A Phase 1B Study of Infigratinib in Combination With Tamoxifen in Hormone Receptor Positive, HER2 Negative, FGFR Altered Advanced Breast Cancer
Phase: PHASE1
Conditions: Breast Cancer, HER2-negative Breast Cancer, ER Positive Breast Cancer, PR-Positive Breast Cancer
Sponsor: Jennifer Lee Caswell-Jin

A Phase 1B Study of Infigratinib in Combination with Tamoxifen in  
Hormone Receptor-positive, HER2-negative, FGFR-altered Advanced Breast Cancer  
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A Phase 1B Study of Infigratinib in Combination with Tamoxifen in Hormone 
Receptor-Positive, HER2-Negative, FGFR-Altered Advanced Breast Cancer  
Coordinating Center 
Stanford Cancer Institute 
875 Blake Wilbur Drive 
Stanford, CA  94305  
Protocol Director  
Jennifer L Caswell-Jin, MD 
Assistant Professor of Medicine (Oncology) 
269 Campus Dr, CCSR 1145C 
Stanford Medicine at Stanford University; M/C 5769 
Stanford, CA  94305-5769 
Telephone:  650-724-3250 
e-mail:  caswell@stanford.edu   
Sub-Investigators 
George W Sledge, Jr, MD 
Professor of Medicine 
Stanford Medicine at Stanford Univ M/C 5151 
269 Campus Drive West; CCSR 1115  
Stanford, CA 94305-5151 
Phone  650-724-4397 
e-mail:  gsledge@stanford.edu 
Christina Curtis, PhD, MSc 
Assistant Prof of Medicine (Oncology) & Genetics 
Lorry Lokey Building/SIM1 Campus Dr, Suite G2120C  
Stanford Medicine at Stanford Univ  
Stanford, CA 94305 
Tel:  650-498-9943 
e-mail:  cncurtis@stanford.edu  
Biostatisticians 
Kristen Cunanan, PhD 
1701 Page Mill Road 
Palo Alto, CA 94304 
Tel:  650-723-7356 
e-mail:  cunanank@stanford.edu 
Manisha Desai, PhD 
1070 Arastradero Road, Room 305 
Palo Alto, CA 94304 
Tel:  650-725-1946 
e-mail:  manisha.desai@stanford.edu 
Vandana Sundaram, MPH 
1701 Page Mill Road 
Stanford, CA 94305 
Telephone:  650-736-4367 
e-mail:  sund@stanford.edu 
Clinical Research Coordinator 
Allison Zhang, MPH 
780 Welch Road 
Palo Alto, CA 94305 
Telephone:  650-736-5790 
e-mail:  axkong@stanford.edu 
 
 
IRB-53650  
BRS0113 
IND-149509 
NCT04504331 
Version 11 / Version Date:  11 November 2021  
Initial SRC Approval Date:  06 April 2020 (for version 27 March 2020)   

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TABLE OF CONTENTS  
PROTOCOL SYNOPSIS ............................................................................................................ 6 
SCHEMA .................................................................................................................................... 8 
LIST OF ABBREVIATIONS AND DEFINITION OF TERMS ....................................................... 9 
1. 
OBJECTIVES ................................................................................................................ 10 
1.1. 
PRIMARY OBJECTIVE ....................................................................................................... 10 
1.2. 
SECONDARY OBJECTIVES ................................................................................................ 10 
1.3. 
EXPLORATORY OBJECTIVES ............................................................................................. 10 
2. 
BACKGROUND ............................................................................................................ 10 
2.1 
STUDY DISEASE .............................................................................................................. 10 
2.2 
STUDY AGENT................................................................................................................. 11 
2.3 
RATIONALE ..................................................................................................................... 19 
2.4 
SCREENING TUMOR SEQUENCING ASSAYS ....................................................................... 21 
2.5 
STUDY DESIGN ............................................................................................................... 21 
2.6 
CORRELATIVE STUDIES BACKGROUND ............................................................................. 22 
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES ............................. 23 
3.1 
INCLUSION CRITERIA ....................................................................................................... 24 
3.2 
EXCLUSION CRITERIA ...................................................................................................... 27 
3.3 
INFORMED CONSENT PROCESS ........................................................................................ 31 
3.4 
STUDY TIMELINE ............................................................................................................. 31 
4. 
TREATMENT PLAN ...................................................................................................... 31 
4.1  
GENERAL CONCOMITANT MEDICATION AND SUPPORTIVE CARE GUIDELINES ....................... 32 
4.2 
CRITERIA FOR REMOVAL FROM STUDY ............................................................................. 36 
4.3 
ALTERNATIVES ................................................................................................................ 37 
5. 
INVESTIGATIONAL AGENT INFORMATION ............................................................... 37 
5.1 
INVESTIGATIONAL AGENT ................................................................................................. 37 
5.2 
AVAILABILITY ................................................................................................................... 38 
5.3 
AGENT ORDERING ........................................................................................................... 38 
5.4 
AGENT ACCOUNTABILITY ................................................................................................. 39 
6. 
DOSE MODIFICATIONS ............................................................................................... 39 
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES ............................................. 47 

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7.1 
POTENTIAL ADVERSE EVENTS .......................................................................................... 47 
7.2 
ADVERSE EVENTS DEFINITIONS ....................................................................................... 48 
7.3 
ADVERSE EVENTS REPORTING......................................................................................... 49 
7.4 
REPORTING SERIOUS ADVERSE EVENTS .......................................................................... 49 
7.5 
PREGNANCY ................................................................................................................... 50 
8. 
CORRELATIVE/SPECIAL STUDIES ............................................................................ 51 
8.1 
LABORATORY CORRELATIVE STUDIES .............................................................................. 51 
9. 
STUDY CALENDAR ..................................................................................................... 53 
10. 
MEASUREMENTS ........................................................................................................ 58 
10.1  
PRIMARY ENDPOINT ......................................................................................................... 58 
10.2  
SECONDARY ENDPOINTS .................................................................................................. 60 
10.3  
OUTCOMES FOR CLINICALTRIALS.GOV .............................................................................. 60 
11. 
REGULATORY CONSIDERATIONS ............................................................................ 62 
11.1 
INSTITUTIONAL REVIEW OF PROTOCOL ............................................................................. 62 
11.2 
DATA SHARING WITH COLLABORATORS  ........................................................................... 62 
11.3 
DATA AND SAFETY MONITORING PLAN .............................................................................. 62 
11.4 
DATA MANAGEMENT PLAN ............................................................................................... 63 
12. 
STATISTICAL CONSIDERATIONS .............................................................................. 63 
12.1 
STATISTICAL DESIGN AND SAMPLE SIZE DETERMINATION .................................................. 63 
12.2 
INTERIM ANALYSES ......................................................................................................... 63 
12.3 
DESCRIPTIVE STATISTICS AND EXPLORATORY DATA ANALYSIS .......................................... 63 
12.4 
PRIMARY SAFETY ANALYSIS............................................................................................. 63 
12.5 
SECONDARY SAFETY ANALYSIS ....................................................................................... 64 
12.6 
EFFICACY ANALYSIS ........................................................................................................ 64 
12.7 
ANALYSIS POPULATION .................................................................................................... 65 
12.8 
ACCRUAL CONSIDERATIONS ............................................................................................ 65 
12.9 
CRITERIA FOR FUTURE STUDIES ...................................................................................... 65 
13. 
REFERENCES .............................................................................................................. 66 
APPENDICES........................................................................................................................... 69 
APPENDIX A:  LIST OF PROHIBITED MEDICATIONS AND SUBSTANCES  .......................................... 69 
APPENDIX B:  LIST OF DRUGS TO BE USED WITH CAUTION WHILE ON STUDY ............................... 70 

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APPENDIX C:  RECIST V1.1 ..................................................................................................... 71 
 
Document History 
Date 
Summary 
27 March 2020 
Initial version to SRC (approved 6 April 2020) 
29 April 2020 
 
Document History table added 
 
Number of subjects corrected (up to 36 total) 
 
Cohort 1 dose levels clarified 
 
ClinicalTrials.gov outcomes adjusted 
 
Minor typography and syntax 
30 July 2020 
 
Cohort 1 infigratinib dose levels increased from 2 dose levels (100 mg and 125 mg) to 
3 dose levels (75 mg, 100 mg, and 125 mg). 
 
Cohort 1 recommended infigratinib dose when 0 of 3 or 1 of 6 subjects experience a DLT 
in their first 2 cycles at that dose. 
 
Intra-subject dose escalation allowed in Cohort 1 only, such that if a subject starts at 
infigratinib 100 mg and remains on-study after 2 cycles with no DLTs seen, they will 
begin receiving infigratinib 125 mg, and the number of DLTs in Cycles 3 and 4 will count 
toward the primary endpoint in Cohort 1 at this dose. 
 
Number of subjects adjusted for Cohort 1 (minimum 3 total instead of 6 total) and for both 
Cohorts together (maximum 33 instead of 36). 
 
Clarification for Cohort 2 that expansion to 12 subjects at recommended dose should 
include N = 6 IC2, and N = 6 IC6. 
 
Multiplexed ion beam imaging (MIBI) mentioned as another possible in situ proteomic 
method for exploratory analysis, in addition to Digital Spatial Profiling (DSP)  
 
Research tissue biopsies to be sent to the Curtis lab for processing 
21 August 2020  
Administrative changes, updates, and corrections  
31 August 2020  
Moved ondansetron from Appendix A to Appendix B. 
 
Corrections to the following: 
o 
Cohort 2 treatment group numbering as 4 to 6, not 3 to 5 (in Section 2.5). 
o 
Table 4 was mislabeled as Figure 1 (in section 2.5).  
o 
AE drug relationship are to be determined for infigratinib, tamoxifen (Cohort 1);  
fulvestrant (Cohort 2);  or palbociclib (Cohort 2), removing gemcitabine plus cisplatin 
(in Section 7.3). 
o 
REDCap will be used as data management, rather than OnCore (in Section 11.3). 
 
Administrative changes, updates, and corrections, including the addition of hyperlinks 
(not highlighted)  

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23 Sept 2020 
 
QED Therapeutics will be notified within 24 hours of learning of occurrence of an SAE, 
Suspected Unexpected Serious Adverse Reactions or pregnancy event (Sections 7.4 and 
7.5), instead of within 7 days. 
 
QED Therapeutics will supply the Case Report Forms for SAE and Pregnancy events to 
be reported to QED.  QED may be notified via by email (SAEintake@covance.com) using 
their provided CRFs or upload to electronic SAE portal (Sections 7.4 and 7.5). 
 
Instead of within 7 days, Suspected Unexpected Serious Adverse Reactions will be 
submitted to the FDA via an IND amendment within 15 days, and within 7 days for 
life-threatening conditions and death (Section 7.4), to match with the defined FDA 
guidance document on reporting. 
 
Eliminating pharmacokinetics assessments per QED Therapeutics, as the data collection 
is no longer required 
1 Oct 2020 
Removes Cohort 2 throughout 
9 Oct 2020 
The frequency of echocardiogram (ECHO) monitoring has been adjusted to Baseline, 
Cycle 2 Day 1, and End of Treatment. 
5 Apr 2021 
 
Dr. Jennifer Caswell-Jin is assuming the role of IND-holder, Principal Investigator, and 
Protocol Director. 
 
In Section 5.1.2, the allowed dosing time interval for infigratinib was revised to be 
24 ± 4 hour for consistency with the Pharmacy Manual (Section 7.0).  Clarified that 
infigratinib should be dosed in the morning when possible, with the understanding that 
there may be scheduling limitations at times (eg, delay in drug dispense on days with 
clinic visit). 
 
Updated Study Calendar (Section 9).  
o 
Added Complete Metabolic Panel as an optional assessment in the “Other 
Follow-up” timepoint. 
o 
Clarified in footnote 25 that only clinical indicated assessments need to be performed 
beyond 30 days.  
o 
Clarified that “End of Treatment/Withdrawal” should be 0 to 14 days from the 
decision made to discontinue study treatment (previously 0 to 14 days from 
final dose) to match footnote 23. 
 
Administrative changes, updates, and corrections 
28 Oct 2021 
 
Updates regulatory status information for infigratinib (Section 2.2)  
 
Updates Participant Selection and Enrollment Procedures (Section 3) to identify the 3rd 
reviewer of eligibility to be a member of the study team (eg, investigator or back-up study 
coordinator) 
 
Specifies / elaborates that the tamoxifen dosing window is 4 to 8 hours after infigratinib 
administration. 
 
Identifies QED Therapeutic’s partner, the Helsinn Group, throughout the protocol, 
including for data sharing / access (Section 11.2).  
 
Administrative changes, updates, and corrections.  
11 Nov 2021 
 
Updates safety reporting in sections 7.4 and 7.5, per manufacturer’s request 
 

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PROTOCOL SYNOPSIS 
TITLE 
A Phase 1B Study of Infigratinib in Combination with 
Tamoxifen in Hormone Receptor-Positive, HER2-Negative 
FGFR-Altered Advanced Breast Cancer 
STUDY PHASE 
1B 
INDICATION 
Advanced breast cancer, ER and/or PR+, HER2-.  Additional 
inclusion and exclusion criteria outlined in n Section 3.1 and 
Section 3.2. 
INVESTIGATIONAL 
PRODUCT  
Cohort 1:  Infigratinib + Tamoxifen  
PRIMARY 
OBJECTIVE 
Identify the recommended dose of infigratinib to be used in 
combination with the FDA-approved dose and schedule of tamoxifen. 
SECONDARY 
OBJECTIVES 
1. Estimate the incidence of treatment-emergent adverse events.  
2. Estimate the objective tumor response rate.  
3. Estimate progression-free survival.  
4. Estimate the clinical benefit rate. 
EXPLORATORY 
OBJECTIVES 
1. Establish viable tumor-derived organoid cultures to study in vitro 
tumor response to combination targeted therapy.  
2. Examine cell-free DNA from plasma across therapy to identify 
markers of therapeutic resistance.  
3. Examine tumor and microenvironmental changes across therapy 
using in situ proteomics. 
STUDY 
POPULATION 
Eligible subjects will be adults with ER-positive and/or PR-positive, 
HER2-negative breast cancer and radiographic evidence of 
metastatic disease, or locally recurrent unresectable disease.  
Women must be postmenopausal.  Due to length, the Eligibility 
Criteria are only presented in one instance.  See Section 3 
Participant Selection and Enrollment Procedures. 

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PROTOCOL SYNOPSIS 
TREATMENT 
SUMMARY 
Infigratinib is an oral selective FGFR1-3 inhibitor that has been tested 
in phase 1 and 2 clinical trials as a single agent.  This phase 1B 
study will assess the safety and tolerability of infigratinib in 
combination with the FDA-approved dose and schedule of tamoxifen 
(Cohort 1).  In Cohort 1, up to 3 dose levels of infigratinib will be 
evaluated:  125 mg;  100 mg;  and 75 mg, starting with the middle 
dose level (100 mg).  Infigratinib will be administered orally daily, 
3 weeks on, 1 week off.  Subjects will also be given tamoxifen 20 mg 
orally continuously.  If toxicity presents, individual subjects may 
dose-reduce by 25 mg infigratinib per reduction, to a lower limit of 
75 mg infigratinib (See Sections 2.5 and 6).  
Treatment with study drug will continue for 18 months or confirmed 
disease progression, unacceptable toxicity deemed probably-related 
to study drug, whichever occurs first, or other reasons outlined in 
Section 4.3.  
SAMPLE SIZE  
Up to 12 subjects evaluable (minimum 3), not including subject 
replacement.  
 

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SCHEMA  
  
Eligible patients
•
Metastatic or locally recurrent 
unresectable breast cancer
•
ER+ or PR+
•
HER2-
•
ECOG 0-2
Cohort 1
• Infigratinib 125 or 100 or 75 mg 
(3+3) orally daily 3 weeks on, 1 
week off, starting with 100 mg
• Tamoxifen 20 mg orally daily 
continuously
Primary endpoint:
Incidence of dose-limiting toxicities in 
cycles 1-2
Secondary endpoints:
Incidence of treatment-emergent 
adverse events
Objective tumor response
Progression-free survival
Durable clinical benefit
IC2 or 
 

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LIST OF ABBREVIATIONS AND DEFINITION OF TERMS 
AE 
Adverse event 
ASCO-CAP 
American Society of Clinical Oncology-College of American Pathologists 
CBC 
Complete blood count 
CLIA 
Clinical Laboratory Improvement Amendments 
CNS 
Central nervous system 
CR 
Complete Response 
CRF 
Case report/record form 
CTCAE 
Common Terminology Criteria for Adverse Events 
ctDNA 
Circulating tumor deoxyribonucleic acid 
CYP3A 
Cytochrome P450 3A 
DLT 
Dose-limiting Toxicity 
DSMB 
Data Safety Monitoring Board 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram  
ER 
Estrogen receptor 
FDA 
Food and Drug Administration 
FFPE 
Formalin-fixed paraffin-embedded 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast growth factor receptor 
FISH 
Fluorescence in situ hybridization 
HR 
Hormone receptor 
IC 
Integrative Cluster 
IHC 
Immunohistochemistry 
IRB 
Institutional Review Board 
LLN  
Lower limit of normal 
MAD 
Maximum administered dose 
METABRIC 
Molecular Taxonomy of Breast Cancer International Consortium 
MTD 
Maximum tolerated dose 
OCT 
Optical coherence tomography 
ORR 
Objective response rate  
PFS 
Progression-free survival  
PD 
Progressive Disease 
PR 
Progesterone receptor 
RECIST 
Response evaluation criteria in solid tumors 
RR 
Response rate 
SAE 
Serious adverse event 
SD 
Stable disease 
TCGA 
The Cancer Genome Atlas 
TEAE 
Treatment-emergent adverse event 

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1. 
OBJECTIVES  
1.1. 
Primary Objective  
 
Determine the maximum (no greater than 125 mg) dose of infigratinib used in 
combination with the FDA-approved dose and schedule of tamoxifen (Cohort 1), in terms 
of the number of dose-limiting toxicities observed in the first 2 cycles of therapy in 
subjects with hormone receptor-positive, HER2-negative advanced breast cancer.  
1.2. 
Secondary Objectives  
 
Estimate the incidence of treatment-emergent adverse events (serious and non-serious).  
 
