Clinical trial NCT04228042
Conditions: Renal Pelvis and Ureter Urothelial Carcinoma
Sponsor: M.D. Anderson Cancer Center
Start date: 2020-07-28; Completion date: 2024-04-17
Enrollment: 15 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This phase Ib trial studies the side effects of infigratinib before surgery in treating patients with upper tract urothelial cancer. Infigratinib may stop the growth of tumor cells by blocking the activities of a gene called FGFR needed for cell growth. Giving infigratinib before surgery may cause the tumor to shrink, which may make the surgical procedure easier and/or reduce the need for more extensive surgery.

Detailed description:
PRIMARY OBJECTIVE:

I. Evaluate the tolerability of infigratinib in patients with low-grade and high-grade platinum ineligible upper tract urothelial carcinoma (UTUC).

SECONDARY OBJECTIVES:

I. Assess tolerability in those with GFR 30-49. II. Evaluate the objective response rate (complete response \[CR\] + partial response \[PR\]) of infigratinib after 2 cycles in UTUC with and without FGFR3 alterations.

III. Correlate tumor tissue FGFR3 alteration (presence/absence, alteration type, and clonal status) with response and occurrence/severity of adverse events (AEs) such as hyperphosphatemia.

IV. Evaluate upper tract, bladder and local/distant recurrence within 12 months.

V. Evaluate renal function pre-treatment and after two treatments. VI. Evaluate patient-reported quality of life (QOL) outcomes during treatment.

EXPLORATORY OBJECTIVES:

I. Explore intra-tumor heterogeneity, gene expression profiles, and changes in tumor microenvironment using single cell ribonucleic acid (RNA) sequencing (scRNA-seq) and mass cytometry by time-of-flight (CyTOF) pre and post treatment to identify potential mechanisms of response and/or resistance, and correlation with the occurrence/severity of AEs.

II. Explore urinary/upper tract washing FGFR3 alterations as potential biomarker for detection and response.

III. Explore cell free deoxyribonucleic acid (cfDNA) for detection of FGFR3 alterations and as a predictor of response.

OUTLINE:

Patients receive infigratinib orally (PO) once daily (QD) on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery.

After completion of study treatment, patients are followed up at 30 days, then every 3 months for up to 1 year after surgery.

Arms: arm 1: Patients receive infigratinib PO QD on days 1-21. Treatment repeats every 28 days for up to 2 cycles in the absence of disease progression or unacceptable toxicity. During weeks 8-9 (at least 48 hours after last dose of infigratinib), patients undergo surgery.
Interventions: intervention 1: Infigratinib intervention 2: Quality-of-Life Assessment intervention 3: Questionnaire Administration intervention 4: Surgical Procedure
Intervention descriptions: intervention 1: Given PO intervention 2: Ancillary studies intervention 3: Ancillary studies intervention 4: Undergo surgery

Protocol documents:
Prot_SAP_000.pdf: 
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MD Anderson IND Sponsor Cover Sheet 
Protocol ID 
2019-0557/MOD009 
Protocol Title 
Tolerability and Activity of Neoadjuvant Infigratinib, an Inhibitor of FGFR, 
in Upper Tract Urothelial Carcinoma 
Protocol Phase 
1b 
Protocol Version 
7 
Version Date 
9/23/2022 
Protocol PI 
Mehrad Adibi 
Department 
Urology 
IND Sponsor 
MD Anderson Cancer Center 
IND # 
147103 


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Tolerability and Activity of Neoadjuvant Infigratinib, an 
Inhibitor of FGFR, in Upper Tract Urothelial Carcinoma 
 
 
 
 
 
 
Investigational Product: Infigratinib 
Phase of Development 
Phase 1b 
Investigator: 
Dr. Mehrad Adibi 


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LIST OF ABBREVIATIONS and definition of terms 
 
Abbreviation Term/Definition 
AE 
adverse event 
ALT/SGPT 
alanine aminotransferase/serum glutamic-pyruvic transaminase 
ANC 
absolute neutrophil count 
ASCO 
American Society of Clinical Oncology 
AST/SGOT 
aspartate aminotransferase/serum glutamic-oxaloacetic transaminase 
AUA 
American Urological Association 
AUCss 
area under the concentration-time curve over the dosing interval (24 hours) at steady- 
state 
BCRP 
breast cancer resistance protein 
BGJ398 
infigratinib 
BICC1 
bicaudal c homolog 1 
BOR 
best overall response 
cfDNA 
cell-free deoxyribonucleic acid 
CFR 
Code of Federal Regulations 
CI 
confidence interval 
CL/F 
apparent (oral) clearance 
Cmax 
maximum observed plasma concentration after drug administration 
Cmin 
measured concentration at the end of a dosing interval 
CR 
complete response 
CRO 
contract research organization 
Css 
average plasma concentration at steady-state 
CT 
computed tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CV 
coefficient of variation 
CYP 
cytochrome p 
CYP3A4 
cytochrome P450 family 3 subfamily A member 4 
CyTOF 
cytometry by time-of-flight 
DEB-TACE 
drug eluting bead-TACE 
DMC 
Data Monitoring Committee 
DNA 
deoxyribonucleic acid 
ECG 
electrocardiogram 
ECHO 
echocardiogram 


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Abbreviation Term/Definition 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
electronic case report form 
EDC 
electronic data capture 
eGFR 
estimated glomerular filtration rate 
EORTC 
European Organization for Research and Treatment of Cancer 
EOS 
end of study 
EOT 
end of treatment 
EPO 
erythropoietin 
ESMO 
European Society of Medical Oncology 
FAX 
facsimile 
FDA 
Food and Drug Administration 
FFPE 
Formalin-Fixed, Paraffin-Embedded 
FGFR 
fibroblast growth factor receptor 
FGFR1 
fibroblast growth factor receptor 1 
FGFR2 
fibroblast growth factor receptor 2 
FGFR3 
fibroblast growth factor receptor 3 
FGFR4 
fibroblast growth factor receptor 4 
FGR3 
fibroblast growth factor receptor 3 
FMS 
Feline McDonough Sarcoma 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony-stimulating factor 
GFR 
Glomerular filtration rate 
GI 
gastrointestinal 
GM-CSF 
granulocyte-macrophage colony-stimulating factor 
HR 
hazard ratio 
IC50 
half maximal inhibitory concentration 
ICF 
informed consent form 
ICH 
International Council for Harmonisation 
IEC 
Independent Ethics Committee 
IND 
Investigational New Drug 
IRB 
Institutional Review Board 
ITT 
intent-to-treat 
IV 
intravenous 


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Abbreviation Term/Definition 
K-M 
Kaplan-Meier 
KMT2C 
lysine methyltransferase 2C 
KMT2D 
lysine-specific methyltransferase 2D 
KMT6A 
lysine N-methyltransferase 6A 
LLOQ 
lower limit of quantification 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
mitogen activated protein kinase kinase 
MRI 
magnetic resonance imaging 
MTD 
maximum tolerated dose 
MUGA 
multiple gated acquisition 
NCCN 
National Comprehensive Cancer Network 
nM 
nanomolar 
NUx 
Nephroureterectomy 
N0 
No cancer in nearby lymph nodes 
OC 
operating characteristics 
ORR 
overall response rate 
OS 
overall survival 
OTC 
over the counter 
PD 
progressive disease 
PET 
positron emission tomography 
PFS 
progression-free survival 
PHI 
protected health information 
PIK3CA 
phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit alpha 
PK 
pharmacokinetics 
PR 
partial response 
QD 
once a day 
QOL 
quality of life 
QTcF 
QTc corrected by Fridericia's formula 
Racc 
accumulation ratio calculated as Cmin steady-state/Cmin 
RBC 
red blood cell 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria in Solid Tumors 


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Abbreviation Term/Definition 
RFS 
recurrence-free survival 
RNA 
ribonucleic acid 
RNAseq 
Ribonucleic acid sequencing 
RPTD 
recommended phase 2 dose 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
stable disease 
TACE 
transarterial chemoembolization 
TCGA 
The Cancer Genome Atlas 
TdP 
Torsades de Pointes 
tmax 
time at which the maximum observed concentration (Cmax) occurs 
TMP/SMX DS trimethoprim and sulfamethoxazole 
TP53 
tumor protein p53 
UCC 
urothelial cell carcinoma 
ULN 
upper limit of normal 
UNK 
unknown 
URS 
Ureteroscopy 
UTMDACC 
University of Texas MD Anderson Cancer Center 
UTUC 
Upper tract urothelial carcinoma 
Ux 
Ureterectomy 
WBC 
white blood cell 
WOCBP 
woman of childbearing potential 
ypT0 
complete pathologic response after treatment 
ypT1 
pathologic superficial invasion after treatment 


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1. 
SCHEDULE OF ASSESSMENTS 
 
 
SCRE E NI N G 
PHAS E 
TREATMENT PHASE 
FOLLOW UP PHASE 
VISIT/CYCLE 
SCREENINGa 
CYCLE #1 
CYCLE #2 
PRE-OP/ 
SAFETY 
VISIT 
SURGERY 
POST-OP 
FOLLOW-UP 
1-YEAR 
FOLLOW-UP 
Scheduling window 
(days) 
-28 to -1 
1 
29(±7) 
57 (±14) 
30 post-op 
(±14) 
365 post-op 
(±30) 
Informed Consent 
X 
Eligibility Criteria 
X 
Medical History 
X 
X 
Physica l Examination 
X 
X 
X 
X 
Vita l Signs 
X 
X 
X 
X 
X 
X 
URS/Tumor Mapping 
X 
X 
Xb 
Nephroureterectomy 
X 
Surgica l Specimen 
Assessment/Tumor 
Ma pping 
X 
X 
Ophthalmic Assessment
X 
X 
Xd 
Sa fety Laboratoriesc 
X 
X 
X 
X 
X 
X 
Urina lysis 
X 
X 
X 
X 
X 
Pregna ncy Test 
X 
X 
X 
X 
X 
12-lea d ECG 
X 
X 
Echocardiogram 
X 
AE Assessment 
X 
X 
X 
X 
X 
Concomitant Meds 
X 
X 
X 
X 
X 
X 
EORTC QLQ-C30 
QOL Questionnaire 
X 
X 
X 
Drug Dispensing 
X 
X 
Drug Accountability 
X 
Blood for Correlatives 
X 
X 
X 
Urine for Correla tives 
X 
X 
X 
Tissue for Correla tives 
X 
X 


 
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Abbreviations 
a. Baseline/screening assessments that are conducted within 3 days prior to first treatment 
can be used to satisfy the Day 1 requirements. Every effort must be made to follow the 
schedule outlined. 
b. CT scan and cystoscopy (+/- URS) 
c. Blood draw (phosphate level testing only) on Day 14 (+/-7 days) 
d. as per physician discretion 


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2. 
BACKGROUND 
Upper tract urothelial carcinoma (UTUC) is typically considered similar as bladder urothelial 
cancer just occurring upstream in the ureter or renal pelvis, but there are unique molecular 
and clinical aspects that differentiate it from its more common counterpart. Unique aspects of 
UTUC include causation by exposure to aristolochic acid (found in many eastern herbal 
remedies and accounting for the high rates in the East), high rates of microsatellite instability, 
strong predisposition in those with Lynch syndrome, and high rates of FGFR3 mutations. 
Generally, treatments are allocated based on biopsy showing low grade versus high grade 
disease. Treatments for those with low-grade disease include endoscopic management only, 
which allows preservation of kidney function but is associated with multiple procedures and 
high rates of recurrence. Endoscopic treatment of UTUC is often imperatively needed to 
avoid placing older patients on dialysis, or in those with low-grade, low-volume disease who 
wish to retain their kidney and avoid major surgery. Limitations of endoscopic management 
include the need to perform multiple procedures in staged fashion, an inability to manage 
large volume disease, and a 30-80% recurrence rate. No standard adjuvant therapy exists in 
this population although many, including us, have tried topical therapies with variable 
success rates of 40-70% RFS. The standard accepted treatment however is surgery with 
nephroureterectomy or ureterectomy (NUx/Ux), which creates or worsens existing renal 
insufficiency in many cases, and is associated with high complication rates given the 
typically elderly population. Ureteroscopic (URS) management is an option that can preserve 
the kidney but is associated with significant recurrence rates. 
Patients with high-grade disease are preferentially treated with neoadjuvant chemotherapy 
followed by NUx/Ux with lymph node dissection, or initial NUx/Ux followed by adjuvant 
chemotherapy. Reductions in kidney function limit the effective delivery of adjuvant therapy. 
Based on our seminal work showing significant downstaging and improved survival, the first 
intergroup prospective trial for this disease showed that the majority of patients had 
downstaging to ypT1 or less with a 14% ypT0N0 rate (Censits-Hoffman J et al, AUA 2018). 
As one of the highest recruitment sites for this trial, however, we noted a 50 -70% screen 
failure rate for this population, rendering a significant portion of patients ineligible. Thus, for 
both low and high risk patients, there are still major unmet needs. 
Recent genomic studies indicate a high rate of FGR3 mutations in patients with UTUC. We 
reported an integrated, comprehensive genomic study on UTUC, using whole exome 
sequencing, RNAseq, and protein expression. These data confirm that the most common 
mutation in UTUC occurs in FGFR3 (74.1% prevalence for the entire cohort of 31 patients). 
Low-grade UTUC tumors were associated with a 92% rate of FGFR3 mutations, and, more 
interestingly, high-grade with a 60% rate of FGFR3 mutations, much higher than is seen in 
bladder cancer (19% in TCGA bladder cohort, if all somatic mutations, fusions, and 
amplifications are counted), and largely consistent with another UTUC genomic study from 
Memorial Sloan Kettering. Other mutations in order of decreasing f requency were KMT2D, 
PIK3CA, TP53, KMT2C, and KMT6A. Mutations of other FGFR subtypes were identified at 
a much low rate. Expression profiling revealed 4 subtypes that do not exactly match the 
subtypes described for bladder cancer, with 2 of the 4 subtypes having 100% rate of FGFR3 
mutations but with varying clinical correlates between these 2 subtypes. 


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The emerging data from infigratinib, an inhibitor of FGFR1-3, showed a well-tolerated drug 
with activity against tumors with FGFR alterations. This represents a unique opportunity to 
study the tolerability of this compound in those without metastatic disease but who have a 
great need for therapeutic options, and also provides an opportunity to study the inhibition of 
FGFR-related pathways in UTUC. In a recently published study (Pal S et al, Cancer 
Discovery 2018) in patients with incurable urothelial cancer, the most common adverse 
events were asymptomatic, reversible laboratory derangements: hyperphosphatemia (46%), 
elevated creatinine (42%), fatigue (37%), constipation (37%), anemia (36%) and decreased 
appetite (33%). The most common grade 3/4 AEs were hyperlipesemia (10%), and fatigue, 
hypophosphatemia, and palmar-plantar erythrodysesthesia each at 7%. The current proposal 
involves patients with localized and locally advanced disease, who may have a different 
tolerability profile as well as different motivations to pursue novel therapeutic options. 
Given its relatively low serious adverse event profile, the high rates of FGFR3 mutations in 
UTUC, and the major unmet needs for this disease, sufficient rationale exists to further study 
its activity in UTUC. We propose a study in patients with localized/locally advanced UTUC 
in order to further understand tolerability and biologic consequences of FGFR inhibition with 
a biomarker-informed neoadjuvant study, which could help inform a future phase 2 e fficacy 
study in this population. 
 
