or 
chair more than 50% of waking hours. 
4 
100% bedridden.  Completely disabled.  Cannot carry on any self-care.  Totally 
confined to bed or chair. 
5 
Dead.