Estimate the objective tumor response rate (ORR) in subjects with measurable disease.  
 
Estimate the progression-free survival (PFS).  
 
Estimate the durable clinical benefit rate.  
1.3. 
Exploratory Objectives  
 
Establish viable tumor-derived organoid cultures to study in vitro tumor response to 
combination targeted therapy  
 
Examine cell-free DNA from plasma across therapy to identify markers of therapeutic 
resistance  
 
Examine tumor and microenvironmental changes across therapy using in situ 
proteomics.  
2. 
BACKGROUND  
2.1 
Study Disease  
Advanced-stage, or metastatic, breast cancer remains incurable in the vast majority of cases, 
with an estimated median survival of approximately 3 years. 1  Hormone receptor-positive (HR+) 
disease is generally viewed as less aggressive than triple-negative or HER2+ breast cancer, but 
recent data from our group suggest that a subset of HR+ breast cancers are highly aggressive, 
exhibiting recurrence rates higher than triple-negative breast cancers or HER2+ breast cancers 
in the era prior to trastuzumab. 2  These high-risk HR+ breast cancer subtypes classify as one of 
four integrative clusters (ICs or “IntClusts”), each defined by a characteristic gene amplification 
as follows. 2,3  
 
IC1, defined by RPS6KB1 (17q23)  
 
IC2, defined by FGF3/4/19 and CCND1 (11q13).  IC2 is associated with a poor 
prognosis amongst ER-positive tumors, with a 10-year disease-specific survival rate of 
only about 50%.  
 
IC6, defined by FGFR1 (8p12).  IC6 is associated an intermediate prognosis and a 
10-year disease-specific survival of around 60%.  
 
IC9, defined by MYC (8q24)  

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Notably for IC2, FGF3/4/19 and CCND1 are tightly located within the 11q13 genomic region and 
are almost universally amplified together as a cassette in breast cancer; 2,3 thus amplification of 
either is generally consistent with amplification of both.  FGFR1 amplifications occur in 
approximately 10% and CCND1/FGF3/4/19 amplifications in approximately 6% of early-stage 
ER+/HER2- breast cancers; 2,3  proportions are likely higher in advanced-stage breast cancer 
given the higher rates of recurrence.  While these characteristic amplifications are almost 
universally present within tumors classifying as the relevant integrative subtype, the converse is 
not true:  in the METABRIC cohort, approximately one quarter of HR+/HER2- tumors that carry 
the CCND1 amplification classify as integrative subtype 2, and approximately half of those that 
carry the FGFR1 amplification classify as integrative subtype 6.  It is plausible that these 
amplifications may be passenger events rather than driver events in the tumors that do not 
classify as the relevant integrative subtypes.  
The current treatment paradigm for these tumors does not include testing for integrative subtype 
or targeting the subtype-defining gene amplifications.  Metastatic HR+/HER2- breast cancer is 
typically treated in the first line with endocrine therapy (most commonly an aromatase inhibitor), 
often in combination with a CDK4/6 inhibitor 4-6; in the second line, endocrine therapy is 
typically used again, either alone, in combination with a CDK4/6 inhibitor if not used in the 
first-line 7-9, or in combination with an mTOR inhibitor. 10  After progression on two lines of 
endocrine therapy, the disease is often considered endocrine-resistant and treated with 
sequential single-agent chemotherapies until progression. 11  There is an urgent need to find 
more effective therapies for HR+/HER2- metastatic breast cancer, and we hypothesize that 
targeting the FGFR axis in tumors that may be driven by FGFR signaling, as defined either by 
amplification or integrative subtype, may improve outcomes for patients with these tumor types.  
This study evaluates the safety and efficacy of infigratinib, an FGFR 1 to 3 inhibitor, in 
combination treatment for eligible HR+/HER2- breast cancer patients whose tumors classify as 
the IC2 or IC6 subtypes (see criterion 2 in Section 3.1).  As noted above, IC2 and IC6 are 
associated with alternations in FGF and/or FGFR. 
2.2 
Study Agent - Infigratinib  
2.2.1 Regulatory status:  Infigratinib (BGJ398) was approved by FDA as Truseltiq pursuant the 
Accelerated Approval regulations on 28 May 2021 for the indication of previously-treated, 
unresectable, locally-advanced or metastatic cholangiocarcinoma with a fibroblast growth factor 
receptor 2 (FGFR2) fusion or other rearrangement, in adults.  
2.2.2 Mechanism of action:  Infigratinib (BGJ398) is an orally-bioavailable, potent, selective 
inhibitor of the fibroblast growth factor receptors (FGFR 1-3, but 60-fold less active on FGFR4).  
The FGFR family of receptor tyrosine kinases consists of four members (FGFR1-4), which serve 
as the high affinity receptors for 22 FGF ligands.  These growth factors control cell proliferation, 
migration, angiogenesis, apoptosis, and differentiation.  A subfamily of FGF ligands including 
FGF19 additionally act as endocrine hormones. 12  
2.2.3 Pharmacokinetics:  The pharmacokinetics of infigratinib was investigated in mouse, rat, 
and dog after oral and intravenous administration.  In all 3 species, the clearance and the 

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volume of distribution at steady state was high.  The terminal elimination half-life in plasma was 
9.3 hours in mouse, 4.5 hours in rat, and 3.1 hours in dog.  The absolute bioavailability was 
2.4% in dog and approximately 30% in mouse and rat.  In oncology patients, the mean terminal 
elimination half-life on Day 1 was 3 to 7 hours; accumulation was observed with daily dosing at 
doses ≥ 60 mg, with mean accumulation ratio ranging from 3 to 8 on Day 15 and Day 28.  
2.2.4 Metabolism:  The in vitro metabolism of [14C]-infigratinib was studied in hepatocytes from 
rat, dog, and human.  Two main biotransformation pathways were observed in all species 
investigated:  N-oxidation to BQR917 (predominant pathway in dog) and D-deethylation to 
BHS697 (predominant pathway in human) (in rat, the two pathways were of similar importance).  
Additional biotransformation pathways included glutathione conjugation, O-demethylation, 
hydrolysis, C-hydroxylation, and others.  The in vivo metabolism of [14C]-infigratinib was studied 
in rats and dogs, and of unlabeled infigratinib in dogs and humans.  13 metabolites were 
identified and semi-quantified in human plasma with the cleavage product CQM157 the most 
abundant one; all except 1 minor metabolite were also detected in rat and/or dog plasma after 
oral dosing.  
2.2.5 Major route of elimination:  The major route of elimination in rats and dogs dosed orally or 
intravenously with [14C]-infigratinib was the feces.  Urinary excretion amounted to ≤ 6.5% of 
dose.  In rats, 2.6% of the dose was recovered in bile and 0.16% in urine.  In dogs, 1.5% of the 
dose was recovered in urine.  
2.2.6 Potential for drug interactions:  Infigratinib is likely subject to a major intestinal metabolic 
first-pass effect via cytochrome P450 3A (CYP3A), and consequently, concomitant use with 
CYP3A inhibitors or inducers is expected to have clinical implications.  Accordingly, strong 
inhibitors or inducers or CYP3A4, as well as narrow therapeutic index substrates of CYP3A4, 
are prohibited on this study (Appendix A);  moderate inhibitors or inducers of CYP3A4, as well 
as sensitive CYP3A substrates, are to be used with caution on this study (Appendix B).  
2.2.7 Safety in animal studies:  Repeated-dose toxicity studies were performed in rat and dog 
and are summarized below:  
 
Infigratinib increased serum fibroblast growth factor 23 (FGF23) and serum calcium 
and/or phosphorus, associated with ectopic mineralization (mostly lungs and kidneys) 
and bone growth plate thickening and increased trabecular bone.  Generally these 
changes were either reversible or showed a trend toward reversibility.  FGF23 is 
secreted by osteocytes and acts on the kidney to decrease reabsorption and increase 
excretion of phosphorus; it is hypothesized that inhibition of the FGF23/FGFR pathway 
leads to the observed phosphorus elevation with infigratinib.  
 
Vasculopathy was observed in rat studies at higher dose levels; in dog studies, this was 
observed only in the gallbladder.  
 
In rats and dogs increases in alanine aminotransferase, aspartate aminotransferase, 
and/or decreases in glucose were noted.  These changes were either without correlative 
histopathological findings or (in dogs at high doses) with minimal liver cell necrosis as 
well as bile ducts hypertrophy/hyperplasia.  

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 
There was an accumulation of foam cell aggregates in the lung.  
 
Decreases in reticulocyte, platelet, total white blood cells, neutrophils, and lymphocytes 
as well as bone marrow hypocellularity were noted at higher doses.  
 
Cornea opacity (trend towards reversibility) as well as epithelial thinning for the tongue 
and nasal cavity (reversible) as well as incisors (not reversible) were observed.  
 
Longer hair/fur was noted starting at approximately week 8 and continuing through 
recovery.  In dogs, reversible atrophy of the sebaceous gland was seen.  
2.2.8 Efficacy in animal studies:  In vivo studies in mice and rats have shown that significant 
tumor growth inhibition and tumor regression can be achieved with infigratinib in a variety of 
FGFR-dependent tumor xenograft models, at well tolerated doses when given orally once per 
day.  
2.2.9 Safety in humans:  Infigratinib has been evaluated in cancer patients in two phase 1 
studies in patients with advanced solid malignancies (NCT01697605 and NCT01004224) and 
three phase 2 studies (NCT01975701 in glioblastoma; NCT02150967 in cholangiocarcinoma, 
and NCT02160041 in solid tumors and/or hematologic malignancies).  It has also been 
evaluated in combination with the PI3K alpha specific inhibitor BYL719 in a phase 1b study 
(NCT01928459), a combination no longer being pursued.  Approximately 650 subjects (healthy 
adult volunteers and adult patients with malignancies) have received infigratinib. 
Dose-limiting toxicities:  There were no DLTs reported in NCT01697605.  In NCT01004224, 
where infigratinib was given as a single agent, there was one DLT in the 100 mg cohort (out of 
6 subjects) (Grade 3 AST/ALT elevation), one DLT in the 125 mg cohort (out of 8 subjects) 
(hyperphosphatemia greater than 14 days despite adequate therapy), and 2 DLTs in the 150 mg 
cohort (out of 6 subjects) (one Grade 3 AST/ALT elevation and one Grade 1 corneal toxicity).  
The maximum tolerated dose was determined to be 125 mg daily.  The 3 weeks on / 1 week off 
schedule was implemented based on observations of the timing and duration of drug 
interruptions during Cycle 1 necessitated by episodes of hyperphosphatemia:  median time to 
drug interruption during continuous dosing was 22 days and median duration of the interruption 
was 7 days.  
Treatment-emergent adverse events:  Table 1 summarizes adverse events, regardless of 
relationship, to infigratinib as a single agent at the maximum tolerated dose of 125 mg, 
3 weeks on, 1 week off (N = 433 subjects), and Table 2 summarizes Grade 3 to 4 adverse 
events.  The on-target effects on calcium-phosphorus homeostasis result in the observed 
increases in calcium (13.4% any grade, 3.2% Grade 3-4), phosphorus (61.2% any grade, 
6.7% Grade 3 to 4), and creatinine (23.8% any grade).  These are not associated with clinical 
symptoms and in general have been mild to moderate in severity, manageable, and reversible.  
Guidelines for management of on-target hyperphosphatemia have been implemented.  
Ocular adverse events (corneal or retinal) occur in about 50% of subjects, but in general are 
mild to moderate in severity and reversible: for example, Grade 1 to 2 dry eye was reported in 
21.5% and Grade 1 to 2 blurry vision in 9.9%.  Grade 3 ocular events occurred in 3% of 
subjects; no Grade 4 ocular events have been reported.  Grade 3 adverse events of cataract 
(N = 3, 0.7%), visual impairment (N = 2, 0.5%), and keratitis (N = 2, 0.5%) were the events that 

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occurred in more than one subject; others were reported once.  Adverse events of 
blurred vision, visual impairment, and keratitis led to study drug discontinuation for N = 2, 0.5% 
subjects each.  Since the cornea and retina were identified from preclinical safety studies as a 
potential target organ of interest, protocol-mandated ophthalmologic examinations have been 
performed routinely and frequently throughout studies.  
Subjects have been monitored for potential QT prolongation: N = 3 (0.7%) of subjects have had 
a new QTc value > 500 msec, N = 4 (1.0%) have had a QTcF change of > 60 msec, and 
N = 63 (15.0%) have had a QTcF change > 30 and ≤ 60 msec.  None of these events was 
considered serious nor led to treatment withdrawal or dose reduction/interruption.  Subjects 
have also been monitored for potential decrease in ventricular ejection fraction by 
echocardiogram or multi-gated acquisition.  N = 6 (1.4%) of subjects had a Grade 2 abnormality 
(no Grade 3-4 events), which did not lead to study drug discontinuation.  
Other notable adverse events include stomatitis (34.9%) and alopecia (26.8%).  

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Table 1: Adverse events occurring in ≥ 10% of adult oncology subjects  
treated with infigratinib monotherapy 
 

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Table 2:  Grade 3 or 4 adverse events occurring in ≥ 1.0% of  
adult oncology subjects treated with infigratinib monotherapy 
 
Serious adverse events:  Serious adverse events (SAEs) to single-agent infigratinib are 
summarized in Table 3.  The most common SAEs reported (approximately 2%) were pyrexia, 
dyspnea, general physical health deterioration, sepsis, vomiting, abdominal pain, anemia, 
hypercalcemia, and pneumonia.  Most of the SAEs would be expected for oncology subjects 
and for the indications under study.  

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Table 3:  SAEs occurring in 0.5% of adult oncology subjects  
treated with infigratinib monotherapy 
 
Deaths:  Of the 433 subjects treated with infigratinib monotherapy, N = 45 (10.4%) have died 
on-treatment.  Most deaths were deemed related to study indication / disease progression.  
One death due to cardiac arrest and 1 death due to intestinal ischemia were considered to be 
related to study drug.  

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2.2.10 Efficacy in humans:  In NCT01004224, a phase 1 dose-escalation study, 4 of 36 subjects 
with non-small cell lung cancer and 3 of 8 subjects with urothelial carcinoma achieved partial 
response (Figure 1). 13  Of the 26 subjects with metastatic breast cancer (21 with FGFR1 
amplification), 4 had reduced tumor burden but did not achieve partial response (3 with FGFR1 
amplification). 13  In addition, of the 37 additional subjects with urothelial carcinoma, 
12 achieved partial response and 1 achieved complete response (CR). 14  In NCT02150967, 
15 of 59 subjects achieved partial response.  
  
Figure 1.  Waterfall plots of best change from baseline in the size of target lesions for patients treated at 
least 100 mg infigratinib.  From Nogova et al (2016) JCO.  
Subsequently, in a phase 2 study of infigratinib 125 mg orally daily 3 weeks on / 1 week off in 
N = 67 subjects with metastatic urothelial carcinoma with FGFR3 alterations, an overall 
response rate of 25.4% and a disease control rate of 64.2% was observed. 14  In another 
phase 2 study of infigratinib 125 mg orally daily 3 weeks on / 1 week off in N = 61 subjects with 
advanced or metastatic cholangiocarcinoma containing FGFR2 fusions or other FGFR 
alterations, an overall response rate of 14.8% and a disease control rate of 75.4% was 
observed. 15  
2.2.11 Additional information:  Further details are available in the Investigator’s Brochure, which 
is included with the IRB submission.  This study will be conducted under IND 147595 
(pre-assigned).  Infigratinib was approved by FDA as Truseltiq pursuant the Accelerated 
Approval regulations on 28 May 2021 for the indication of previously-treated, unresectable, 
locally-advanced or metastatic cholangiocarcinoma with a fibroblast growth factor 
receptor 2 (FGFR2) fusion or other rearrangement, in adults.  