2.1. 
Overview of Disease Pathogenesis, Epidemiology and Current 
Treatment 
2.2. 
Overview of Infigratinib 
Infigratinib is an orally bioavailable, potent and selective inhibitor of FGFRs 1-3, which has 
demonstrated anti-tumor activity in preclinical in vitro and in vivo tumor models harboring 
FGFR genetic alterations (data on file). Infigratinib belongs to the pyrimidinyl aryl urea 
chemical class and its chemical name is 3-(2,6-Dichloro-3,5- dimethoxyphenyl)-1-{6-[4-(4- 
ethyl-1-piperazin-1-yl)phenylamino]-pyrimidinyl-4-yl}-1methylurea phosphate(1:1). 
Please refer to the Investigator’s Brochure for additional information on infigratinib. 
2.3. 
Preclinical Experience with Infigratinib 
At the cellular level, infigratinib selectively inhibits the kinase activity of FGFR1, FGFR2 
and FGFR3, as measured by inhibition of receptor autophosphorylation, with half maximal 
inhibitory concentration (IC50) values of 3 to 7 nM for FGFR1, FGFR2 and FGFR3. 
Infigratinib is less selective for FGFR4, with an IC50 of 168 nM. In cellular kinase selectivity 
assays, the most potently inhibited kinases, in addition to the FGFRs, were vascular 
endothelial growth factor receptor 2 and FMS-related tyrosine kinase 1, with IC50 values of 
1510 nM and 1591 nM, respectively (data on file). 
Consistent with inhibition of FGFR autophosphorylation, infigratinib inhibits FGFR 
downstream signaling and proliferation of human cancer cell lines harboring genetic 
alterations of the FGFRs. These include, among others, lung and breast cancer cell lines with 
FGFR1 gene amplification, gastric cancer with FGFR2 gene amplification, endometrial 
cancer with FGFR2 mutations and bladder cancer with FGFR3 mutations or FGFR3 
translocations (Wesche et al., 2011; Guagnano et al., 2012; Konecny et al., 2013). 


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In vivo, infigratinib is widely distributed to tissues in the rat. A battery of in vivo safety 
pharmacology studies in rats and dogs did not reveal any effects on central nervous or 
respiratory systems and on hemodynamic or electrocardiographic parameters, respectively. 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, infigratinib did lead to 
increases in serum fibroblast growth factor 23 and serum phosphorous associated with 
partially reversible ectopic mineralization (kidney, lung, vascular and digestive systems) 
along with largely reversible changes in renal function parameters and bone growth plate 
thickening / retention of the primary spongiosa in rats (≥ 10 mg/kg/day) and dogs 
(≥ 10 mg/kg/day). These effects were deemed to be on-target effects mediated by 
pharmacological inhibition of FGFR. 
The no observed adverse effect level in the dog and rat was 1 mg/kg. 
 
2.4. 
Clinical Experience with Infigratinib 
2.4.1. 
Clinical Pharmacokinetics and Phase 1 Data 
The pharmacokinetics (PK) of infigratinib and its active metabolites have been evaluated 
following single and repeat daily doses in a phase 1 study (CBGJ398X2101). 
Following a single dose, median Tmax was approximately 2-3 hours. Infigratinib had a 
relatively short median elimination half-life ranging from 2.69 to 5.71 hours on Day 1. 
Despite the relatively short half -life on Day 1, accumulation was observed with daily dosing 
at doses ≥ 60 mg, likely due to auto-inhibition of CYP3A4 mediated clearance pathways 
(data on file). Mean accumulation ratio (Racc) ranged from 3 to 8 on Days 15 and 28. The 
interpatient variability was high for infigratinib. 
In the single agent, first-in-human phase 1 study (CBGJ398X2101), infigratinib was 
evaluated at 9 different dose levels and 3 different dose schedules, ranging from 5 mg/day to 
150 mg/day. Eight dose levels were administered on the once daily continuous 28-day cycle 
schedule, and one dose level was administered on a twice a day continuous 28-day cycle 
schedule. One subject at 100 mg experienced Grade 3 alanine aminotransferase (ALT) and 
aspartate aminotransferase (AST) elevation, 1 subject at 125 mg daily experienced 
hyperphosphatemia, and 2 subjects at 150 mg experienced Grade 1 corneal toxicity 
(1 subject) and Grade 3 ALT and AST elevation (1 subject). The dose of infigratinib 125 mg 
once daily continuously was declared as the maximum tolerated dose (MTD). 
While dose levels of 100 mg QD and higher were tolerated by subjects, the majority of 
subjects experienced reversible hyperphosphatemia, which led to study drug interruptions 
(data on file). An evaluation of the drug administration records for subjects prior to receiving 
prophylactic phosphate-lowering therapy indicated that the median time until first dose 
interruption was approximately 22 days and the median duration of interruption was 7 days. 
This observation led to the introduction of an expansion arm to evaluate the administration of 
125 mg QD on a 3 week on (21 days) / 1 week off (7 days) schedule in 28-day cycles. 
Subjects treated with this alternative dosing schedule required less dose interruption (n=24, 
49.0%) compared with subjects treated with 125 mg continuously (n=40, 70.2%). Thus, 
infigratinib 125 mg once daily on a 3 weeks on/1 week off schedule was declared as the 
recommended phase 2 dose (RPTD). 


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In the dose escalation cohort of 92 subjects, no complete response (CR) was observed, and 
4 subjects had partial response (PR) (1 subject at 100 mg; 3 subjects at 125 mg continuous 
dose). 
Of the 173 subjects treated at the 125 mg continuous or intermittent schedule, CR was 
observed in 2 subjects (1.2%), and 22 subjects (12.7%) had PR. The ORR (95% confidence 
interval [CI]) and disease control rate (95% CI) were 13.9% (9.10, 19.94) and 49.1% (41.47, 
56.83), respectively. 
The median PFS for all subjects treated at the MTD/RPTD was 3.12 months (95% CI: 2.10, 
3.65 months). 
Please refer to Investigator’s Brochure for more details regarding phase 1 studies and 
pharmacokinetics. 
 
2.4.2. 
Clinical Safety 
 
The majority of Study BGJ398X2101 patients (99.0%) evaluable f or safety experienced at 
least one AE, with a Grade 3/4 AE reported in 58.7%, regardless of study treatment 
relationship. The incidence of Grade 3/4 AEs was similar at the MTD (52.6%). The majority 
of these patients (95.7%) experienced at least 1 AE suspected to be study treatment related, 
with Grade 3/4 AEs suspected to be study treatment related reported in 38.0%. The incidence 
of Grade 3/4 AEs suspected to be study treatment related (38.0%) was similar at the MTD 
(31.6%). 
The most common AEs (occurring in ≥ 30% of all patients, all grades), regardless of study 
treatment relationship were: hyperphosphataemia (65.4%), constipation (39.9%), decreased 
appetite (37.5%), fatigue (36.1%), stomatitis (34.1%), and nausea (32.2%). Th e most 
common AEs suspected to be study treatment related (occurring in ≥ 30% of all patients, all 
grades) were: hyperphosphatemia (63.5%) and stomatitis (33.7%). 
 
The most commonly reported Grade 3/4 AEs (in ≥4% of all patients), regardless of study 
treatment relationship were: hyperlipasaemia (6.7%), hypophosphatemia (6.3%), ALT 
elevation (5.3%), hyperphosphatemia (4.8%), and fatigue (4.8%). The most frequently 
occurring Grade 3/4 AEs suspected to be study treatment related (in ≥4% of all patients) 
were: hyperlipasaemia (5.8%), hyperphosphatemia (4.8%), and ALT increased (4.8%). 
 
A total of 57 deaths (27.4%) occurred during the study, and most of these deaths were due to 
disease progression (24.0%). Of the total deaths, 11.1% were on-treatment deaths; of these, 
8.6% patients died due to disease progression, 2 patients died due to sepsis, and 1 patient 
each died due to respiratory failure, cardiac arrest, and unknown reason. 
 
At least one SAE (occurring in ≥5% patients) of any grade, regardless of study treatme nt 
relationship, was reported in a total of 37.5%, with a similar incidence reported at the MTD 
(40.4%). SAEs suspected to be drug-related were reported in 8.6% of patients. The most 
commonly reported SAEs, by preferred term (occurring in ≥5% patients) were: general 
physical health deterioration (2.9%); pneumonia (2.9%); vomiting (2.9%); dyspnoea (2.4%); 
and, hypercalcaemia (2.4%). 


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Adverse events leading to study drug discontinuation were reported in a total of 14.4%. Most 
commonly reported AEs leading to discontinuation of study drug, in all patients, by preferred 
term were: visual impairment, hypercalcemia, hypercreatininaemia, hyperlipesaemia, and 
palmar-plantar erythrodysaethesia syndrome in 1.0% each. Twenty-one patients (10.1%) 
discontinued treatment due to AEs that were suspected to be related to study treatment. The 
common suspected AEs leading to study treatment discontinuation were: visual impairment, 
hypercalcemia, hypercreatininaemia, hyperlipasaemia, and palmar-plantar erythrodysaethesia 
syndrome in 1.0% each. 
 
AEs requiring dose interruption or reduction occurred in 68.3% of patients. The most 
common AEs (incidence ≥ 10%) requiring dose adjustment or temporary in terruptions 
regardless of study drug relationship were hyperphosphatemia (28.8%) and 
hypercreatininaemia (15.9%). 
Overall, Grade 3 hematology abnormalities were reported in 13.9%, of which, two SAEs of 
anemia were reported in 2 patients (one patient had Grade 2 anemia and the other had 
Grade 3 anemia). New or worsened Grade 4 hematology abnormality of lymphocytes 
decrease was reported in 1.5% of patients. 
Eye-related AEs were reported in a total of 44.7% of patients. Of these, AEs suspected to be 
study treatment related were reported in 33.7%. There was one Grade 2 SAE of keratitis 
reported which was suspected to be treatment related and led to study drug discontinuation 
(BGJ398X2101 Clinical Study Report; Pal et al 2018). 
Please refer to the Infigratinib Investigator Brochure for additional safety information. 
 
2.4.3. 
Clinical Efficacy 
 
Efficacy data for all patients in the dose escalation and dose expansion parts of Study 
BGJ398X2101 are available in the Investigators Brochure. The following efficacy data 
presented are for study expansion part patients with UCC. 
 
Arm 4 of the expansion part of Study BGJ398X2101 included 67 patients with 
advanced/metastatic UCC with FGFR3 mutations or FGFR gene fusions who had either 
progressed on or were intolerant of platinum-based chemotherapy, or had contraindications to 
platinum-based chemotherapy. Permitted FGFR3 mutations included mutations in exon 7 
(R248C, S249C), exon 10 (G372C, A393E, Y375C), or exon 15 (K652M/T, K652E/Q). 
Permitted FGFR3 gene fusions included, but were not limited to the FGFR3-TACC3 fusion. 
Patients were treated with oral BGJ398 125 mg/day for 21 days followed by 7 days without 
treatment as 28-day cycles. 
 
All 67 patients were evaluable for response. Seventeen patients (25.4%) had responses (1 CR 
and 16 PR). Forty-three patients (64.2%) had disease control (CR + PR + SD). Sixteen 
patients (23.9%) had progressive disease and eight patients (11.9%) had an indeterminate 
response. One patient with an indeterminate response by Response Evaluation Criteria in 
Solid Tumors (RECIST) criteria actually had a pathologic complete response; however, due 
to changing imaging modalities between assessments, the response was reported as unknown. 
The patient had primary bladder cancer and a histologically confirmed metastasis in the 
humerus. During BGJ398 treatment, the patient had surgical resection of a suspected 


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pathologic fracture of the humerus. Histologic assessment revealed no evidence of residual 
disease (BGJ398X2101 Clinical Study Report; Pal et al 2018). 
 
Please refer to the Infigratinib Investigator Brochure for additional efficacy information. 
 
 
 
2.5. 
Rationale 
2.5.1. 
Study Rationale and Purpose 
Given the relatively low serious adverse event profile of Infigratinib, the high rates of FGFR3 
mutations in UTUC, and the major unmet needs for this disease, sufficient rationale exists to 
further study its activity in UTUC. We propose a study in patients with localized/locally 
advanced UTUC in order to further understand the tolerability and biologic consequences of 
FGFR inhibition with a biomarker-informed neoadjuvant study, which will help inform a 
future phase 2 efficacy study, as well as a phase 3 adjuvant study in this population. 
 
2.5.2. 
Rationale for the Study Design 
This neoadjuvant, window of opportunity trial will allow the evaluation of tolerability by a 
drug previously exposed only to metastatic patients. In the process, we also have an 
opportunity to study response rates of UTUC and immunologic consequences of FGFR3 
inhibition. Arguments supporting this trial are: 1) A strong scientific rationale with an 
obligation to study this drug given the very high rates of FGFR3 alterations in this 
population, 2) an unmet clinical need, and 3) supportive Phase 1 data. 
 
2.5.3. 
Rationale for Dose and Regimen Selection 
In this study, subjects will receive 125 mg QD of infigratinib on a 3 week on (21 day) /1 
week off (7 day) schedule in 28-day cycles, for a total of 2 cycles. This dose level and 
regimen is based on experiences from previous phase 1 and 2 trials. 
 