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2.3 
Rationale  
2.3.1 Rationale for combination of infigratinib with endocrine therapy:  An analysis of 
1,980 subjects with molecular data and 20 years of follow-up was recently performed.  In this 
work, it was found that tumors classifying as integrative subtype 2 (characterized by the 
11q13/14 amplification including FGF3/4/19 and accounting for approximately 5% of all 
HR+/HER2- breast tumors) or integrative subtype 6 (characterized by the 8p12 amplification 
including FGFR1 and account for approximately 5% of all HR+/HER2- tumors) exhibit an 
exceedingly high risk of distant relapse up to 20 years post-diagnosis (median 42 to 55%). 2  
Substantial improvement in progression-free survival has been seen in HR+/HER2- metastatic 
breast cancer with the addition of CDK4/6 inhibition to endocrine therapy, 4-9 but virtually all 
tumors will eventually progress, leading to breast cancer-related death.  The current treatment 
paradigm of metastatic HR+/HER2- FGF(R)-altered breast cancer does not include inhibition of 
the FGFR pathway.  As a single agent in humans, infigratinib has shown some antitumor activity 
in pre-treated metastatic breast cancers with FGFR1 amplification, but not achieving the level of 
a partial response (Figure 1). 13  Breast tumors with FGF(R) pathway alterations are in urgent 
need of more effective therapies, and we propose that combining infigratinib with endocrine 
therapy could achieve this goal.  
Accumulating preclinical and clinical data suggests that FGFR1 amplification may drive 
endocrine therapy resistance in breast cancer. 16,17  For example, FGFR1-amplified cell lines 
showed resistance to 4-hydroxytamoxifen, which was reversed by RNA silencing of FGFR1. 18  
ER+/FGFR1-amplified tumors treated with letrozole prior to surgery did not show decreases in 
proliferation as measured by Ki67 as is typically seen in sensitive tumors, and this primary 
resistance to aromatase inhibition appeared to be mediated by an upregulation of FGFR1 and 
FGF ligand expression allowing persistent activation of estrogen response. 17  Similarly, another 
study found that time to progression on first-line endocrine therapy was shorter in 
FGFR1-amplified ER+ metastatic breast cancers than in ER+ metastatic breast cancers that 
were not FGFR1-amplified, a difference not seen for first-line chemotherapy. 19  Combining 
lucitanib (a non-selective FGFR inhibitor) with fulvestrant improved growth inhibition of 
ER+/FGFR1-amplified cell lines and patient-derived xenografts. 17  Another study validated the 
finding of intrinsic endocrine therapy resistance in ER+/FGFR1-amplified primary tumors, and 
also reported a similar phenomenon for tumors with CCND1/FGF3/4/19 amplification. 20  
In sum, these data provide a rationale for combining infigratinib with endocrine therapy may 
overcome the intrinsic endocrine therapy resistance of ER+/FGFR1-amplified or 
ER+/CCND1/FGF3/4/19-amplified tumors.  For those subjects whose tumors have 
demonstrated primary or secondary resistance to endocrine therapy (ie, by progression on an 
aromatase inhibitor or fulvestrant), adding FGFR inhibition may allow these tumors to sensitize 
to endocrine therapy.  
Notably, FGFR inhibition in combination with fulvestrant has been attempted previously in 
breast cancer, in a phase 2, randomized, placebo-controlled study of dovitinib in combination 
with fulvestrant in postmenopausal subjects with hormone receptor-positive, HER2-negative 

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breast cancer that progressed during or after prior endocrine therapy. 21  This study of 
N = 97 subjects showed median progression-free survival of 5.5 months in the dovitinib arm and 
5.5 months in the placebo arm (HR 0.68) in the overall cohort.  Findings were not significantly 
different in the FGF pathway-amplified subgroup (N = 31):  median PFS 10.9 months in the 
dovitinib arm and 5.5 months in the placebo arm (HR 0.64).  However, dovitinib is one of several 
non-selective multi-kinase inhibitors with greater impact on VEGFR than FGFR (another 
example is lucitinib), and subsequent studies have strongly suggested that these multi-kinase 
inhibitors may not effectively inhibit the FGFR pathway in subjects. 22,23  The efficacy of FGFR 
inhibition is most established thus far in FGFR-altered (most commonly FGFR3-mutated) 
advanced urothelial carcinoma, the setting for which the selective FGFR inhibitor erdafitinib 
received FDA approval as Balversa on 12 April 2019 (Accelerated Approval).  Dovitinib was 
studied in this setting as well in a phase 2 study that treated N = 12 FGFR3-mutated and N = 31 
FGFR3-wild-type advanced urothelial cancer subjects. 24  In this study, the ORR in the 
FGFR3-mutated subgroup was 0% (3.2% in the wild-type subgroup).  Also, and importantly, no 
hyperphosphatemia was observed in these subjects, nor in other subjects who have been 
treated with dovitinib.  Hyperphosphatemia is a key on-target effect of FGFR inhibition and its 
absence with dovitinib and other multi-kinase inhibitors suggests poor FGFR inhibition. 22,23  
Conversely, in the phase 2 study of FGFR-altered advanced urothelial cancer that led to 
erdafitinib’s approval, the ORR was 32% (28 of 87 subjects) with 69% experiencing 
hyperphosphatemia, 25 and in a similar phase 2 study of infigratinib, the ORR was 25% 
(16 of 67 subjects) with 50% experiencing hyperphosphatemia. 14  Dovitinib is no longer widely 
considered an effective FGFR inhibitor, 22,23 while the new generation of selective FGFR 
inhibitors are rapidly gaining ground in establishing their efficacy in FGFR-altered 
cancers. 14,15,25  We therefore believe it is time to assess the hypothesis that selective FGFR 
inhibition in combination with endocrine therapy may have a benefit for FGFR-altered hormone 
receptor-positive advanced breast cancer patients.  
2.3.2 Comparison to other active trials: To our knowledge, there are 2 active clinical trials 
examining FGFR inhibition in combination with endocrine therapy in metastatic breast cancer, 
one of which also adds CDK4/6 inhibition.  NCT04024436 opened October 2019 and is a 
nonrandomized phase 2 study will administer TAS-120 (Taiho) in combination with fulvestrant to 
4 cohorts, 3 of which will have an FGFR2 amplification and 1 of which will have a high-level 
(ratio to centromere ≥ 5) FGFR1 amplification.  Neither of these studies will examine the efficacy 
of FGFR inhibition in combination with endocrine therapy in tumors harboring amplification of 
the ligand (FGF3; integrative subtype 2).  The hypothesis driving the present trial is that the 
unique drivers identified via integrative subtyping (a subset of tumors with FGFR1 amplification 
classifying as integrative subtype 6; and a subset of tumors with FGF3 amplification classifying 
as integrative subtype 2) will be uniquely sensitive to FGFR inhibition.  
2.3.3 Rationale for dose of tamoxifen:  The dose and schedule selected for tamoxifen 
(20 mg/day by mouth continuously) is FDA-approved for the treatment of ER+ metastatic breast 
cancer.  

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2.4 
Screening Tumor Sequencing Assays  
Potential subjects will be eligible if their tumor classifies as integrative cluster 2 (IC2) or 6 (IC6) 
based on the results of the FoundationOne (F1CDx) FDA-approved assay.  There are 
11 validated integrative subtypes or clusters of breast cancer, defined initially from the 
METABRIC cohort based on the integration of genomic copy number alterations and 
transcriptional profiles. 3  Our recent study examining 20 years of clinical follow-up from 
1,980 subjects in the initial METABRIC cohort revealed substantial variability in the risk of 
relapse amongst HR+/HER2- subjects. 2  In particular, integrative subtypes 1, 2, 6, and 9 
exhibited exceedingly high (median 42 to 55%) risk of distant relapse up to 20 years 
post-diagnosis.  Each of these integrative subtypes is characterized by distinct copy number 
amplification events and concomitant over-expression of candidate driver genes:  integrative 
subtype 2 has the FGF3/FGF4/FGF19, CCND1 (11q13/14) amplification and integrative 
subtype 6 has the FGFR1 (8p12) amplification.  While these characteristic amplifications are 
almost universally present within tumors classifying as the relevant integrative subtype, the 
converse is not true:  only approximately one-quarter of ER+/HER2- tumors that carry the 
CCND1/FGF3/4/19 amplification classify as integrative subtype 2, and approximately one-half of 
ER+/HER2- tumors that carry the FGFR1 amplification classify as integrative subtype 6. It is 
plausible that these amplifications may be passenger events rather than driver events in the 
tumors that do not classify as the relevant integrative subtypes.  Using additional information 
from targeted sequencing panels can improve the accuracy of integrative cluster classification, 
and we hypothesize better delineate in which tumors the FGFR pathway is the oncogenic driver 
than the simple presence of the amplification. 2,3  Thus, subjects will be eligible if their tumor’s 
F1CDx results are consistent with integrative cluster 2 or 6, per the classifier.  The classifier was 
developed to predict integrative cluster classification from the copy number values and 
mutational status of the genes on the F1CDx panel in two large cohorts of breast tumors, 
METABRIC 3 and The Cancer Genome Atlas 28.  This classifier will be applied to the integer 
copy number values and gene mutation calls generated by the F1CDx assay and analysis. 
2.5 
Study Design  
 
The primary purpose for this study is treatment.  The protocol is designed to evaluate 
one or more interventions for treating a disease, syndrome, or condition.  
 
The interventional model is Sequential.  
 
The number of intervention arms is up to 3.  
 
The study will be not be masked (not blinded).  
 
The study will be not be randomized.  
This is a phase 1b study evaluating the safety and tolerability of infigratinib.  Cohort 1 will utilize 
the combination of tamoxifen and infigratinib.  We anticipate that this combination may play a 
role in the future development of infigratinib for hormone receptor-positive breast cancer, 
necessitating the establishment of their safety.  For example, tamoxifen and infigratinib might be 
used in the early-stage, (neo)adjuvant setting as well as the late-stage, metastatic setting. 

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In Cohort 1, up to 3 dose levels of infigratinib may be evaluated (125 mg;  100 mg;  and 75 mg) 
in combination with tamoxifen.  This pilot study is a necessary step for the future development of 
infigratinib in combination with tamoxifen and will serve as a safety run-in evaluation for a 
follow-up study.  For this cohort, a 3 + 3 design will be employed starting at 100 mg, and 
allowing subjects who start at 100 mg to escalate to 125 mg (see Section 12.4). 
2.6 
Correlative Studies Background 
2.6.1 Organoid cultures:  Three-dimensional organoid cultures established from viable tumor 
cells have the potential to re-capitulate in vitro subject- and tumor-specific phenotypes, enabling 
the study of drug response and tumor evolution in the lab. 32-34  Tumor organoid cultures can be 
established as a renewable source of tissue for in vitro and in vivo experimentation; they are 
amenable to high-throughput drug screens and complementing xenograft-based approaches.  
Organoid culture can be used to evaluate the efficacy of novel therapeutic agents in specific 
genetic contexts.  It is planned to establish organoids from tumors in this study, classifying as 
integrative subtypes 2 and 6, allowing testing of novel drug combinations to improve response 
and overcome resistance to FGFR inhibition in these high-risk subgroups.  Furthermore, as 
these organoids will be treated in vitro with the same agents that the study subjects from whose 
tumors they were derived will be, we will be able to compare response between the in vitro and 
subjects.  We will also be able to compare the genomic alterations that arise with treatment in 
subjects (Section 2.6.2) with those that arise with treatment in the organoids.  These 
experiments may inform our understanding of genomic determinants of sensitivity and 
resistance to FGFR inhibition, as well as the optimal combinations of therapies to produce 
response in FGFR-altered breast tumors.  
2.6.2 Cell-free DNA analyses:  Cell-free DNA is believed to be representative of the 
heterogeneity present even in micro-metastatic lesions. 35  Thus, it may better capture the 
spectrum of subclonal populations with the potential to grow in response to therapy than serial 
tumor biopsies.  Furthermore, it has been shown that cell-free DNA sequencing can detect and 
characterize clonal dynamics in metastatic breast cancer. 36-38  It is planned to collect blood from 
subjects prior to initiation of study drug, after the first 2 weeks of therapy, and at time of 
confirmed progression.  The blood samples will be separated into plasma and buffy coat and 
banked.  Sequencing (eg, whole-exome or whole-genome) of the cell-free DNA extracted from 
these banked plasma samples will allow us to identify novel mutations or copy number changes 
that appear at time of progression in subjects who initially responded, as well as to compare 
baseline genomic changes between responders and non-responders.  The banked buffy coat 
samples will allow us to identify somatic variants that act as driver mutations and compare them 
to a matched normal sample through tumor-normal whole-genome sequencing.  Furthermore, 
we can cross-reference these findings with genomic findings in the organoid models 
(Section 2.6.1).  These analyses may allow us to identify genetic mechanisms of resistance to 
the study drug and/or endocrine therapy.  
2.6.3 Proteomic profiling:  Proteomic changes may be examined in tumor cells and the 
surrounding microenvironment in situ to delineate compensatory signaling pathways and 
mechanisms of response/resistance to the evaluated targeted agents.  Paired pre- and 

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post-treatment tissue samples from the trial may be profiled on the Nanostring GEOMx Digital 
Spatial Profiling (DSP) platform (Research Use Only) 39,40 or with mutiplexed ion beam 
imaging (MIBI). 41-43  There is growing evidence that functional heterogeneity in the tumor and 
microenvironment contribute to treatment response, highlighting the importance of spatially 
resolved approaches such as DSP.  DSP enables geographic and phenotypic selection of tissue 
regions – for example, those that are enriched for pancytokeratin-positive tumor cells.  
Molecular changes observed with treatment may inform intelligent combinations of therapy in 
the future to overcome primary resistance or enhance treatment response.  
3. 
PARTICIPANT SELECTION AND ENROLLMENT PROCEDURES  
Inclusion and Exclusion Criteria are provided on Participant Eligibility Checklist following.  This 
document may be extracted from this document for use in screening potential subjects.  
The Participant Eligibility Checklist in the following subsection must be completed in its entirety 
for each subject prior to registration.  The Participant Eligibility Checklist may be extracted from 
this document for use in screening potential subjects.  The completed, signed, and dated 
checklist must be retained in the subject’s study file, and the study’s Regulatory Binder.  
Screening results will be collectively documented on the Study Participant Log.  
Pursuant to Stanford Medicine SOP “Confirmation of Participant Eligibility in Clinical Trials,” the 
treating Physician (investigator);  the Study Coordinator;  and a third reviewer from the study 
team (eg, investigator or back-up study coordinator) will verify that the subject’s eligibility is 
accurate; complete; and legible in source records.  A description of the eligibility verification 
process should be included in the EPIC or other Electronic Medical Record progress note.  
 

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Participant Eligibility Checklist  
I. 
Protocol Information  
Protocol Title: 
A Phase 1B Study of Infigratinib in Combination with Tamoxifen in 
Hormone Receptor-Positive, HER2-Negative, FGFR-Altered Advanced 
Breast Cancer 
eProtocol number: 
OnCore number: 
IRB-53650  
BRS0113  
Principal Investigator 
[per 21CFR§312.3(b)]: 
Jennifer L Caswell-Jin, MD 
II. 
Subject Information  
Subject name / Unique ID: 
/ 
Gender  
  Male   
 Female   
3.1 
Inclusion Criteria 
Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
1. History of biopsy-proven ER-positive and/or 
PR-positive, HER2-negative breast cancer and 
radiographic evidence of metastatic disease, or 
locally recurrent unresectable disease.  ER-positivity 
and PR-positivity are defined as ≥ 1% cells staining 
positive by immunohistochemistry.  HER2-negativity 
is defined by IHC or FISH, per ASCO-CAP 2018 
guidelines 
 
 
 
2. Cancer subtype indicative of alterations to the 
fibroblast growth factor ligand or receptor 
(FGF/FGFR alteration):  Predicted integrative 
(IntClust) subtype classification of IC2 or IC6 
according classifier on targeted sequencing data 
from FoundationOne.  
 
 
 

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Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
3. Evaluable or measurable disease. 
Cohort 1 only:  Evaluable or measurable disease, 
as defined by RECIST v1.1.  Bone-only disease is 
acceptable. 
 
 
 
4. ≥ 18 years old  
 
 
 
5. Eastern Cooperative Oncology Group (ECOG) 
performance status 0 to 2 
 
 
 
6. Prior cancer therapy (except for endocrine therapy, 
denosumab, or bisphosphonates) must be 
discontinued for 2 weeks prior to initiation of study 
drugs.  Recovery from adverse events of previous 
cancer therapies to baseline or Grade 1 except for 
alopecia or stable Grade 2 neuropathy.  
Radiotherapy must also be completed at least 
2 weeks prior to initiation of study drugs  
 
 
 
7. Absolute neutrophil count (ANC) ≥ 1,000/mm3  
 
 
 
8. Platelets ≥ 75,000/mm3  
 
 
 
9. Hemoglobin ≥ 9.0 g/dL 
 
 
 
10. Total bilirubin ≤ 1.8 mg/dL (unless documented 
Gilbert’s disease) 
 
 
 
11. Aspartate aminotransferase (AST) and alanine 
aminotransferase (ALT) < 90 U/L  
 
 
 
12. Estimated glomerular filtration rate (GFR) 
≥ 45 mL/min  
 
 
 
13. Phosphorus between 2.5 and 4.5 mg/dL, inclusive  
 
 
 
14. Total corrected (for albumin) serum calcium 
between 8.5 and 10.5 mg/dL, inclusive 
 
 
 
15. Amylase < 200 U/L 
 
 
 
16. Lipase < 120 U/L 
 
 
 
17. Ability to understand and the willingness to sign a 
written informed consent document 
 
 
 

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Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
18. Agrees to take sevelamer, if indicated, and has no 
contraindications to use of this medication (that is: 
known hypersensitivity to sevelamer or component 
of the formulation; bowel obstruction; active bowel 
mucosal injury such as ulcerative colitis or 
gastrointestinal bleeding). 
 
 
 
19. Agrees to follow low-phosphate diet, if indicated  
 
 
 
20. Able to swallow and retain oral medication 
 
 
 
21. Women must be postmenopausal, defined as 
(at least one of):   
• ≥ 60 years of age; 
• amenorrhea for at least 24 months; 
• amenorrhea for at least 12 months with  
  serum estradiol < 20 pg/mL; 
• prior bilateral oophorectomy;  
  OR  
• treatment with a luteinizing hormone (LH)- 
  releasing hormone agonist (such as  
  goserelin acetate or leuprolide acetate) initiated  
  at least 28 days prior to study enrollment.   
 
 
 
22. Women being treated with a LH-releasing agonist 
but who are otherwise of childbearing potential (did 
not undergo total hysterectomy or bilateral tubal 
ligation at least 6 weeks before first dose of study 
drug) must have a negative pregnancy test within 
7 days of the first dose of study drug. 
 
 
 
23. Women who are being treated with an LH-releasing 
agonist but are otherwise of childbearing potential 
must agree to use barrier contraception or an 
intrauterine device while taking study drug and for 
3 months following their last dose of study drug.  
Alternatively, total abstinence is acceptable if 
preferred by the subject.  
 
 
 

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Prospective Participant Must MATCH  
ALL these Inclusion Criteria to be Eligible 
Yes No 
Supporting 
Documentation * 
24. Sexually-active men must agree to 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 during intercourse 
with a male partner to prevent delivery of the drug 
via seminal fluid.  
 
 
 
3.2 
Exclusion Criteria 
Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes No 
Supporting 
Documentation * 
1. History of another primary malignancy within 3 years 
except adequately treated in situ carcinoma of the 
cervix or non-melanoma carcinoma of the skin or 
any other curatively treated malignancy that is not 
expected to require treatment for recurrence during 
the course of the study.   
 
 
 
2. Neurologic symptoms related to central nervous 
system metastases requiring increasing doses of 
corticosteroids.  Note that subjects with central 
nervous system metastases ARE eligible if they are 
on a stable corticosteroid dose for at least 2 weeks 
preceding study entry. 
 
 
 
3. 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.   
 
 
 

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Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes No 
Supporting 
Documentation * 
4. Current evidence of extensive tissue calcification 
including, but not limited to, the soft tissue, kidneys, 
intestine, myocardium, and lung with the exception 
of calcified lymph nodes, minor pulmonary 
parenchymal calcifications, and asymptomatic 
coronary calcification.   
 
 
 
5. Impairment of gastrointestinal (GI) function or GI 
disease that may significantly alter the absorption of 
oral infigratinib (eg, ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, small bowel resection). 
 
 
 
6. Current evidence of endocrine alterations of 
calcium/phosphate homeostasis, eg, parathyroid 
disorders, history of parathyroidectomy, tumor lysis, 
or tumoral calcinosis. 
 
 
  
7. Currently receiving or planning during study 
participation to receive 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.  See Appendix A for 
a list of prohibited concomitant medications and 
supplements. 
 
 
 
8. Has 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. 
 
 
 
9. Have used amiodarone within 90 days prior to first 
dose of study drug. 
 
 
 
10. Has 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.  See Appendix A for a list of 
prohibited concomitant medications and 
supplements. 
 
 
 

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Prospective Participants Must NOT Match  
ANY of These Exclusion Criteria  
Yes No 
Supporting 
Documentation * 
11. Has used calcium or vitamin D within 3 days prior to 
first dose of study drug.  Calcium supplementation 
may subsequently be used as clinically indicated 
(for hypocalcemia) on study. 
 
 
 
12. Have clinically significant cardiac disease including 
any of the following:  
a. Congestive heart failure requiring treatment 
(New York Heart Association Grade ≥ 2), left 
ventricular ejection fraction (LVEF) < 50% or 
local lower limit of normal as determined by 
multiple gated acquisition (MUGA) scan or 
echocardiogram (ECHO), or uncontrolled 
hypertension (refer to the European Society of 
Cardiology and European Society of 
Hypertension guidelines [Williams et al., 2018])  
b. Presence of Common Terminology Criteria for 
Adverse Events (CTCAE) v5.0 Grade ≥ 2 
ventricular arrhythmias, atrial fibrillation, 
bradycardia, or conduction abnormality  
c. Unstable angina pectoris or acute myocardial 
infarction ≤ 3 months prior to first dose of study 
drug  
d. Corrected QT interval-Fredericia (QTcF) > 470 
msec (males and females).  Note:  If the QTcF is 
> 470 msec in the first electrocardiogram (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 
 
 
 
13. Have had a recent (≤ 3 months) transient ischemic 
attack or stroke.   
 
 
 
14. Pregnant or nursing  
 
 
 
* All subject files must include supporting documentation to confirm subject eligibility.  The 
method of confirmation can include, but is not limited to, laboratory test results, radiology test 
results, subject self-report, and medical record review.  

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V. 
Statement of Eligibility  
By signing this form of this trial I verify that this subject is:  
 eligible / 
 ineligible  
for participation in the study.  This study is approved by the Stanford Cancer Institute Scientific 
Review Committee, the IRB of record, and has finalized financial and contractual agreements as 
required by Stanford School of Medicine’s Research Management Group.   
Study Coordinator printed name: 
Date:  
Signature: 
 
Investigator printed name: 
Date:  
Signature: 
 
Triple-check reviewer printed name: 
Date:  
Signature: 
 

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3.3 
Informed Consent Process  
All subjects must be provided a consent form describing the study with sufficient information for 
subjects to make an informed decision regarding their participation.  Subjects must sign the IRB 
approved informed consent prior to participation in any study specific procedure.  The subject 
must receive a copy of the signed and dated consent document.  The original signed copy of the 
consent document must be retained in the medical record or research file.  
3.4 
Study Timeline  
Primary Completion:  
It is anticipated that the study will reach primary completion (30 days after final subject 
completes treatment with study agents) 24 months from the time the study opens to accrual.  
Study Completion:  
It is anticipated that the study will reach study completion (final date on which data are 
collected) 36 months from the time the study opens to accrual.  
4. 
TREATMENT PLAN  
Potential subjects who preliminarily meet inclusion criteria and exclusion criteria as determined 
by study staff (for example, the investigator or clinical research coordinator) will meet with study 
staff to review the study and informed consent in detail.  At this time, inclusion and exclusion 
criteria will be confirmed with the subjects and treating clinicians as necessary.  
All eligible subjects (meeting criteria described in Section 3) will receive the drug combination of 
infigratinib with tamoxifen.  Once a dose level for infigratinib is determined, Cohort 1 will close.  
All subjects in whom a research biopsy of a disease site is deemed feasible and safe by the 
investigator will be required to undergo a biopsy to donate 4 to 8 cores of tumor tissue before 
and on-treatment to be used for research purposes, including genomic/transcriptomic/proteomic 
analysis and organoid culture derivation as described in Section 2.6.  The on-treatment biopsy 
is recommended to occur on Day 15 of treatment, but any time on treatment is acceptable.  
Tissue will be transported to the Curtis lab for processing and analysis.  Subjects who require a 
tumor biopsy for eligibility assessment will undergo the collection of tissue cores for research 
simultaneously, whenever possible.  Archival tumor tissue, including stored at Stanford 
University and at other institutions, may be obtained for use for tissue correlative studies as 
well.  Only tissue not needed for diagnostic purposes will be used for research.  
Subjects in Cohort 1 will receive tamoxifen 20 mg orally continuously starting on Day 1 and will 
additionally receive infigratinib orally daily 3 weeks on, 1 week off (28-day cycle) at the dose 
level dictated by study protocol (125 mg, 100 mg, or 75 mg).  
Subjects will continue receiving cycles as above until 18 months on treatment, progression, or 
unacceptable toxicity (or other reasons outlined in Section 4.3).  If toxicity is deemed per the 
investigator to be related to endocrine therapy (tamoxifen) and not infigratinib, subjects will be 
given the option of continuing infigratinib only (without endocrine therapy) until progression.   

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Details on study procedures during Screening, Treatment, and Post-Treatment are provided in 
the Study Calendar and footnotes (Section 9).  
4.1 
General Concomitant Medication and Supportive Care Guidelines  
4.1.1 Concomitant Medication 
Administration of other anticancer therapies within 2 weeks of enrollment, except ongoing 
administration of a bisphosphonate drug or denosumab as treatment for bone metastasis or 
ongoing administration of a luteinizing hormone-releasing hormone agonist (such as goserelin 
acetate or leuprolide acetate) or other endocrine therapy, is prohibited.  
Palliative radiotherapy on study is permitted for the treatment of painful bony lesions providing 
the lesions were known at the time of study entry and the investigator clearly indicates that the 
need for palliative radiotherapy is not indicative of disease progression.  In view of the current 
lack of data about the interaction of infigratinib with radiotherapy, infigratinib treatment should be 
interrupted during palliative radiotherapy, resuming infigratinib treatment after recovery to 
≤ Grade 1 radiotherapy-related toxicity.  
Details for specific medications prohibited while on study are provided in Appendix A.  The 
rationale for the restricted medications is provided below.  
Strong inhibitors of CYP3A4 such as the ones listed in Appendix A 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 A are prohibited.  Please note 
that the list may not be exhaustive.  
Subjects must also avoid the consumption of grapefruits;  grapefruit juice;  grapefruit hybrids;  
pomegranates;  star fruits;  pomelos;  Seville oranges;  or juice within 7 days prior to the first 
dose of infigratinib and throughout the treatment period due to a potential CYP3A4 interaction 
with study drug.  
Medications that increase the serum levels of phosphorus and/or calcium are prohibited.  
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 A.  Please note that the list might not 
be comprehensive.  
Medications that are allowed but should be administered with caution are provided in 
Appendix B.  The rationale for these medications is provided below.  
Infigratinib is characterized by pH-dependent solubility, and therefore, medicinal products that 
alter the pH of the upper GI tract may alter the solubility of infigratinib, and limit bioavailability.  
These agents include, but are not limited to, proton pump inhibitors (eg, omeprazole), 
H2-antagonists (eg, ranitidine) and antacids.  If possible, proton pump inhibitors should be 
avoided due to their long PD effect and replaced with H2-antagonists or antacids.  Study drug 
should be taken ≥ 2 hours before or 10 hours after dosing with a gastric protection agent.  

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Infigratinib is a substrate of CYP3A4.  Therefore, moderate inhibitors and inducers should be 
used with caution if an alternative is not available.  If anticoagulation is required, heparin and/or 
low-molecular-weight heparins or direct thrombin inhibitors and/or Factor Xa inhibitors that are 
not metabolized by CYP3A4 (eg, dabigatran, edoxaban) are preferred.  If unavoidable, 
anticoagulants that are CYP3A4 substrates and have a narrow therapeutic index [eg, warfarin 
sodium or any other coumadin-derivative anticoagulants or certain direct thrombin inhibitors 
(eg, argatroban or Factor Xa inhibitors, eg, rivaroxaban)] should be used with caution.  
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 B 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 B for list of drugs that need to be used with caution.  Please note that the list 
might not be comprehensive.  
Otherwise, concomitant treatment considered necessary for the subject’s well-being may be 
given at discretion of the treating physician.  All concomitant medications (including herbal 
supplements and vitamins), blood products, as well as interventions (eg, paracentesis, etc.) 
received by subjects from screening until the end of study visit will be recorded in the CRF.  
4.1.2 Supportive Care Guidelines  
Any palliative and supportive care for disease related symptoms, including any medication or 
therapy for a concurrent medical condition are permitted, except if specifically prohibited below.  
Hematopoietic Growth Factors  
Hematopoietic growth factors [eg, erythropoietin (EPO), granulocyte colony-stimulating factor 
(G-CSF), granulocyte-macrophage colony-stimulating factor (GM-CSF)] and blood transfusions 
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), the 
National Comprehensive Cancer Network (NCCN), or other appropriate regional societies.  

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Management of Hyperphosphatemia  
Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of the 
FGFR pathway.  
The goal of a low-phosphate diet, when one is recommended per management strategy below, 
is to restrict dietary phosphate to 600 to 800 mg/day by avoiding high-phosphate foods.  
High-phosphate foods include dairy products;  meats, nuts, and other high-protein foods;  
processed foods;  and dark colas.  In general, subjects will be instructed to liberalize their diet 
on days they are not taking infigratinib (including Days 22 to 28, and during interruption of 
infigratinib for indications other than hyperphosphatemia), unless their serum phosphorus is 
currently > 5.5 mg/dL.  Similarly, subjects who are taking sevelamer (phosphate-lowering 
medication) will be instructed to hold it on days they are not taking infigratinib (including 
Days 22 to 28, and during interruption of infigratinib for indications other than 
hyperphosphatemia), unless their serum phosphorus is currently > 5.5 mg/dL.  
Below is the recommended management strategy for hyperphosphatemia.  Section 6 also 
outlines instructions for when to interrupt and/or dose-reduce infigratinib in addition to these 
recommendations for management.  Notably, these instructions for increased monitoring of 
serum phosphorus, interruption, and dose reduction begin if serum phosphorus > 7.0 mg/dL.  
All subjects will have a serum phosphorus checked on C1D4:  
 
If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
 
If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a low-phosphate 
diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
All subjects will have a serum phosphorus checked on Cycle 1 Day 15:  
 
For subjects who are not currently following a low-phosphate diet or taking sevelamer:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
 
For subjects who are currently following a low-phosphate diet and taking sevelamer:  
o If serum phosphorus < 5.0 mg/dL, subjects will be given the option of liberalizing 
their diet or stopping the sevelamer (not both).  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to increase 
the dose of sevelamer to 1200 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to increase the dose of 
sevelamer to 1600 mg orally 3 times daily with meals.  
Subsequent (after Cycle 1) management of hyperphosphatemia is as follows:  
 
For subjects who are not currently following a low-phosphate diet or taking sevelamer:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  

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o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
 
For subjects who are currently either following a low-phosphate diet or taking sevelamer, 
but not both:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 800 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to follow a 
low-phosphate diet and to take sevelamer 1200 mg orally 3 times daily with meals.  
 
For subjects who are currently following a low-phosphate diet and taking sevelamer 
800 mg orally 3 times daily:  
o If serum phosphorus > 5.5 and ≤ 7.0 mg/dL, subjects will be instructed to increase 
sevelamer to 1200 mg orally 3 times daily with meals.  
o If serum phosphorus > 7.0 mg/dL, subjects will be instructed to increase sevelamer 
to 1600 mg orally 3 times daily with meals.  
 
For subjects who are currently following a low-phosphate diet and taking sevelamer 
1200 mg orally 3 times daily:  
o If serum phosphorus > 5.5 mg/dL, subjects will be instructed to increase sevelamer 
to 1600 mg orally 3 times daily with meals.  
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 the diarrhea to 
tolerable levels, study drug should be temporarily interrupted or dose reduced (see Section 6).  
Management of Skin Toxicity  
Alopecia: 
Grade 1 
Consider minoxidil 5% (OTC) solution or foam once daily to scalp. 
Grade 2 
Consider minoxidil 5% (OTC) solution or foam twice daily to scalp.  Consider 
fluocinonide 0.05% solution daily to scalp. 
Palmar-plantar erythrodysesthesia syndrome:  See also Section 6 for when to interrupt or 
dose-reduce infigratinib (Grade 3). 
Grade 1 
Consider urea 20% or ammonium lactate 12% lotions twice daily to hands and feet. 
Grade 2 or 3  
 
Consider urea 20% or ammonium lactate 12% lotions twice daily to hands and feet.  
Consider fluocinonide 0.05% solution twice daily to hands and feet. 

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Paronychia:  Also see Section 6 for when to interrupt or dose-reduce infigratinib (Grade 3). 
Grade 1 to 3 
Consider cefadroxil 500 mg orally twice daily or TMP/SMX orally twice daily for 14 days.  
Soak for 15 minutes daily in white vinegar in tap water 1:1.  Obtain bacterial cultures to 
confirm sensitivity to antimicrobial.  Consult dermatology. 
Stomatitis:  Subjects should be instructed to follow good oral hygiene during therapy.  
Prophylactic dexamethasone 10 mg/5 mL swish/spit 4 times a day for the first 8 weeks can be 
considered for prevention of stomatitis, 44 for example, for subjects who have had significant 
stomatitis from previous cancer therapies.  Also see Section 6 for when to interrupt or 
dose-reduce infigratinib (Grade 3). 
Grade 1 
Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times 
daily. 
Grade 2 
Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times 
daily AND doxepin 10 mg/mL swish and spit 1 teaspoon 5 mL every 6 hours as needed 
for pain. 
Grade 3 
Consider dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) 3 times 
daily AND doxepin 10 mg/mL solution swish and spit 1 teaspoon 5 mL every 6 hours as 
needed for pain.  Consider clotrimazole 10 mg lozenges four times daily. 
 