OBJECTIVES AND ENDPOINTS 
2.6. 
Objectives 
The primary objective is to evaluate the tolerability of infigratinib in patients with low- 
grade and high-grade platinum ineligible UTUC. 
The secondary objectives are to: 
• Assess tolerability in those with GFR 30-49 
• Evaluate the objective response rate (CR+PR) of infigratinib after 2 cycles in UTUC 
with and without FGFR3 alterations 
• Correlate tumor tissue FGFR3 alteration (presence/absence, alteration type, and clonal 
status) with response and occurrence/severity of AEs such as hyperphosphatemia 


2 0 1 9 -0 5 5 7  
Se pte m ber 2 3 , 2 0 2 2 
Pa ge 1 5  
 
 
 
•  E v al u at e, bl a d d er a n d l ocal/ dista nt rec urre nce wit hi n 1 2 m o nt hs i n t h ose u n der g oi n g 
N U x/ U x a n d u p p er tr act, bla dder, a n d l ocal/ dista nt rec urre nce wit hi n 1 2 m o nt hs i n 
t h ose u n d er g oi n g e n d osc o pic ma na ge me nt.  
•  E val uate  r e n al f u n cti o n pre -treat me nt a n d  after t w o treat me nts. 
•  E val uate  p ati e nt -r e p ort e d q ualit y of  life ( Q O L) o ut c o mes d uri n g  treat me nt. 
T he e x pl or at or y o bj ecti ves  are t o:  
•  E x pl ore i ntr a-t u m or het er o ge neit y, ge ne e x pressi o n pr ofiles, a n d c ha n ges i n t u m or 
micr o e n vir o n m e nt usi n g si n gle cell R N A s e q u e nci n g (s c R N A-se q) a n d C y T O F pre 
a n d  p ost  treat m e nt t o i de ntif y p ote ntial mec ha nis ms  of  res p o nse a n d/ or resista nce, a n d 
c orrel ati o n wit h t he occ urre nce/se verit y of  A Es.  
•  E x pl ore uri nar y/ u p p er tract w as hi n g F G F R 3 alt erati o ns as p ote ntial bi o mar ker f or 
detecti o n a n d  res p o nse 
•  E x pl ore cf D N A  f or detecti o n  of  F G F R 3  alterati o ns  a n d as a pre di ct or of  res p o nse 
 
2.7. 
E n d p oi nts  
T he pri mar y  e n d p oi nt is t he pr o p orti o n of patie nts w h o are n ot a ble t o c o m plete treat me nt d ue 
t o e x cessi ve t o xicit y. T o xicit y will be ta b ulate d b y t y pe, fre q u e nc y, a n d s e verit y of A Es a n d 
seri o us A Es ( S A Es), la b orat or y a b n or m alities, a n d ot her safet y fi n di n gs. 
T he se c o n d ar y e n d p oi nts are: 
 Perce nta ge  of  patie nts  ac hie vi n g a p oi nt  i n ti me o bjecti ve res p o nse (eit h er c o m plete or 
partial r es p o ns e [ C R or P R]) aft er 2 c ycl es of i nfi grati ni b. T u m or ma p pi n g will b e 
p erf or m e d  fr o m t he e n d osc o pic e val uati o n (aft er a n y bi o psies) a n d  t his will  b e  us e d  t o 
c o m p ar e t o pat h ol o gic ( N U x/ U x c o h ort) or ureter osc o pic (e n d osc o p y c o h ort) fi n di n gs 
i n or d er t o det er mi n e  r es p o nses. 
 T u m or m a p pi n g  will  b e  p erf or m e d  b as e d  o n  e n d os c o pic fi n di n gs, n oti n g l o cati o n, 
n u m b er  of  t u m ors, t u m or arc hitect ure, a n d  l ocati o n of  bi o psies; a n d  will  a gai n b e  
perf or me d d uri n g pat h ol o gic e val uati o n a gai n n oti n g size, l ocati o n, n u m ber of t u m ors, 
arc hitect ure, a n d a bse nce of t u m or at a n y pre vi o usl y i de ntifie d t u m or. A differe n ce of 
3 m m will be c o nsi dere d wit hi n err or o f meas ure m e nt. 
 M utati o nal a n al ysis will  b e  p erf or m e d  o n  F F P E  t u m or tiss ue usi n g a c o m pre h e nsi v e 
m utati o n p a n el ( T 2 0 0. 2) w hic h we ha v e us e d i n pri or st u dies a n d i ncl u des all 
pr e vi o usl y i de ntifie d U T U C m utati o ns, i ncl u di n g all rel e v a nt F G F R 3 alterati o ns 
i nclu di n g  h ot  s p ots, c o p y  n u m ber variati o ns a n d  f usi o ns. Bl o o d c ollecte d at baseli n e 
will b e us e d as ger mli ne  s o ur ce. 
 All  a n al ys es  will  b e  p erf or m e d  o n  patie nts  stratifi e d as h a vi n g or  n ot  h a vi n g  F G F R 3 
alterati o ns. Descri pti ve statistics will b e us e d t o s u m mariz e v ari o us cli nical 
p ar a m et ers.  
 T he  s a m e m et h o ds  will  als o b e  us e d  t o e x pl ore t he ass ociati o n  of  A Es  s u c h as 
h y per p h os p hate mia wit h res p o nse.  
 P erce nta ge of  p atie nts  wit h  n o  e vi de nce  of  disease  1 2  m o nt hs after s ur ger y 


2 0 1 9 -0 5 5 7  
Se pte m ber 2 3 , 2 0 2 2 
Pa ge 1 6  
 
 
 
 C ha n ges i n pati e nt r e p ort e d Q O L o ut c o m es will b e m e as ur e d usi n g a vali d ate d 
q u esti o n nair e ( E O R T C Q L Q - C 3 0 v 3),  a d mi nistere d  at 3 ti me  p oi nts: 1.  e nr oll me nt 
( aft er e nr oll m e nt  a n d  bef ore first d os e),  2.  after c o m pleti o n of  2 c ycl es  a n d  pri or t o 
s ur ger y, a n d  3.  at 1 m o nt h p ost o perati ve c hec k.  
 
T he e x pl orat or y e n d p oi nts are: 
T u m or St u dies : 
 Si n gle cell (sc) R N Ase q will b e p erf or m e d o n fres h fr oze n t u m ors usi n g 1 0 x 
G e n o mi cs platf or m. T u m or cell heter o ge n eit y, F G F R 3 ge ne e x pressi o n, a n d t u m or 
micr o e n vir o n m e nt will  b e  pr ofil e d.  All  bi oi nf or matics  data  a n al ysis will  b e perf or me d 
i n t he M D A n d ers o n Ge n o mics c ore as p art of t he Rare T u m or I nitiati ve Pr o gra m 
( 2 0 1 4- 0 9 3 8) 
 M ulti ple x  i m m u n o hist oc he mistr y will  b e  p erf or m e d  usi n g F F P E  tiss ue ( bi o ps y a n d  
fi nal pat h ol o gic s p eci me n) a n d u n der g o i nterr o gati o n f or i m m u n ol o gic st u dies b y t he 
M D A n ders o n Rar e T u m or I nitiati ve Pr o gra m. F or patie nts wit h a c o m plet e res p o nse 
wit h o ut resi d ual t u m or, t he be d of t he lar gest pretreat me nt t u m or ( bas e d o n t u m or 
ma p) will be use d f or i m m u ne st u dies. 
 Tiss ue pri oritizati o n: Gi ve n t he p ote ntiall y li mite d bi o ps y sa m ples, use of bi o ps y a n d 
pat h ol o gic t u m or tiss ue will b e pri oritize d i n t he f oll o wi n g or d er a n d s o urces: 1. 
M utati o nal a n al ysis ( F F P E), 2.  R N Ase q  (fres h f o z e n), 3.  T M A  ( F F P E). 
Bi o m ar kers : 
V oi de d uri ne will be c oll ecte d pr ef ere ntiall y b ut will be s u bstit ute d wit h selecti ve u p per tract 
was hi n gs w h e n v oi de d uri ne is n ot a vaila ble or i ns ufficie nt. Uri ne a n d bl o o d will be c ollecte d 
at 3 ti me p oi nts ( pretreat me nt/e nr oll me nt, after c o m pleti o n of i nfi grati ni b 
treat me nt/ pre o perati vely, a n d 3 0 da ys p ost o perati vel y). Uri ne pr ocessi n g f oll o ws esta blis he d 
sta n dar d o per ati n g pr oce d ures. Sa m ples are st ore d at - 8 0 oC a n d t he n se nt t o F o x C hase 
Ca ncer Ce nter f or f urt her a nal ys es ( Dr. P hil A b b os h la b orat or y, wit h w h o m we ha ve a n 
e xiste nt c olla b orati o n a n d M T A). D N A is is olate d fr o m t he uri ne sa m ple a n d D N A is 
c hec k e d f or q u alit y, t y picall y yiel di n g se veral micr o gra ms of hi g h m olec ular wei g ht D N A. 
D N A is als o is olate d fr o m P B M C  pri or t o i nitiati o n of t hera p y t o use as a ger mli ne refere nce 
sa m ple. D N A fr o m ger mli ne a n d pre/ p ost-treat me nt/ p ost- o p ti me p oi nts are s u bjecte d ne xt 
ge n erati o n se q u e nci n g usi n g t he H al o Ple x H S platf or m wit h a tar gete d d e pt h of 1 0 0 0 X 
c o veri n g 5 4 w ell c har act erize d ca ncer ge nes. T hese ge nes are e nric he d i n patie nts wit h 
ur ot helial car ci n o ma (i ncl u di n g F G F R 3). H al o Ple x H S uses pre- a m plificati o n si n gle m olec ule 
ta gs t o filter ta q err ors occ urri n g d uri n g P C R, t h us greatl y e n ha n ci n g t he p o wer t o detect rare 
alleles. I n preli mi nar y e x peri me nts, o ur a p pr o ac h was vali date d t o be hi g hl y se nsiti ve a n d 
acc ur ate, det ecti n g > 6 0 % of t u m or tiss ue m utati o ns i n t he uri ne a n d i de ntif yi n g a d diti o nal 
m utati o ns i n t he uri ne t hat a  
re n ot s ee n i n tiss ue. Uri ne will b e c h aract eriz e d f or F G F R 3 h ots p ots or ot her misse nse 
varia nts a n d we will trac k t hei r v ari a nt allele fre q u e n c y i n l o n git u di nal sa m ples. Prese nce of 
p oi nt  m utati o ns i n t he pr e -tr eat m e nt uri ne will  b e  c orrelate d  wit h  pat h ol o gi cal res p o nse as a n 
a pri ori  pr e dicti ve bi o m ar k er.  Se parat el y,  we will  als o c orrelat e cl eara n c e  of  all pre -treat me nt 


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mutations after treatment with infigratinib and after surgery with pathologic response as a 
post hoc biomarker. Correlation will be determined using Fishers exact test for both analyses. 
Cell-free DNA (cfDNA): 
To explore the association of cfDNA with response, we will collect blood at 
pretreatment/enrollment, post-treatment/preoperatively, and 30 days postoperatively (30mL 
each time point). These samples will be processed and stored until tumor studies are 
completed and results available. Of all patients identified as having tumor FGFR3 alterations, 
5 will be randomly selected to have their baseline cfDNA assayed; if 3 or more are found to 
have detectable FGFR3 alterations, then up to 5 more patient baseline samples will be run. 
Those found to have detectable baseline FGFR3 alterations in their cfDNA will have their 
second time point assayed. These results will be correlated to disease burden, pathologic 
findings, disease grade, stage, objective response, and immune correlates. For cfDNA we will 
leverage the availability of a 70-Gene Liquid Biopsy Panel (LBP-70). The validated next 
generation sequencing (NGS)-based panel will be run in the MD Anderson Department of 
Pathology and Laboratory Medicine. Peripheral blood is collected into Streck tubes designed 
to reduce admixture of circulating cfDNA with cellular DNA from blood cells during 
transport. The NGS-based panel is designed to detect single nucleotide variants (SNVs) and 
small insertion-deletions (Indels) in all 70 genes included in the panel. In addition, 
amplifications (copy number variants; CNVs) and fusions (translocations) involving selected 
genes can also be detected. Specifically in regard to this study, the panel is able to detect 
mutations/indels, amplifications, and fusions of FGFR3. The comprehensive liquid biopsy 
test utilizes molecular barcode technology and sophisticated error detection algorithms to 
allow a sensitive and accurate detection of low level mutations. 


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3. 
INVESTIGATIONAL PLAN 
3.1. 
Overall Study and Correlative Design 
 
 
 
 
Figure 1: 
Study Design. Top row shows the clinical design, bottom row the 
correlative data and tissue collected. 
Surgery: 
NUx/Ux or 
URS (weeks 8- 
9) 


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4. 
STUDY POPULATION 
4.1. 
Inclusion Criteria 
 
1. 
Low grade UTUC, or high grade UTUC and not eligible for cis-platin neoadjuvant 
chemotherapy either due to medical comorbidities (eg, cardiac dysfunction, hearing loss, 
GFR<50), or based on <49% risk prediction of non-organ confined disease by clinical 
nomogram (Petros F et al Urol Oncol 2019 Apr;37(4):292). 
2. Undergoing: A) Nephroureterectomy or ureterectomy, or B) ureteroscopic 
management 
3. Have adequate pre-treatment biopsy tissue available for mutational analysis, as 
determined by the study pathologist, prior to enrollment. Any biopsy of index UTUC 
tissue available within 8 weeks of enrollment may be used. Patients with recurrent 
low grade UTUC can have tissue used within 12 weeks of enrollment at the PIs 
discretion. 
4. Calculated or measured creatinine clearance ≥30 mL/min. 
5. Have an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 2. 
6. Are able to read and/or understand the details of the study and provide written 
evidence of informed consent as approved by IRB/IEC. 
7. Have recovered from AEs of previous systemic anti-cancer therapies to baseline or 
Grade 1, except for alopecia. 
8. Are able to swallow and retain oral medication. 
9. Are willing and able to comply with scheduled visits, treatment plan and laboratory 
tests. 
10. f a woman of childbearing potential (WOCBP), must have a negative pregnancy test 
within 7 days of the first dose of study drug. A woman is not of childbearing potential 
if she has undergone surgical sterilization (total hysterectomy, or bilateral tubal 
ligation or bilateral oophorectomy at least 6 weeks bef ore taking study drug) or if she 
is post-menopausal and has had no menstrual bleeding of any kin d including 
menstrual period, irregular bleeding, spotting, etc., for at least 12 months, with an 
appropriate clinical profile, and there is no other cause of amenorrhea (e.g., hormonal 
therapy, prior chemotherapy). 
WOCBP and males whose sexual partners are WOCBP must agree to use barrier 
contraception and a second form of highly effective contraception (Clinical Trials 
Facilitation Group, 2014) while receiving study drug and for 3 months following their 
last dose of study drug. Alternatively, total abstinence is also considered a highly 
effective contraception method when this is in line with the preferred and usual 
lifestyle of the subject. Periodic abstinence (e.g., calendar, ovulation, symptothermal, 
post-ovulation methods) and withdrawal are not acceptable methods of contraception. 
Sexually active males must use a condom during intercourse while taking drug and 
for 3 months after the last dose of the study drug and should not father a child during 
this period. A condom is required to be used also by vasectomized men as well as 


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during intercourse with a male partner to prevent delivery of the drug via seminal 
fluid. 
4.2. 
Exclusion Criteria 
1. Have a history of another primary malignancy within 3 years except: a. adequately 
treated in situ carcinoma of the cervix, non-melanoma carcinoma of the skin, b. any 
other untreated cancer deemed by treating physician to be at low risk for progression 
during the study period (such as low or intermediate risk prostate cancer), c. 
curatively treated malignancy that is not expected to have recurrence or require 
treatment during the course of the study. 
2. Have uncontrolled bladder cancer. Patients with bladder cancer must have bladder 
cleared of disease by transurethral resection prior to initiating treatment and must not 
be at need for systemic therapy. 
3. Have any other medical condition that would, in the investigator’s judgment, prevent 
the subject’s participation in the clinical study due to safety concerns or compliance 
with clinical study procedures. 
4. Have current evidence of corneal or retinal disorder/keratopathy including, but not 
limited to, bullous/band keratopathy, corneal abrasion, inflammation/ulceration, 
keratoconjunctivitis, confirmed by ophthalmologic examination. Subjects with 
asymptomatic ophthalmologic conditions assessed by the investigator to pose minimal 
risk for study participation may be enrolled in the study. 
5. Have a history and/or current evidence of extensive tissue calcification including, but 
not limited to, the soft tissue, kidneys, intestine, myocardium, vasculature and lung 
with the exception of calcified lymph nodes, minor pulmonary parenchymal 
calcifications, and asymptomatic coronary calcification. 
6. 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). 
7. Have current evidence of endocrine alterations of calcium/phosphate homeostasis, 
e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral 
calcinosis etc. 
8. Are currently receiving treatment with agents that are known strong inducers or 
inhibitors of CYP3A4 and medications which increase serum phosphorus and/or 
calcium concentration. Subjects are not permitted to receive enzyme-inducing anti- 
epileptic drugs, including carbamazepine, phenytoin, phenobarbital, and primidone. 
9. 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. 
10. 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. 
11. Have used amiodarone within 90 days prior to first dose of study drug. 