 
4.2 
Criteria for Removal from Study  
Subjects may withdraw from treatment at any time at their own request, or they may be 
withdrawn at the discretion of the investigator for safety, behavioral, or administrative reasons.  
Reasons for subject discontinuation of study treatment may include:  
 
Objective disease progression according to RECIST criteria v1.1;  
 
18 months of study drug therapy has been completed;  
 
Global deterioration of health status requiring discontinuation;  
 
Unacceptable toxicity deemed per investigator to be related to study drug, which may 
also be an adverse event;  
 
Significant protocol violation;  
 
Lost to follow-up;  
 
Subject refused further treatment;  
 
Study terminated by the investigator or sponsor;  
 
Death;  
 
Pregnancy.  

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Reasons for subject withdrawal from study follow-up may include:  
 
Completed study follow-up;  
 
Study terminated by the PI or infigratinib distributor QED Therapeutics;  
 
Lost to follow-up;  
 
Refusal for further follow-up for survival;  
 
Start of an alternative treatment regimen;  
 
Death.  
If a subject does not return for a scheduled visit, every effort should be made to contact the 
subject.  In any circumstance, every effort should be made to document subject outcome, if 
possible.  The investigator should inquire about the reason for withdrawal, request the subject to 
return for a final visit, and follow-up with the subject regarding any unresolved adverse events.  
The early termination final visit should include all assessments listed for the End of Treatment 
visit.  If the subject withdraws consent for disclosure of future information, no further study 
specific evaluations should be performed, and no additional data should be collected.  The 
investigators may retain and continue to use any data collected before such refusal for further 
follow-up.  
4.3 
Alternatives  
Standard treatment options for HR+/HER2- metastatic breast cancer after progression on 
endocrine therapy in combination with a CDK4/6 inhibitor include alternative endocrine therapy, 
sometimes in combination with an mTOR inhibitor (everolimus), or one of numerous 
chemotherapy options (eg, taxanes, anthracyclines, capecitabine, gemcitabine, and 
vinorelbine).  For the potential subset of subjects who not yet received a CDK4/6 inhibitor, 
standard treatment for HR+/HER2- metastatic breast cancer that has not progressed on 
endocrine therapy in combination with a CDK4/6 inhibitor is endocrine therapy in combination 
with a CDK4/6 inhibitor or, in select subjects with lower-risk disease, endocrine therapy alone.  
5. 
INVESTIGATIONAL AGENT INFORMATION  
5.1 
Investigational Agent  
For a summary, see Section 2.2.  For complete details, see Investigator’s Brochure, provided as 
a separate document.  
5.1.1 Infigratinib Dosage Form  
Hard gelatin capsules in dosage strengths from 25 mg and 100 mg (expressed as mg of 
infigratinib free-base).  Excipients will include microcrystalline cellulose, lactose monohydrate, 
HPMC2910, crospovidone, colloidal silicon dioxide, magnesium stearate, and hard gelatin 
capsule.  Infigratinib will be manufactured under Good Manufacturing Practice for investigational 
use.  

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5.1.2 Subject Instructions for Infigratinib Dosing  
Subjects should be instructed to take the daily dose of infigratinib in the morning as much as 
their schedule and appointment allow, at approximately the same time each day (24 ± 4 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.  
Subjects in Cohort 1 should take their daily dose of tamoxifen 4 to 8 hours after their dose of 
infigratinib. 
If the subject forgets to take the scheduled dose of infigratinib in the morning, he/she should not 
take the dose more than 4 hours after the usual time and should continue treatment 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 (eg, omeprazole), H2-antagonists 
(eg, 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.  
5.1.3 Packaging and Labeling  
Infigratinib capsules will be packaged in high-density polyethylene bottles with child-resistant 
closures.  Labels will include storage conditions for the drug.  
5.2 
Availability  
QED Therapeutics will supply infigratinib drug product.  
5.3 
Agent Ordering  
Infigratinib will be shipped by QED Therapeutics to the Investigational Drug Service at Stanford 
University Medical Center, shipping address:  
Stanford Health Care 
Stanford University 
Investigational Drug Service 
300 Pasteur Dr, Room H0302 
Stanford, CA, USA 94305  

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5.4 
Agent Accountability  
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 in the infigratinib group 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 and/or 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 can be destroyed at the site if permitted by local regulations.  
Alternatively, the study drug can be destroyed at a third-party depot.  
6. 
DOSE MODIFICATIONS  
Individually, each subject will be allowed up to dose-reduce to 75 mg infigratinib, as follows (see 
also Table 5).  
 
If a subject’s infigratinib dose is 125 mg, 2 dose reductions of infigratinib are permitted.  
 
If a subject’s infigratinib dose is 100 mg, 1 dose reduction of infigratinib is permitted.  
 
If a subject’s infigratinib dose is 75 mg, no dose reduction of infigratinib is permitted, with 
infigratinib treatment discontinuation the only option.  
Subjects should discontinue infigratinib if toxicities persist following dose reductions to the 
lowest level allowed, unless it has been discussed and approved by the QED Therapeutics’ 
Medical Monitor.  
Following resolution of toxicity to baseline or ≤ Grade 1, or ≤ Grade 2 for hematologic toxicities, 
treatment is resumed at either the same or lower dose of study drug as per the criteria in 
Table 6.  Adverse event lab abnormalities outlined in Table 6 should be followed at least weekly 
until the specified resolution.  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 7.3. 
Table 5.  Dose Modification Scheme for Infigratinib 
Dose Reduction  
Dose level 3 
(Starting) Dose level 2 
Dose level 1 
Infigratinib 
125 mg 
100 mg 
75 mg 

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In exceptional situations, study drug may continue even if the subject experienced one of the 
treatment stopping rules.  The decision to allow for continuation of treatment will be made on a 
case-by-case basis following discussion between QED Therapeutics and the investigator. 
Table 6.  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 
Grade 1 and 2:  QTcF ≥ 481msec 
and  ≤ 500 msec (asymptomatic) 
Maintain dose level of infigratinib.  
Two additional ECGs separated by at least 5 minutes should be 
performed to confirm the finding.  If the finding is confirmed, single 
ECG assessments should be performed every 2 weeks for 
2 additional cycles, or as clinically indicated.  If abnormality is 
detected, 2 additional ECGs separated by at least 5 minutes should 
be performed to confirm the finding.  
 If ECG assessments show no QTcF ≥ 481 msec, for subsequent 
cycles ECG monitoring will be performed at each subsequent visit, 
per visit schedule.  
 If ECG assessments are still abnormal (QTcF ≥ 481 msec and 
≤ 500 msec), then ECG monitoring must continue every 2 weeks 
for all subsequent cycles. 
Grade 3:  QTcF > 500msec or 
> 60 ms change from baseline as 
identified on the ECG by the 
investigator 
Hold infigratinib.  Two additional ECGs separated by at least 5 
minutes should be performed to confirm the finding.  If the finding is 
confirmed, the subject should be admitted to the hospital for at least 
24 hours of continuous telemetry; once confirmed no further 
prolongation of QTc and no arrhythmias over 24 hour period, subject 
can be discharged.  After discharge, subject should return to clinic 
weekly for ECG until normalization.  
 Exclude other causes of QTcF prolongation such as hypokalemia, 
hypomagnesaemia, and decreased blood oxygenation.  
 Subjects should receive appropriate electrolyte replacement and 
should not receive further infigratinib until electrolytes are 
documented to be within normal limits.  
Once the QTcF prolongation has resolved, subjects may be re-treated 
at one lower dose level at the investigator’s discretion. 

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Table 6.  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 
Grade 3:  QTcF > 500msec or 
> 60 ms change from baseline as 
identified on the ECG by the 
investigator (continued) 
Single ECG assessments should be performed for 2 additional cycles 
every 2 weeks or as clinically indicated.  If abnormality is detected, 2 
additional ECGs separated by at least 5 minutes should be performed 
to confirm the finding.  
 If ECG assessments show no QTcF ≥ 481 msec, ECG monitoring 
will be performed at each subsequent visit, per visit schedule for 
subsequent cycles.  
 If ECG assessments are still abnormal (QTcF ≥ 481 msec and 
≤ 500 msec), then ECG monitoring must continue every 2 weeks or 
as clinically indicated, for all subsequent cycles.  
 Subjects who experience recurrent QTcF ≥ 500msec after one 
dose reduction will be withdrawn from study.  
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. 
Grade 4:  Torsade de pointes or 
polymorphic ventricular 
tachycardia or signs/symptoms of 
serious arrhythmia 
Discontinue infigratinib.  
A plasma sample for determination of infigratinib concentration should 
be obtained with the time of sample collection noted. 
Cardiac Disorders – Others 
Grade ≥ 3 OR Congestive heart 
failure Grade ≥ 2 
Discontinue infigratinib. 
INVESTIGATIONS-HEMATOLOGY * 
ANC Decreased (Neutropenia)* 
Grade 3 (ANC 
< 1.0 to 0.5 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or 
baseline, then  
 If resolved within ≤ 7 days, maintain dose level of infigratinib  
 If resolved between > 7 days and 14 days, decrease by 
1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Grade 4 (ANC < 0.5 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE ≤ Grade 2, decrease 
by 1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 

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Table 6.  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 
Febrile Neutropenia * 
General Comment:  Consider administering G-CSF per NCCN guidelines (Version 2.2019) “Management 
of Neutropenia”:  that is, if any of the following risk factors for an infection-associated complication are 
present – sepsis syndrome, age > 65 years, ANC < 100/mcL, clinically documented infection, invasive 
fungal infection, hospitalization at the time of fever, or prior episode of febrile neutropenia. 
Grade 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 ≤ 2, then  
 If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib.  
 If not resolved within 7 days, discontinue subject from study drug 
Grade 4 
Discontinue infigratinib. 
Anemia *  
General Comment:  Consider packed RBC transfusion for hemoglobin < 7 g/dL, or < 8 g/dL for subjects 
with preexisting cardiovascular disease, per AABB guidelines, or if the investigator suspects the subject is 
symptomatic from anemia.   
Grade 3 (hemoglobin < 8.0 g/dL) 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Grade ≤ 2 or baseline, then maintain dose level 
Grade 4 
Hold dose of infigratinib until resolved or corrected to CTCAE 
Grade ≤ 2 or baseline, then decrease by 1 dose level 
Platelet Count Decreased (Thrombocytopenia) * 
Grade 3 (platelet 
< 50 to 25 × 109/L) without 
≥ Grade 2 bleeding 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or 
baseline  
 If resolved within ≤ 7 days, maintain dose level of infigratinib  
 If resolved between > 7 days and 14 days, decrease by 
1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Grade 3 (platelet 
< 50 to 25 × 109/L) with bleeding 
or Grade 4 (platelet < 25 × 109/L) 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2 or 
baseline, then decrease by 1 dose level  
 If not resolved within ≤ 14 days, discontinue infigratinib 

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Table 6.  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 
INVESTIGATIONS – RENAL 
Serum Creatinine 
Grade ≥ 2 
If serum creatinine CTCAE Grade ≥ 2 has been demonstrated in 
conjunction with hyperphosphatemia, serum creatinine levels must be 
repeated at least weekly until resolution.  24-hour urine collection 
should be obtained as clinically indicated for total phosphate, calcium, 
protein, and creatinine clearance.  Ultrasound examination of the 
kidneys should be performed as indicated to evaluate de-novo 
calcifications until resolution or stabilization of creatinine. 
Grade 2 (≥ 2.00 to 3.0 × ULN or 
2.0 to 3.0 × baseline) 
Hold dose of infigratinib until resolved to Grade ≤ 1 or baseline  
 If resolved within ≤ 7 days, maintain dose level of infigratinib  
 If resolved between > 7 days and 14 days, decrease by 
1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Grade ≥ 3 (> 3.0 × ULN or 
> 3 × baseline) 
Discontinue infigratinib 
INVESTIGATIONS – HEPATIC 
AST or ALT 
 
Grade 3 (> 5.0 to 20.0 × ULN) 
without bilirubin elevation 
> 2.0 × ULN 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1 or 
baseline  
 If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib  
 If not resolved within ≤ 7 days, discontinue infigratinib 
Grade 4 (> 20.0 × ULN) without 
bilirubin elevation > 2.0 × ULN 
Discontinue infigratinib 
AST or ALT and Bilirubin 
AST or ALT > 3.0 to 5.0 × ULN 
and total bilirubin > 2.0 × ULN 
without liver metastasis or 
evidence of disease progression 
in the liver 
Hold dose of infigratinib until both transaminases and bilirubin 
resolved to CTCAE Grade ≤ 1 or baseline.  
 If resolved within ≤ 7 days, decrease by 1 dose level of infigratinib.  
 If not resolved within ≤ 7 days, discontinue infigratinib 
AST or ALT > 5.0 × ULN and total 
bilirubin > 2.0 × ULN 
Discontinue infigratinib 

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Table 6.  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 
LABORATORY / METABOLIC DISORDERS 
Asymptomatic Amylase and/or Lipase Elevation 
General Comment: Assess for symptoms of acute pancreatitis (abdominal pain or tenderness), and, if 
present, consider a CT scan or other imaging study to assess the pancreas, liver, and gallbladder to 
confirm the diagnosis of acute pancreatitis and assess for complications. 
Grade 3 (> 2.0 to 5.0 × ULN) 
 Hold dose of infigratinib until resolved to CTCAE Grade ≤ 2  
 decrease by 1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
For recurrent Grade 3 asymptomatic lipase or amylase elevation 
despite dose reduction, infigratinib should be held and continuation of 
therapy should be discussed with the medical monitor following 
resolution to ≤ Grade 2. 
Grade 4 (> 5.0 × ULN) 
For any Grade 4 asymptomatic lipase or amylase elevation, 
infigratinib should be held and continuation of therapy should be 
discussed with the medical monitor following resolution to ≤ Grade 2. 
Hyperphosphatemia 
Serum phosphorus 
> 5.5 to 7.0 mg/dL 
Maintain dose level of infigratinib and optimize phosphate lowering 
therapy (see “Management of Hyperphosphatemia” in Section 4.2). 
Serum phosphorus > 7.0 mg/dL 
If serum phosphorus is > 7.0 mg/dL, serum phosphorus should be 
monitored every 2 to 3 days until ≤ 7.0 mg/dL.  
For serum phosphorus that is > 7.0 mg/dL for more than 7 days, or for 
a single serum phosphorus > 9.0 mg/dL:  
 Hold infigratinib dose until resolved to serum 
phosphorus ≤ 5.5 mg/dL.  
For serum phosphorus that is > 7.0 mg/dL for more than 7 days:  
 Restart infigratinib at the same dose level with increased 
phosphate binder dosing if the subject did not receive maximal 
phosphate binder dosing (sevelamer 1600 mg 3 times daily).  
 Reduce one dose level of infigratinib if the subject had received 
maximal phosphate lowering therapy (sevelamer 1600 mg 
three times daily).  Continue maximal phosphate binder dosing.  
For serum phosphorus that is > 9.0 mg/dL:  
 Reduce one dose level of infigratinib.  Restart infigratinib with 
maximal phosphate binder dosing.  
It is recommended that phosphate binder dosing continues during 
infigratinib dose interruptions for hyperphosphatemia. 

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Table 6.  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 
Hypercalcemia 
Serum calcium Grade 2 
Hold infigratinib dose until resolved to Grade 1 or baseline:  
 If resolved within ≤ 7 days after suspending infigratinib, maintain 
dose level  
 If resolved between > 7 days and 14 days after suspending 
infigratinib, decrease by 1 dose level  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Serum calcium ≥ Grade 3 
Discontinue subject from study drug 
NERVOUS SYSTEM DISORDERS 
Any Grade 2 neurotoxicity 
Omit dose of infigratinib until resolved to CTCAE Grade ≤ 1, then 
decrease by 1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Any Grade ≥ 3 neurotoxicity 
Discontinue infigratinib 
GASTROINTESTINAL SYSTEM DISORDERS 
Pancreatitis 
Grade ≥ 2 
Discontinue infigratinib 
Diarrhea 
General Comment:   
Antidiarrheal medication is recommended at the first sign of 
abdominal cramping, loose stools or overt diarrhea 
Grade 1 
Maintain dose level of infigratinib, initiate anti-diarrheal treatment  
Grade 2 
 Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  
 Optimize anti-diarrheal treatment  
 For reoccurrence of diarrhea CTCAE Grade 2, hold dose of 
infigratinib until resolved to CTCAE Grade ≤ 1, decrease infigratinib 
by 1 dose level 
Grade 3 
 Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  
 Optimize anti-diarrheal treatment  
 Decrease infigratinib by 1 dose level  
 For reoccurrence of diarrhea CTCAE Grade 3, despite optimal 
antidiarrheal treatment, discontinue infigratinib 
Grade 4 
Discontinue infigratinib 

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Table 6.  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 
Vomiting 
 
Grade 2 not controlled by optimal 
anti-emetic therapy 
Hold infigratinib doses until ≤ Grade 1, decrease by 1 dose level  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Grade 3 not controlled by optimal 
anti-emetic therapy, or Grade 4 
Discontinue infigratinib 
EYE DISORDERS (CONFIRMED BY OPHTHALMOLOGIC EXAMINATION) 
Retinal Disorders 
Grade 2 central serous 
retinopathy and central serous 
retinopathy -like events 
Hold infigratinib until resolved to ≤ Grade 1 and continue 
ophthalmologic evaluation  
 If resolved within ≤ 14 days, decrease infigratinib by 1 dose level  
 If resolved after > 14 days, discontinue infigratinib 
Grade ≥ 1 retinal vein occlusion, 
Grade 3 or 4 central serous 
retinopathy and central serous 
retinopathy-like events, and 
Grade 3 or 4 other eye disorders 
Discontinue infigratinib 
Other Ocular/Visual Toxicity 
Grade ≥ 3 
Discontinue infigratinib 
  
SKIN DISORDERS 
Palmar-plantar erythrodysesthesia syndrome 
Grade 3 
Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume 
infigratinib at decrease by 1 dose level 
Paronychia 
Grade 3 
Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume 
infigratinib at decrease by 1 dose level. 
Stomatitis 
Grade 3 
Hold dose of infigratinib until resolved to Grade ≤ 1, and then resume 
infigratinib at decrease by 1 dose level. 
Grade 4 
Discontinue infigratinib 

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Table 6.  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 
GENERAL DISORDERS 
Fatigue 
Grade ≥ 3 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1  
 If resolved within ≤ 7 days, maintain dose level of infigratinib.  
 If resolved after > 7 days, discontinue infigratinib 
OTHER CLINICALLY SIGNIFICANT AEs 
Grade 3 
Hold dose of infigratinib until resolved to CTCAE Grade ≤ 1, then 
decrease by 1 dose level of infigratinib  
 If not resolved within ≤ 14 days, discontinue infigratinib 
Grade 4 
Discontinue infigratinib 
Abbreviations:  AE, adverse event; ALT, alanine aminotransferase; ANC, absolute neutrophil count; AST, 
aspartate 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.  
7. 
ADVERSE EVENTS AND REPORTING PROCEDURES  
7.1 
Potential Adverse Events  
7.1.1 Related to Study Drug (Infigratinib)  
 
Adverse events related to calcium/phosphorous homeostasis are expected and 
on-target effects of infigratinib.  Hyperphosphatemia in particular is a reliable 
biomarker of pathway inhibition and rapidly normalizes upon drug discontinuation 
without sequelae.  Among 433 subjects treated with infigratinib monotherapy, 
hyperphosphatemia was seen in 62% and in 7% it was Grade 3 or 4.  Adverse 
events associated with calcium/phosphate imbalance (including soft tissue 
mineralization or ectopic calcifications) have been rare.  There have been 
3 suspected unexpected SAEs reported related to calcium/phosphorus homeostasis:  
(1) hepatic failure due to lesion calcification occurring over 6 months after study drug 
discontinuation, (2) one episode of hypercalcemia, and (3) one episode of 
hypophosphatemia/hypocalcemia.  
 
Ophthalmologic adverse events may occur with infigratinib, and mandated 
ophthalmologic examinations have been performed routinely and frequently.  Most of 
these events are Grade 1 or 2: for example, dry eye in 22% and blurry vision in 10%.  
Grade 3 ocular events have occurred in 3%, and no Grade 4 ocular events have 
occurred.  Grade 3 ocular events included cataract (0.7%), visual impairment (0.5%), 
and keratitis (0.5%).   
 
Gastrointestinal adverse events are frequently reported.  For subjects treated with 
monotherapy, the most frequent GI AEs (regardless of relationship to study drug) 
were constipation (37%), decreased appetite (30%), nausea (29%), diarrhea (27%), 
vomiting (20%), and dyspepsia (15%).  Stomatitis was reported in 35%, and in 5% 
was Grade 3 or 4.  

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 
Skin, hair, and nail changes are frequently reported.  For subjects treated with 
monotherapy, 27% experienced alopecia, 13% experienced dry skin, and 12% 
experienced palmar-plantar erythrodysaesthesia syndrome. 
 
For others, please see Section 2.2 (especially Tables 2 to 4) and the 
Investigator’s Brochure.  
7.1.2 Related to Tamoxifen (Cohort 1) (reported percentages are from N = 3,094 subjects in 
the ATAC trial)  
 
Hot flashes (64%) (placebo 48%)  
 
Vaginal discharge (30%) (placebo 15%)  
 
Nausea (26%) (placebo 24%)  
 
Fluid retention (32%) (placebo 30%)  
 
Mood disturbances  
 
Thrombotic events (0.8% deep vein thrombosis, 0.5% pulmonary embolism, 0.4% 
superficial phlebitis)  
 
For others, please see tamoxifen package insert from the FDA.  
7.2 Adverse Event Definitions  
An AE is defined as the appearance of (or worsening of any pre-existing) undesirable sign(s), 
symptom(s), or medical condition(s).  
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, ie, defined as an event that jeopardizes the subject or may 
require medical or surgical intervention to prevent one of the outcomes listed above  
 
Requires in-patient 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 out-patient 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  
Abnormal laboratory values or test results constitute AEs only if they induce clinical signs or 
symptoms, are considered clinically significant, require therapy (eg, hematologic abnormality 
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 

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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.  
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.  
7.3 
Adverse Events Reporting 
Adverse events (AEs) will be documented and recorded at each scheduled or unscheduled visit, 
including end-of-treatment and during follow-up, using NCI CTCAE v5.0.  Subjects will be 
followed for AEs for 30 days after the last treatment administration or until all drug-related 
toxicities have resolved (or the Investigator determines in his/her clinical judgment that no 
further improvement is expected), whichever is later.  For serious adverse events (SAEs), the 
active reporting period will be from the time that the subject provides informed consent, which is 
obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related 
procedure and/or receiving investigational product, through and including 30 calendar days after 
the last administration of the investigational product.  SAEs experienced by a subject after the 
active reporting period has ended should be reported if the Investigator becomes aware of 
them.  
Conditions already present at the time of informed consent should be recorded in the Medical 
History CRF.  
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.  
The following information is to be captured in the CRF for each AE:  severity grade 
(CTCAE v5.0, Grade 1 to 5); duration (start and end dates); relationship to study drug 
(infigratinib or tamoxifen) (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.  
7.4 
Reporting Serious Adverse Events  
Every SAE, regardless of suspected causality, occurring after the subject has signed informed 
consent through 30 days after the subject has taken his/her last dose of study drug, will be 

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reported to the Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) using 
the study-specific CRF, and to Helsinn Healthcare SA by email (drug-safety@helsinn.com) 
using their provided CRFs, within 24 hours of learning of its occurrence.  Following review by 
the Stanford DSMC, events meeting the IRB definition of ‘Unanticipated Problem’ will be 
reported to the IRB using eProtocol within 10 working days of DSMC review, or within 
5 working days for deaths or life-threatening experiences.  Any SAEs experienced after this 
30-day period should only be reported to the DSMC 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 an expected event as per the current Investigator’s Brochure or Package Insert 
(new occurrence or increased frequency) and is thought to be related to the study drug (a 
Suspected Unexpected Serious Adverse Reaction, “SUSAR”), it must also be reported to 
Helsinn Healthcare SA via email (drug-safety@helsinn.com) using their provided CRFs within 
24 hours of learning of the event and to the FDA via an IND Safety Report within 15 days 
(7 days if life-threatening or death).  QED Therapeutics and partner, the Helsinn Group, will be 
responsible to send investigator notifications to investigators involved with infigratinib studies.  
7.5 
Pregnancy  
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 the Stanford DSMC and Helsinn 
Healthcare SA (via email at drug-safety@helsinn.com) using their provided CRFs within 
24 hours of learning of its occurrence.   
For Stanford DSMC reporting, 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 the Stanford DSMC and Helsinn Healthcare SA (via email at 
drug-safety@helsinn.com) using their provided CRFs.  

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8. 
CORRELATIVE/SPECIAL STUDIES  
Two types of specimens, tumor tissues and plasma, will be collected for correlative studies. 
8.1 
Laboratory Correlative Studies 
8.1.1 Tumor Tissue Collection and Processing 
8.1.1.1 Collection of Specimen(s) 
Fresh tumor tissue will be collected on subjects participating in the study during the 
pre-treatment and on-treatment research biopsies, which are mandatory if deemed safe 
and feasible by the investigator.  Procedures will be done according to best clinical 
practice guidelines as are all procedures at Stanford Hospital.  Four to eight 
research-specific core biopsies will be taken, depending on the biopsy site and 
investigator assessment of safety and feasibility.  Research biopsies will not be taken if 
there is felt to be more than minimal additional risk.   Details on processing of specimens 
are provided in the lab manual. 
8.1.1.2 Coding of specimens for privacy protection 
Study staff (eg, the protocol director or clinical research coordinator) will create a 
unique anonymous identifier for each specimen at time of subject data collection and 
entry into the secure REDCap database.  The unique anonymized identifier will be 
assigned sequentially within each cohort (eg, INF1001, INF1002, etc; INF2001, 
INF2002, etc).  All tissue specimens will be labeled with this anonymous identifier and 
no subject-identifiable information.  The link between anonymous identifier and subject 
information will be stored in the secure REDCap database. 
8.1.2 Plasma Collection and Processing  
8.1.2.1 Collection of Plasma Specimen(s)  
20 cc of blood will be collected in black and tan top Streck Cell-Free DNA BCT tubes at 
screening or on Cycle 1 Day 1, on Cycle 1 Day 15 (± 3 days), and then again at End of 
Treatment.  Details on processing of specimens are provided in the lab manual. 
8.1.2.2 Coding of specimens for privacy protection 
As with the tissue specimens (Section 8.1.1), plasma specimens will be labeled with the 
same anonymous identifier and no subject-identifiable information.  The link between 
anonymous identifier and subject information will be stored in the secure REDCap 
database. 

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9.  STUDY CALENDAR 
Protocol Activity 
Screening 
On Treatment (1 Cycle = 28 days) 
Post-Treatment 
(Within  
21 days of 
Cycle 1, 
Day 0) 
Cycle 1 
Cycle 2 
Cycles  3 
End of Treatment / 
withdrawal (0 to 14 days 
from decision to 
discontinue) 23 
30-day 
Follow-up 
Safety Visit 
(+ 7 days) 24 
Other 
Follow-up25 
Day 1 
(± 3 days) 
Day 4 
(± 1 day) 
Day 15 
(± 3 days) 
Day 1 
(± 3 days) 
Day 15 
(± 3 days) 
Day 1 (± 3 days) 
Informed Consent 1 
X 
 
 
 
 
 
 
 
 
 
Medical/Tumor History 2 
X 
 
 
 
 
 
 
 
 
 
Physical Examination (within 
24 hours prior to start of each 
cycle)3 
X 
X 
 
X 
X 
 
X 
X 
X 
(X) 
ECOG Performance Status 4 
X 
X 
 
X 
X 
 
X 
X 
X 
(X) 
Safety Labs/Measurements 
Vital Signs (within 24 hours 
prior to start of each cycle) 5 
X 
X 
 
X 
X 
 
X 
X 
X 
(X) 
Hematology (CBC, differential, 
platelets) 6 
X 
X 
 
X 
X 
X 
X 
X 
 
(X) 
Complete metabolic panel 7 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Amylase, lipase 8 
X 
X 
 
X 
X 
X 
X 
X 
 
(X) 
Calcium, magnesium, 
phosphorus 9 
X 
X 
X 
X 
X 
X 
X 
X 
 
(X) 
Urinalysis 10 
X 
 
 
 
 
 
 
 
 
 
Pregnancy Test 11 
X 
X 
 
 
 
 
 
X 
 
 
Electrocardiogram 12 
X 
 
 
 
X 
 
C4D1, C6D1 (± 7 days) then 
every 6 cycles (all ± 14 days) 
X 
 
 
Transthoracic echocardiogram 
13 
X 
 
 
 
X 
 
 
X 
 
 
Ophthalmology evaluation 14 
X 
 
 
 
X ± 7 da
ys 
 
C3D1, C4D1, C6D1 (± 7 days), 
then every 3 cycles (± 14 days) 
X 
 
 

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Protocol Activity 
Screening 
On Treatment (1 Cycle = 28 days) 
Post-Treatment 
(Within  
21 days of 
Cycle 1, 
Day 0) 
Cycle 1 
Cycle 2 
Cycles  3 
End of Treatment / 
withdrawal (0 to 14 days 
from decision to 
discontinue) 23 
30-day 
Follow-up 
Safety Visit 
(+ 7 days) 24 
Other 
Follow-up25 
Day 1 
(± 3 days) 
Day 4 
(± 1 day) 
Day 15 
(± 3 days) 
Day 1 
(± 3 days) 
Day 15 
(± 3 days) 
Day 1 (± 3 days) 
Registration 1 
 7 days bef 
Cycle 1, 
Day 1 
 
 
 
 
 
 
 
 
 
Treatment 
Infigratinib administration 15 
 
Daily as 3 weeks on / 
1 week off 
 for entire cycle 
3 weeks on / 
1 week off 
3 weeks on / 
1 week off 
 
 
 
Cohort 1:  Tamoxifen 
administration 16 
 
 
Continuous 
Continuous 
Continuous 
 
 
 
Tumor Assessment 
CT (chest, abdomen, pelvis) 17 
X 
 
 
 
 
 
C3D1 (+7 days), then every 
2 cycle (± 7 days) 
(X) 
 
 
Plasma collection 18 
 
X 
 
X 
 
 
 
X 
 
 
Research tumor biopsy 19 
X 
 
 
X 
 
 
 
 
 
 
Tumor sequencing 20 
X 
 
 
 
 
 
 
 
 
 
Other Clinical Assessment 
Adverse event assessment 21 
X 
Monitor and record at every study visit 
X 
X 
X 
Concomitant medications 22 
X 
Monitor and record at every study visit 
X 
X 
 
1.  Informed Consent:  Must be obtained prior to undergoing any study specific procedure and may occur prior to the 21-day screening period.  Registration will considered to be 
signed informed consent with triple-signed eligibility checklist, with the final signature being the Stanford Principal Investigator or his/her designee.  
2.  Medical History / Tumor History:  To be collected within 21 days prior to C1D1.  Includes history of other diseases (active or resolved) and concomitant illnesses.  Oncology 
history includes information on prior regimens (including dosing and duration of administration, description of best response observed, recurrence date), surgery and radiation 
therapy.  It also includes review of the predicted integrative subtype from FoundationOne.  These assays may also be done during screening, as indicated (see footnote 22, “Tumor 
sequencing”).  
3.  Physical Examination:  Includes an examination of major body systems.  Weight for the purposes of dose calculation will be recorded at screening and within 7 days pre-dose 
Day 1 of each cycle.  Weight will also be collected at End of Treatment.  Height will be measured at baseline.  

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4.  ECOG Performance Status:  
Score 
Definition  
0 
Fully active, able to carry on all pre-disease activities without restriction  
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a light or sedentary nature, eg, light house work or office work  
2 
Ambulatory and capable of all selfcare but unable to carry out any work activities.  Up and about more than 50% of waking hours  
3 
Capable of only limited selfcare, confined to bed or chair more than 50% of waking hours  
4 
Completely disabled.  Cannot carry on any selfcare.  Totally confined to bed or chair  
5 
Dead  
5.  Vital signs:  Blood pressure, pulse rate, and body temperature to be recorded in the same position, either supine or sitting.  
6.  Hematology:  No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  On treatment, to be performed prior to dosing with study 
medications unless otherwise indicated.  Lab abnormalities that are adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in 
Table 6.  
7.  Complete metabolic panel:  No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  Lab abnormalities that are adverse events 
specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6.  
8.  Amylase, lipase:  No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  Lab abnormalities that are adverse events specified in 
Table 6 must be followed at least weekly until resolution to the grade specified in Table 6.  
9.  Calcium, magnesium, phosphorus (serum):  No need to repeat on C1D1 if baseline assessment performed within 72 hours prior to that date.  Lab abnormalities that are 
adverse events specified in Table 6 must be followed at least weekly until resolution to the grade specified in Table 6.  
10.  Urinalysis:  Macroscopic or microscopic.  
11.  Pregnancy Test:  For female subjects of childbearing potential, a serum or urine pregnancy test must be performed within 7 days of first day of study drug and at 
end-of-treatment.  Additional pregnancy test to be repeated when potential pregnancy is suspected.  
12.  Electrocardiogram:  12-lead ECG to be performed during Screening, at Cycle 2 Day 1 (± 3 days), Cycle 4 Day 1 (± 7 days), Cycle 6 Day 1 (± 7 days), and then every 6 cycles 
(± 14 days), and at End-of-Treatment.  Additional assessments should be conducted as clinically indicated. 
13.  Echocardiogram:  Transthoracic echocardiogram to be performed during Screening, at Cycle 2 Day 1 (± 3 days), and at End-of-Treatment.  Additional assessments should be 
conducted as clinically indicated.  
14.  Ophthalmology evaluation:  Ophthalmologic examination will be performed by an ophthalmologist during Screening, on Day 1 (± 7 days) of Cycles 2, 3, 4 and 6;  then every 
3 cycles (± 14 days);  and at End-of-Treatment, as well as urgently with any new onset of visual symptoms.  These assessments will include visual acuity testing, slit lamp 
examination of the anterior eye segment, intraocular pressure, dilated fundoscopy, and retinal optical coherence tomography (OCT).  Additional examinations such as specular 
microscopy (that enables a magnified, direct view of the corneal epithelium) and corneal pachymetry will be performed as clinically indicated.  
15.  Infigratinib Administration:  One cycle of infigratinib will be provided to subjects at the beginning of each cycle.  Starting dose level of infigratinib for individual subjects will be 
as defined by study protocol, and may be either 125 mg;  100 mg;  or 75 mg infigratinib, each dose level administered as 3 weeks on, 1 week off for every 28-day cycle.   
16.  Tamoxifen Administration:  In Cohort 1, tamoxifen will be prescribed to subjects and will be started at 4 to 8 hours after the administration of infigratinib, starting on Cycle 1 
Day 1.  Dose is tamoxifen 20 mg/day by mouth continuously.  
17.  Tumor assessment by imaging:  Baseline CT imaging can be done within 28 days prior to C1D1 (versus 21 days for all other baseline/screening assessments).  Assessment 
of response will be made using RECIST v1.1.  Antitumor activity will be assessed through radiological tumor assessments conducted at baseline, on treatment every 8 weeks and 
whenever disease progression is suspected (eg, symptomatic deterioration).  After 12 months of therapy, imaging can be spaced out to every 12 weeks at the Investigator’s 
discretion.  To be repeated at End of Treatment/Withdrawal only if not done in the previous 4 weeks.  Confirmation of response (CR/PR) should be done at least 4 weeks after the 
initial response.  The allowable time window for disease assessments is ± 7 days, on treatment, starting from C1D1, except for the first post baseline assessment (+ 7-day window 
allowed).  Timing should follow calendar days and should not be adjusted for delays in cycle starts.  