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12. Are currently using therapeutic doses of warfarin sodium or any other coumadin - 
derivative anticoagulants or using direct thrombin inhibitors (e.g., argatroban) or 
Factor Xa inhibitors (e.g., rivaroxaban) that are primarily metabolized by CYP3A4. 
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 allowed. 
13. Have insufficient bone marrow function: 
a. Absolute neutrophil count (ANC) < 1,000/mm3 (1.0 × 109/L) 
b. Platelets < 100,000/mm3 (75 ×109/L) 
c. Hemoglobin < 9.0 g/dL 
14. Have insufficient hepatic and renal function: 
a. Total bilirubin > 1.5 × upper limit of normal (ULN) (unless documented 
Gilbert’s syndrome) 
b. AST/ serum glutamic-oxaloacetic transaminase (SGOT) and ALT/ serum 
glutamic-pyruvic transaminase (SGPT) > 2.5 × ULN (AST and ALT 
> 5 × ULN in the presence of liver involvement of cholangiocarcinoma) 
c. Calculated or measured creatinine clearance of < 30 mL/min 
15. Have amylase or lipase > 2.0 × ULN 
16. Have abnormal calcium-phosphate homeostasis: 
a. Inorganic phosphorus > ULN 
b. Total corrected serum calcium >ULN 
17. Have clinically significant cardiac disease including any of the following: 
a. Congestive heart failure requiring treatment (New York Heart Association 
Grade ≥ 2), LVEF < 50% or local lower limit of normal as determined by 
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 
or later 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 subject meets eligibility in this regard 
e. Known history of congenital long QT syndrome 
18. Have had a recent (≤ 3 months) transient ischemic attack or stroke 


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5. 
TREATMENTS 
5.1. 
Treatments Administered 
Patients will receive infigratinib 125 mg orally every day for a total of 2 cycles. Each cycle 
will consist in 28 days, with a schedule of 3 weeks on, 1 week off. Surgery will be performed 
during weeks 8-9 (week 8 being the off-week of 2nd cycle), and patients will have taken last 
dose of Infigratinib at least 48 hours prior to surgery. 
If patients are not able to tolerate the study drug, every effort will be made to schedule the 
surgery as soon as possible after the patient has recovered and/or the investigator determines 
it is the best course of action for the patient. 
 
5.2. 
Information on Infigratinib 
5.2.1. 
Subject Instructions for Infigratinib Dosing 
Subjects should be instructed to take the daily dose of infigratinib in the morning, at 
approximately the same time each day (24 ± 2 hour interval). 
Infigratinib should be taken in the fasted state at least 1 hour before or 2 hours after a meal. It 
should be taken with a large glass of water (~250 mL) and consumed over as short a time as 
possible. Subjects should be instructed to swallow the capsules whole and not chew them. 
If the subject forgets to take the scheduled dose of infigratinib in the morning, he/she should 
not take the dose more than 2 hours after the usual time and should continue treatme nt the 
next day. Any doses that are missed should be skipped altogether and should not be replaced 
or made up at the next scheduled dosing. 
If vomiting occurs following dosing with infigratinib, re-dosing is not permitted the same 
day. Dosing should resume the next day. 
Infigratinib is characterized by pH-dependent solubility; therefore, medicinal products that 
alter the pH of the upper GI tract may alter the solubility of infigratinib and limit 
bioavailability. These agents include, but are not limited to, proton pump inhibitors (e.g., 
omeprazole), H2-antagonists (e.g., ranitidine) and antacids. If possible, proton pump 
inhibitors should be avoided due to their long pharmacodynamic effect and replaced with 
H2-antagonists or antacids. Infigratinib should be taken at least 2 hours before or 10 hours 
after dosing with a gastric protection agent. 
Subjects must 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. This is due to a potential CYP3A4 
interaction with study drug. Normal oranges and orange juice are allowed. 
Last dose of Infigratinib should be at least 48 hours prior to surgery. 
 
5.2.2. 
Description and Dispensing of Infigratinib 
Infigratinib will be supplied as hard gelatin capsules for oral use at dose strengths of 25 and 
100 mg. Excipients will include microcrystalline cellulose, lactose monohydrate, 
HPMC2910, crospovidone, colloidal silicon dioxide, magnesium stearate, and hard gelatin 


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capsule. Infigratinib will be manufactured under Good Manufacturing Practice for 
investigational use. 
 
5.2.3. 
Packaging and Labeling 
Infigratinib capsules will be packaged in high density polyethylene bottles with child resistant 
closures. Study drug labels will be in the local language and comply with the legal 
requirements of each country. Labels will include storage conditions for the drug. 
 
5.2.4. 
Study Drug Accountability, Handling, and Disposal 
Infigratinib capsules will be received by designated personnel at the study site, handled and 
stored safely and properly, and kept in a secured location to which only the investigator and 
designated site personnel have access. Upon receipt, infigratinib should be stored according 
to the instructions specified on the drug label and in the Investigator’s Brochure . Refer to the 
Pharmacy Manual for further details. 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of infigratinib in a drug accountability log. Subjects will be asked to return all used and 
unused bottles of infigratinib and packaging on a regular basis, at the end of the study, or at 
the time of study drug discontinuation. Drug accountability will be assessed by the 
investigator’s delegated study personnel, and captured in a subject drug accountability log. 
This information must be captured in the source document at each subject visit. 
At study close-out, infigratinib will be destroyed per UTMDACC Institutional Policy # 
ADM0166. 
 
5.2.5. 
Dose Modifications for Infigratinib 
Each subject will be allowed a maximum of 2 dose reductions as noted in Table 2. Subjects 
should discontinue infigratinib if toxicity persists as per criteria in Table 3. Subject 
management will be based upon investigator evaluations. 
 
5.2.5.1. 
Dose Modifications and Delays 
The following guidelines should be applied: 
Following resolution of toxicity to baseline or ≤ Grade 1, treatment is resumed at either the 
same or lower dose of study drug as per the criteria in Table 2. If treatment is resumed at the 
same dose of study drug, and the same toxicity recurs with the same or worse severity 
regardless of duration, dose must be reduced to the next lower dose level. If treatment is 
resumed at the lower dose of study drug, and the same toxicity recurs with the same or worse 
severity, the subject should have a second dose reduction. 
Subjects who are withdrawn from the study for a study related AE or an abnormal laboratory 
value must be followed as described in Section 5.2.5.2. 
 
Table 1: 
Dose Reduction Scheme for Infigratinib 
 
Dose Reduction 
Starting dose level 0 
Dose level -1 
Dose level -2 


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Infigratinib 
125 mg 
100 mg 
75 mg 


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Table 2: 
Criteria for Interruption and Re-initiation of Infigratinib for AEs 
Considered to be Possibly Related to Infigratinib 
 
Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
CARDIAC DISORDERS 
Cardiac - Prolonged QTcF Interval 
Gra de 1 a nd 2: QTcF ≥ 481msec and ≤ 500 
msec (a symptomatic) 
Ma intain dose level of infigra tinib. 
Two a dditional ECGs separated by a t lea st 5 minutes should be 
performed to confirm the finding. If the finding is confirmed, 
single ECG a ssessments should be performed for 2 a dditional 
cycles a t the same frequency as in Cycle 1, or a s clinica lly 
indica ted. If abnormality is detected, 2 a dditional ECGs separated 
by a t lea st 5 minutes should be performed to confirm the finding. 
• 
If ECG a ssessments show no QTcF ≥ 481 msec, for 
subsequent cycles ECG monitoring will be performed as 
per visit schedule. 
• 
If ECG a ssessments a re still a bnormal (QTcF ≥ 481 msec 
a nd ≤500 msec), then ECG monitoring must continue a t 
the sa me frequency a s in cycle 1 for a ll subsequent 
cycles. 
Gra de 3: QTcF > 500msec as identified on 
the ECG by the investiga tor 
Gra de 4: QTcF > 500 or > 60 msec change 
from baseline and Torsade de pointes or 
Hold infigra tinib. Two a dditional ECGs separated by at least 5 
minutes should be performed to confirm the finding. If the finding 
is confirmed, monitor subject with hourly ECGs until the QTcF 
ha s returned to baseline a nd perform further monitoring a s 
clinica lly indica ted. 
• 
Exclude other causes of QTcF prolongation such as 
hypokalemia, hypomagnesaemia a nd decreased blood 
oxygenation. 
• 
Subjects should receive a ppropriate electrolyte 
repla cement a nd should not receive further infigra tinib 
until electrolytes are documented to be within normal 
limits. 
Once the QTcF prolongation has resolved, subjects may be re- 
trea ted a t one lower dose level a t the investigator’s discretion. 
Single ECG a ssessments should be performed for 2 a dditional 
cycles a t the same frequency as in Cycle 1 or a s clinica lly 
indica ted. If abnormality is detected, 2 a dditional ECGs separated 
by a t lea st 5 minutes should be performed to confirm the finding. 
o If ECG a ssessments show no QTcF ≥ 481 msec, 
ECG monitoring will be performed a s per visit 
schedule for subsequent cycles. 
o If ECG a ssessments a re still a bnormal 
(QTcF ≥ 481 msec a nd ≤500 msec), then ECG 
monitoring must continue a t the same frequency 
a s in cycle 1 or a s clinica lly indica ted, for a ll 
subsequent cycles. 
• 
Subjects who experience recurrent QTcF ≥ 500msec after 
one dose reduction will be withdra wn from study. 
Discontinue infigra tinib. 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
polymorphic ventricular tachycardia or 
signs/symptoms of serious arrhythmia 
If QTcF > 500 msec or > 60 msec change from the baseline is 
observed, a plasma sample for determination of infigratinib 
concentration should be obtained with the time of sample 
collection noted. 
Cardiac Disorders – Others 
Gra de ≥ 3, or congestive heart failure 
Gra de ≥ 2 
Discontinue subject from study drug. 
INVESTIGATIONS-HEMATOLOGY 
ANC Decreased (Neutropenia) 
Gra de 3 (ANC < 1.0 - 0.5 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or 
ba seline, then 
• 
If resolved within ≤ 7 da ys, maintain dose level of 
infigra tinib 
• 
If resolved between > 7 da ys a nd 14 days, ↓ 1 dose level 
of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Gra de 4 (ANC < 0.5 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE ≤ Gra de 1, 
↓ 1 dose level of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Febrile Neutropenia 
Gra de 3 (ANC < 1.0 × 109/L, single 
temperature of > 38.3°C or a sustained 
temperature of ≥ 38.0°C) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1, then 
• 
If resolved within ≤ 7 da ys, ↓ 1 dose level of infigra tinib. 
• 
If not resolved within 7 days, discontinue subject from 
study drug 
Gra de 4 
Discontinue subject from study drug 
Anemia 
Gra de 3 (hemoglobin <8.0 g/dL) 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Gra de ≤ 1 or ba seline, then maintain dose level 
Gra de 4 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Gra de ≤ 1 or ba seline, then ↓ 1 dose level 
Platelet Count Decreased (Thrombocytopenia) 
Gra de 3 (pla telet < 50 - 25 × 109/L) without 
≥ Gra de 2 bleeding 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or 
ba seline 
• 
If resolved within ≤ 7 da ys, maintain dose level of 
infigra tinib 
• 
If resolved between > 7 da ys a nd 14 days, ↓ 1 dose level 
of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Gra de 3 (pla telet < 50 - 25 × 109/L) with 
bleeding or Gra de 4 (pla telet < 25 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or 
ba seline, then ↓ 1 dose level 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
INVESTIGATIONS – RENAL 
Serum Creatinine 
Gra de ≥ 2 
If serum creatinine CTCAE Grade ≥ 2 ha s been demonstrated in 
conjunction with hyperphosphatemia, serum creatinine levels 
must be repeated at lea st weekly until resolution. 24-hour urine 
collection should be obtained a s clinically indicated for total 
phosphate, calcium, protein, a nd creatinine clearance. Ultra sound 
exa mination of the kidneys should be performed a s indicated to 
eva luate de-novo calcifications until resolution or stabiliza tion of 
crea tinine. 
Gra de 2 (≥ 2.00- 3.0 × ULN or 2.0-3.0 × 
ba seline) 
Hold dose of infigratinib until resolved to Gra de ≤1 or ba seline 
• 
If resolved within ≤ 7 da ys, maintain dose level of 
infigra tinib 
• 
If resolved between > 7 da ys a nd 14 days, ↓ 1 dose level 
of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Gra de ≥ 3 (> 3.0 × ULN or >3 × ba seline) Discontinue subject from study drug 
INVESTIGATIONS – HEPATIC 
AST or ALT 
Gra de 3 (> 5.0 - 20.0 × ULN) without 
bilirubin eleva tion > 2.0 × ULN 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or 
ba seline 
• 
If resolved within ≤ 7 da ys↓ 1 dose level of infigratinib 
• 
If not resolved within ≤ 7 da ys, discontinue subject from 
study drug 
Gra de 4 (> 20.0 × ULN) without bilirubin 
eleva tion > 2.0 × ULN 
Discontinue subject from study drug 
AST or ALT and Bilirubin 
AST or ALT > 3.0 – 5.0 × ULN a nd total 
bilirubin > 2.0 × ULN without liver 
metastasis or evidence of disease 
progression in the liver 
Hold dose of infigratinib until both tra nsaminases and bilirubin 
resolved to CTCAEGra de ≤ 1 or ba seline. 
• 
If resolved within ≤ 7 da ys, ↓ 1 dose level of infigra tinib. 
• 
If not resolved within ≤ 7 da ys, discontinue subject from 
study drug 
AST or ALT > 5.0 × ULN a nd total 
bilirubin > 2.0 × ULN 
Discontinue subject from study drug 
LABORATORY / METABOLIC DISORDERS 
Asymptomatic Amylase and/or Lipase Elevation 
Genera l Comment: 
A CT sca n or other imaging study to a ssess the pancreas, liver, 
a nd ga llbladder should be performed a s clinically indicated within 
1 week of the first occurrence of any CTCAE ≥ Gra de 3 a mylase 
a nd/or lipa se 
Gra de 3 (> 2.0 - 5.0 × ULN) 
• 
Hold dose of infigratinib until resolved to CTCAE 
Gra de ≤ 2 
• 
↓ 1 dose level of infigra tinib 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
For recurrent Gra de 3 a symptomatic lipa se or a mylase elevation 
despite dose reduction, drug should be held a nd continuation of 
thera py should be discussed with the medical monitor following 
resolution to ≤ Gra de 2. 
Gra de 4 (> 5.0 × ULN) 
For a ny Gra de 4 a symptomatic lipa se or a mylase elevation, drug 
should be held a nd continuation of therapy should be discussed 
with the medical monitor following resolution to ≤ Gra de 2. 
Hyperphosphatemia 
Serum phosphorus > 5.5 – 7.0 mg/dL 
Ma intain dose level of infigra tinib and optimize phosphate 
lowering thera py a s clinically indicated 
Serum phosphorus > 7.0 mg/dL for more 
tha n 7 days despite maximal phosphate- 
lowering thera py 
Or, single serum phosphorus > 9.0 mg/dL 
rega rdless of duration or dose of phosphate 
lowering thera py 
(Optimize/maximize dose and schedule of 
phosphate lowering therapy in a ccordance 
with pa ckage insert, country or institutional 
guidelines) 
• 
Hold infigra tinib dose until resolved to serum 
phosphorus ≤ 5.5 mg/dL. 
• 
Resta rt infigra tinib at the sa me dose level with maximal 
phosphate binder dosing if the subject did not receive 
ma ximal phosphate binder dosing for serum phosphorus 
> 7.0 mg/dL for > 7 da ys. 
• 
Reduce one dose level of infigratinib if the subject had 
received maximal phosphate lowering therapy for serum 
phosphorus > 7.0 mg/dL for > 7 da ys or if subject had a 
one-time serum phosphorus of > 9.0 mg/dL. Restart 
infigra tinib with maximal phosphate binder dosing. 
It is recommended that phosphate binder dosing continues during 
infigra tinib dose interruptions for hyperphosphatemia a nd that 
serum phosphorus valuesbe monitored frequently, e.g., every 2- 
3 da ys. 
Phosphate binder dosing should be held during the week off 
infigra tinib therapy each cycle (Da ys 22-28) unless serum 
phosphorus is not normalized and during infigra tinib dose 
interruptions for non-hyperphosphatemia AEs. 
Hypercalcemia 
Serum ca lcium Gra de 2 
Hold infigra tinib dose until resolved to Gra de 1 or baseline: 
• 
If resolved within ≤ 7 da ys a fter suspending infigra tinib, 
ma intain dose level 
• 
If resolved between > 7 da ys a nd 14 days a fter 
suspending infigra tinib, ↓ 1 dose level 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Serum ca lcium ≥ Gra de 3 
Discontinue subject from study drug 
NERVOUS SYSTEM DISORDERS 
Any Gra de 2 neurotoxicity 
Omit dose of infigra tinib until resolved to CTCAE Gra de ≤ 1, then 
↓ 1 dose level of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Any Gra de ≥ 3 neurotoxicity 
Discontinue subject from study drug 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
GASTROINTESTINAL SYSTEM DISORDERS 
Pancreatitis 
Gra de ≥ 2 
Discontinue subject from study drug 
Diarrhea 
Genera l Comment: 
Antidia rrheal medication is recommended at the first sign of 
a bdominal cra mping, loose stools or overt diarrhea 
Gra de 1 
Ma intain dose level of infigra tinib, initia te anti-diarrheal treatment 
Gra de 2 
• 
Hold dose of infigratinib until resolved to CTCAE 
Gra de ≤ 1 
• 
Optimize a nti-diarrheal trea tment 
• 
For reoccurrence of diarrhea CTCAE Gra de 2, hold dose 
of infigra tinib until resolved to CTCAEGra de ≤ 1, 
↓ infigra tinib by 1 dose level 
Gra de 3 
• 
Hold dose of infigratinib until resolved to CTCAE 
Gra de ≤ 1 
• 
Optimize a nti-diarrheal trea tment 
• 
↓ infigra tinib by 1 dose level 
• 
For reoccurrence of diarrhea CTCAE Gra de 3, despite 
optimal a ntidiarrheal treatment, discontinue subject from 
study drug 
Gra de 4 
Discontinue subject from study drug 
Vomiting 
Gra de 2 not controlled by optimal a nti- 
emetic therapy 
Hold infigra tinib doses until ≤ Gra de 1, ↓ 1 dose level 
• 
If not resolved within ≤ 14 days, discontinue subject 
from study drug 
Gra de 3 not controlled by optimal a nti- 
emetic therapy or Gra de 4 
Discontinue subject from study drug 
EYE DISORDERS (CONFIRMED BY OPHTHALMOLOGIC EXAMINATION) 
Retinal Disorders 
Gra de 2 central serous retinopathy a nd 
centra l serous retinopathy -like events 
Hold infigra tinib until resolved to ≤ Gra de 1 a nd continue 
ophthalmologic evaluation 
• 
If resolved within ≤ 14 days, ↓ infigratinib by 1 dose 
level 
• 
If resolved after > 14 da ys, discontinue infigratinib 
Gra de 3 central serous retinopathy a nd 
centra l serous retinopathy-like events a nd 
a ny other Gra de 3 eye disorders 
Hold infigra tinib until resolved to Gra de ≤ 1 
• 
If resolved within ≤ 14 days, ↓ infigratinib by 1 dose 
level 
• 
If resolved after > 14 da ys, discontinue infigratinib 
Gra de ≥ 1 retina l vein occlusion, Gra de 4 
centra l serous retinopathy a nd central serous 
retinopathy-like events, a nd Gra de 4 other 
eye disorders 
Discontinue subject from study drug 
  Other Ocular/Visual Toxicity 
 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
Gra de ≥ 3 
Hold infigra tinib until resolution to ≤ Gra de 1 
• 
If resolution within ≤ 14 days, ↓ 1 dose level 
• 
If resolved after > 14 da ys, discontinue infigratinib 
GENERAL DISORDERS 
Fatigue 
Gra de ≥ 3 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 
• 
If resolved within ≤ 7 da ys, maintain dose level of 
infigra tinib. 
• 
If resolved after > 7 da ys, discontinue subject from study 
drug 
SKIN AND SUBCUTANEOUS TISSUE DISORDERS 
Alopecia 
Gra de 1 
Continue infigratinib 
• 
Minoxidil 5% (OTC) solution or foam once daily to scalp 
Gra de 2 
Continue infigratinib 
• 
Minoxidil 5% (OTC) solution or foam twice daily to scalp 
• 
Fluocinonide 0.05% solution daily to scalp 
Palmar-plantar erythrodysesthesia syndrome 
Gra de 0/1 
Continue infigratinib 
• 
Urea 20% or a mmonium la ctate 12% lotions bid to hands and 
feet 
Gra de 2 
Continue infigratinib 
• 
Urea 20% or a mmonium la ctate 12% bid to hands a nd feet 
• 
Fluocinonide 0.05% cream bid to hands a nd feet 
Gra de 3 
Hold infigra tinib until resolved to Gra de ≤1 
• 
Urea 20% or a mmonium la ctate 12% bid to hands a nd feet 
• 
Fluocinonide 0.05% cream bid to hands a nd feet 
Paronychia 
Gra de 1 
Continue infigratinib 
• 
Clinda mycin 1% solution around and under nails tid 
• 
Soa k for 15 minutes daily in white vinegar in ta p water 1:1 
Gra de 2 
Continue infigratinib 
• 
Cefa droxil 500mg bid or TMP/SMX DS bid for 14 days 
• 
Soa k for 15 minutes daily in white vinegar in ta p water 1:1 
• 
Obta in bacterial cultures to confirm sensitivity to 
a ntimicrobial 
• 
Derma tology consultation 


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Worst Toxicity CTCAE (v5.0) Grade 
(Unless Otherwise Specified) 
Recommended Dose Modifications any Time During a Cycle 
of Therapy 
Gra de 3 
Hold infigra tinib until resolved to Gra de ≤1 
• 
Cefa droxil 500mg bid or TMP/SMX DS bid for 14 days 
• 
Obta in bacterial cultures to confirm sensitivity to 
a ntimicrobial 
• 
Derma tology consultation 
Stomatitis 
Gra de 1 
Gra de 2 
Gra de 3 
Continue infigratinib 
• 
Dexa methasone elixir 0.5mg/mL swish a nd spit 1 teaspoon 
(5mL) tid. 
Continue infigratinib 
• 
Dexa methasone elixir 0.5mg/mL swish a nd spit 1 teaspoon 
(5mL) tid. 
Hold infigra tinib until resolved to Gra de ≤1 
• 
Dexa methasone elixir 0.5 mg/mL swish a nd spit 1 teaspoon 
(5 mL0 tid 
• 
Clotrimazole 10 mg lozenges qid 
OTHER CLINICALLY SIGNIFICANT AEs 
Gra de 3 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1, then 
↓ 1 dose level of infigra tinib 
• 
If not resolved within ≤ 14 days, discontinue subject from 
study drug 
Gra de 4 
Discontinue subject from study drug 
Abbrevia tions: AE, a dverse event; ALT, a lanine aminotransferase; ANC, a bsolute neutrophil count; AST, 
a spartate aminotransferase; CT, computed tomography; CTCAE, Common Terminology Criteria for Adverse 
Events; ECG, electrocardiogram; QTcF, QTc corrected by Fridericia 's formula; ULN, upper limit of normal. 


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5.2.5.2. 
Follow-up for Toxicities 
Subjects whose study drug is interrupted or permanently discontinued due to an AE or clinically 
significant laboratory value, must be followed up at the discretion of the investigator until 
resolution or stabilization of the event, whichever comes first. Clinical experts or specialists, 
such as, but not limited to, an ophthalmologist, endocrinologist, or dermatologist, should be 
consulted as deemed necessary. Further guidelines and recommendations for the management of 
specific infigratinib-induced toxicities (hyperphosphatemia, diarrhea) are provided in Table 2. 
All subjects must be followed up for AEs and SAEs for 30 days following last dose of 
infigratinib or until surgery, whichever occurs last. 
 
5.3. 
Compliance 
The investigator or responsible site personnel should instruct the subject to take infigratinib 
exactly as prescribed to promote compliance. All dosages prescribed and dispensed to the subject 
and all dose changes or missed doses during the study must be recorded 
 
5.4. 
Supportive Care Guidelines 
5.4.1. 
Infigratinib Group 
Any palliative and supportive care for disease related symptoms, including any medic ation or 
therapy for a concurrent medical condition are permitted, except if specifically prohibited below. 
Hematopoietic Growth Factors 
Hematopoietic growth factors (e.g., erythropoietin [EPO], granulocyte colony -stimulating factor 
(G-CSF), granulocyte-macrophage colony-stimulating factor [GM-CSF]), and blood transfusions 
<2 weeks prior to enrollment are not to be administered prophylactically or to be used to meet 
eligibility criteria. However, these drugs may be administered as per the label of these agents or 
as dictated by local practice or guidelines established by the American Society of Clinical 
Oncology (ASCO), ESMO, or other appropriate regional societies. 
Management of Hyperphosphatemia 
Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of the 
FGFR pathway. While on infigratinib, subjects should avoid foods that are especially high in 
phosphate and, if possible, should restrict dietary phosphate to 600 – 800 mg/day. High- 
phosphate foods include dairy products; meats, nuts, and other high-protein foods; processed 
foods; and dark colas. Prophylactic phosphate binders, started in the evening of first dose of 
study drug, should be considered (e.g., sevelamer 800 mg three times a day with meals). Subjects 
who have experienced hyperphosphatemia should take a phosphate binder such as sevelamer, 
sacroferric oxyhydroxide, lanthanum carbonate, ferric citrate, etc. within 30 minutes of a meal on 
the day while taking infigratinib. Once the subject has had hyperphosphatemia, the subject 
should remain on a low phosphate diet, if possible, and take phosphate binder on the days 
infigratinib is taken, even if the serum phosphorus is normalized. The dose and schedule for 
phosphate lowering therapy should be in accordance with the package insert, country, or 


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institutional practice. For patient with GFR 30-49, phosphate binders will be started with first 
dosing and phosphate levels will be followed every 3 -4 days for the first week of treatment and 
then phosphate-binder dosage and serum phosphate level monitoring modified depending on 
serum phosphate levels. An example of a phosphate lowering regimen to manage 
hyperphosphatemia is provided for consideration below: 
• Start sevelamer 800 mg three times a day with meals 
• For serum phosphorus > 5.5 – 7.0 mg/dL 
o Increase the dose of sevelamer up to 1200 mg every 8 hours 
• For serum phosphorus > 7.0 – 9.0 mg/dL 
o Increase the dose of sevelamer up to 1600 mg (2 tablets per meal) every 8 hours 
o Consider adding acetazolamide two to three 250 mg tablets per day. 
During the infigratinib cycle, subjects do not need to be on a low phosphate diet or take a 
phosphate binder during their 1-week off period unless serum phosphorus is not normalized. 
Management of Diarrhea 
Subjects should be instructed to notify their physician immediately at the first signs of poorly 
formed or loose stool or an increased frequency of bowel movements. Administration of 
antidiarrheal/anti-motility agents is recommended at the first sign of diarrhea as initial 
management. Some subjects may require concomitant treatment with more than one antidiarrheal 
agent. When therapy with antidiarrheal agents does not control th e diarrhea to tolerable levels, 
study drug should be temporarily interrupted or dose reduced per Table 2. 
5.5. 
Prior and Concomitant Medications 
At Screening, subjects are to be asked about their history of prior therapies (including p rior 
anticancer therapy); investigators are to check for use of any disallowed prior medications, as 
outlined in the exclusion criteria for the study (Section 4.2). 
All prescription and non-prescription medications administered from the time of first dose of 
study drug through 30 days after last dose are to be recorded for each subject on the appropriate 
page of the eCRF. Dates for the start and stop of each concomitant medication are to be 
recorded, as well as the reason for administration (particularly if administered for an AE). Any 
changes in dose of concomitant medications are to also be recorded. 
 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as well as 
estrogen replacement hormone treatment. 
 
5.5.1.1. 
Permitted Concomitant Therapy Requiring Caution and/or Action 
Details for specific medications which require action and/or caution while on study in subjects 
taking infigratinib are provided in Appendix 1. The rationale for these medications is provided 
below. 


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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. 
Infigratinib was shown to inhibit the CYP3A4 in in vitro assays, thus suggesting an increased 
risk of drug interactions with concomitant medications that are metabolized by CYP3A4. 
Infigratinib is a substrate of CYP3A4. Therefore, moderate inhibitors and inducers should be 
used with caution if an alternative is not available. 
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 Appendix 1 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. 
Preliminary clinical data have shown that infigratinib has no effect on cardiac conduction or 
ECG intervals (see current version of the infigratinib Investigator’s Brochure). However, 
medications that have the potential to prolong the QT/QTc interval or induce Torsade de Pointes 
(possible and conditional risk of TdP/QT prolongation) are allowed with caution. Investigators at 
their discretion may co-administer such medications, but subjects should be carefully monitored . 
See Appendix 1 for list of drugs that need to be used with caution. Please note that the list might 
not be comprehensive. 
 
5.5.1.2. 
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 (e.g., CYP, BCRP). 
Details for specific medications prohibited while on study are provided in Appendix 2. The 
rationale for the restricted medications is provided below. 
Other investigational therapies must not be used while the subject is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy, and surgery) other than the study drug 
must not be given to subjects while the subject is on study drug. If such agents are required, then 
the subject must be discontinued from study drug. 
Strong inhibitors of CYP3A4 such as the ones listed in Appendix 2 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 Appendix 2 are prohibited. Please note that 
the list may not be exhaustive. 


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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. 
Preliminary clinical data have shown that infigratinib has no effect on cardiac conduction or 
ECG intervals (See current version of the infigratinib Investigator’s Brochure). However, 
medications that are known to prolong the QT/QTc interval or induce TdP (risk of TdP/QT 
prolongation) are prohibited. List of these medications is given in Appendix 2. Please note that 
the list might not be comprehensive. 
5.6. 
Non-drug Therapies 
Any significant non-drug therapies (including physical therapy, herbal/natural medications, and 
blood transfusions) administered from the time of first dose of study drug through 30 days after 
last dose are to be recorded for each subject on the appropriate page of the eCRF. Dates for the 
start and stop of each therapy are to be recorded, as well as the reason for administration 
(particularly if administered for an AE). 
Non-drug therapies are prohibited if they appear on any of the prohibited medication lists for any 
clinical pharmacology or PK property of the drug (e.g., CYP, BCRP) (see Appendix 2. 


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6. 
SUBJECT WITHDRAWAL AND STUDY TERMINATION 
6.1. 
Subject Withdrawal 
6.1.1. 
Discontinuation of Study Drug 
Subjects must be discontinued from study drug for: 
• Pregnancy 
In addition, subjects may be discontinued from study drug for any of the following reasons: 
• AE 
• Protocol deviation, including non-compliance with dosing regimen 
• Lost to follow-up (defined as no contact after 3 documented attempts by phone followed 
by 1 attempt via certified letter) 
• Subject request 
• Investigator request 
• Death 
6.1.2. 
Withdrawal from Study 
Subjects have the right to withdraw from the study at any time without prejudice. Study drug 
must be discontinued and no further assessments conducted. Further attempts to contact the 
subject are not allowed unless safety findings require communication or follow-up. Patients 
withdrawing after enrollment but prior to receipt of study drug will be considered screen failures. 
Subjects may also be discontinued from the study for the following reasons: 
• Subject request 
• Investigator request 
• Lost to follow-up (defined as no contact after 3 documented attempts by phone followed 
by 1 attempt via certified letter) 
 
• Discontinuation of the study by the IND Office, or the supporting drug company 
• Study complete 
• Death 
6.2. 
Study Termination 
End of Trial is defined as the time at which all patients enrolled in the study have completed the 
last study visit and data from those visits have been reviewed by the Investigator or designee. 


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Premature termination of this study may occur at any time because of a regulatory authority 
decision, change in opinion of the IRB, drug safety concerns, or at the discretion of the IND 
Office, or the supporting drug company. In addition, the IND Office, or the supporting drug 
company retains the right to discontinue development of infigratinib at any time. If termination 
becomes necessary, the IND Office, or the supporting drug company will inform the appropriate 
regulatory authorities of the termination and the reason. The Principal Investigator will inform 
the IRB of the same. In terminating the study, the IND Office, or the supporting drug company 
and the Principal Investigator will assure that adequate consideration is given to the protection of 
the patients’ interests. 


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7. 
STUDY VISITS AND PROCEDURES 
7.1. 
Main Informed Consent 
The subject will sign the study’s informed consent form (ICF) prior to conducting any study- 
specific procedures. The study team will be allowed to use standard of care 
assessments/procedures that were done prior to obtaining consent if these fall within the allowed 
time window. 
7.2. 
Screening (Day −28 to −1) 
After the main ICF is signed, screening activities will include the following: 
• Collection of blood, tissue and urine for correlative studies 
• Demography 
• ECOG performance status 
• Relevant medical history/current medical conditions 
• Diagnosis and extent of cancer 
• Prior anticancer therapy 
• Height and weight 
• AEs 
• Prior medication use 
• Physical examination 
• Vital signs 
• Ophthalmic assessment 
• Blood draw for hematology, chemistry, and coagulation assessment 
• Urinalysis (macro, micro only if necessary) 
• Pregnancy test (blood or urine) for WOCBP (within 7 days before first dose of study 
drug) 
• 12-lead ECG 
• Cardiac imaging (ECHO) 
• URS/Tumor Mapping 
• EORTC QLQ-C30 QOL Questionnaire 


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7.3. 
Treatment Period: Day 1 
Before the start of dosing on Day 1, the following assessments are to be performed. 
Baseline/screening assessments that are conducted within 7 days prior to first treatment can be 
used to satisfy the Day 1 requirement. 
• Weight 
• Prior and concomitant medication use 
• Symptom-directed physical examination (if needed) 
• Vital signs 
• Blood draw for hematology, chemistry; blood draw for coagulation, if clinically indicated 
• Urinalysis (micro- or macroscopic), if clinically indicated 
• Pregnancy test (blood or urine) for WOCBP 
• AEs 
7.4. 
Rest of Treatment Period 
Throughout the treatment period, subjects will be monitored for AEs and concomitant 
medication use. Other safety assessments, including symptom-directed physical examinations; 
vital signs; ophthalmic assessment, laboratory measures (hematology, blood chemistry, 
coagulation, pregnancy) and urinalysis; and 12-lead ECG and cardiac imaging will be conducted 
at the times indicated in the schedule of assessments in Section 1. (Note: Blood draws for 
laboratory measures may be drawn and measured at a local diagnostic lab) 
 
7.5. 
Pre-op Visit 
All patients will be required to return to clinic for pre-operative assessment within 14 days prior 
to the surgical procedure. Assessments will include the following: 
• Weight 
• Concomitant medication use 
• Physical examination 
• Vital signs 
• Blood draw for hematology, chemistry 
• Collection of blood and urine for correlative studies 
• Pregnancy test (blood or urine) for WOCBP 
• 12-lead ECG 
• AEs 
• EORTC QLQ-C30 QOL Questionnaire 


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NOTE: Collection of tissue for correlative studies at surgery 
 
7.6. 
30-day Safety Follow-up Visit 
All subjects must complete safety follow-up assessments 30 days (+/- 14 days) after the last dose 
of the study drug or surgery, whichever occurs last. Information relating to anticancer therapies 
taken since discontinuation of study drug and AEs (including concomitant medication taken for 
ongoing AEs) will be collected for 30 days after the last dose of the study drug. Assessments will 
include the following: 
• Vital signs 
• Ophthalmic assessment (per treating physician’s discretion) 
• Blood draw for hematology, chemistry 
• Urinalysis (macro, micro only if necessary) 
 
• Collection of blood and urine for correlative studies 
• Pregnancy test (blood or urine) for WOCBP 
• EORTC QLQ-C30 QOL Questionnaire 
 
 
7.7. 
End of Study 
All subjects must complete one last visit approximately one year (+/- 30 days) after 
discontinuation or study treatment or surgery, whichever occurred last. Assessments will include 
the following: 
• Relevant medical history/current medical conditions 
• Physical examination 
• Vital signs 
• Blood draw for hematology, chemistry 
• CT scan and cystoscopy(+/- URS) 


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8. 
STUDY ASSESSMENTS 
8.1. 
Efficacy Assessments 
Efficacy will be assessed by tumor response to study drug. To assess each subject’s response, the 
surgical specimen will be assessed/compared against the pre-treatment tumor mapping (Section 
12.3, Appendix 3) 
 
Table 3: 
Response Criteria for UTUC Lesions 
 
Response criteria 
Evaluation of target lesions 
Complete Response (CR): Disappearance of all target lesions as documented in Tumor Mapping. 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all mapped lesions, 
taking as reference the baseline sum of diameters. 
Progressive Disease (PD): At least a 20% increase in the sum of diameters of mapped lesions, taking 
as reference the smallest sum on study (this includes the baseline sum if 
that is the smallest on study). In addition to the relative increase of 20%, 
the sum must also demonstrate an absolute increase of at least 5 mm.a Or 
the appearance of one or more new lesions. 
Stable Disease (SD): 
Neither sufﬁcient shrinkage to qualify for PR nor sufﬁcient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study. 
Abbrevia tions: CR, complete response; PD, progressive disease; PR, pa rtial response; SD, sta ble disease. 
a The a ppearance of one or more new lesions is a lso considered progression. 
Source: Eisenhauer et a l 2009 
 
 
Table 4 (NOT APPLICABLE TO THIS STUDY, KEPT FOR TABLE REFERENCING): 
Response Criteria for Non-target Lesions 
 
Response criteria 
Evaluation of non-target lesions 
Complete Response (CR): Disappearance of all non-target lesions and normalization of tumor 
marker level. 
Progressive Disease (PD): Unequivocal progression of existing non-target lesions or the appearance 
of one or more new lesions. 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
Abbrevia tions: CR, complete response; PD, progressive disease. 
Source: Eisenhauer et a l 2009 
Note: Unequivocal progression in non-target lesions must be substantial a nd generally sufficient to require change in 


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thera py. The increase in overall disea se burden should be comparable in magnitude to the increase that would be 
required to declare PD for measurable disease: i.e. a n increase in tumor burden representing a n a dditional 73% 
increa se in ‘volume’ (which is equivalent to a 20% increase diameter in a measurable lesion). 
 
Table 5: 
Overall Lesion Response at each Assessment 
 
Target lesions 
Non-target lesions 
New lesions 
Overall lesion 
response 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all 
evaluated 
No 
PR 
SD 
Non-PD or not all 
evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
Abbrevia tions: CR, complete response; NE, not evaluable; PD, progressive disease; PR, partial response; SD, sta ble 
disea se. 
Source: Eisenhauer et a l 2009 
 
 
 
8.2. 
Safety Assessments 
The investigator (or physician designee) is responsible for verifying and providing source 
documentation for all adverse events and assigning the attribution for all adverse events for 
subjects enrolled. 
The safety evaluation will be based on AE reporting, laboratory parameters, vital signs, physical 
examinations, 12-lead ECGs, cardiac imaging, and ophthalmic assessments. Tolerability will be 
assessed by the incidence of AEs leading to study drug discontinuation. 


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8.2.1. 
Adverse Events 
 
8.2.1.1. 
Definitions 
An Adverse Event is defined as any untoward medical occurrence in a p atient regardless of its 
causal relationship to study treatment. An AE can be any unfavorable and unintended sign 
(including any clinically significant abnormal laboratory test result), symptom, or disease 
temporally associated with the use of the study treatment, whether or not it is considered to be 
study drug(s) related. Included in this definition are any newly occurring events and any previous 
condition that has increased in severity or frequency since the administration of study therapy.An 
SAE is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
o Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
o 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 
o Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
o Social reasons and respite care in the absence of any deterioration in the subject’s 
general condition 
 
8.2.1.2. 
Clarifications for AE Definitions 
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (e.g., hematologic ab normality 
that requires transfusion or hematological stem cell support), or require changes in study drug(s). 
Progression of underlying malignancy is not considered as an AE if it is clearly consistent with 
the suspected progression of the underlying cancer as defined by RECIST criteria v1.1, or other 
criteria as determined by protocol. Hospitalization due solely to the progression of underlying 
malignancy should NOT be reported as an SAE. 
Clinical symptoms of progression may be reported as AEs if the symptom cannot be determined 
as exclusively due to the progression of the underlying malignancy, or does not fit the expected 
pattern of progression for the disease under study. 


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Symptomatic deterioration may occur in some subjects. In this situation, progression is evident 
in the subject’s clinical symptoms, but is not supported by the tumor measurements. Or, the 
disease progression is so evident that the investigator may elect not to perform further disease 
assessments. In such cases, the determination of clinical progression is based on symptomatic 
deterioration. These determinations should be a rare exception as every effort should be made to 
document the objective progression of underlying malignancy. 
If there is any uncertainty about an AE being due to progression of the disease under study, it 
should be reported as an AE or SAE. 
 
8.2.1.3. 
Recording Adverse Events 
AEs will only be captured if they are ≥ Grade 3 and are reported to be causally related with the 
investigational study drug. 
Conditions already present at the time of informed consent should be recorded in the Medical 
History eCRF. These baseline conditions will be graded at study entry and monitored 
throughout the study. If at any point there is a worsening of the baseline condition to ≥ Grade 3 
this will also be captured in the eCRF and reported accordingly. 
AEs (including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate AE. 
AEs exclusively related to surgery will not be collected in the databa se. 
The following information is to be captured in the eCRF for each AE: severity grade (CTCAE 
v5.0 Grade 1-5); duration (start and end dates); relationship to study drug (reasonable possibility 
that AE is related: No, Yes); action taken with respect to study drug (none, dose reduction, 
temporarily interrupted, permanently discontinued, unknown, not applicable); whether 
medication or therapy was given (no concomitant medication/non-drug therapy given, 
concomitant medication/non-drug therapy given); outcome (not recovered/not resolved, 
recovered/resolved, recovering/resolving, recovered/resolved with sequelae, fatal, unknown); 
and whether the event is serious and seriousness criteria. 
AE monitoring should be done from the time of informed consent and continue through 30 days 
after the last dose of study drug. 
 
 
8.2.1.4. 
Reporting Serious Adverse Events 
An adverse event or suspected adverse reaction is considered “serious” if, in the view of either 
the investigator or the sponsor, it results in any of the following outcomes: 
• Death 
• A life-threatening adverse drug experience – any adverse experience that places the patient, 
in the view of the initial reporter, at immediate risk of death from the adverse experience as 


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it occurred. It does not include an adverse experience that, had it occurred in a more severe 
form, might have caused death. 
• Inpatient hospitalization or prolongation of existing hospitalization 
• A persistent or significant incapacity or substantial disruption of the ability to conduct 
normal life functions. 
• A congenital anomaly/birth defect. 
 
 
Important medical events that may not result in death, be life-threatening, or require 
hospitalization may be considered a serious adverse drug experience when, based u pon 
appropriate medical judgment, they may jeopardize the patient or subject and may require 
medical or surgical intervention to prevent one of the outcomes listed in this definition. 
Examples of such medical events include allergic bronchospasm requiring intensive treatment in 
an emergency room or at home, blood dyscrasias or convulsions that do not re sult in inpatient 
hospitalization, or the development of drug dependency or drug abuse (21 CFR 312.32). 
• Important medical events as defined above, may also be considered serious adverse events. 
Any important medical event can and should be reported as an SAE if deemed appropriate 
by the Principal Investigator or the IND Sponsor, IND Office. 
• All events occurring during the conduct of a protocol and meeting the definition of a SAE 
must be reported to the IRB in accordance with the timeframes and procedures outlined in 
“The University of Texas M. D. Anderson Cancer Center Institutional Review Board 
Policy for Investigators on Reporting Serious Unanticipated Ad verse Events for Drugs and 
Devices”. Unless stated otherwise in the protocol, all SAEs, expected o r unexpected, must 
be reported to the IND Office, regardless of attribution (within 5 working days of 
knowledge of the event). 
• All life-threatening or fatal events, that are unexpected, and related to the study drug, must 
have a written report submitted within 24 hours (next working day) of knowledge of the 
event to the Safety Project Manager in the IND Office. 
• Unless otherwise noted, the electronic SAE application (eSAE) will be utilized for safety 
reporting to the IND Office and MDACC IRB. 
• Serious adverse events will be captured from the time of the first protocol-specific 
intervention, until 30 days after the last dose of drug, unless the participant withdraws 
consent. Serious adverse events must be followed until clinical recovery is complete an d 
laboratory tests have returned to baseline, progression of the event has stabilized, or there 
has been acceptable resolution of the event. 
• Additionally, any serious adverse events that occur after the 30 day time period that are 
related to the study treatment must be reported to the IND Office. This may include the 
development of a secondary malignancy. 


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Reporting to FDA: 
• Serious adverse events will be f orwarded to FDA by the IND Sponsor (Safety Project 
Manager IND Office) according to 21 CFR 312.32. 
 
 
It is the responsibility of the PI and the research team to ensure serious adverse events are 
reported according to the Code of Federal Regulations, Good Clinical Practices, the protocol 
guidelines, the sponsor’s guidelines, and Institutional Review Board policy. 
 
 
Investigator Communications with Supporting Drug Company 
SAEs causally related with study procedures will be captured on a SAE Report Form an d must 
be reported to Helsinn Healthcare SA (email: drug-safety@helsinn.com) within 24 hours of 
learning of its occurrence. 
To ensure subject safety, every SAE, regardless of suspected causality, occurring after the 
subject has taken the first dose of study drug through 30 days after the subject has taken his/her 
last dose of study drug must be reported to Helsinn Healthcare SA on the SAE eCRF within 24 
hours of learning of its occurrence. Any SAEs experienced after this 30 -day period should only 
be reported to Helsinn Healthcare SA if the investigator suspects a causal relationship to the 
study drug. 
Any additional information for the SAE including recurrent episodes, complications, or 
progression of the initial SAE must be reported as follow-up to the original episode within 24 
hours of the investigator receiving the follow-up information. An SAE occurring at a different 
time interval or otherwise considered completely unrelated to a previously reported one should 
be reported separately as a new event. 
Follow-up information is submitted in the same way as the original SAE Report. Each 
reoccurrence, complication, or progression of the original event should be reported as a follow- 
up to that event regardless of when it occurs. The follow-up information should describe whether 
the event has resolved or continues, if and how it was treated, and whether the subject continued 
or withdrew from study participation. 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert (new 
occurrence) and is thought to be related to the study drug, a Helsinn Healthcare SA Associate 
may urgently require further information from the investigator for Health Authority reporting. 
Helsinn Healthcare SA may need to issue an investigator notification, to inform all investigators 
involved in any study with the same drug that this SAE has been reported. Suspected Unexpected 
Serious Adverse Reactions will be collected and reported to the competent authorities and 
relevant ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
SAEs in association with surgery will be reported if the investigator discerns association with the 
study drug. If the SAE is related to surgery alone, it will not be reported. 


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8.2.1.5. 
Follow up of Adverse Events 
All AEs should be treated appropriately. If a concomitant medication or non-drug therapy is 
given, this action should be recorded in the electronic medical record. 
Once an AE is detected, it should be followed until its resolution or until it is judged to be 
permanent, and assessment should be made at each visit (or more frequently, if necessary) of any 
changes in severity, the suspected relationship to the study drug, the interventions required to 
treat it, and the outcome. 
All SAEs should be followed per standard of care until resolution or stability. 
 
8.2.2. 
Pregnancies 
All females of child bearing potential are to undergo pregnancy testing (blood or urine) at the 
times specified under the schedule of assessments table. 
Female subjects must be discontinued from study drug in the event of pregnancy. 
To ensure subject safety, each pregnancy of a subject or partner of a male subject occurring 
while the subject is on study drug must be reported to Helsinn Healthcare SA within 24 hours 
of learning of its occurrence. The pregnancy should be followed up to determine outcome, 
including spontaneous or voluntary termination, details of the birth, and the presence or absence 
of any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
Consent to report information regarding pregnancy and pregnancy outcomes should be obtained 
from the partner of the male subject. 
Pregnancy of a subject or partner of a male subject should be recorded on a Pregnancy 
Notification Form and entered on the Pregnancy eCRF. Pregnancy follow-up should be recorded 
and include an assessment of the possible relationship to the study drug of any pregnancy 
outcome. Pregnancy and pregnancy follow-up should be reported to Helsinn Healthcare SA 
(email: drug-safety@helsinn.com). 
Any SAE experienced by a subject during pregnancy must be reported on the applicable SAE 
Report Form. 
 
8.2.3. 
Laboratory Parameters 
Laboratory tests will be collected and analyzed on the scheduled day, even if study drug is being 
withheld. More frequent assessments may be performed at the discretion of the investigator and 
if medically indicated, and should be recorded on the Unscheduled Visit eCRFs. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (e.g., 
require dose modification and/or interruption of study drug, lead to clinical symptoms or signs, 
or require therapeutic intervention), whether specifically requested in the protocol or not, will be 
recorded on the AE eCRF page. Laboratory data will be summarized using the CTCAE v5.0. 


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Table 6: 
Safety Laboratory Parameters 
Test Category 
Test Name 
Hematology 
Hematocrit, hemoglobin, RBC counts, WBC counts with differentials, pla telets 
Biochemistry 
Albumin, a lkaline phosphatase, ALT (SGPT), AST (SGOT), ca lcium (can be corrected), 
chloride, crea tinine, blood urea nitrogen, potassium, sodium, magnesium, phosphate 
Direct bilirubin, indirect bilirubin, total bilirubin, total protein, urea, uric a c id, a mylase, 
lipa se 
Urina lysis 
Ma croscopic panel (dipstick) (blood, glucose, ketones, pH, protein, specific gra vity). 
Microscopic panel (RBC, WBC) 
Coa gulation 
Prothrombin time or international normalized ra tio, partial thromboplastin time 
Abbrevia tions: ALT, a la nine aminotransferase; AST, a spartate aminotransferase; RBC, red blood cell; SGOT, serum 
gluta mic-pyruvic transaminase; SGPT, serum glutamic-oxaloacetic tra nsaminase; WBC, white blood cell 
 
8.2.4. 
Vital Signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed in the same 
position, either sitting or supine, before dosing at the times specified in . Vital signs should be 
assessed on the scheduled day, even if study drug is being withheld. More frequent examinations 
may be performed at the discretion of the investigator and if medically indicated. 
8.2.5. 
Physical Examinations 
A complete physical examination (including height and weight) must be performed at the 
Screening and at all other times indicated in Section 1, targeted, symptom-based physical 
examinations are to be performed, as needed. 
 
8.2.6. 
Electrocardiograms and Cardiac Imaging 
For each subject, 12-lead ECGs and ECHO are to be performed at the Screening Visit. A 12- 
lead ECG will be performed at the Pre-Op visit. Additional assessments should be obtained as 
dictated by symptoms. 
 
8.2.7. 
Ophthalmic Assessments 
Ophthalmologic examination will be performed by an ophthalmologist, or optometrist who is 
supervised by an ophthalmologist, at the times indicated in Section 1. These assessments will 
include visual acuity testing, slit lamp examination of the anterior eye segment, intraocular 
pressure, and fundoscopy. Additional examinations such as specular microscopy (that enables a 
magnified, direct view of the corneal epithelium), corneal pachymetry, retinal optical coherence 
tomography (OCT), and dilated fundoscopy will be performed as clinically indicated. 


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9. 
STATISTICAL PLAN: 
The primary objective is to evaluate the safety and tolerability of infigratinib as neoadjuvant 
therapy. Up to 20 patients will be enrolled in the study. The study will estimate proportion of 
patients who are not able to complete treatment (discontinuation) due to excessive toxicity along 
with the 90% exact confidence interval (NOTE: excessive toxicity is defined as treatment related 
adverse events that cause patients not to complete 2-cycles of planned treatment schedule). 
Toxicities will be tabulated using frequency and percentage by grade and their relations to 
treatment. Assuming a 30% of discontinuation due to excessive toxicity, the 90% confidence 
interval would be (13.1%, 46.9%) with a sample size of 20. Toxicity data will be summarized for 
the whole group of patients and for patients with eGFR≥50 and eGFR 30-49 separately. The 
safety analysis included all patients who received at least one dose of infigratinib. 
 
Toxicity monitoring: 
The study will monitor the incidence of not completing treatment or delay >14 days of surgery 
due to excessive toxicity using this monitoring rule. That is stop the trial early if Prob (Ptox > 0.3 
| data) > 0.85. Where Ptox denotes the proportion of patients not being able to complete 
treatment or delay >14 days of surgery. The corresponding stopping boundaries are that the trial 
will be stopped early if at any time it is observed that (n of patients not completing treatment or 
delay >14 days of surgery due to excessive toxicity / N of patients treated) >= 3/5, 4/(6-8), 5/(9- 
10), 6/(11-13), 7/(14-16), and 8/(17-19). This stopping rule will be applied for each cohort of 
eGFR≥50 and eGFR 30-49 separately. If one cohort stops early due to excessive toxicity, the 
other will continue accruing as per protocol criteria and toxicity monitoring rule. 
 
The following table displays the operating characteristics for safety monitoring, assuming prior 
distribution for Ptox is beta(0.3, 0.7) and for a maximum sample size of 20. Since we do not have 
information for proportions of eGFR≥50 and eGFR 30-49, it would not be feasible to assess OCs 
for each cohort. 
OCs for toxicity monitoring using a maximum sample size of 20 
Rate of discontinued 
treatment due to 
toxicity/intolerance 
Probability of early stop 
Avg. N of patients treated 
0.1 
0.012 
19.8 
0.2 
0.10 
18.7 
0.3 
0.341 
16.0 
0.4 
0.655 
12.4 
0.5 
0.886 
9.0 
 
The secondary efficacy endpoint is objective response after 2 cycle treatment of infigratinib. We 
will estimate the objective response rate along with the 90% confidence interval. Fisher’s exact 
test will be used to explore the difference in response between the two cohorts of patients. 


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Descriptive statistics will be used to summarize quantifications as continuous variables and 
frequency and percentage along with 90% CI will be used to summarize categorical variables. 
Wilcoxon rank sum test and Fisher’s exact test will be used to explore the association between 
objective response and secondary outcomes, e.g. cfDNA, expression of markers, FGFR3 
alteration type. The same methods will also be used to explore the association of AEs such as 
hyperphosphatemia with response. Recurrence at 12 months will be summarized using 
proportion and 90% confidence interval as a binary outcome, and also be estimated using the 
Kaplan-Meier method as a time to event variable. The association between time to event 
variables and markers will be explored using log rank test and univariable Cox model. With the 
small sample size, the analysis will probably only descriptive. The analysis will be performed in 
all patients and by FGFR3 alteration status if applicable. For data collected using the EORTC 
QLQ-C30 questionnaire, we calculate raw score (RS) and linear transformed score (Score) for 
each of the five functional scales, three symptom scales, a global health status / QOoL scale, and 
six single items at each time point [Reference: Fayers PM, Aaronson NK, Bjordal K, Groenvold 
M, Curran D, Bottomley A, on behalf of the EORTC Quality of Life Group. The EORTC QLQ- 
C30 Scoring Manual (3rd Edition). Published by: European Organisation for Research and 
Treatment of Cancer, Brussels 2001]. For each of these scales, paired t test or Wilcoxon signed 
rank test will be used to evaluate the changes of the Scores between two time points. Linear 
mixed models will also be fitted to evaluate the changes in Scores over time. 
 
 
9.1.1.1. 
Adverse Events: Safety analyses will be performed for all subjects who receive at 
least one dose of study drug according to the treatment they receive. 
AEs will be considered to be treatment emergent if the event occurs on or after the first 
administration of protocol specified treatment and within last dose date + 30 days. The subject 
incidence rates of AEs will be tabulated by system organ class, preferred term and severity grade 
for all treatment emergent, serious, treatment related, and serious treatment related AEs. Each of 
these outputs will include tabulation by maximum severity f or each system organ class and 
preferred term as reported by the investigator based on CTCAE, version 5.0. Summary tables 
will be provided separately for AEs leading to study drug discontinuation. All “on study drug” 
deaths, ie, deaths that occur within 30 days after last dose of study drug, will be summarized. 
Listings and/or narratives of “on study drug” deaths, serious and significant AEs, including study 
drug discontinuation due to AEs, will also be provided. 
The summaries of the subject incidence rates of treatment emergent AEs by system organ class 
and preferred term reported AEs will also be provided for subgroups defined by age, sex, and 
race (if feasible). 
 
9.1.1.2. 
Other Safety Findings 
Laboratory parameters for hematology and serum blood chemistry will be summarized at 
baseline, by visit, and at the last observed value. Additionally, the maximum and minimum 
observed post baseline values will be summarized along with the change from baseline to the 
maximum observed value, minimum observed value and last observed value. Tables of shifts in 
severity (by CTCAE version 5.0) from baseline for selected laboratory parameters and selected 


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time points may also be provided. Graphical representations of aggregate data may also be 
presented for parameters of interest. 
Vital signs, physical examination results, ophthalmic assessment and ECG and cardiac imaging 
results will be summarized by treatment group using descriptive statistics (including changes 
from baseline). 
 
9.1.1.3 
Safety and Efficacy Monitoring 
 
The Investigator is responsible for completing a toxicity/efficacy summary report, and 
submitting it to the IND Office Medical Affairs and Safety Group, for review and approval. This 
should be submitted after the first 5 evaluable patients per cohort, complete 2 cycles of study 
treatment, and every 2-3 evaluable patients per cohort, thereafter, as illustrated by the stopping 
boundaries in section 10. 
A copy of the cohort summary should be placed in the Investigator’s Regulatory Binder under 
“sponsor correspondence”. 


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10. 
DATA COLLECTION AND MANAGEMENT 
10.1. 
Data Confidentiality 
Information about study subjects will be kept confidential and managed under applicable laws 
and regulations. Those regulations require a signed subject authorization informing the subject of 
the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 
• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts should 
be made to obtain permission to collect follow-up safety information (e.g., has the subject 
experienced any new or worsened AEs) at the end of their scheduled study period. 
 
10.2. 
Data Collection 
Source documents include hospital or clinical patient charts, pertinent historical medical records, 
laboratory test reports, ECG tracings, pathology reports, radiographs, etc. All source documents 
must be legible. Data reported in RedCap and evidence of patient’s informed consent must be 
documented in source documents. All study data will be maintained in a confidential, password- 
protected, encrypted institutional database. 
 
10.3. 
Study Documentation, Record Keeping and Retention of Documents 
A CRF must be completed for each patient for whom informed consent for the study is obtained. 
The CRFs must be maintained by properly trained and delegated site representatives. The 
Principal Investigator has responsibility for ensuring the authenticity, accuracy, completeness 
and timeliness of all data collected in the CRF. 
The study site will maintain a Site Trial Master File in accordance with GCPs. 
The Investigator shall retain all records indefinitely. 


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11. 
REGULATORY AND ETHICAL CONSIDERATIONS 
11.1. 
Regulatory and Ethical Compliance 
11.2. 
Responsibilities of the Investigator and IRB/IEC/REB 
The protocol and the proposed ICF must be reviewed and approved by a properly constituted 
Institutional Review Board/Independent Ethics Committee/Research Ethics Board 
(IRB/IEC/REB) before study start 
The investigator will be responsible for informing IRBs and/or IECs in the event of early 
termination of the trial. 
11.3. 
Informed Consent Procedures 
Eligible subjects may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent. 
Informed consent must be obtained before conducting any study-specific procedures (i.e., all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the subject source documents. The date when a subject’s informed consent is 
actually obtained must be captured in the eCRF and the medical records for the subject. 
A copy of the ICF must be given to the subject or to the person signing the form. 
Women of child bearing potential should be informed that takin g the study drug may involve 
unknown risks to the fetus if pregnancy were to occur during the study and agree that in order to 
participate in the study they must adhere to the contraception requirement for the duration of the 
study. If there is any question that the subject will not reliably comply, they should not be 
entered in the study. 
11.4. 
Confidentiality of Study Documents and Subject Records 
The investigator must ensure anonymity of the subjects; subjects must not be identified by names 
in any documents submitted to QED Therapeutics. Signed ICFs and subject enrollment log kept 
at the site to enable subject identification must be kept strictly confidential. 


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12. 
Appendices 
12.1. 
Appendix 1: List of Concomitant Medications 
In general, the use of any concomitant medication deemed necessary for the care of the subject is 
permitted in this study, except as specifically prohibited below. Combination administration of 
study drugs could result in drug-drug interactions that could potentially lead to reduced activity 
or enhanced toxicity of the concomitant medication and/or infigratinib. 
The following lists are based on the Indiana University School of Medicine’s “Clinically 
Relevant” Table (Flockhart Table™) and supplemented with the FDA draft guidance. 
Table 7: 
Drugs to be used with Caution While on Study 
 
Category 
Drug Names 
Sensitive CYP3A substrates 
afentanyl, alpha-dihydroergocryptine, alprazolam, amlodipine, 
aplaviroc, aprepitant, aripiprazole, atorvastatin, boceprevir, 
brecanavir, brotizolam, budesonide, buspirone, capravirine, 
casopitant, cerivastatin, chlorpheniramine, darifenacin, darunavir, 
dasatinib, diazepam, diltiazem, dronedarone, ebastine, eletriptan, 
eplerenone, everolimus, felodipine, fluticasone, imatinib, lovastatin, 
lumefantrine, lurasidone, maraviroc, midazolam, neratinib, 
nevirapine, nifedipine, nisoldipine, nitrendipine, perospirone, 
pimozide, quetiapine, quinine, ridaforolimus, saquinavir, sildenafil, 
simvastatin, tadalafil, tamoxifen, telaprevir, telithromycin, 
ticagrelor, tipranavir, tolvaptan, trazodone, triazolam, vardenafil, 
verapamil, vicriviroc, vincristine 
Moderate inhibitors of CYP3A4 
amprenavir, aprepitant, atazanavir, cannabinoids, casopitant, 
cimetidine, ciprofloxacin, darunavir, diltiazem, dronedarone, 
erythromycin, fosamprenavir, imatinib, metronidazole, Schisandra 
sphenanthera, sertraline, suboxone, tofisopam, verapamil, 
zafirlukast 
Moderate inducers of CYP3A4 
bosentan, cotrimoxazole, efavirenz, etravirine, ethosuximide, 
genistein, metyrapone, mexiletine, modafinil, nafcillin, ritonavir, 
talviraline, thioridazine, tipranavir 
Medications which alter the pH 
of the GI tract a,b 
antacids, H2antagonists (e.g., ranitidine), proton-pump inhibitors 
(e.g., omeprazole) 
Medications that have possible 
risk of TdP/QT prolongation 
alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, dronedarone, eribulin, escitalopram, famotidine, 
felbamate, fingolimod, foscarnet, fosphenytoin, gatifloxacin, 
gemifloxacin, granisertron, iloperidone, indapamide, isradipine, 
lapatinib, levofloxacin, lithium, moexipril, nicardipine, nilotinib, 
octreotide, ofloxacin, ondansetron, oxytocin, paliperidone, 
pasireotide, quetiapine, ranolazine, risperidone, roxithromycin, 
sertindole, sunitinib, tacrolimus, tamoxifen, telithromycin, 
tizanidine, vardenafil, venlafaxine, voriconazole, ziprasidone 


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Category 
Drug Names 
Medications that have 
conditional risk of TdP/QT 
prolongation 
amiptriptyline, amisulpride, ciprofloxacin, clomipramine, 
desipramine, diphenhydramine, doxepin, fluconazole, fluoxetine, 
galantamine, imipramine, itrazonazole, ketoconazole, nortriptyline, 
paroxetine, protriptyline, ritonavir, sertraline, solifenacin, trazodone, 
trimethoprim-sulfa, trimipramine 
BCRP substrates 
atorvastatin, irinotecan, methotrexate, rosuvatstatin, 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; Indiana University School of Medicine, 2016. 
 
12.2. 
Appendix 2: List of Prohibited Medications and Substances 
 
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, micronazole, 
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 
Narrow therapeutic index 
substrates of CYP3A4 
alfentanil, astemizole, cisapride, cyclosporine, diergotamine, 
dihydroergotamine, ergotamine, fentanyl thioridazine, pimozide, 
quinidine, sirolimus, tacrolimus, terfanadine 
warfarin sodium or any other coumadin-derivative anticoagulants, 
direct thrombin inhibitors (e.g., argatroban), and Factor Xa 
inhibitors (e.g., rivaroxaban) 


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Category 
Drug Names 
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 


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12.3. 
Appendix 3a: Tumor Mapping FormUreteroscopy 
 
 
 
 
 
Lesion no. 
Size (mm x mm) 
Location (*see legend below) 
Architecture (villous, 
papillary, sessile) 
Other 
1 
2 
3 
4 
5 
 
1. 
Renal pelvis (anterior, posterior, medial, lateral) 
5. UPJ 
2. 
Upper calyx (or infundibulum) 
6. Proximal ureter 
3. 
Middle calyx (or infundibulum) 
7. Mid ureter 
4. 
Lower calyx (or infundibulum) 
8. Distal ureter 


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Appendix 3b: Tumor Mapping Form Pathology 
 
 
 
 
Lesion no. 
Size (mm x mm) 
Location (*see legend below) 
Architecture (carpeting, 
papillary, sessile) 
Other 
1 
2 
3 
4 
5 
 
1. 
Renal pelvis (anterior, posterior, medial, lateral) 
5. UPJ 
2. 
Upper calyx (or infundibulum) 
6. Proximal ureter 
3. 
Middle calyx (or infundibulum) 
7. Mid ureter 
4. 
Lower calyx (or infundibulum) 
8. Distal ureter 


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12.4 Appendix 4: Correlative and Laboratory Studies 
Tumor studies: 
 
 
• 
Tumor mapping will be performed based on endoscopic findings, noting location, number of 
tumors, tumor architecture, and location of biopsies; and will again be performed  after 
Infigratinib during pathologic evaluation (NUx/Ux cohort)  or URS evaluation (endoscopic 
cohort, with reasonable attempt to biopsy any residual tumor) again noting size, location, number 
of tumors, architecture, and absence of tumor at any previously identified tumor. A difference of 
3mm will be considered within error of measurement. 
• 
Mutational analysis will be performed on FFPE tumor tissue using a comprehensive mutation 
panel (T200.2) which we have used in prior studies and includes all previously identified UTUC 
mutations, including all relevant FGFR3 alterations including hot spots, copy number variations 
and fusions. Blood collected at baseline will be used as germline source 
• 
Single cell (sc)RNAseq will be performed on fresh frozen tumors using 10x Genomics platform. 
Tumor cell heterogeneity, FGFR3 gene expression, and tumor microenvironment will be profiled. 
All bioinformatics data analysis will be performed in the MD Anderson Rare Tumor Initiative 
Program. 
• 
Multiplex IHC will be performed from FFPE tissue (biopsy and final pathologic specimen or 
repeat biopsies in the endoscopic cohort) and undergo interrogation for immunologic studies, 
including lymphocyte subtypes and expression of relevant markers such as PD1, PD-L1, ICOS, 
among others. These data will be compared between FGFR3 mutant and wild-type tumors to 
evaluate the differences of the immunological environment between these two groups of tumors. 
• 
Tissue prioritization: Given the potentially limited biopsy samples, use of biopsy and pathologic 
tumor tissue will be prioritized in the following order and sources: 1. Mutational analysis (FFPE), 
2. RNAseq (fresh fozen), 3. TMA (FFPE). 
 
Urinary biomarkers: 
 
Voided urine will be collected preferentially but will be substituted with selective upper tract 
washings when voided urine is not available or insufficient. Preliminary data shows that urinary 
mutation clearance after neoadjuvant chemotherapy is strongly associated with pathologic 
complete response in radical nephroureterectomy and radical cystectomy specimens. Mutation 
clearance may therefore serve as a more general biomarker of response to other therapies such as 
FGFR3 inhibition, but this has yet to be rigorously tested. In order to further investigate this 
phenomenon in the current trial, urine and blood will be collected at 3 time points 
(pretreatment/enrollment, after completion of infigratinib treatment/preoperatively, and 
30 days postoperatively). Urine processing follows established standard operating procedures. 
Samples are stored at -80oC and then sent to Fox Chase Cancer Center for further analyses (Dr. 
Phil Abbosh laboratory, with whom we have an existent collaboration and MTA). DNA is 
isolated from the urine sample and DNA is checked for quality, typically yielding several 
micrograms of high molecular weight DNA. DNA is also isolated from PBMC prior to initiation 


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of therapy to use as a germline reference sample. DNA from germline and pre/post- 
treatment/post-op time points are subjected next generation sequencing using the HaloPlexHS 
platform with a targeted depth of 1000X covering 54 well characterized cancer genes. These 
genes are enriched in patients with urothelial carcinoma (including FGFR3). HaloPlexHS uses 
pre-amplification single molecule tags to filter taq errors occurring during PCR, thus greatly 
enhancing the power to detect rare alleles. In preliminary experiments, our approach was 
validated to be highly sensitive and accurate, detecting >60% of tumor tissue mutations in the 
urine and identifying additional mutations in the urine that are not seen in tissue. Urine will be 
characterized for FGFR3 hotspots or other missense variants and we will track their 
variant allele frequency in longitudinal samples. Presence of point mutations in the pre- 
treatment urine will be correlated with pathological response as an a priori predictive 
biomarker. Separately, we will also correlate clearance of all pre -treatment mutations after 
treatment with infagratinib and after surgery with pathologic response as a post hoc 
biomarker. Correlation will be determined using Fishers exact test for both analyses. 
 
Cell-free DNA (cfDNA) assessment: 
 
To explore the association of cfDNA with response, we will collect blood at 
pretreatment/enrollment, post-treatment/preoperatively, and 30 days postoperatively (30mL each 
time point). These samples will be processed and stored until tumor studies are completed and 
results available. Of all patients identified as having tumor FGFR3 alterations, 5 will be 
randomly selected to have their baseline cfDNA assayed; if 3 or more are found to have 
detectable FGFR3 alterations, then up to 5 more patient baseline samples will be run. 
Those found to have detectable baseline FGFR3 alterations in their cfDNA will have their 
second time point assayed. These results will be correlated to disease burden, pathologic 
findings, disease grade, stage, objective response, and immune correlates . For cfDNA we 
will leverage the availability of a 70-Gene Liquid Biopsy Panel (LBP-70). The validated next 
generation sequencing (NGS)-based panel will be run in the MD Anderson Department of 
Pathology and Laboratory Medicine. Peripheral blood is collected into Streck tubes designed to 
reduce admixture of circulating cfDNA with cellular DNA from blood cells during transport. The 
NGS-based panel is designed to detect single nucleotide variants (SNVs) and small insertion - 
deletions (Indels) in all 70 genes included in the panel. In addition, amplifications (copy number 
variants; CNVs) and fusions (translocations) involving selected genes can also be d etected. 
Specifically in regard to this study, the panel is able to detect mutations/indels, amplifications, 
and fusions of FGFR3. The comprehensive liquid biopsy test utilizes molecular barcode 
technology and sophisticated error detection algorithms to allow a sensitive and accurate 
detection of low level mutations.