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18.  Plasma collection:  Two Streck tubes will be collected on Cycle 1 Day 1 prior to study drug initiation, on Cycle 1 Day 15 (± 3 days), and at End of Treatment.  Buffy coat 
separated from the same blood collection will be used for tumor-normal sequencing. 
19.  Tumor biopsy:  A pre-treatment and on-treatment tumor biopsy is mandatory if deemed safe (not posing more than minimal additional risk) and feasible by the investigator.  
The on-treatment tumor biopsy is recommended to be performed on or around Day 15 of therapy, but can be performed at any time on therapy per protocol.  
20.  Tumor sequencing:  If a potential subject has not had FoundationOne tumor sequencing performed, allowing assessment of predicted integrative subtype, this assay may be 
sent to determine eligibility.  
21.  Adverse event assessments:  Adverse events (AEs) will be documented and recorded at each scheduled or unscheduled visit, including end-of-treatment and during 
follow-up, using NCI CTCAE v5.0.  Subjects will be followed for AEs for 30 days after the last treatment administration or until all drug-related toxicities have resolved (or the 
Investigator determines in his/her clinical judgment that no further improvement is expected), whichever is later.  For serious adverse events (SAEs), the active reporting period will 
be from the time that the subject provides informed consent, which is obtained prior to the subject’s participation in the study, ie, prior to undergoing any study-related procedure 
and/or receiving investigational product, through and including 30 calendar days after the last administration of the investigational product.  SAEs experienced by a subject after the 
active reporting period has ended should be reported if the Investigator becomes aware of them.  The reporting period for non-serious AEs will be from the time the subject has 
taken at least one dose of study treatment through Day 30 after last dose.  If a subject begins a new anticancer therapy, the AE reporting period for non-serious AEs will end at the 
time the new treatment is started.  
22.  Concomitant medications:  Concomitant medications will be recorded from 30 days prior to the start of study treatment through 30 days after the last dose of study treatment.  
Concomitant medications will be collected at each scheduled or unscheduled visit, including at end-of-treatment.  All concomitant medications should be recorded in the CRF 
including supportive care drugs (eg, anti-emetic treatment and prophylaxis), herbal supplements or vitamins, the drugs used to treat adverse events or chronic diseases, and 
non-drug supportive interventions (eg, transfusions).  
23.  End of Treatment:  To be performed 0 to 14 days after the decision made to discontinue study drug.  Obtain these assessments if not completed during the previous week on 
study.  CT scan should be performed at End of Treatment unless CT scan was performed within the previous 4 weeks.  
24.  30-Day Follow-Up Safety Visit:  Performed 30 to 37 days after last dose of study drug.  Information related to concomitant medications and adverse events will be collected for 
30 days after the last dose of the study drug.  
25.  Follow-Up:  Subjects continuing to experience toxicity following discontinuation of study treatment will continue to be followed including for adverse events, at least every week 
(± 3 days) for 4 weeks, and subsequently every 4 weeks (± 7 days), until resolution or determination, in the clinical judgment of the Investigator, that no further improvement is 
expected.  If a follow-up is required beyond 30 to 37 days after last dose of study drug, not all assessments need to be performed.  Only assessments that are clinically indicated are 
necessary for this timepoint. 

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10. 
MEASUREMENTS  
10.1  Primary endpoint:  
The primary endpoint is the incidence of dose-limiting toxicities (DLTs) in the first 2 cycles of 
therapy at a specific dose.  In Cohort 1, in a subset of subjects who start at infigratinib 100 mg 
and complete 2 cycles with no DLTs and who remain on study for Cycles 3 and 4, the dose of 
infigratinib will be increased to 125 mg starting with Cycle 3 and the number of DLTs in Cycles 3 
and 4 will be counted toward the primary endpoint (for the 125 mg dose), in addition to the 
number of DLTs in Cycles 1 and 2 (for the 100 mg dose).  For all other subjects, the primary 
endpoint will be the number of DLTs in Cycles 1 and 2. 
DLTs will be graded using NCI CTCAE (Common Terminology Criteria for Adverse Events), 
v5.0.  DLTs will be defined as an adverse event (AE) or abnormal laboratory value at least 
possibly related to therapy with infigratinib including those AEs and abnormal laboratory values 
that result in a failure to meet the criteria for re-treatment.  The criteria for defining a DLT, which 
are pre-specified based on the pre-clinical toxicity of infigratinib, are listed in Table 7.  
Individual subjects who had a DLT may be retreated, after recovery, at the next lowest dose 
level.  
Investigators will notify QED Therapeutics within 7 days of any DLTs observed.  
Table 7.  Criteria for defining dose-limiting toxicities 
TOXICITY 
DLT CRITERION 
Skipped/ 
delayed dose 
The inability to administer infigratinib on ≥ 75% of scheduled treatment days 
during cycle 1 at that dose (ie, ≥ 16 days of the 21 days of planned treatment) due 
to unresolved adverse event of any grade and considered at least possibly, 
probably, or definitely related to the study drug.  
Delay in 2nd cycle administration at that dose due to failure of recovery from a 
possibly, probably, or definitely related adverse event to Grade ≤ 1 or baseline by 
Day 43 (Day 28 of Cycle 1 + 15 days), except for alopecia. 
Blood/ bone 
marrow 
Neutropenia  
    • Febrile, CTCAE Grade ≥ 3. 
    • CTCAE Grade ≥ 3 for > 7 consecutive days  
Thrombocytopenia 
    • CTCAE Grade 3 for > 7 consecutive days and/or with signs of  
clinically significant bleeding. 
    • CTCAE Grade 4  
Anemia CTCAE Grade 4 
Renal/ 
genitourinary 
Creatinine: 
    • CTCAE Grade 1 for > 7 consecutive days and serum inorganic phosphorus  
       > 5.5 mg/dL and/or serum total calcium x serum inorganic phosphorus  
       > 55 mg2/dL2 and despite phosphorus lowering therapy for ≥ 14 days  
    • CTCAE Grade 2 for > 7 consecutive days  
    • CTCAE Grade ≥ 3 

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Table 7.  Criteria for defining dose-limiting toxicities 
TOXICITY 
DLT CRITERION 
Hepatic 
Bilirubin: 
    • CTCAE Grade 2 for > 7 consecutive days  
    • CTCAE Grade ≥ 3  
AST or ALT: 
    • Grade 3 for > 7 consecutive days 
    • CTCAE Grade 4 
Hy’s Law 
    • ALT or AST ≥ 3 x upper limit of normal (ULN)  
      AND 
    • Serum total bilirubin > 2 x ULN 
For patients with known hepatic metastases: 
    • AST or ALT > 8 x ULN 
      OR 
    • AST or ALT > 5 x ULN for ≥ 14 days 
Pancreas 
Pancreatitis CTCAE Grade ≥ 2  
Amylase/lipase (serum-high):  CTCAE Grade ≥ 3 asymptomatic amylase and/or  
   asymptomatic lipase not reversible to CTCAE Grade ≤ 2 within 7 days 
Cardiac 
QTcF interval > 500ms  
Other cardiac CTCAE Grade ≥ 3 
Constitutional 
Fatigue CTCAE Grade 3 for > 7 consecutive days  
Fatigue CTCAE Grade 4 
Ocular/visual 
Any ocular/visual toxicity CTCAE Grade ≥ 3. 
Gastrointestinal 
CTCAE Grade 3 or 4 nausea/vomiting and/or diarrhea despite the use anti-emetic 
and anti-diarrhea therapy, respectively 
Metabolic/ 
laboratory 
Hyperphosphatemia (serum-high): 
    • Serum inorganic phosphorus > 7.0 mg/dL for > 7 consecutive days despite  
       phosphorus-lowering therapy for at least 14 days. 
    • Serum inorganic phosphorus > 9.0 mg/dL, despite phosphorus-lowering  
       therapy for at least 14 days. 
    • Serum inorganic phosphorus > 10.0 mg/dL  
Hypercalcemia (serum-high) 
    • Serum calcium CTCAE Grade 2 for > 7 consecutive days. 
    • Serum calcium CTCAE Grade ≥ 3. 
Other 
Any death not clearly due to the underlying disease or known, extraneous causes. 
Clinical evidence for any grade (CTCAE Grade ≥ 1) of ectopic, de-novo- 
calcification within the soft tissue including the peri-articular spaces and vascular 
as well as visceral tissues (eg, kidney, lung, stomach, myocardium, etc.)  
Any other CTCAE Grade 3 or 4 non-hematological toxicity except with following 
exclusions: 
    • Alkaline phosphatase CTCAE Grade ≥ 3. 
    • Lymphocytopenia CTCAE Grade ≥ 3 unless considered clinically significant. 

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10.2 
Secondary endpoints:  
1. Incidence of treatment-emergent adverse events (TEAE).  A TEAE is defined as an 
adverse event with initial onset or increasing in severity after the first dose of study 
treatment until 30 days after last dose of study drug.  TEAEs will be assessed and 
documented at each scheduled or unscheduled visit during the reporting period.  Each 
TEAE will be assessed according to whether it is serious or non-serious, whether it is 
expected or unexpected according to the Investigator’s Brochure, and whether it is 
related or unrelated to the study treatment.  Each TEAE will be assigned a grade 
according to CTCAE v5.0.  A serious adverse event is one that results in death, is 
life-threatening, requires in-patient hospitalization or causes prolongation of existing 
hospitalization, results in persistent or significant disability/incapacity, may have caused 
a congenital anomaly/birth defect, or requires intervention to prevent permanent 
impairment or damage.  Pregnancy during the reporting period will be classified as a 
serious adverse event.  
2. Objective tumor response, per RECIST v1.1 (see Appendix C), in subjects with 
measurable disease.  An objective tumor response can be observed at any time on 
study between 8 weeks after starting therapy (C3D1) through 18 months after starting 
therapy.  
3. Progression-free survival (PFS), defined as the number of days to either progressive 
disease as defined per RECIST v1.1 or death.  
4. Clinical benefit, defined as an objective tumor response or stable disease at 6 months, 
defined per RECIST v1.1 (see Appendix C).  
10.2.1 Measurement Methods  
For those subjects with bone-only disease, RECIST v1.1 criteria will not be used to assess 
response.  Subjects will stop study drug at when disease is deemed by the investigator to have 
progressed.  
10.2.2 Measurement Time Points  
Antitumor activity will be assessed through radiological tumor assessments conducted at 
baseline, on treatment every 8 weeks (± 7 days), and whenever disease progression is 
suspected (eg, symptomatic deterioration).  After 12 months of therapy, imaging can be spaced 
out to every 12 weeks (± 7 days) at the Investigator’s discretion.  Studies will be repeated at 
End of Treatment/Withdrawal only if not done in the previous 4 weeks.  Confirmation of 
response (CR/PR) should be done at least 4 weeks after the initial response.  Timing should 
follow calendar days (starting from C1D1) and should not be adjusted for delays in cycle starts.  
10.3 Outcomes for ClinicalTrials.gov  
The outcomes for ClinicalTrials.gov represent the study objectives.  

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10.3.1 Primary Outcome  
Primary Outcome Title:  Dose-limiting Toxicity (DLT)  
Primary Outcome Measure Description:  The primary outcome for this study is 
dose-limiting toxicities (DLTs) during the first 2 cycles of therapy at a specific dose.  All 
grades per the Common Terminology Criteria for Adverse Events (CTCAE).  DLT is defined 
as a related and clinically-significant adverse event (AE), including missed doses due to a 
related AE.  Due to limited number of characters that can present in this field, it is not 
possible to consistently provide additional details across all sub-elements of this outcome.  
See protocol.  The outcome is expressed as the number of DLT events by the assigned 
infigratinib dose level, a number without dispersion.  
Time Frame:  8 weeks.  
10.3.2 Secondary Outcomes  
1.  Outcome Title:  Treatment-emergent Adverse Events (TEAE)  
Outcome Measure Description:  Treatment-emergent adverse events (TEAEs) are 
defined as adverse events of any grade with initial onset or increasing in severity after 
the first dose of study treatment until 30 days after last dose of study drug.  Pregnancy 
during the reporting period will be classified as a serious adverse event.  The outcome 
will be expressed as the number of events by the infigratinib dose level at the time of the 
event, stratified by relatedness and Common Terminology Criteria for Adverse Events 
(CTCAE) grade.  The result is a number without dispersion.  
Time Frame:  2 years  
2.  Outcome Title:  Objective Tumor Response  
Outcome Measure Description:  Objective tumor response will be assessed as 
achieving a Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Complete 
Response (CR) or a Partial Response (PR).  The outcome will be reported as the 
number of subjects by each participant’s final infigratinib dose level that achieve an 
overall response (OR) to treatment, ie, CR or PR, within 18 months of starting treatment.  
The outcome will be reported as a number without dispersion.  RECIST criteria are:  
• CR = Disappearance of all target lesions  
• PR = ≥ 30% decrease in the sum of the longest diameter of target lesions  
• Overall Response (OR) = CR + PR  
• Progressive disease (PD) = 20% increase in the sum of the longest diameter of target 
lesions, and/or the appearance of one or more new lesion(s)  
• Stable disease (SD) = Small changes that do not meet any of the above criteria  
Time Frame:  up to 18 months  
3.  Outcome Title:  Progression-free Survival (PFS)  
Outcome Measure Description:  Progression-free survival (PFS) means the subject is 
alive without return or relapse of the tumor.  The outcome is defined as the number of 

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days to either progressive disease as defined per RECIST v1.1 or death, by each 
participant’s final infigratinib dose level, and reported as the median PFS with full range.  
RECIST criteria are:  
• CR = Disappearance of all target lesions  
• PR = ≥ 30% decrease in the sum of the longest diameter of target lesions  
• Overall Response (OR) = CR + PR  
• Progressive disease (PD) = 20% increase in the sum of the longest diameter of target 
lesions, and/or the appearance of one or more new lesion(s)  
• Stable disease (SD) = Small changes that do not meet any of the above criteria  
Time Frame:  Up to 2 years.  
4.  Outcome Title:  Clinical Benefit  
Outcome Measure Description:  Clinical benefit will be assessed as achieving a 
Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 Complete Response (CR) ; 
Partial Response (PR); or Stable Disease (SD).  The outcome will be reported as the 
number of subjects by each participant’s final infigratinib dose level that achieve a CR; 
PR; or SD, within 6 months of starting treatment.  The outcome will be reported by 
treatment and dose level as a number without dispersion.  RECIST criteria are:  
• CR = Disappearance of all target lesions  
• PR = ≥ 30% decrease in the sum of the longest diameter of target lesions  
• SD = Small changes that do not meet any of the above criteria  
• Progressive disease (PD) = 20% increase in the sum of the longest diameter of target 
lesions, and/or the appearance of one or more new lesion(s)  
• SD = Small changes that do not meet any of the above criteria  
Time Frame:  up to 6 months  
11. 
REGULATORY CONSIDERATIONS  
11.1 
Institutional Review of Protocol  
This study will be conducted under IND 147595 for infigratinib (pre-assigned).  Infigratinib was 
approved by FDA as Truseltiq pursuant the Accelerated Approval regulations on 28 May 2021 
for the indication of previously-treated, unresectable, locally-advanced or metastatic 
cholangiocarcinoma with a fibroblast growth factor receptor 2 (FGFR2) fusion or other 
rearrangement, in adults 
The protocol, the proposed informed consent and all forms of subject information related to the 
study (eg, advertisements used to recruit subjects) will be reviewed and approved by the 
Stanford IRB and Stanford Cancer Institute Scientific Review Committee (SRC).  Any changes 
made to the protocol will be submitted as a modification and will be approved by the IRB prior to 
implementation.  The Protocol Director will disseminate the protocol amendment information to 
all participating investigators.  

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11.2 
Data Sharing with Collaborators   
Distributor QED Therapeutics expects to share data from this study with the Helsinn Group 
(collaborator/partner).  
11.3 
Data and Safety Monitoring Plan  
The Stanford Cancer Institute Data and Safety Monitoring Committee (DSMC) will be the 
monitoring entity for this study.  The DSMC will audit study-related activities to determine 
whether the study has been conducted in accordance with the protocol, local standard operating 
procedures, FDA regulations, and Good Clinical Practice (GCP).  This may include review of the 
following types of documents participating in the study:  regulatory binders, case report forms, 
eligibility checklists, and source documents.  In addition, the DSMC will regularly review serious 
adverse events and protocol deviations associated with the research to ensure the protection of 
human subjects.  Results of the DSMC audit will be communicated to the IRB and the 
appropriate regulatory authorities at the time of continuing review, or in an expedited fashion, as 
needed.  
11.4 
Data Management Plan  
The Protocol Director, or designee, will prepare and maintain adequate and accurate subject 
case histories with observations and data pertinent to the study.  Study specific Case Report 
Forms (CRFs) will document treatment outcomes for data analysis.  Case report forms will be 
created in the Stanford Research Electronic Data Capture (REDCap) and will be maintained by 
the Protocol Director, co-Protocol Director, and clinical research coordinator team.  All subjects 
will be registered in the OnCore database, allowing the Stanford SRC to judge the aggregate 
accrual and stopping rules for the study.  
12. 
STATISTICAL CONSIDERATIONS  
12.1 
Statistical Design and Sample Size Determination  
Statistical analyses of this non-randomized, phase 1B study will be primarily descriptive in 
nature.  Formal statistical methods will not be used to determine the number of subjects per 
cohort/dose level in this phase 1B study.  Summary statistics for discrete variables will be 
provided as frequencies and for continuous variables as the mean, standard deviation, median, 
and ranges.  
Cohort 1 will utilize the combination of tamoxifen and infigratinib at 3 infigratinib dose levels 
(125 mg;  100 mg;  and 75 mg).  This combination may play a role in the future development of 
infigratinib for hormone receptor-positive breast cancer, necessitating the establishment of their 
safety.  For example, tamoxifen and infigratinib might be used in the early-stage, (neo)adjuvant 
setting as well as the late-stage, metastatic setting.  Therefore, the design is based on patient 
resources and current drug development.  
12.2 
Interim analyses 
There will be no additional statistical stopping rules other than the 3+3 design rule for Cohort 1 
as described in Section 2.5, and there will be no planned interim analysis.  

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12.3 
Descriptive Statistics and Exploratory Data Analysis 
The exploratory elements described in Section 1.3 will be included in the descriptive statistics 
and exploratory data analyses. 
12.4 
Primary Safety Analysis  
Cohort 1 (infigratinib plus tamoxifen) will follow the 3+3 design evaluating 3 infigratinib doses 
levels, starting at 100 mg infigratinib 3 weeks on/1 week off) and moving to, if needed, 75 mg or 
125 mg infigratinib 3 weeks on/1 week off.  Given the nature of this cohort to be a safety run-in 
and the limited number of available subjects for this population, intra-subject dose-escalation 
will be allowed.  The risk with intra-subject dose-escalation is that a dose may be declared 
overly toxic when the toxicities should be attributed to the number of cycles rather than the 
dose, but it is believed this is a conservative approach focused on subject safety.  
Initially, 3 subjects will be treated at 100 mg for 2 cycles.  If there are no DLTs observed in a 
subject at 100 mg after 2 cycles, the subject will escalate to 125 mg for 2 additional cycles.  If 
1 DLT is observed at 100 mg, an additional 3 subjects will be treated at 100 mg.  If 
2 or more DLTs are observed at 100 mg, an additional 3 subjects will be treated at 75 mg.  If 
1 DLT is observed at 75 mg, an additional 3 subjects will be treated at 75 mg.  If no DLTs are 
observed in the first 3 subjects at 100 mg, but 1 DLT is observed at 125 mg, an additional 
3 subjects will be treated at 125 mg.  If 2 or more DLTs are observed at 125 mg, Cohort 1 will 
close.  If a dose achieves no DLTs in 3 subjects after 2 cycles or 1 DLT in 6 subjects after 
2 cycles, that dose will be declared safe for use in the main phase 2 trial. 
If a subject withdraws prior to the completion of the first 2 cycles of therapy without having 
experienced a DLT, an additional subject will be enrolled at that dose level.  
12.5 Secondary Safety Analysis  
The secondary safety analysis relates to the incidence of treatment-emergent adverse events 
(TEAEs).  TEAEs are those with initial onset or increasing in severity after the first dose of study 
treatment.  TEAEs will be graded by the investigator according to the Common Terminology 
Criteria for Adverse Events (CTCAE) version 5.0 and coded using the Medical Dictionary for 
Regulatory Activities (MedDRA).  The number and percentage of subjects who experienced any 
AE, serious AE (SAE), treatment-related AE, and treatment-related SAE will be summarized 
according to worst toxicity grades.  The summaries will present AEs both on the entire study 
period and by cycle (Cycle 1 and Cycles beyond 1) in Cohort 1.  
Laboratory Test Abnormalities  
The number and percentage of subjects who experienced laboratory test abnormalities will be 
summarized according to worst toxicity grade observed for each laboratory assay.  The 
analyses will summarize laboratory tests both on the entire study period and by cycle (Cycle 1 
and Cycles beyond 1).  For laboratory tests without CTCAE grade definitions, results will be 
categorized as normal, abnormal, or not done.  

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12.6  Efficacy Analysis  
Tumor response will be presented in the form of subject data listings that include, but are not 
limited to:  
 
The classified integrative subtype (IC2 or IC6)  
 
Received (maximum) dose  
 
Overall tumor response at each imaging assessment point  
 
Best overall response  
In addition, disease progression date, death date, date of first response, and last tumor 
assessment date will be listed, together with progression-free survival.  A Kaplan-Meier plot will 
be created for progression-free survival overall, for IC2-classified tumors separately, and for 
IC6-classified tumors separately. 
12.7 
Analysis Population  
All subjects who received at least one dose of the study drug (infigratinib) will be analyzed for 
the safety and efficacy outcomes outlined in sections 12.4;  12.5;  and 12.6.  
12.8  Accrual Considerations  
There are approximately 600 new breast cancer patients seen annually at the Stanford Cancer 
Institute, an estimated 50 percent metastatic and 60% HR-positive, HER2-negative.  Based on 
METABRIC, we estimate that approximately 5% of HR-positive, HER2-negative tumors are 
integrative subtype 2 and 5% are integrative subtype 6. 2,3  We thus anticipate approximately 
20 eligible subjects per year, adequate for the accrual goals.  If accrual unexpectedly falls short, 
additional clinical sites may be added to the study.  
12.9 
Criteria for future studies  
If an MTD for infigratinib in combination with tamoxifen is identified with an acceptable number 
of DLTs (see Section 12.4), the combination will be deemed acceptable for future studies in this 
biomarker-selected population of advanced breast cancer.  Should this combination prove safe, 
the study team is planning additional studies to assess efficacy in multiple populations of breast 
cancer subjects whose tumors harbor FGFR pathway alterations.  

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APPENDICES  
APPENDIX A:  List of prohibited medications and substances 
Category 
Drug Names 
Strong inhibitors of CYP3A4 
clarithromycin, conivaptan, fluconazole, fluvoxamine, indinavir, 
itraconazole, ketoconazole, lopinavir, mibefradil, miconazole, 
nefazodone, nelfinavir, norfloxacin, posaconazole, ritonavir, 
saquinavir, telithromycin, voriconazole  
  
grapefruit, grapefruit juice, grapefruit hybrids, pomegranates, 
star fruits, pomelos, Seville oranges or products containing 
juice of these fruits   
Strong inducers of CYP3A4 
avasimibe, carbamazepine, nevirapine, phenobarbital, 
phenytoin, pioglitazone, primidone, rifabutin, rifampin, St.  
John's wort, troglitazone 
Medications which increase 
serum phosphorus and/or 
calcium 
calcium, parathyroid hormone, phosphate, vitamin D (including 
multivitamins containing vitamin D) 
Medications with established 
potential for QT prolongation or 
TdP 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US 
market), azithromycin, bepridil (off US market), chloroquine, 
chlorpromazine, cisapride (off US market), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, domperidone 
(not on US market), dronedarone, droperidol, erythromycin, 
escitalopram, flecainide, halofantrine, haloperidol, ibutilide, 
levofloxacin, levomethadyl (off US market), mesoridazine (off 
US market), methadone, moxifloxacin, 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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APPENDIX B:  List of drugs to be used with caution while on study  
 
Category 
Drug Names 
CYP3A substrates with narrow 
therapeutic index 
alfentanil, cyclosporine, diergotamine, dihydroergotamine, 
ergotamine, fentanyl, sirolimus, tacrolimus, terfenadine, 
warfarin sodium or any other coumadin-derivative 
anticoagulants, direct thrombin inhibitors (eg, argatroban), and 
Factor Xa inhibitors (eg, rivaroxaban) 
Moderate inhibitors of 
CYP3A4 
amprenavir, aprepitant, atazanavir, cannabinoids, casopitant, 
cimetidine, ciprofloxacin, darunavir, diltiazem, fosamprenavir, 
imatinib, metronidazole, Schisandra sphenanthera, sertraline, 
suboxone, tofisopam, verapamil, zafirlukast 
Moderate inducers of CYP3A4 bosentan, cotrimoxazole, efavirenz, etravirine, ethosuximide, 
genistein, metyrapone, mexiletine, modafinil, nafcillin, 
talviraline, tipranavir 
Medications which alter the pH 
of the GI tract a,b 
antacids, H2antagonists (eg, ranitidine), proton-pump inhibitors 
(eg, omeprazole) 
Medications that have possible 
risk of TdP/QT prolongation 
alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, eribulin, famotidine, felbamate, fingolimod, 
foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, granisertron, 
iloperidone, indapamide, isradipine, lapatinib, lithium, moexipril, 
nicardipine, nilotinib, octreotide, ofloxacin, ondansetron, 
oxytocin, paliperidone, pasireotide, quetiapine, ranolazine, 
risperidone, roxithromycin, sertindole, sunitinib, tamoxifen, 
tizanidine, vardenafil, venlafaxine, ziprasidone 
Medications that have 
conditional risk of TdP/QT 
prolongation 
amitriptyline, amisulpride, ciprofloxacin, clomipramine, 
desipramine, diphenhydramine, doxepin, fluoxetine, 
galantamine, imipramine, nortriptyline, paroxetine, protriptyline, 
sertraline, solifenacin, trazodone, trimethoprim-sulfa, 
trimipramine 
BCRP substrates 
atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin, 
sulfasalazine, topotecan 
Abbreviations: BCRP, breast cancer resistance protein;  CYP, cytochrome p; F DA, 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.  
 

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APPENDIX C:  RECIST v1.1  
Measurable Lesions  
 
Lesions that can be accurately measured in at least one dimension.  
 
Lesions with longest diameter twice the slice thickness and at least 10 mm or greater when 
assessed by CT or MRI (slice thickness 5 to 8 mm).  
 
Superficial lesions with longest diameter 10 mm or greater when assessed by caliper.  
 
Malignant lymph nodes with the short axis 15 mm or greater when assessed by CT.  
NOTE:  The shortest axis is used as the diameter for malignant lymph nodes, longest axis for all 
other measurable lesions.  
Non-measurable disease  
Non-measurable disease includes lesions too small to be considered measurable (including 
nodes with short axis between 10 and 14.9 mm) and truly non-measurable disease such as 
pleural or pericardial effusions, ascites, inflammatory breast disease, leptomeningeal disease, 
lymphangitic involvement of skin or lung, clinical lesions that cannot be accurately measured 
with calipers, abdominal masses identified by physical exam that are not measurable by 
reproducible imaging techniques.  
 
Bone disease:  Bone disease is non-measurable with the exception of soft tissue 
components that can be evaluated by CT or MRI and meet the definition of measurability at 
baseline.  
 
Previous local treatment:  A previously irradiated lesion (or lesion subjected to other local 
treatment) is non-measurable unless it has progressed since completion of treatment.  
Normal sites  
 
Cystic lesions:  Simple cysts should not be considered as malignant lesions and should not 
be recorded either as target or non-target disease.  Cystic lesions thought to represent 
cystic metastases can be measurable lesions, if they meet the specific definition above.  
If non-cystic lesions are also present, these are preferred as target lesions.  
 
Normal nodes:  Nodes with short axis < 10 mm are considered normal and should not be 
recorded or followed either as measurable or non-measurable disease.  
RECORDING TUMOR ASSESSMENTS  
All sites of disease must be assessed at baseline.  Baseline assessments should be done as 
close as possible prior to study start.  For an adequate baseline assessment, all required scans 
must be done within 28 days prior to treatment and all disease must be documented 
appropriately.  If baseline assessment is inadequate, subsequent statuses generally should be 
indeterminate.  
Target lesions  
All measurable lesions up to a maximum of 2 lesions per organ, 5 lesions in total, representative 
of all involved organs, should be identified as target lesions at baseline.  Target lesions should 

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be selected on the basis of size (longest lesions) and suitability for accurate repeated 
measurements.  Record the longest diameter for each lesion, except in the case of pathological 
lymph nodes for which the short axis should be recorded.  The sum of the diameters (longest for 
non-nodal lesions, short axis for nodal lesions) for all target lesions at baseline will be the basis 
for comparison to assessments performed on study.  
 
If two target lesions coalesce, the measurement of the coalesced mass is used.  If a large 
target lesion splits, the sum of the parts is used.  
 
Measurements for target lesions that become small should continue to be recorded.  If a 
target lesion becomes too small to measure, 0 mm should be recorded if the lesion is 
considered to have disappeared; otherwise, a default value of 5 mm should be recorded.  
NOTE:  When nodal lesions decrease to < 10 mm (normal), the actual measurement should still 
be recorded.  
Non-target disease  
All non-measurable disease is non-target.  All measurable lesions not identified as target lesions 
are also included as non-target disease.  Measurements are not required but rather 
assessments will be expressed as ABSENT, INDETERMINATE, PRESENT/NOT INCREASED, 
INCREASED.  Multiple non-target lesions in one organ may be recorded as a single item on the 
case report form (eg, ‘multiple enlarged pelvic lymph nodes’ or ‘multiple liver metastases’).  
OBJECTIVE RESPONSE STATUS AT EACH EVALUATION.  
Disease sites must be assessed using the same technique as baseline, including consistent 
administration of contrast and timing of scanning.  If a change needs to be made the case must 
be discussed with the radiologist to determine if substitution is possible.  If not, subsequent 
objective statuses are indeterminate.  
Target disease  
 
Complete Response (CR):  Complete disappearance of all target lesions with the exception 
of nodal disease.  All target nodes must decrease to normal size (short axis < 10 mm).  All 
target lesions must be assessed.  
 
Partial Response (PR):  Greater than or equal to 30% decrease under baseline of the sum 
of diameters of all target measurable lesions.  The short diameter is used in the sum for 
target nodes, while the longest diameter is used in the sum for all other target lesions.  All 
target lesions must be assessed.  
 
Stable:  Does not qualify for CR, PR or Progression.  All target lesions must be assessed.  
Stable can follow PR only in the rare case that the sum increases by less than 20% from the 
nadir, but enough that a previously documented 30% decrease no longer holds.  
 
Objective Progression (PD):  20% increase in the sum of diameters of target measurable 
lesions above the smallest sum observed (over baseline if no decrease in the sum is 
observed during therapy), with a minimum absolute increase of 5 mm.  
 
Indeterminate:  Progression has not been documented; and  
o One or more target measurable lesions have not been assessed; or  

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o Assessment methods used were inconsistent with those used at baseline; or  
o One or more target lesions cannot be measured accurately (eg, poorly visible unless due 
to being too small to measure); or  
o One or more target lesions were excised or irradiated and have not reappeared or 
increased.  
Non-target disease  
 
CR:  Disappearance of all non-target lesions and normalization of tumor marker levels.  All 
lymph nodes must be ‘normal’ in size (< 10 mm short axis).  
 
Non-CR/Non-PD:  Persistence of any non-target lesions and/or tumor marker level above 
the normal limits.  
 
PD:  Unequivocal progression of pre-existing lesions.  Generally, the overall tumor burden 
must increase sufficiently to merit discontinuation of therapy.  In the presence of SD or PR in 
target disease, progression due to unequivocal increase in non-target disease should be 
rare.  
 
Indeterminate:  Progression has not been determined and one or more non-target sites were 
not assessed or assessment methods were inconsistent with those used at baseline.  
New Lesions  
The appearance of any new unequivocal malignant lesion indicates PD.  If a new lesion is 
equivocal, for example, due to its small size, continued assessment will clarify the etiology.  If 
repeat assessments confirm the lesion, then progression should be recorded on the date of the 
initial assessment.  A lesion identified in an area not previously scanned will be considered a 
new lesion.  
Supplemental Investigations  
If CR determination depends on a residual lesion that decreased in size but did not disappear 
completely, it is recommended the residual lesion be investigated with biopsy or fine needle 
aspirate.  If no disease is identified, objective status is CR.  
If progression determination depends on a lesion with an increase possibly due to necrosis, the 
lesion may be investigated with biopsy or fine needle aspirate to clarify status. 

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Objective Response Status at each Evaluation 
Target Lesions 
Non-target Lesions 
New Lesions Objective status 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Indeterminate or Missing 
No 
PR 
PR 
Non-CR/Non-PD, Indeterminate, or Missing 
No 
PR 
SD 
Non-CR/Non-PD, Indeterminate, or Missing 
No 
Stable 
Indeterminate or 
Missing 
Non-PD 
No 
Indeterminate 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD