Clinical trial NCT02150967
Conditions: Advanced Cholangiocarcinoma FGFR2 Gene Mutation
Keywords: cholangiocarcinoma, FGFR2 gene fusion, FGFR genetic alteration
Sponsor: QED Therapeutics, Inc., a Bridgebio company
Start date: 2014-07-23; Completion date: 2022-02-07
Enrollment: 143 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is a multi-center, open label, single arm phase II study evaluating BGJ398 (infigratinib) anti-tumor activity in advanced or metastatic cholangiocarcinoma patients with fibroblast growth factor receptor (FGFR) genetic alterations.

Detailed description:
Adult patients with histologically or cytologically confirmed advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations or other FGFR genetic alterations have been enrolled. Subjects must have received at least one prior regimen containing gemcitabine with or without cisplatin for advanced/metastatic disease. Subjects should have had evidence of progressive disease following their prior regimen or if prior treatment was discontinued due to toxicity must have continued evidence of measurable disease. Up to approximately 160 adult patients over age 18, both male and female were planned for enrollment.

Three cohorts of subjects comprise the study population:

Cohort 1: subjects with FGFR2 gene fusions (ie, fusions or rearrangements \[formerly translocations\]).

Cohort 2: subjects with FGFR genetic alterations other than FGFR2 gene fusions or rearrangements.

Cohort 3: subjects with FGFR2 gene fusions or rearrangements who have received a prior FGFR inhibitor.

All subjects received oral BGJ398 (infigratinib), once-daily, on a three weeks on (21 days), one week off (7 days) schedule. One treatment cycle consists of 28 days.

Notes:

Cohort 1 was pre-specified as the primary analysis population. Results of these analyses were previously disclosed (posted 22 June 2022). There were no additional efficacy or safety endpoints to assess in Cohort 1 after primary completion (01 March 2021).

Cohorts 2 and 3 were added at protocol amendment (PA) 4 to support only exploratory efficacy objectives of the study. These cohorts were ongoing the time of primary completion (01 March 2021). After interim review of the data from these cohorts (as permitted by the protocol) only limited efficacy was observed and the sponsor terminated the study early. Therefore, a formal efficacy analysis was not performed for Cohorts 2 and 3. However, baseline characteristics and safety data were analyzed.

Arms: arm 1: To estimate the anti-tumor activity of BGJ398 (infigratinib)
Interventions: intervention 1: BGJ398 (infigratinib)
Intervention descriptions: intervention 1: Capsule for oral use

Protocol documents:
Prot_000.pdf: 
1 
 
PI 
PI 
 
 
 
 
Clinical Development 
Infigratinib (BGJ398) 
Protocol CBGJ398X2204 
 
A phase II multicenter, single arm study of oral BGJ398 in adult 
patients with advanced or metastatic 
cholangiocarcinoma with FGFR2 gene fusions or other 
FGFR genetic alterations who failed or are intolerant to platinum-based 
chemotherapy 
Sponsor 
QED Therapeutics, Inc. 
One Ferry Building, Suite 220 
San Francisco, CA 94111 
Medical Monitor 
MD 
Executive Director, 
QED Therapeutics, Inc. 
EUDRACT number 
2013-005085-19 
Development phase 
II 
 
Protocol Version Number 
Date 
00 (original protocol) 
21-Feb-2014 
01 (Amendment 1) 
11-Mar-2015 
02 (Amendment 2) 
24-Jan-2017 
04 (Amendment 3) 
19-Sep-2018 
05 (Amendment 4) 
24-Apr-2019 
05.1 (Amendment 4.1; UK-specific) 
24-Apr-2019 
06 (Amendment 5) 
15-Jan-2020 
 
Property of QED Therapeutics 
Confidential 
May not be used, divulged, published, or otherwise disclosed without the consent of QED Therapeutics. 
PI 


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Investigator’s Agreement 
 
 
I have read Protocol CBGJ398X2204 and agree to conduct the study as outlined. I agree 
to maintain the confidentiality of all information received or developed in connection 
with this protocol. 
 
 
 
 
Printed Name of Investigator 
 
 
 
 
Signature of Investigator 
 
 
 
 
Date 
 
 
 
 
Study Site Name 
 
 
 
 
Study Site Number 
 
 
Signature on this page assures the sponsor that, to the best of the investigator’s 
knowledge, the affiliated Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) operates in accordance with the 
governing regulations, and that the investigator understands, and agrees to abide by, all 
governing regulatory obligations and the International Council for Harmonisation (ICH) 
Guideline for Good Clinical Practice (GCP) and country and regional (local) 
requirements while conducting this clinical investigation. Additionally, investigator 
agrees to give access to all relevant data and records to QED Therapeutics monitors, 
auditors, QED Therapeutics Clinical Quality Assurance representatives, designated 
agents of QED Therapeutics, IRBs/IECs/REBs, and regulatory authorities as required. 


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TABLE OF CONTENTS 
TABLE OF CONTENTS ................................................................................................. 3 
LIST OF FIGURES .......................................................................................................... 7 
LIST OF TABLES ............................................................................................................ 7 
LIST OF ABBREVIATIONS .......................................................................................... 8 
GLOSSARY OF TERMS ............................................................................................... 10 
AMENDMENT 5 (15-JAN-2020) .................................................................................. 11 
AMENDMENT 4 (24-APR-2019) .................................................................................. 14 
AMENDMENT 3 (19-SEP-2018) ................................................................................... 18 
AMENDMENT 2 (24-JAN-2017) .................................................................................. 24 
AMENDMENT 1 (11-MAR-2015) ................................................................................. 28 
PROTOCOL SUMMARY ............................................................................................. 31 
1 
BACKGROUND ...................................................................................................... 34 
1.1 
Overview   of   disease   pathogenesis,   epidemiology   and   current 
treatment .............................................................................................................. 34 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) ......................................................................................................... 35 
1.2.1 
Overview of BGJ398 ..................................................................................... 35 
2 
RATIONALE ........................................................................................................... 37 
2.1 
Study rationale and purpose .............................................................................. 37 
2.2 
Rationale for the study design ............................................................................ 38 
2.3 
Rationale for dose and regimen selection ......................................................... 40 
3 
OBJECTIVES AND ENDPOINTS ........................................................................ 41 
4 
STUDY DESIGN ..................................................................................................... 42 
4.1 
Description of study design ................................................................................ 42 
4.2 
Timing of interim analyses and design adaptations ......................................... 45 
4.3 
Assessment of potential mechanisms of resistance ........................................... 46 
4.4 
Definition of end of the study ............................................................................. 46 
4.5 
Early study termination ..................................................................................... 46 
5 
POPULATION ......................................................................................................... 46 
5.1 
Patient population ............................................................................................... 46 
5.2 
Inclusion criteria ................................................................................................. 47 
5.2.1 
Additional inclusion criteria for Cohort 3 .................................................. 48 
5.3 
Exclusion criteria ................................................................................................ 48 
5.3.1 
Additional exclusion criteria for Cohort 3 .................................................. 51 
6 
TREATMENT .......................................................................................................... 51 
6.1 
Study treatment ................................................................................................... 51 
6.1.1 
Dosing regimen .............................................................................................. 51 
6.1.2 
Ancillary treatments ..................................................................................... 53 
6.1.3 
Treatment duration ...................................................................................... 53 
6.2 
Dose modifications .............................................................................................. 53 
6.2.1 
Dose modifications and dose delay .............................................................. 53 
6.2.2 
Follow-up for toxicities ................................................................................. 62 
6.2.3 
Anticipated risks and safety concerns for the study drug ......................... 62 
6.3 
Concomitant medications ................................................................................... 62 


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6.3.1 
Permitted concomitant therapy ................................................................... 62 
6.3.2 
Permitted concomitant therapy requiring caution and/or action ............ 65 
6.3.3 
Prohibited concomitant therapy .................................................................. 66 
6.4 
Patient numbering, treatment assignment or randomization ......................... 67 
6.4.1 
Patient numbering ........................................................................................ 67 
6.4.2 
Treatment assignment or randomization ................................................... 67 
6.4.3 
Treatment blinding ....................................................................................... 67 
6.5 
Study drug preparation and dispensation ........................................................ 68 
6.5.1 
Study drug packaging and labeling ............................................................. 68 
6.5.2 
Drug supply and storage .............................................................................. 69 
6.5.3 
Study drug compliance and accountability ................................................ 69 
6.5.4 
Disposal and destruction .............................................................................. 69 
7 
VISIT SCHEDULE AND ASSESSMENTS .......................................................... 70 
7.1 
Study flow and visit schedule ............................................................................. 70 
7.1.1 
Molecular pre-screening ............................................................................... 74 
7.1.2 
Screening ........................................................................................................ 74 
7.1.3 
Treatment period .......................................................................................... 75 
7.1.4 
Discontinuation of study treatment ............................................................. 76 
7.1.5 
Withdrawal of consent .................................................................................. 76 
7.1.6 
Follow-up period ........................................................................................... 77 
7.1.7 
Lost to follow-up ........................................................................................... 78 
7.2 
Assessment types ................................................................................................. 78 
7.2.1 
Efficacy assessment ....................................................................................... 78 
7.2.2 
Safety and tolerability assessment ............................................................... 79 
7.2.3 
Pharmacokinetics .......................................................................................... 83 
7.2.4 
Biomarkers .................................................................................................... 86 
8 
SAFETY MONITORING AND REPORTING .................................................... 89 
8.1 
Adverse events ..................................................................................................... 89 
8.1.1 
Definition and reporting ............................................................................... 89 
8.1.2 
Laboratory test abnormality ........................................................................ 91 
8.2 
Serious adverse events ........................................................................................ 92 
8.2.1 
Definitions ...................................................................................................... 92 
8.2.2 
Reporting ....................................................................................................... 93 
8.3 
Emergency blinding of treatment assignment .................................................. 94 
8.4 
Pregnancies .......................................................................................................... 94 
8.5 
Warning and precautions ................................................................................... 95 
8.6 
Data monitoring committee ............................................................................... 95 
8.7 
Steering committee .............................................................................................. 95 
9 
DATA COLLECTION AND MANAGEMENT ................................................... 95 
9.1 
Data confidentiality ............................................................................................. 95 
9.2 
Site monitoring .................................................................................................... 96 
9.3 
Data collection ..................................................................................................... 96 
9.4 
Database management and quality control ...................................................... 97 
10 STATISTICAL METHODS AND DATA ANALYSIS ........................................ 97 
10.1 
Analysis sets ......................................................................................................... 98 
10.1.1 
Full Analysis Set ............................................................................................ 98 


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10.1.2 
Interim Efficacy Analysis Set 1 for Cohort 1 ............................................. 98 
10.1.3 
Interim Analysis Set 2 for Cohort 1 ............................................................ 99 
10.1.4 
Sensitivity Analysis Set for Cohort 1 ........................................................... 99 
10.1.5 
Interim Analysis Set for Cohort 3 ............................................................... 99 
10.1.6 
Per-Protocol Set ............................................................................................ 99 
10.1.7 
Pharmacokinetic analysis set ....................................................................... 99 
10.2 
Patient demographics/other baseline characteristics .................................... 100 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ............. 100 
10.3.1 
Study treatment ........................................................................................... 100 
10.3.2 
Concomitant therapies ................................................................................ 100 
10.3.3 
Compliance .................................................................................................. 100 
10.4 
Primary objective .............................................................................................. 100 
10.4.1 
Variable ........................................................................................................ 100 
10.4.2 
Statistical hypothesis, model, and method of analysis ............................. 100 
10.4.3 
Handling of missing values/censoring/discontinuations .......................... 101 
10.5 
Secondary objectives ......................................................................................... 101 
10.5.1 
Secondary efficacy objectives and variables ............................................. 101 
10.5.2 
Safety objectives and variables .................................................................. 102 
10.5.3 
Pharmacokinetics ........................................................................................ 104 
10.5.4 
Resource utilization .................................................................................... 106 
10.5.5 
Patient-reported outcomes ......................................................................... 106 
10.6 
Exploratory objectives ...................................................................................... 106 
10.6.1 
Biomarkers .................................................................................................. 107 
10.6.2 
Objectives for Cohorts 2 and 3 .................................................................. 108 
10.7 
Interim analysis ................................................................................................. 108 
10.8 
Sample size calculation ..................................................................................... 109 
10.8.1 
Cohort 1 ....................................................................................................... 109 
10.8.2 
Cohorts 2 and 3 ........................................................................................... 109 
10.9 
Power for analysis of key secondary variables ............................................... 110 
11 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES ...................................................................................................... 110 
11.1 
Regulatory and ethical compliance ................................................................. 110 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ................................. 110 
11.3 
Informed consent procedures .......................................................................... 111 
11.4 
Discontinuation of the study ............................................................................ 111 
11.5 
Publication of study protocol and results ....................................................... 111 
11.6 
Study documentation, record keeping and retention of documents ............. 112 
11.7 
Confidentiality of study documents and patient records .............................. 113 
11.8 
Audits and inspections ...................................................................................... 113 
11.9 
Financial disclosures ......................................................................................... 113 
12 PROTOCOL ADHERENCE ................................................................................ 113 
12.1 
Amendments to the protocol ............................................................................ 113 
13 REFERENCES (AVAILABLE UPON REQUEST) ........................................... 115 
14 APPENDICES ........................................................................................................ 117 
14.1 
Appendix 1: List of concomitant medications ................................................ 117 
14.2 
Appendix 2: List of prohibited medications ................................................... 119 


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14.3 
Appendix 3: Guidelines for assessments of response ..................................... 120 
14.3.1 
Introduction ................................................................................................. 120 
14.3.2 
Disease measurability ................................................................................. 120 
14.3.3 
Methods of tumor measurement - general guidelines .............................. 121 
14.3.4 
Baseline documentation of target and non-target lesions ........................ 123 
14.3.5 
Follow-up evaluation of target and non-target lesions ............................ 124 
14.3.6 
Follow-up and recording of lesions ............................................................ 124 
14.3.7 
Non-nodal lesions ........................................................................................ 124 
14.3.8 
Nodal lesions ................................................................................................ 124 
14.3.9 
Determination of target lesion response .................................................... 125 
14.3.10 
Determination of non-target lesion response ............................................ 127 
14.3.11 
New lesions ................................................................................................... 128 
14.3.12 
Evaluation of overall lesion response ........................................................ 128 
14.4 
Appendix 4: FGFR1/2/3 Allowed Mutations (Known Activating 
Mutations) .......................................................................................................... 130 
14.5 
Appendix 5: List of Highly Effective Methods of Contraception ................. 131 


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LIST OF FIGURES 
Figure 1: 
Study Design ............................................................................................ 43 
 
LIST OF TABLES 
Table 1: 
Objectives and related endpoints for Cohort 1 and overall 
study ......................................................................................................... 41 
Table 2: 
Objectives and related endpoints for Cohorts 2 and 3 ........................ 41 
Table 3: 
Dose and treatment schedule ................................................................. 51 
Table 4: 
Dose reduction table ............................................................................... 54 
Table 5: 
Criteria for interruption and re-initiation of BGJ398 treatment ....... 55 
Table 6: 
Recommended Management of Alopecia, Palmar-Plantar 
Erythrodysesthesia Syndrome, Paronychia, and Stomatitis ............... 65 
Table 7: 
Visit evaluation schedule for all cohorts ............................................... 71 
Table 8: 
ECOG performance status ..................................................................... 80 
Table 9: 
Clinical laboratory parameters collection plan .................................... 82 
Table 10: 
Pharmacokinetic blood collection time points for patients 
(applicable for patients enrolled under amendment 1 and 
patients on sparse PK sample group) .................................................... 84 
Table 11: 
Pharmacokinetic blood collection time points for patients (for 
first 20 patients treated with FMI III [Cohort 1] and all 
patients treated with FMI IV [Cohort 2 and 3]: extensive PK 
group) ....................................................................................................... 85 
Table 12: 
Biomarker sample collection plan ......................................................... 87 
Table 13: 
Non-compartmental pharmacokinetic parameters ............................ 105 
Table 14: 
95% CI examples corresponding to observed numbers of 
patients considered to have benefited from treatment 
(Cohorts 2 and 3) ................................................................................... 110 
Table 15: 
Drugs to be used with caution while on study .................................... 117 
Table 16: 
List of prohibited medications and substances while on study ......... 119 
Table 17: 
Response criteria for target lesions ..................................................... 125 
Table 18: 
Response criteria for non-target lesions .............................................. 127 
Table 19: 
Overall lesion response at each assessment ........................................ 129 


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LIST OF ABBREVIATIONS 
AE 
Adverse Event 
ALT/SGPT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolutely Neutrophil Count 
AST/SGOT 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC0-24 
Area Under the Curve 0-24 h 
BCRP 
Breast Cancer Resistance Protein 
BICC1 
Bicaudal C homolog 1 
BUN 
Blood Urea Nitrogen 
CI 
confidence interval 
CL 
Clearance 
Cmax 
Maximum Concentration 
CNS 
Central Nervous System 
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CSF 
Colony Stimulating Factor 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CYP 
Cytochrome P 
DLT 
Dose limiting toxicity 
DNA 
Deoxyribonucleic Acid 
ECC 
Extrahepatic cholangiocarcinoma 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report/Record Form 
EOT 
End of Treatment 
FAS 
Full Analysis Set 
FGFR 
Fibroblast Growth Factor receptor 
FGFR1 
Fibroblast Growth Factor receptor 1 
FGFR2 
Fibroblast Growth Factor receptor 2 
FGFR3 
Fibroblast Growth Factor receptor 3 
FLT1 
Fms-related tyrosine kinase 1 
FMI I 
Final Market Image version 1 
FMI III 
Final Market Image version 3 
FMI IV 
Final Market Image version 4 
GI 
Gastrointestinal 
hCG 
human chorionic gonadotrophin 
hERG 
Human Ether-à-go-go-Related Gene 
IB 
Investigator’s Brochure 
IC50 
Half maximal Inhibitory Concentration 
ICC 
Intrahepatic cholangiocarcinoma 
ICF 
Informed Consent Form 
IEC 
Independent Ethics Committee 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
K-M 
Kaplan-Meier 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry 
LLN 
lower limit of normal 
LLOQ 
Lower Limit of Quantification 
LVEF 
Left Ventricular Ejection Fraction 
MEK 
mitogen-activated protein kinase kinase 


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MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gated acquisition scan 
N 
Sample size 
NSCLC 
Non-small cell lung cancer 
NYHA 
New York Heart Association 
OCT 
optical coherence tomography 
ORR 
Overall Response Rate 
OS 
Overall survival 
PD 
Pharmacodynamics 
PFS 
Progression-free survival 
P-gp 
P-glycoprotein 
PK 
Pharmacokinetics 
PPS 
Per protocol set 
PR 
Partial Response 
PT 
Prothrombin time 
qd 
once a day 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase II dose 
RT 
Radiation therapy 
RT_PCR 
Reverse transcription polymerase chain reaction 
SAE 
Serious Adverse Event 
SAP 
Statistical Analysis Plan 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
TdP 
Torsades de Pointes 
tmax 
The time at which the maximum observed concentration (Cmax) occurs 
ULN 
Upper Limit of Normal 
Vss 
Volume of distribution at steady state 
WBC 
White Blood Cell 


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GLOSSARY OF TERMS 
Assessment 
A procedure used to generate data required by the study 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.: q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.) 
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug.” 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival. 
Stage related to study timeline A major subdivision of the study timeline; begins and ends with major 
study milestones such as enrollment, randomization, completion of 
treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer has 
spread from the original site to other parts of the body. 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later. 
Study treatment 
Includes any drug or combination of drugs in any study arm administered to 
the patient (subject) as part of the required study procedures, including 
placebo and active drug run-ins. 
In specific examples, it is important to judge investigational treatment 
component relationship relative to a study treatment combination; study 
treatment in this case refers to the investigational and noninvestigational 
treatments in combination. 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking study treatment for any 
reason; may or may not also be the point/time of premature patient 
withdrawal 
Supportive treatment 
Refers to any treatment required by the exposure to a study treatment, e.g. 
premedication of vitamin supplementation and corticosteroid for 
pemetrexed disodium. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
collected using specified assessments at specified time points. 


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AMENDMENT 5 (15-JAN-2020) 
Amendment rationale 
 
The primary purpose of this amendment is to: 
 
• Revise based on updates to standards for safety and study conduct for BGJ398. 
• Add second interim analysis. 
Changes to the protocol 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strikethrough for deletions and underlines for insertions. 
 
• Title page: Updated the Medical Monitor from 
MD, to 
MD; updated protocol version history. 
 
• Investigator’s Agreement: Added statement of purpose for signature. 
• Synopsis, Purpose and Rationale; Section 1.2.1; Section 2.2: Corrected “pan-FGFR 
inhibitor” to “FGFR 1-3 inhibitor” (with corresponding data, in Section 1.2.1.1). 
 
• Synopsis, Population; Section 2.2; Section 4.1: Clarified number of patients with and 
without FGFR2 gene fusions or translocations in Cohort 1. 
 
• Synopsis, Main Inclusion Criteria; Section 5.2 (inclusion criteria 2 and 3); 
Section 7.1; Section 7.2.4: Clarified requirements for determination of FGFR gene 
alterations. 
 
• Synopsis, Main Inclusion Criteria; Section 5.2 (inclusion criteria 4 and 5); 
Sections 14.3.3, 14.3.14, and 14.3.15 (Appendix 3): Removed “or evaluable” from 
disease criteria. 
 
• Synopsis, Main Exclusion Criteria; Section 5.3 (exclusion criterion 5): Removed 
“corneal abrasion” as a disqualifying disorder; other edits for consistency. 
 
• Synopsis, Investigational and reference therapy; Section 1.2.1: Defined BGJ398 as 
“infigratinib,” noting other names/codes, for consistency. 
 
• Section 1.2.1.1: Updated BGJ398’s effect on kinase activity for consistency with the 
current Investigator’s Brochure. 
 
• Section 1.2.1.2: Replaced outdated clinical safety and efficacy information with a 
referral to the current Investigator’s Brochure. 
 
• Section 1.2.1.2.3 (old)/1.2.1.2.1 (new); Section 6.3.2; Section 14.1 (Appendix 1); 
Section 14.2 (Appendix 2): Added description of midazolam study, which resulted in 
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revised QED standards (outlined Section 6.3.2, Section 14.1 [Appendix 1], and 
Section 14.2 [Appendix 2]). 
 
• Section 2.3; Section 7.1; Section 7.2.3.1; Section 10.5.3: Revised to specify that all 
patients in Cohorts 2 and 3 (who are treated with FMI IV) will undergo extensive PK 
sampling, and data will be assessed and compared with data from patients treated 
with FMI III. 
 
• Section 4.1 (subheading: Survival follow-up), Section 7.1.6 (subheading: Survival 
follow-up period): Revised to allow survival follow-ups at more frequent intervals. 
 
• Section 4.2: Revised to eliminate obsolete content and to clarify previous data 
reviews. 
 
• Section 4.2; Section 10: Revised to specify two formal interim analyses planned for 
Cohort 1. A Sensitivity Analysis Set for Cohort 1 was also defined (Section 10). 
 
• Section 5.3: Removed exclusion criteria 12, 13, and 14. 
• Section 5.3: Specified more precise criterion for patients with Gilbert syndrome and 
specified use of Cockcroft-Gault formula. 
 
• Section 5.3: Exclusion criterion 14 (formerly 17) was made more precise. 
• Section 5.3: Exclusion criterion 17 (formerly 20) was revised to cite the Clinical 
Trials Facilitation Group 2014 guideline and for consistency with other BGJ398 
protocols. 
 
• Section 5.3: Added exclusion criterion 20. 
• Section 6 and 6.1: Specified “hard gelatin capsules” for BGJ398 oral administration. 
Updated and clarified instructions for BGJ398 administration. 
 
• Section 6.2.1; Section 6.2.2; Section 6.2.3; Section 6.3.1; Section 6.3.2: Clarified 
dose modifications and delays, consistent with other BGJ398 protocols, including 
changes and additions to Table 5 (primarily for serum creatinine, blood bilirubin, 
hypophosphatemia, and hyperphosphatemia) and management of those and other 
potential study drug effects (primarily in Section 6.3.1) and of permitted concomitant 
therapy (Section 6.3.2). 
 
• Section 6.3.3; Section 14.1 (Appendix 1); Section 14.2 (Appendix 2): Removed 
medications with a known risk of QT/QTc interval prolongation or torsade de pointes 
from prohibited concomitant therapy (Section 6.3.3 and Appendix 14.2). These 
medications were included in Table 15, Drugs to be used with caution while on study 
(Appendix 14.1). This change was made because preliminary PK-QTc analysis of 
BGJ398 did not show a relationship between drug concentration and QTc 
prolongation. 


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• Section 7.1; Section 7.2: Clarified screening and visit windows and in-clinic study 
drug administration. Added footnote (Table 7) to clarify FGFR2 gene fusion or 
translocation requirements. Removed provision for replacement of patients in Cohorts 
2 and 3 for PK sampling purposes. Clarified molecular pre-screening procedures, as 
well as imaging requirements and guidelines. Clarified ophthalmic assessments. 
Added that retinal OCT can images may be collected centrally. Clarified 
circumstances for study treatment discontinuation. Added detail for extensive PK 
sampling (Table 11). Added detail for assessment of biomarkers. 
 
• 
Section 8.1.1: Removed inconsistent sentence regarding AE reporting. 
• Section 8.2.2; Section 8.4: Replaced Chiltern Drug Safety with Covance Safety. 
Replaced the email address GlobalSAEInbox@chiltern.com with the email address 
SAEintake@covance.com. 
 
• Section 8.4: Clarified follow-up for pregnancy. 
• Section 9.1: Updated data confidentiality. 
• Section 9.4: Updated database management and quality control. 
• Section 11.3: Clarified informed consent procedures. 
• Section 11.7: Updated confidentiality of study documents and patient records. 
• Section 13: Updated reference list. 
• Section 14.3.16 (Appendix 3); Section 14.4 (Appendix 4): Moved references to 
Section 13. 
 
• Section 14.5 (Appendix 5): Added list of highly effective methods of contraception 
excerpted from the Clinical Trials Facilitation Group 2014. 
 
• Throughout: Removed “et al” from citations in text, according to updated QED 
standards, and other administrative or editorial changes. 
 
 
IRBs/IECs 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Study centers are required to update and 
submit for approval a revised informed consent that takes into account the changes 
described in this protocol amendment. 


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AMENDMENT 4 (24-APR-2019) 
Amendment rationale 
 
The primary purpose of this amendment is to: 
 
• Revise assessment of overall response for the primary endpoint for patients with 
FGFR2 gene fusions or translocations from confirmation by investigator to 
confirmation by independent central confirmation (according to FDA advice), and 
change investigator assessment of overall response from a primary to a secondary 
objective. 
 
• Include an interim analysis, occurring when the patients enrolled prior to 
amendment 2 have potentially been followed up for at least 10 months after their 
initial exposure to study treatment. 
 
• Revise the RECIST criteria guidelines (Appendix 3, Section 14.3) to be consistent 
with published criteria. 
 
• Include 2 additional cohorts, allowing enrollment of patients with known FGFR1, 2, 
or 3 activating mutation or FGFR1 or 3 fusions or translocations (Cohort 2; 
20 patients) and patients with FGFR2 gene fusions or translocations after previous 
treatment with gemcitabine-containing regimen followed by progression on an FGFR 
inhibitor (excluding BGJ398) (Cohort 3; 10 or 20 patients). Rationale is provided in 
Section 2.2. 
 
• Include an interim analysis for Cohort 3 when the first 10 patients who receive study 
treatment have the potential to complete their second scheduled scan; this analysis is 
to determine if an additional 10 patients will be added to the cohort. 
 
• Clarify that 108 patients with FGFR2 gene fusions or translocations will be included 
in Cohort 1, and this sample size is the basis of statistical analyses for this group. 
 
• Allow another formulation of BGJ398 (ie, final market image version 4, or FMI IV) 
to be administered to patients, with accompanying pharmacokinetic analysis and 
analysis comparing the 3 formulations administered in the study. 
 
• Extend follow-up for survival from one year to 5 years after discontinuation of study 
treatment or until patients have died, withdrawn consent, or been lost to follow-up. 
 
• Exclude patients with history and/or current evidence of extensive tissue calcification 
of the vascular system (according to FDA advice). 
 
• Modify criteria for interruption and re-initiation of BGJ398 treatment (Table 5) in 
accordance with QTc evaluation plan submitted to FDA and for consistency with 
other ongoing studies of BGJ398. 


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PI 
PI 
 
• Include retinal optical coherence tomography (OCT) in the ophthalmic examination. 
• Revise PK sparse sampling times. 
• Add section describing adverse event reporting for overdose of BGJ398 and for Hy’s 
Law criteria. 
 
• Add statement that any suspected transmission of an infectious agent via a medicinal 
product will be considered an SAE at study centers in the EU. 
 
• Revise and update list of drugs to be used with caution on study (Table 15) and list of 
prohibited medication while on study (Table 16). 
 
• Add FGFR1/2/3 known activating mutations list for Cohort 2 inclusion criteria 
(Appendix 4, Section 14.4.). 
 
• Change the Medical Monitor from 
MD, MSCE, to 
MD. 
• Revert to original protocol version numbering (ie, undo the version numbering that 
was reassigned for versions 00, 01, and 02 in amendment 3); consequently, no 
version 03 exists for this protocol, and protocol version numbering now corresponds 
with protocols distributed for study conduct. 
 
• Revise administrative details and edits for consistency and clarity throughout the 
protocol, notably including (1) collapse of Section 8.3.1 (now deleted) into Section 
8.1.1 to eliminate redundancy and inconsistency and (2) revision of nomenclature 
from “FMIv3” to “FMI III” for consistency within the BGJ398 development program. 
 
Changes to the protocol 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
 
• Title page: Changed the Medical Monitor name and contact information. Changed the 
protocol version numbering. 
 
• Clinical Protocol Approval Page: Removed from protocol and replaced by separate 
approval page (not included within the protocol). 
 
• Protocol Summary: Revised to account for amendment changes in the main body. 
• Section 1.2.1.2.3: Clinical pharmacokinetics: Revised Tmax from 2 hours to 3-4 hours. 
• Section 2.2, Rationale for the study design: Added description for all cohorts, with 
rationale for Cohorts 2 and 3. 
 
• Section 2.3, Rationale for dose and regimen selection: Added description and 
rationale for the FMI IV formulation of BGJ398. 


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• Section 3, Objectives and endpoints: Clarified objectives for Cohort 1 and the overall 
study. Added objectives and endpoints for Cohorts 2 and 3. 
 
• Section 4, Study design: Described new cohorts and revised total number of patients 
to be enrolled in the study. Added description of interim analyses. Added footnote 
about screening assessments to Figure 1. Changed survival follow-up period from 
1 year to 5 years. Described interim analyses planned. Clarified the definition of end 
of the study. 
 
• Section 5, Population: Added entry criteria specific to Cohorts 2 and 3. Added 
“vascular system” to exclusion criterion #6. Added exclusion criterion #22 for all 
cohorts. 
 
• Section 6, Treatment: Added FMI IV formulation. Clarified dosing instructions. 
Changed dosing window from 24±2 hours to 24±4 hours. Described the timing of 
FMI IV administration. Added that proton pump inhibitors should be avoided. 
Revised criteria for interruption and re-initiation of BGJ398 treatment to be consistent 
with other ongoing studies. Clarified prohibited concomitant therapy for “other 
investigational and antineoplastic therapies.” Added description of FMI III and FMI 
IV drug supply. 
 
• Section 7, Visit Schedule and Assessments: Added footnotes to Table 7 to clarify 
assessments. Changed screening period from -28 days to -21 days and added footnote 
to Table 7 to clarify. Added a Day 15 visit for Cycles 4-6 to accommodate new PK 
sampling times. Clarified that no further imaging is required for patients who have 
documented radiographic disease progression and continue study treatment. Clarified 
molecular pre-screening for the cohorts. Added OCT as an ophthalmic assessment. 
Added 4-hour post-dose ECG assessment on Cycle 1 Days 1 and 15, and clarified 
recording of ECGs and cardiac imaging assessments. Defined PK sampling by cohort. 
Added sparse PK sampling times for newly enrolled patients at 4 hours post-dose on 
Cycle 1 Days 1 and 15; and added PK sampling pre-dose and 4 hours post-dose on 
Day 15 of Cycles 2-6 (Table 10). Added explanation of future research and storing of 
biological samples for such research in cholangiocarcinoma. 
 
• Section 8, Safety Monitoring and Reporting: Revised to eliminate redundancy and 
inconsistency among Sections 8.1.1, 8.1.2, and 8.1.3. Removed Section 8.1.3. Added 
subsections to describe reporting overdose of BGJ398 and Hy’s Law potential AEs. 
Clarified reporting of pregnancy and follow-up. 
 
• Section 10, Statistical Methods and Data Analysis: Revised to account for analyses of 
new cohorts. Refined definitions of analysis sets and clarified and updated all 
analyses based on the new cohorts and definitions. Overall response rate (ORR) 
analysis was updated from Bayesian to Frequentist approach; the ORR will be 
estimated with exact binomial 95% confidence interval (CI). Revised sample size 
calculations based on new cohorts and analysis groups. Revised plans for interim 
analyses. 


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• Section 13, References (Available upon Request): Added 3 new references. 
• Section 14, Appendices: Appendix 1: Revised list of drugs to be used with caution. 
• Section 14, Appendices: Appendix 2: Revised list of prohibited medication. 
• Section 14, Appendices: Appendix 3: Revised RECIST criteria guidelines to be 
consistent with published criteria and simplified to consolidate details and move them 
to more relevant sections (ie, Section 10). 
 
• Section 14, Appendices: Appendix 4: Added appendix to list FGFR1/2/3 allowed 
mutations for qualification for study entry. 
 
IRBs/IECs 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Study centers are required to update and 
submit for approval a revised informed consent that takes into account the changes 
described in this protocol amendment. 


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Protocol No. CBGJ398X2204 
 
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AMENDMENT 3 (19-SEP-2018) 
Amendment Rationale 
 
The main purpose of this amendment is to change the Sponsor name from Novartis to 
QED Therapeutics and provide safety reporting information for the clinical research 
organization working with QED Therapeutics. 
 
Changes to the protocol 
 
1. Administrative updates are made throughout the protocol to change Sponsor from 
“Novartis” to “QED Therapeutics”. 
 
2. Title Page was changed to remove Protocol Authors and replace with Medical 
Monitor; Sponsor name was also added. Added logo for QED. 
 
3. Added dates for each protocol amendment to the Title Page of the protocol. 
 
4. Added an Investigator’s Signature page. 
 
5. List of Abbreviations was updated to remove abbreviations not used in the protocol. 
 
6. Section 2.3. 
 
Changed From: 
 
Patients enrolled in this study will receive 125 mg qd of BGJ398 on a 3 weeks on (21 
day) /1 week off (7 day) schedule. This dose level and regimen is based on 
experiences from the CBGJ398X2101 trial. 
 
Changed To: 
 
Patients enrolled in this study will receive 125 mg qd of BGJ398 on a 3 weeks on (21 
day) /1 week off (7 day) schedule in 28-day cycles. This dose level and regimen is 
based on experiences from the CBGJ398X2101 trial. 
 
7. Section 6.1.3 
 
Changed From: 
 
All patients will receive BGJ398 daily on a three week on (21 days), one week off (7 
days) schedule in 28-day cycles. Patients may continue treatment with BGJ398 until 
the patient experiences unacceptable toxicity, disease progression, and/or treatment is 
discontinued at the discretion of investigator or withdrawal of consent. 
 
Changed To: 
 
All patients will receive BGJ398 daily on a three week on (21 days), one week off (7 
days) schedule in 28-day cycles. Patients may continue treatment with BGJ398 until 


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the patient experiences unacceptable toxicity, disease progression, and/or treatment is 
discontinued at the discretion of investigator or withdrawal of consent, or death. 
 
8. Section 6.5.3.2 
 
Changed From: 
 
At study close-out, and, as appropriate during the course of the study, the investigator 
will return all used and unused study treatment, packaging, drug labels, and a copy of 
the completed drug accountability log to the Novartis monitor or to the Novartis 
address provided in the investigator folder at each site. 
 
Changed To: 
 
At study close-out, and, as appropriate during the course of the study, the investigator 
will provide access to all used and unused study treatment, packaging, drug labels, 
and a copy of the completed drug accountability log to the monitor. 
 
9. Section 6.5.4 
 
Changed From: 
 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply 
group or third party, as appropriate. Drug supply can be destroyed at the site if 
permitted by local regulations. 
 
Changed To: 
 
The study drug can be destroyed at the site if permitted by local regulations. 
Alternatively, the study drug can be destroyed at a third party depot. 
 
10. Section 7.1 (Table 5: Visit Evaluation Schedule): Removed reference to Section 7.1.5 
of the protocol on the row for Tumor Response per RECIST 1.1 (the section reference 
was incorrect) and changed the reference on the row for Survival Follow-up from 
Section 7.1.5 to 7.1.6. Also removed footnote a, is it did not seem to be relevant. 
 
11. Section 7.2.3.1: Added the missing volume (3mL) to the PK sampling table for the 2 
hour postdose assessment at Cycle 1 Day 2. 
 
12. Section 7.2.4.1 and 7.2.4.2: Removed reference to the Sponsor’s laboratory manual in 
the following sentence. 
 
The sample collection must be captured on the appropriate eCRF and requisition 
page(s). Detailed instructions for the collection, handling, labeling, and shipment of 
samples are outlined in the CRO Laboratory Manuals or Novartis lab manual. 


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13. Section 8.2.2. 
 
Changed From: 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment must be reported to Novartis within 24 hours of 
learning of its occurrence. Any SAEs experienced after this 30 days period should 
only be reported to Novartis if the investigator suspects a causal relationship to the 
study treatment…... 
 
….. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and submit the completed form within 24 hours to Novartis. 
Detailed instructions regarding the submission process and requirements for 
signatures are to be found in the investigator folder provided to each site. 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the Novartis study treatment, a 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently 
require further information from the investigator for Health Authority reporting. 
Novartis may need to issue an Investigator Notification (IN), to inform all 
investigators involved in any study with the same drug that this SAE has been 
reported. 
Changed To: 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring 
after the patient has provided informed consent and until at least 30 days after the 
patient has stopped study treatment must be reported to Chiltern Drug Safety (email: 
GlobalSAEInbox@chiltern.com; FAX: 1-888-726-8416) within 24 hours of learning 
of its occurrence. Any SAEs experienced after this 30 days period should only be 
reported to Chiltern Drug Safety if the investigator suspects a causal relationship to 
the study treatment…... 
 
….. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE 
Report Form in English, and submit the completed form within 24 hours to Chiltern 
Drug Safety (email: GlobalSAEInbox@chiltern.com; FAX: 1-888-726-8416). 
Detailed instructions regarding the submission process and requirements for 
signatures are to be found in the investigator folder provided to each site. 
If the SAE is not previously documented in the Investigator’s Brochure or Package 
Insert (new occurrence) and is thought to be related to the study treatment, a Chiltern 
Drug Safety associate may urgently require further information from the investigator 
for Health Authority reporting. Chiltern Drug Safety may need to issue an 
Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. 


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14. Section 8.4 
 
Changed From: To ensure patient safety, each pregnancy occurring while the patient 
is on study treatment must be reported to Novartis within 24 hours of learning of its 
occurrence. 
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by 
the investigator to the oncology Novartis Drug Safety and Epidemiology (DS&E) 
department. 
 
Changed To: To ensure patient safety, each pregnancy occurring while the patient is 
on study treatment must be reported to Chiltern Drug Safety (email: 
GlobalSAEInbox@chiltern.com; FAX: 1-888-726-8416) within 24 hours of learning 
of its occurrence. 
 
Pregnancy should be recorded on a Clinical Study Pregnancy Form and reported by 
the investigator to Chiltern Drug Safety (email: GlobalSAEInbox@chiltern.com; 
FAX: 1-888-726-8416). 
 
15. Section 10.6.1.1 
 
Changed From: As the project standard, PD markers collected in the clinical 
database will be analyzed by Novartis Oncology BDM. 
 
Changed To: PD markers collected in the clinical database will be analyzed by QED 
Therapeutics or designated CRO. 
 
16. Section 11.5 
 
Changed From: In addition, results of interventional clinical trials in adult patients 
are posted on www.novartisclinicaltrials.com, a publicly accessible database of 
clinical study results within 1 year of study completion (i.e., LPLV), those for 
interventional clinical trials involving pediatric patients within 6 months of study 
completion. 
 
……For the Novartis Guidelines for the Publication of Results from Novartis- 
sponsored Research, please refer to www.novartis.com. 
 
Changed To: In addition, results of interventional clinical trials will be posted 
publically per local regulations. 
 
17. Section 14.3 (Appendix 3): Removed the row for Document Type. 


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Document type: 
TA Specific Guideline 
Document status: 
Version 3.1: 29-Nov-2011 
Version 3.0: 19-Oct-2009 
Version 2.0: 18-Jan-2007 
Version 1.0: 13-Dec-2002 
 
 
18. Section 14.3.1 (Appendix 3) 
 
Changed From: 
 
The efficacy assessments described in Section 14.3.2 and the definition of best 
response in Section 14.3.17 are based on the RECIST 1.1 criteria but also give more 
detailed instructions and rules for determination of best response. Section 14.3.18 is 
summarizing the “time to event” variables and rules which are mainly derived from 
internal discussions and regulatory consultations, as the RECIST criteria. do not 
define these variables in detail. Section 14.3.28 of this guideline describes data 
handling and programming rules. This section is to be referred to in the RAP 
(Reporting and Analysis Plan) to provide further details needed for programming. 
 
Changed To: 
 
The efficacy assessments described in Section 14.3.2 and the definition of best 
response in Section 14.3.17 are based on the RECIST 1.1 criteria but also give more 
detailed instructions and rules for determination of best response. Section 14.3.27 of 
this guideline describes data handling and programming rules. 
 
19. Section 14.3.18 (Appendix 3) 
 
Changed From: 
 
 14.3.18 
Time to event variables 
 
Changed To: 
 
[no text- there was nothing but a header for this section of the appendix; all 
subsequent sections were renumbered accordingly] 
 
20. Minor editing and formatting changes were made. Due to errors in the protocol file 
received from Novartis, the Table of Contents and Lists of Tables and Figures were 
regenerated. In doing so, the figures and tables were renumbered, as follows: 


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OLD FIGURE NUMBER 
NEW FIGURE NUMBER 
Figure 4-1 
Figure 1 
OLD TABLE NUMBER 
NEW TABLE NUMBER 
Table 3-1 
Table 1 
Table 6-1 
Table 2 
Table 6-2 
Table 3 
Table 6-3 
Table 4 
Table 7-1 
Table 5 
Table 7-2 
Table 6 
Table 7-3 
Table 7 
Table 7-4 
Table 8 
Table 7-5 
Table 9 
Table 7-6 
Table 10 
Table 10-1 
Table 11 
Table 10-2 
Table 12 
Table 10-3 
Table 13 
Table 10-4 
Table 14 
Table 14-1 
Table 15 
Table 14-2 
Table 16 
Table 14-3 
Table 17 
Table 14-4 
Table 18 
Table 14-5 
Table 19 
Table 14-6 
Table 20 
Table 14-7 
Table 21 
 
 
 
IRBs/IECs 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit 
for approval a revised informed consent that takes into account the changes described in 
this protocol amendment. 


QED Therapeutics 
Amended Protocol Version 06 (15-Jan-2020) 
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Protocol No. CBGJ398X2204 
 
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AMENDMENT 2 (24-JAN-2017) 
Amendment rationale 
 
The primary purpose of this amendment is to: 
 
1. Increase enrollment to approximately 120 patients in order to 1) introduce a new drug 
formulation, Final market image version 3 (FMIv3) and 2) allow further evaluation of 
the safety and preliminary efficacy signal observed in the first 61 patients enrolled. 
Enrollment will be restricted to those patients with intrahepatic cholangiocarcinoma 
whose tumors have FGFR2 gene fusions/translocations; patients with other FGFR 
genetic alterations will not be enrolled. The increased sample size will permit more 
precise estimation of response rate, duration of response and progression free 
survival. 
 
Of the 61 patients enrolled to the BGJ398X2204 study (30-Jun-2016), there were 58 
patients evaluable for preliminary assessment of efficacy (with valid baseline and at 
least one valid post-baseline assessment). In these 58 patients, the investigator- 
assessed ORR (confirmed responses only) is 15.5%. Disease control rate is 79.3% (46 
patients). Additionally, out of the 37 patients who achieved stable disease, 6 patients 
achieved PR in one scan (did not have subsequent scan confirming the PR). Of the 61 
patients, 39 (63.9%) had a PFS event (3 deaths and 36 patients progressed as per 
RECIST). The median PFS is estimated at 175 days (95% CI: 130 – 230 days). 
 
Final Market Image version 3 (FMIv3) will replace the current drug formulation 
(FMIv1) in the current study for all patients enrolled following the implementation of 
this protocol amendment. These two formulations have been previously compared in 
two separate studies [CBGJ398X2103 and CBGJ398X2106] to the clinical service 
form which was used to establish MTD of BGJ398 at 125 mg qd [CBGJ398X2101]. 
Cross-study comparison of the exposures (AUC and Cmax) between FMIv3 and 
FMIv1 indicated that exposure of BGJ398 from the FMIv3 formulation is about 21- 
35% higher than that of FMIv1 (21% for AUCinf, 29% for Cmax and 35% for AUClast). 
Although BGJ398 has demonstrated high interpatient variability in exposure at the 
125 mg dose, on average, steady-state concentrations provide target coverage over the 
dosing interval at doses associated with efficacy. As observed events with BGJ398 
are readily monitorable and considered manageable, patient’s doses can be 
individually titrated to maximize therapeutic potential and minimize toxicity across a 
wide exposure range. Thus, the dose of FMIv3 125 mg qd should pose no additional 
safety concerns. However, pharmacokinetics, safety and tolerability data from the 
first 20 patients treated with FMIv3 up to the end of cycle 1 of treatment will be 
assessed and compared with the historical data from patients treated with FMIv1. 
Serial blood samples will also be collected from the remaining patients in this study 
to further characterize the pharmacokinetic properties of FMIv3 in this patient 
population. 


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2. In order to allow for independent confirmation of the response rate, duration of 
response, and progression-free survival results, initiate independent review of 
radiologic assessments by an imaging CRO designated by Novartis. 
 
3. Update biomarker strategy: 
 
a. Add cell free DNA (cf DNA) sampling to explore correlation between genetic 
alterations in tumor tissue at baseline, clinical response and development of 
resistance 
 
b. Discontinue CA19-9 sample collection as the test is not used across the majority 
of sites for disease assessment 
 
c. Discontinue whole blood collection for exploratory germline analysis as this will 
no longer be analyzed 
 
d. Remove language pertaining to the Novartis optional companion sample 
collection protocol as it is no longer applicable for this protocol. 
 
4. Reduce frequency of cardiac imaging at cycle 3 and cycle 4 as there is no cardiac risk 
observed with BGJ398 
 
5. Pregnancy and contraception language have been updated 
 
6. Correct typographical errors and inconsistencies throughout the document. 
 
Changes to the protocol 
 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underline for insertions. 
 
• Protocol summary: Updated to reflect changes based on the amendment  Section 
1.2.1.2.1 Clinical safety: Added safety data available to date. 
 
• Section 1.2.1.2.2 Clinical efficacy: Added efficacy data available to date. 
• Section 1.2.1.2.3 Clinical pharmacokinetics: Updated to reflect current understanding 
of pharmacokinetic data 
 
• Section 2.3 Rationale for dose and regimen selection: Updated to include FMIv3 
• Section 3 objectives and related endpoints: Added objective related to PK of FMIv3 
• Section 3 objectives and related endpoints: Added exploratory analysis of circulating 
tumor DNA, removed CA19-9 biomarker analysis as it is not commonly available at 
participating centers 


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• Section 4.1- Study design: Total patients to be enrolled has been updated to 
“approximately 120” 
 
• Section 4.3- Assessment of potential mechanism of resistance: Removed reference to 
optional companion sample collection as this is no longer applicable for the study 
 
• Section 5.1- Updated to restrict enrollment to FGFR2 fusion/translocations 
• Section 5.2- Inclusion criteria: Removed reference to other FGFR genetic alterations. 
As of this amendment, patients with only FGFR2 fusion/translocations will be 
enrolled. 
 
• Section 5.3: Updated exclusion criteria regarding pregnancy contraception 
requirements. Requirement for use of contraception after the last dose of BGJ398 
remains unchanged. 
 
• Section 6.1- Study treatment: Added language regarding introduction of FMIv3 
• Section 6.3 Concomitant medications: Added clarification for use of concomitant 
medications that are listed in both Appendix 1 (List of concomitant medications) and 
Appendix 2 (List of prohibited medications). 
 
• Section 7.1.2- Screening: removed language regarding screening window to make it 
consistent with other sections 
 
• Section 7.1, Table 7-1 Visit evaluation schedule: Added blood collection for 
exploratory biomarker- circulating tumor DNA analysis 
 
• Section 7.1, Table 7-1 Visit evaluation schedule: Removed germline whole blood 
collection as the exploratory analysis will not be performed 
 
• Section 7.1, Table 7-1 Visit evaluation schedule: Removed CA19-9 assessment as test 
is not routinely available at all participating centers 
 
• Section 7.1. Table 7-1 Visit evaluation schedule: Removed cardiac imaging 
requirement at cycle 3 and cycle 4 as there is no known cardiac risk noted based on 
available data 
 
• Section 7.1. Table 7-1 Visit evaluation schedule: Removed footnote “c” related to 
companion sample collection 
 
• Section 7.1.4 Discontinuation of study treatment: revised language regarding study 
treatment discontinuation 
 
• Section 7.1.5 Withdrawal of consent: new section added for withdrawal of consent 


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• Section 7.1.7 Lost to follow-up: New section regarding those patients lost to follow- 
up 
 
• Section 7.2.1- Efficacy: Added information related to tumor evaluation by 
independent review 
 
• Section 7.2.3- Pharmacokinetics: Added information related to PK analysis 
• Section 7.2.4.3- Exploratory biomarkers: Removed whole blood germline analysis 
sampling 
 
• Section 7.2.4.4- Exploratory biomarkers: Added section on blood sampling for 
circulating 
DNA 
 
• Section 7.2.4.5- CA19-9 assessment: removed the section as this is no longer being 
collected for this study 
 
• Table 7-4- Pharmacokinetic blood collection time points for patients: updated the title 
to add sparse PK sampling requirement 
 
• Table 7-5 - Pharmacokinetic blood collection time points for patients: added new 
table for collection of extensive PK samples for first 20 patients treated with FMIv3 
 
• Table 7-6- Biomarker sample collection plan: updated to remove germline blood 
sample and added blood sample for cell free DNA analysis 
 
• Section 8.1.3.1- Safety: Updated the reporting language for SAEs 
• Section 9.4- Database management and quality control: removed language regarding 
companion sample collection 
 
• Section 10- Statistical method and data analysis: Updated to reflect the data analysis 
in terms of formulation change 
 
• Section 11.5- Publication of study protocol and results: New section regarding 
Novartis' publication policy 
 
IRBs/IECs 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit 
for approval a revised informed consent that takes into account the changes described in 
this protocol amendment. 


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AMENDMENT 1 (11-MAR-2015) 
Amendment rationale 
 
The purpose of this amendment is as follows: 
 
• Inclusion/Exclusion criteria were modified to clarify patient eligibility and align with 
standard of care treatment practice for cholangiocarcinoma. 
 
• Hyperphosphatemia management guidelines were updated to provide more detail 
regarding the prophylaxis of hyperphosphatemia and how to modify BGJ398 dose 
administration in response to elevated serum phosphorous levels. 
 
• Serum creatinine and creatinine clearance exclusion criteria were revised to align 
with current medical practice and provide consistency across BGJ398 protocols. 
BGJ398 has not been demonstrated to be nephrotoxic. 
 
• Evaluations of cardiac function by echocardiogram/MUGA scan were added on day 1 
of cycles 2, 3 and 4 to monitor changes in left ventricular ejection fraction (LVEF) 
and make monitoring frequency consistent across BGJ398 protocols. Asymptomatic 
and reversible decreases in LVEF have been noted in patients treated with BGJ398. 
 
• The emergence of acquired resistance to therapy is a major problem for patients with 
cancer. Under this amendment, language has been inserted to allow the collection of 
tumor tissue at baseline and upon the development of acquired resistance to treatment 
as described in the optional companion sample collection protocol. The purpose of 
these samples and a sample of normal tissue to aid in the identification of somatic 
variants in the tumor is to identify genetic changes in the tumor that may underlie 
treatment resistance. Two blood samples are also collected to test the potential value 
of circulating cell free tumor DNA as a possible replacement in some circumstances 
for tumor biopsies. 
 
• Minor inconsistencies, edits, and typographical errors that were identified after the 
finalization of the original protocol have been corrected with this amendment. 
 
Changes to the protocol 
 
• Updated Protocol Summary to further clarify inclusion criteria regarding patient 
eligibility coming off a prior regimen due to toxicity 
 
• Updated Section 1.2.1.2.1, clinical safety 
• Updated Section 1.2.1.2.2, clinical efficacy 
• Updated Section 4.3 with wording regarding the Novartis companion sample 
collection protocol to study the mechanism of drug treatment resistance 


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• Updated Section 5.1 to further clarify Inclusion criteria regarding patient eligibility 
coming off a prior regimen due to toxicity 
 
• Updated Section 5.2, inclusion criteria #1 to add that patients with cancers of the 
gallbladder and ampulla of Vater are not eligible and inclusion criteria #5 to further 
clarify patient eligibility 
 
• Updated Section 5.3, exclusion criteria #1 to add that patients are ineligible if they 
had prior treatment with a MEK or selective FGFR inhibitor, #16, clarified the 
creatinine/creatinine clearance criteria, #8 removed “History and/or, #11 and Section 
6.1.1.1 for consistency on which fruits are prohibited, #17 to allow for corrected total 
calcium, #18 to read 470 msec. 
 
• Updated Section 6.1.1.1 to clarify administration of BGJ398 
• Updated the lipase/amylase elevation information, hyperphosphatemia management 
and creatinine clearance information in Table 6-3 
 
• Removed Table 6-4 as the information was duplicative and the information can be 
found in Table 6-3 
 
• Revised Section 6.3, Concomitant medications 
• Revised Section 6.3.2, QT/QTc interval prolongation or torsade de pointes 
medications 
 
• Revised Section 6.3.3, Prohibited concomitant therapy to include information on 
known risk of QT/QTc interval prolongation or torsades de pointes medications 
 
• Removed RSTANCE2101 language from Section 7.1 to be replaced in Section 9 
(Data Collection and Management) 
 
• Updated Table 7-1 to include clarifications regarding the Novartis companion sample 
collection protocol information 
 
• Updated Table 7-3 to allow for corrected total calcium 
• Updated Section 7.2.2.7 to clarify time frame intervals for cardiac assessments. 
• Updated Section 8.2.2 to include SAE information regarding the Novartis companion 
sample collection protocol 
 
• Updated Section 9.4 to include the language required for the Novartis sample 
collection protocol regarding data management 
 
• Revised Appendix 1, Table 14-1 


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• Revised Appendix 2, Table 14-2 
• Minor inconsistencies, edits and typographical errors that were identified after the 
finalization of the original protocol have been corrected with this amendment. 
Changes to specific sections of the protocol are shown in the track change version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
 
IRBs/IECs 
 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. The changes 
described in this amended protocol require IRB/IEC approval prior to implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit 
for approval a revised informed consent that takes into account the changes described in 
this protocol amendment. 


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PROTOCOL SUMMARY 
 
Protocol number 
CBGJ398X2204 
Title 
A phase II multicenter, single arm study of oral BGJ398 in adult patients 
with advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions 
or other FGFR genetic alterations who failed or are intolerant to platinum- 
based chemotherapy 
Brief title 
A single arm study of oral BGJ398 in adult patients with advanced or 
metastatic cholangiocarcinoma 
Sponsor and Clinical 
Phase 
QED Therapeutics, Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
This study is designed to evaluate the efficacy of the targeted, selective 
FGFR 1-3 inhibitor BGJ398 when administered as a single agent to patients 
with genetically selected advanced or metastatic cholangiocarcinoma 
through estimation of the overall response rate. 
Molecular characterization of these tumors at baseline and at the time of 
progression may allow for increased understanding of potential treatment 
combinations, as well as primary and acquired resistance mechanisms. 
Primary Objective 
(Cohort 1) 
To evaluate the efficacy of single agent BGJ398 in patients with advanced or 
metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations or 
other FGFR genetic alterations as measured by overall response assessed by 
central imaging review according to RECIST v1.1. 
Secondary Objectives 
(Cohort 1 and Overall 
Study) 
Cohort 1: To further evaluate the efficacy of single agent BGJ398 as 
measured by overall response assessed by investigator; progression free 
survival, best overall response, disease control assessed by investigator and 
by central imaging review as per RECIST 1.1; and overall survival. 
Cohort 1: To characterize the safety and tolerability of single agent BGJ398 
by type, frequency, and severity of AEs and SAEs. 
Overall study: To determine selected trough and 2-hr or 4-hr plasma 
concentrations of BGJ398 and its metabolites. 
Overall study: To characterize the pharmacokinetic profile of BGJ398 FMI 
III and FMI IV formulations. 
Study design 
This is a multi-center, open label, single arm phase II study evaluating 
BGJ398 anti-tumor activity in advanced or metastatic cholangiocarcinoma 
patients with FGFR genetic alterations. Oral, monotherapy BGJ398 will be 
administered once daily for the first 3 weeks (21 days) of each 28-day cycle. 
Treatment period will begin on Cycle 1 Day 1 and will continue until disease 
progression, unacceptable toxicity, withdrawal of informed consent, or 
death. Patients will be evaluated for tumor response radiographically every 8 
weeks until disease progression or discontinuation from study using RECIST 
1.1 criteria. 
Population 
Adult patients with histologically or cytologically confirmed advanced or 
metastatic cholangiocarcinoma with FGFR2 gene fusions or translocations or 
other FGFR genetic alteration who have evidence of radiologic progression 
following a cisplatin-and gemcitabine-containing regimen for advanced 
disease or a gemcitabine-containing regimen for those who are considered 
intolerant to cisplatin will be enrolled. Up to approximately 160 adult 
patients over age 18, both male and female will be enrolled. Three cohorts of 
patients comprise the study population: 


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• 
Cohort 1: ~120 patients, ~106 with FGFR2 gene fusions or 
translocations and 14 with other FGFR genetic alterations enrolled 
under the original protocol and amendment 1. 
• 
Cohort 2: ~20 patients with FGFR genetic alterations other than FGFR2 
gene fusions or translocations. 
• 
Cohort 3: Up to ~20 patients with FGFR2 gene fusions or translocations 
who have received a prior FGFR inhibitor. 
Objectives for Cohorts 2 and 3 are exploratory. 
Main Inclusion criteria 
• 
Patients with histologically or cytologically confirmed 
cholangiocarcinoma at the time of diagnosis. Patients with cancers of the 
gallbladder or ampulla of Vater are not eligible. 
• 
Written documentation of local laboratory or central laboratory 
determination of the following FGFR gene alterations from a sample 
collected before BGJ398 treatment: 
○ 
Cohort 1: FGFR2 gene fusions or translocations. 
○ 
Cohort 2: one of the following: (a) FGFR1 fusions or translocations, 
(b) FGFR3 fusions or translocations, or (c) FGFR1/2/3 mutation 
known to be an activating mutation and noted in Appendix 4. 
○ 
Cohort 3: FGFR2 gene fusions or translocations. 
• 
Patients must have received at least one prior regimen containing 
gemcitabine with or without cisplatin for advanced or metastatic disease. 
Patients should have had evidence of progressive disease following prior 
regimen, or if prior treatment discontinued due to toxicity must have 
continued evidence of measurable disease 
• 
ECOG performance status ≤ 1 (Patients with ECOG performance status 
of 2 may be considered on a case-by-case basis after discussion with 
QED Therapeutics). 
• 
Cohort 3 only: Documented prior treatment with FGFR inhibitor other 
than BGJ398/infigratinib. 
Main Exclusion criteria 
• 
Prior or current treatment with a mitogen-activated protein kinase 
(MEK) inhibitor (all cohorts), BGJ398/infigratinib (all cohorts), or 
selective FGFR inhibitor (Cohorts 1 and 2 only). 
• 
Current evidence of corneal or retinal disorder/keratopathy including, 
but not limited to, bullous/band keratopathy, inflammation or ulceration, 
keratoconjunctivitis, confirmed by ophthalmic examination 
• 
History and/or current evidence of extensive tissue calcification 
including, but not limited to, the soft tissue, kidneys, intestine, 
myocardium, vascular system, and lung with the exception of calcified 
lymph nodes, minor pulmonary parenchymal calcifications, and 
asymptomatic coronary calcification 
• 
Impairment of gastrointestinal (GI) function or GI disease that may 
significantly alter the absorption of oral BGJ398 (eg, ulcerative diseases, 
uncontrolled nausea, vomiting, diarrhea, malabsorption syndrome, small 
bowel resection) 
• 
Current evidence of endocrine alterations of calcium/phosphate 
homeostasis, eg, parathyroid disorders, history of parathyroidectomy, 
tumor lysis, tumoral calcinosis etc. 
• 
Concurrently receiving or planning to receive during participation in this 
study, treatment with agents that are known strong inhibitors or inducers 
of CYP3A4. Medications which increase serum phosphorus and/or 
calcium concentration are excluded (Refer to Appendix 2 for list of 
prohibited medications). Patients are not permitted to receive enzyme- 
inducing anti-epileptic drugs. 


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• 
Cohort 3 only: Known existence of a V564F mutation in the FGFR2 
gene. 
Investigational and 
reference therapy 
Infigratinib (also known as BGJ398, BBP-831, and infigratinib phosphate) 
administered as monotherapy 
Efficacy assessments 
Tumor response according to RECIST Version 1.1, and survival 
Safety assessments 
Adverse event (AE) reporting and changes from baseline in laboratory 
parameters, vital signs, ophthalmic assessment, cardiac imaging 
Other assessments 
Pharmacokinetic assessment: Blood samples will be collected for the 
measurement of the plasma concentrations of BGJ398 and its metabolites. 
Biomarker assessment: Archival or newly obtained tumor samples will be 
collected to explore mechanisms of resistance to cancer treatment through 
analysis of next generation DNA sequencing data from tumor samples at 
baseline and after the development of disease progression (whenever 
available). 
Blood samples will be collected at screening and throughout the study for 
cell free DNA analysis to explore correlation with genetic alterations in 
tumor tissue at baseline, clinical response and development of resistance 
Data analysis 
Data will be analyzed by QED Therapeutics and/or designated CRO. It is 
planned that the data from participating centers in this protocol will be 
combined, so that an adequate number of patients will be available for 
analysis. Data will be summarized with respect to demographic and baseline 
characteristics, efficacy and safety observations and measurements and all 
relevant PK and PD measurements. Categorical data will be presented as 
frequencies and percentages. For continuous data, mean, standard deviation, 
median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
Key words 
BGJ398, cholangiocarcinoma, FGFR2 gene fusions or translocations, FGFR 
genetic alterations, platinum-containing regimen, molecular pre-screening, 
RECIST 1.1 


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1 BACKGROUND 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
 
Cholangiocarcinoma is a rare, heterogeneous malignancy which originates from the 
neoplastic transformation of cholangiocytes into intrahepatic, perihilar, or distal 
extrahepatic tumors (Alpini 2001). In the United States, approximately 3,000 patients are 
diagnosed with cholangiocarcinoma of both the intra- and extrahepatic biliary system 
annually. Cholangiocarcinoma is more prevalent in Asia and Middle East, mostly 
because of a common parasitic infection of the bile duct (American Cancer Society 
2012). Men are slightly more likely to develop cholangiocarcinoma, while incidence 
increases with age in both sexes (Patel 2002). 
 
Usually, cholangiocarcinomas are adenocarcinomas and have poor prognosis with limited 
treatment alternatives. This is partly due to the late onset of symptoms and relative 
resistance to the therapies currently available. Moreover, conventional chemotherapy and 
radiation therapy (RT) have not been shown to be effective in prolonging long-term 
survival. Photodynamic therapy combined with stenting has been reported to be effective 
as a palliative treatment; however, it is not curative (Sirica 2005). In April 2010, the 
ABC-02 trial was published, which was the first phase III randomized, controlled trial in 
this patient population where patients were randomly assigned to receive cisplatin plus 
gemcitabine or gemcitabine alone (Valle 2010). In this study, the combination of 
gemcitabine/cisplatin demonstrated improved progression-free survival (PFS) and overall 
survival (OS) compared to gemcitabine alone. The median overall survival was 11.7 
months in the cisplatin–gemcitabine group and 8.1 months in the gemcitabine group. The 
median progression-free survival was 8.0 months in the cisplatin–gemcitabine group and 
5.0 months in the gemcitabine-only group. Still, cholangiocarcinoma patients relapsing 
after first line therapy have few therapeutic options, and there is no established second 
line standard of care. Response rates to currently available therapy are in the single digits. 
 
The most recent guidelines regarding treatment of advanced biliary tract cancers, 
developed by the National Comprehensive Cancer Network (NCCN), recommend the use 
of gemcitabine, capecitabine, or 5-fluorouracil (5-FU), either as single agents or in 
combination with a platinum analog (oxaliplatin or cisplatin), or the combination of 
gemcitabine and capecitabine, with the combination of gemcitabine and cisplatin 
receiving a category 1 recommendation. None of these agents are FDA approved 
primarily for use in biliary tract cancers. Moreover, multi-agent chemotherapeutic 
approaches do not confer a durable benefit in patients with metastatic and/or relapsed 
disease, and fewer than 5% of patients survive 5 years after diagnosis of advanced 
disease. Thus, there is a real need to develop novel therapeutic strategies for 
cholangiocarcinoma based on exploiting select molecular targets that would significantly 
impact clinical outcomes. Molecular alterations implicated in the dysregulation of 
cholangiocarcinoma cell growth and survival, aberrant gene expression, and invasion and 
metastasis have been considered potential therapeutic targets (Sirica 2005). 


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1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
 
1.2.1 
Overview of BGJ398 
 
BGJ398 (infigratinib; also known as BBP-831 and infigratinib phosphate) is an orally 
bio-available, potent and selective and ATP-competitive inhibitor of fibroblast growth 
factor receptors (FGFRs) 1-3, which has demonstrated anti-tumor activity in preclinical, 
in vitro and in-vivo tumor models harboring FGFR genetic alterations. BGJ398 belongs 
to the pyrimidinyl aryl urea chemical class and its chemical name is 3-(2,6-dichloro-3,5- 
dimethoxyphenyl)-1-{6-[4-(4-ethylpiperazin-1-yl)phenylamino]-pyrimidin-4-yl}-1- 
methylurea phosphate (1:1). 
 
Please refer to the current Investigator’s Brochure for the most recent information on 
BGJ398. 
 
1.2.1.1 
Nonclinical experience 
 
At the cellular level, BGJ398 selectively inhibits the kinase activity of FGFR1, FGFR2, 
FGFR3, as measured by inhibition of receptor autophosphorylation with IC50 values of 
4 - 5 nM for FGFR1, FGFR2 and FGFR3. Infigratinib is less potent in inhibiting FGFR4, 
with an IC50 of 164 nM for FGFR4. 
 
Consistent with inhibition of FGFR autophosphorylation, BGJ398 inhibits FGFR 
downstream signaling and proliferation of human cancer cell lines harboring genetic 
alterations of the FGFRs. These include, among others, lung and breast cancer cell lines 
with FGFR1 gene amplification, gastric cancer with FGFR2 gene amplification, 
endometrial cancer with FGFR2 mutations and bladder cancer with FGFR3 mutations or 
FGFR3 translocations (Wesche 2011). In line with its cellular activity, BGJ398 shows 
anti-tumor activity in multiple models bearing FGFR genetic alterations (Guagnano 2012; 
Konecny 2013). 
 
1.2.1.1.1 
Animal drug metabolism and pharmacokinetics 
 
In all species tested, BGJ398 exhibited a high plasma CL (clearance) and a large Vss 
(Volume of distribution at steady state). The compound is highly bound to plasma 
proteins (~ 98%) but does not preferentially distribute to red blood cells. BGJ398 is 
widely distributed to tissues in the rat and has a high affinity to melanin containing 
tissues. In vitro hepatic systems metabolize BGJ398 predominantly to 2 
pharmacologically active metabolites: BHS697 and BQR917. Biotransformation of 
BGJ398 to both metabolites was observed in human hepatocyte cultures. The compound 
is a P-gp and BCRP substrate and also inhibits BCRP mediated transport with an IC50 
value of 0.21μM. In addition, in vitro data indicate that BGJ398 is primarily a CYP3A4 
substrate. 
 
BGJ398 is a potent reversible inhibitor of CYP3A4 (Ki 0.26μM). The compound also 
reversibly inhibits CYP2C9 and CYP2C19 with Ki of 6.09μM and 4.1μM, respectively 
and CYP2C8 with IC50 of 12μM. BGJ398 is also a time dependent inhibitor of CYP3A4 


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with a KI=37.3 μM and Kinact=0.0547 min -1. In addition, CQM157, a recently 
identified metabolite in circulating plasma from patients, is also shown to be an inhibitor 
of CYP2C8, CYP2C9 and CYP3A4 (IC50 less than 10 μM) and CYP2C19 (IC50 12 μM). 
CQM157 is also an inhibitor of transporters P-gp, BCRP, OATP1B1 and OATP1B3 (IC50 
less than 5 μM). 
 
1.2.1.1.2 
Safety pharmacology and toxicology 
 
BGJ398 showed no evidence of in vitro genotoxicity in Ames and chromosome 
aberration tests and no evidence of phototoxicity in a 3T3 photo-cytotoxicity test. In vitro 
safety pharmacology assessment of BGJ398 revealed a decrease in human Ether-à-go-go- 
related gene (hERG) channel activity with an IC50 of 2.0 μM (1121ng/ml). 
In vivo safety pharmacology studies in rats and dogs did not reveal any effects on central 
nervous or respiratory systems and on hemodynamic or electrocardiographic parameters, 
respectively. 
 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, BGJ398 did lead to 
increases in serum FGF23 and serum phosphorous associated with partially reversible 
ectopic mineralization (kidney, lung, vascular and digestive systems) along with largely 
reversible changes in renal function parameters and bone growth plate thickening / 
retention of the primary spongiosa in rats (≥ 10 mg/kg/day) and dogs (≥ 10 mg/kg/day). 
These effects were deemed to be on-target effects mediated by pharmacological 
inhibition of FGFR. 
 
In rats, corneal changes were found upon 4 weeks of BGJ398 treatment consisting of 
irreversible, slight bilateral opacity with dose-dependent incidence, as assessed by in vivo 
ophthalmology. The clinical/ophthalmoscopic finding was associated with reversible, 
diffuse epithelial keratopathy at the highest dose of 10 mg/kg. In the 2-week rat toxicity 
study, doses of 20 mg/kg/day did lead to vasculopathy associated with moribundity after 
6 administrations. 
 
In dog toxicity study, minimal, fully reversible retention of the primary spongiosa and 
minimal increase in mineralization in lung and kidney without observed functional 
impairment were observed. 
 
1.2.1.2 
Clinical experience 
 
Please refer to the current Investigator’s Brochure for the most recent clinical safety and 
efficacy information on BGJ398. 
 
1.2.1.2.1 
Clinical pharmacokinetics 
 
The pharmacokinetics (PK) of BGJ398 and active metabolites have been evaluated 
following single and repeat daily doses in the ongoing phase I study (CBGJ398X2101). 
At 5 and 10 mg/day, plasma concentrations were low and frequently below the lower 
limit of quantification. Plasma concentrations were consistently quantifiable starting at 
20 mg/day. 


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Following a single dose, median Tmax was approximately 3-4 hours. The mean AUC0-24 
on Day 1 increased approximately 9 fold from 20 to 150 mg. The mean terminal 
elimination half-life on Day 1(T1/2) was 3-7 hr. Despite the relatively short half-life on 
Day 1, accumulation was observed with daily dosing at doses ≥ 60 mg, likely due to auto- 
inhibition of CYP3A4 mediated clearance pathways. Mean accumulation ratio (Racc) 
ranged from 3 to 8 on Days 15 and 28. Since dose interruptions occurred frequently 
following continuous daily dosing of BGJ398, PK parameters on Day 28 should be 
viewed with caution. The interpatient variability was high for BGJ398. 
 
Concentration data from active metabolites BHS697 (desethyl metabolite) and BQR917 
(Noxide) was available across all cohorts. CQM157 (aniline metabolite) was analyzed in 
a few patients following Amendment 6 of the BGJ398X2101 clinical protocol. In most 
patients, BHS697 and BQR917 were measurable at levels of ~5-50%, and <15% of 
parent exposure, respectively. Mean exposures on Day 1 (N=8) for CQM157 relative to 
BGJ398 varied across patients (3% -300%). CQM157 (N=4) did not appear to 
accumulate on daily dosing, whereas accumulation was observed for BGJ398 and 
metabolites BHS697 and BQR917. 
 
In vitro studies indicated that infigratinib inhibits CYP3A4; therefore, a clinical drug- 
drug interaction study (QBGJ389-106) was conducted to assess the effects of multiple 
doses of infigratinib on midazolam (a sensitive CYP3A4 substrate). Midazolam exposure 
in terms of AUCinf and Cmax was minimally reduced (11% and 1%, respectively). For the 
active metabolite, 1-hydroxymidazolam, exposure increased by 19% and 26% for AUCinf 
and Cmax, respectively. Overall, these results indicate that infigratinib had a small effect 
on the metabolism of midazolam and can be considered a weak CYP3A4 inhibitor. As 
such, infigratinib is not expected to have a clinically relevant effect on drugs metabolized 
by CYP3A4. However, due to the weak inhibition, drugs that are CYP3A4 substrates and 
have a narrow therapeutic index should be co-administered with caution. 
 
Please refer to the current Investigator’s Brochure for more details. 
 
2 RATIONALE 
2.1 
Study rationale and purpose 
 
The growing understanding of the genetic alterations involved in the tumorigenesis of 
cholangiocarcinoma provides new therapeutic options for molecular targets. Among other 
genetic alterations, recurrent gene fusions involving the FGFRs are an important class of 
driver mutations in a number of tumor types, including cholangiocarcinoma. 
 
Recently, Wu (2013) reported 24 primary tumors or cell lines with FGFR1, FGFR2, or 
FGFR3 fusions among other targetable gene fusions. These FGFR fusions involve 
numerous protein partners with various functions, which maintain kinase activity after 
formation. The identified gene fusions expressed an FGFR family member as a 5’ or 3’ 
fusion partner with an intact kinase domain, thus suggesting that these may serve as 
potential actionable therapeutic targets via kinase inhibition. Cancer types harboring 
FGFR fusions were quite diverse and included cholangiocarcinoma (n=2), breast cancer 


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(n=4), prostate cancer (n=1), thyroid cancer (n=1), lung squamous cell carcinoma (n=6), 
bladder cancer (n=5), oral cancer (n=1), head and neck squamous cell carcinoma (n=2), 
and glioblastoma (n=2). Two cholangiocarcinoma patients were reported to harbor 
FGFR2-BICC1 fusions. Cells harboring FGFR fusions showed enhanced sensitivity to 
the FGFR inhibitors PD173074 and pazopanib, suggesting that patients with cancer with 
FGFR fusions may benefit from targeted FGFR kinase inhibition (Wu 2013). 
 
In a second study (Arai 2013), two fusion kinase genes, FGFR2-AHCYL1 and FGFR2- 
BICC1 were identified in 2 of 8 cholangiocarcinoma tumor samples by massive-parallel 
whole transcriptome sequencing. Further, RT-PCR and Sanger sequencing analysis of 
102 cholangiocarcinoma specimens (66 intrahepatic cholangiocarcinoma (ICCs) and 36 
extrahepatic cholangiocarcinoma (ECCs) identified seven FGFR2-AHCYL1-positive and 
two FGFR2-BICC1-positive cases, which were identified as oncogenic in an NIH3T3 
transformation assay. Treatment with FGFR inhibitors, including BGJ398, reversed the 
transformed phenotype. In a third study (Jiao 2013), somatic mutations in FGFR2 were 
identified in 4 of 32 (12.5%) intrahepatic cholangiocarcinomas. Thus, FGFR fusions or 
activating mutations could potentially identify a subset of cholangiocarcinoma patients 
who would benefit from targeted FGFR kinase inhibition. 
 
The selective FGFR inhibitor BGJ398 has been shown to specifically inhibit proliferation 
of cancer cells with FGFR genetic alterations; BGJ398 did not alter cell growth in cells 
that did not express FGFR or FGFR was not altered. In vivo, BGJ398 significantly 
inhibited growth of tumors in a dose-dependent manner in various mouse and rat 
xenograft subcutaneous or orthotopic models. These include models of bladder cancer 
with FGFR3 chromosomal rearrangement or FGFR3 mutation (RT112, MGHU3), 
endometrial cancer with FGFR2 mutation (AN3CA), lung cancer with FGFR1 
amplification (NCI-H1581) and gastric cancer with FGFR2 amplification (SNU16). In 
addition, a cholangiocarcinoma patient harboring an FGFR2 gene fusion treated with 
BGJ398 on the BGJ398X2101 study experienced tumor shrinkage. 
 
Thus, on the basis of the activity of BGJ398 in a variety of cancer models harboring 
FGFR genetic alterations (Guagnano 2012), BGJ398 could be used to treat patients with 
cholangiocarcinoma whose tumors harbor FGFR genetic alterations, including the 
recently recognized oncogenic gene fusions. 
 
Based on these data, the current study will treat cholangiocarcinoma patients whose 
tumor have been found to harbor oncogenic FGFR2 fusions or other FGFR genetic 
alterations, which are likely to confer sensitivity to BGJ398. 
 
2.2 
Rationale for the study design 
 
There is no established second line therapy for cholangiocarcinoma that provides patients 
with meaningful clinical benefit. Response rates for non-targeted therapy in this patient 
population have routinely been in the single digits (Valle 2010). On the basis of the 
activity of BGJ398 in a variety of cancer models harboring FGFR genetic alterations 
(Guagnano 2012), including translocations, a robust anti-tumor activity of BGJ398 is 
expected in patients harboring FGFR2 gene fusions or translocations. Thus, a single arm 


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study evaluating response to BGJ398 and durability of response is an appropriate design 
in this patient population. 
 
This study is designed to evaluate efficacy of the targeted, selective FGFR 1-3 inhibitor 
BGJ398 when administered as a single agent to patients with genetically selected 
advanced or metastatic cholangiocarcinoma through estimation of the overall response 
rate and to gain further understanding of the role of FGFR genetic alterations including 
gene fusions in this rare patient population. In addition, molecular characterization of 
these tumors at baseline and at the time of progression may allow for increased 
understanding of potential treatment combinations, as well as primary and acquired 
resistance mechanisms. 
 
Cohort 1 will enroll approximately 120 patients with advanced or metastatic 
cholangiocarcinoma who have evidence of radiologic progression following a cisplatin- 
and gemcitabine-containing regimen for advanced disease or a gemcitabine-containing 
regimen for those who are considered intolerant to cisplatin. This cohort includes 
approximately 106 patients with FGFR2 gene fusions or translocations and 14 patients 
with FGFR genetic alterations other than FGFR2 gene fusions or translocations who were 
enrolled before amendment 2. 
 
Cohort 2 will enroll approximately 20 patients with advanced or metastatic 
cholangiocarcinoma with FGFR genetic alterations other than FGFR2 gene fusions or 
translocations (specifically FGFR1, 2, or 3 activating mutation or FGR1 or 3 fusions or 
translocations) who have evidence of radiologic progression following a cisplatin-and 
gemcitabine-containing regimen for advanced disease or a gemcitabine-containing 
regimen for those who are considered intolerant to cisplatin. While FGFR2 fusions are 
the predominant FGFR genomic alteration seen in cholangiocarcinoma, other FGFR 
alterations do occur. In Cohort 1, 14 patients were enrolled with non-FGFR2 fusions, 
including 7 with FGFR1, 2, or 3 amplifications and 7 with FGFR2 mutations. In the 
7 patients with FGFR2 mutations and response data, 6 (86%) had stable disease (based on 
central review). Patients such as these with other FGFR alterations have no targeted 
treatment options, and these preliminary results compare favorably with outcomes for 
current standard of care. Therefore, Cohort 2 will enroll patients with known FGFR1, 2, 
or 3 activating mutation (See Appendix 4 [Section 14.4] for details of allowed mutations) 
or FGFR1 or 3 fusions or translocations. 
 
Cohort 3 will enroll up to approximately 20 patients with advanced or metastatic 
cholangiocarcinoma with FGFR2 gene fusions or translocations after previous treatment 
with gemcitabine-containing regimen followed by progression on an FGFR inhibitor 
(excluding BGJ398). As multiple FGFR inhibitors (both selective and non-selective) 
have entered into clinical development, it is important to understand the clinical efficacy 
when compounds are used in sequence. Consideration of the diverse mechanisms of 
action and binding pocket interactions for FGFR inhibitors suggests that BGJ398 may 
have activity when used after other FGFR inhibitors (both selective and non-selective). 
The potential for activity of BGJ398 in this population with limited therapeutic options 
supports study of BGJ398 in patients after treatment with and progression on other FGFR 
inhibitors. Approximately 10 patients will initially be enrolled and an additional 


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10 patients will be added if ≥4 patients of the 10 are assessed to be benefiting from study 
treatment as defined in Section 10.8.2. 
 
2.3 
Rationale for dose and regimen selection 
 
Patients enrolled in all cohorts of this study will receive 125 mg qd of BGJ398 on a 3 
week on (21 day) /1 week off (7 day) schedule in 28-day cycles. This dose level and 
regimen is based on experiences from the CBGJ398X2101 trial. 
 
The MTD/RP2D from the CBGJ398X2101 study was identified as 125 mg administered 
once daily (qd) in continuous 28-day cycles. While dose levels of 100 mg qd and higher 
were tolerated by patients, the majority of the patients experienced reversible 
hyperphosphatemia, which led to study drug interruptions. An evaluation of the drug 
administration records for patients prior to receiving prophylactic phosphate-lowering 
therapy, indicated that the median time until first dose interruption was approximately 23 
days and the median duration of interruption was 7 days. This observation led to the 
introduction of an expansion arm in the ongoing CBGJ398X2101 study to evaluate the 
administration of 125 mg qd on a 3 week on (21 days) / 1 week off (7 days) schedule in 
28-day cycles. To date, the majority of patients enrolled in this arm have completed their 
first cycle of therapy without hyperphosphatemia induced dose interruptions, while 
maintaining anti-tumor activity. 
 
According to amendment 2, the final market image version 3 (FMI III) formulation of 
BGJ398 replaced FMI I. These two formulations have been previously compared in two 
separate studies [CBGJ398X2103 and CBGJ398X2106] to the clinical service form 
which was used to establish MTD of BGJ398 at 125 mg qd [CBGJ398X2101]. Cross- 
study comparison of the exposures (AUC and Cmax) between FMI III and FMI I indicated 
that exposure of BGJ398 from the FMI III formulation is about 21-35% higher than that 
of FMI I (21% for AUCinf, 29% for Cmax and 35% for AUClast). Although BGJ398 has 
demonstrated high interpatient variability in exposure at the 125 mg dose, on average, 
steady-state concentrations provide target coverage over the dosing interval at doses 
associated with efficacy. As observed events with BGJ398 are readily monitorable and 
considered manageable, patient’s doses can be individually titrated to maximize 
therapeutic potential and minimize toxicity across a wide exposure range. Thus, the dose 
of FMI III 125 mg qd should pose no additional safety concerns. However, 
pharmacokinetics, safety and tolerability data from the first 20 patients treated with FMI 
III up to the end of cycle 1 of treatment will be assessed and compared with the historical 
data from patients treated with FMI I. Upon review of the data, it may be decided to 
continue dosing all subsequent patients at 125mg or at a lower dose. All decisions will be 
made by the QED Therapeutics study team in conjunction with the Investigators. Serial 
blood samples will also be collected from the remaining patients in this study to further 
characterize the pharmacokinetic properties of FMI III in this patient population. 
 
According to amendment 4, the final market image version 4 (FMI IV) formulation of 
BGJ398 will be used for patients in Cohorts 2 and 3. Additionally, patients in Cohort 1 
will be transitioned for FMI IV when this formulation is available at the study site. 
Pharmacokinetics, safety, and tolerability data from all available patients in Cohorts 2 


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and 3 treated with FMI IV up to the end of cycle 1 of treatment will be assessed and 
compared with the historical data from patients treated with FMI III. 
 
3 OBJECTIVES AND ENDPOINTS 
Objectives and related endpoints are described in Table 1 below. 
 
Table 1: 
Objectives and related endpoints for Cohort 1 and overall 
study 
 
Objective 
Endpoint 
Analysis 
Primary (Cohort 1) 
To evaluate the efficacy of single agent Overall response assessed by central 
Refer to Section 10.4 
BGJ398 in patients with advanced or 
imaging review as per RECIST v1.1 
metastatic cholangiocarcinoma with 
FGFR2 gene fusions or translocations 
or other FGFR genetic alterations 
Secondary 
Cohort 1: To further evaluate the 
Overall response assessed by investigator; Refer to Section 10.5.1 
efficacy of single agent BGJ398 
progression free survival, best overall 
response, disease control assessed by 
investigator and by central imaging review 
as per RECIST 1.1; and overall survival 
Cohort 1: To characterize the safety and Safety: Type, frequency, and severity of 
Refer to Section 10.5.2 
tolerability of single agent BGJ398 
AEs and SAEs; 
Tolerability: dose interruptions, reductions 
and dose intensity 
Overall study: 
Selected trough and 2-hr or 4-hr plasma 
Refer to Section 10.5.3 
To determine selected trough and 2-hr 
or 4-hr plasma concentrations of 
concentration profile and derived PK 
parameters of BGJ398 and its metabolites 
BGJ398 and its metabolites 
For FMI III and FMI IV: Plasma 
To characterize the pharmacokinetic 
profile of BGJ398 FMI III and FMI IV 
concentration profile and derived PK 
parameters of FMI III and FMI IV 
formulations 
Exploratory (Overall Study) 
To assess markers that may correlate 
DNA sequencing of paired biopsies (tumor Refer to Section 10.6 
with genetic alterations in tumor tissue tissue) from patients who progressed and 
at baseline, predictions of response 
analysis of cell free tumor DNA Serial 
and/or resistance (e.g. gene mutations, serum CA19-9 levels 
amplifications, deletion and/or altered 
protein expression or activation) 
 
Table 2: 
Objectives and related endpoints for Cohorts 2 and 3 
 
Exploratory Objectives 
Endpoint 
To characterize the safety and tolerability of BGJ398 in patients 
with advanced or metastatic cholangiocarcinoma with… 
Cohort 2: …FGFR genetic alterations other than FGFR2 gene 
fusions or translocations 
Safety: Type, frequency, and severity of 
AEs and SAEs; 
Tolerability: dose interruptions, 
reductions and dose intensity 
 
 


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Exploratory Objectives 
Endpoint 
Cohort 3: …FGFR2 gene fusions or translocations who have 
received prior FGFR inhibitors 
To evaluate the efficacy of single agent BGJ398 in patients with 
advanced or metastatic cholangiocarcinoma with… 
Cohort 2: …FGFR genetic alterations other than FGFR2 gene 
fusions or translocations 
Cohort 3: …FGFR2 gene fusions or translocations who have 
received prior FGFR inhibitors 
Progression free survival, overall 
response, best overall response, response 
onset, and disease control assessed by 
investigator as per RECIST v1.1, and 
overall survival 
 
 
 
 
 
4 STUDY DESIGN 
4.1 
Description of study design 
 
This is a multi-center, open label, phase II study evaluating BGJ398 anti-tumor activity in 
advanced or metastatic cholangiocarcinoma patients with FGFR genetic alterations. All 
patients will receive BGJ398 once daily on a three week on (21 days), one week off 
(7 days) schedule in 28-day cycles. Up to approximately 160 patients in total will be 
enrolled on the study. 
 
The study has 3 cohorts. Cohort 1 will have approximately 120 patients with advanced or 
metastatic cholangiocarcinoma: 106 with FGFR2 gene fusions or translocations and 14 
with other FGFR genetic alterations enrolled under the original protocol and 
amendment 1. 
 
Cohort 2 will have approximately 20 patients with advanced or metastatic 
cholangiocarcinoma with specific FGFR genetic alterations (refer to Section 5.2). 
 
Cohort 3 will have up to approximately 20 patients with advanced or metastatic 
cholangiocarcinoma with FGFR2 gene fusions or translocations who have received a 
prior FGFR inhibitor excluding BGJ398 (infigratinib). Unlike Cohorts 1 and 2, patients 
are allowed to have previous treatment with an FGFR inhibitor (either selective 
[excluding BGJ398] or nonspecific), as long as the required washout of at least 5 half- 
lives is met. 
 
In order to assess the antitumor activity of BGJ398, patients in all cohorts will be 
evaluated for tumor response radiographically every 8 weeks until disease progression or 
discontinuation from study using RECIST 1.1 criteria. 


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All Patients 
Diagnosis of advanced or metastatic cholangiocarcinoma (N=up to approx. 160 patients) 
• 
FGFR2 gene fusions or translocations / other FGFR genetic alterations 
• 
Progression after cisplatin-and gemcitabine-containing regimen for advanced disease or 
gemcitabine-containing regimen for those who are considered intolerant to cisplatin 
Cohort 1: ~120 patients, 106 with FGFR2 gene fusions or translocations 
Cohort 2: ~20 patients with FGFR genetic alterations other than FGFR2 gene fusions 
or translocations 
Cohort 3: Up to ~20 patients with FGFR2 gene fusions or translocations who have 
received a prior FGFR inhibitor 
Continue treatment until disease 
progression, unacceptable toxicity, 
withdrawal of consent or death 
CT/MRI every 8 weeks and response 
evaluation according to RECIST 1.1 
Follow-up: Patients permanently discontinuing BGJ398 therapy will have visits following the 
End of treatment visit at: 
• 
30-day safety follow-up period (30 days after the last dose of BGJ398) – All patients 
• 
Disease progression follow-up: tumor assessment every 8 weeks – For patients who 
discontinue for any other reason other than disease progression, until disease 
progression or the initiation of subsequent anticancer therapy or death, whichever 
occurs first 
• 
Survival follow-up: every 4 months after discontinuation of study treatment. Survival 
follow-up period for the study will continue for 5 years or until all patients have 
discontinued study treatment or have died, withdrawn consent, or been lost to follow-up – 
All patients 
End of treatment visit within 14 days of the decision to discontinue treatment 
 
Figure 1: 
Study Design 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Screening assessments are to be completed within 21 days prior to the first dose of treatment, except 
for the radiological tumor assessment, which can be performed within 28 days prior to the first dose. 
Screen patients per eligibility criteria (within 21 days of first BGJ398 dose)a 
Molecular prescreening (local or central) for FGFR2 gene fusions or translocations/other 
FGFR genetic alterations 
BGJ398: 125 mg qd oral 
28-day cycle (3 weeks on, 1 week off) 


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Molecular pre-screening 
 
Documented evidence of FGFR2 gene fusions or translocations or other FGFR genetic 
alterations is required in order to begin study related screening procedures. In addition, 
the patient may have additional molecular testing performed on the provided tissue 
sample. 
 
• Evidence can be demonstrated by either locally available data (local laboratory or 
institution-designated sequencing facility) or through the submission of an archival or 
newly obtained tumor sample to a QED Therapeutics designated central laboratory 
for analysis. Tissue requirements are described in Section 7.1.1. 
 
• If local data is not available, the patient must sign the molecular prescreening consent 
to allow for the collection and/or submission of samples for local testing at an 
institution designated laboratory or sequencing facility or to the QED Therapeutics 
designated central laboratory for analysis. 
 
If local data or the results of the central analysis meet inclusion criteria, the patient can 
proceed with the screening procedures. 
 
Screening 
 
Screening assessments must be completed within 21 days prior to the first dose of study 
treatment except for the radiological tumor assessment which should be performed within 
28 days prior to the first dose (Section 7.1.2). 
 
Treatment period 
 
Treatment period will begin on Cycle 1 Day 1 and will continue until disease 
progression, unacceptable toxicity, withdrawal of informed consent, or death 
(Section 7.1.3). 
 
End of treatment (EOT) 
 
The EOT visit occurs within 14 days after of the decision to discontinue study treatment 
(Section 7.1.4). All participating patients must complete this visit even if they had to 
discontinue prematurely. 
 
Follow-up 
 
All patients will be followed up as described in Section 7.1.6. 
 
30-day safety follow-up period 
 
At a minimum, all patients must complete the safety follow-up assessments 30 days after 
their last dose of BGJ398 (Section 7.1.6). 


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Disease progression follow-up period 
 
All patients enrolled in the study who discontinue study treatment for any reason other 
than disease progression will have a tumor assessment every 8 weeks, until disease 
progression or the initiation of subsequent anticancer therapies, or death, whichever 
occurs first. 
 
Survival follow-up period 
 
All patients enrolled in the study will be followed for survival at least every 4 months for 
up to 5 years after discontinuation of treatment (Section 7.1.6). 
 
4.2 
Timing of interim analyses and design adaptations 
 
Safety and efficacy data will be continuously monitored by QED Therapeutics in 
conjunction with the investigators for decision-making purposes. 
 
For Cohort 1, one analysis was performed before amendment 2 based on the 61 patients 
enrolled in the study (30 Jun 2016). Protocol amendment 2 restricted enrollment to 
patients with FGFR2 fusions or translocations, and the formulation was changed from 
FMI I to FMI III. 
 
After 20 patients had been treated with FMI III (for at least one cycle) based on 
amendment 2, a comprehensive review of all relevant data such as PK, safety, dose 
interruptions/reductions, and available efficacy was performed. Upon review of the data, 
it was decided to continue dosing all subsequent patients treated with FMI III at 125mg 
on a 3 weeks on, 1 week off schedule. 
 
In addition, two formal interim analyses for Cohort 1 are planned after amendment 3: 
 
• The first was conducted when the patients enrolled prior to amendment 2 and the 
patients in Cohort 1 with planned extensive PK sample collection (regardless of 
whether extensive PK samples were actually collected) had been followed up for at 
least 10 months after their initial exposure to BGJ398. 
 
• The second will be conducted when all the patients who received BGJ398 at the time 
of the first formal interim analysis have at least 10 months follow-up after their initial 
exposure to BGJ398. 
 
Additionally, for Cohorts 2 and 3, review of data will be performed after a total of 
15 patients in either Cohort 2 or 3 have been treated with FMI IV for at least one cycle. A 
formal interim analysis will be conducted for Cohort 3 when the first 10 patients who 
receive study treatment have the potential to complete their second scheduled scan; this 
analysis is to determine if an additional 10 patients will be added to the cohort (see 
Section 10.8.2). 


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4.3 
Assessment of potential mechanisms of resistance 
 
Patients may have tumor tissue and blood samples collected at baseline and at disease 
progression to study the mechanisms of drug treatment resistance. 
 
4.4 
Definition of end of the study 
 
End of study is defined as the time when the last patient completes the survival follow-up 
as described in Section 7.1.6 and/or when the study is terminated early. 
 
4.5 
Early study termination 
 
The study can be terminated at any time for any reason by QED Therapeutics. Should this 
be necessary, the patient should make every effort to complete their final visit. The same 
assessments should be performed as described in Section 7.1.4 and Section 7.1.5 for a 
prematurely withdrawn patient. The investigator may be informed of additional 
procedures to be followed in order to ensure that adequate consideration is given to the 
protection of the patient’s interests. The investigator will be responsible for informing 
IRBs and/or ECs of the early termination of the trial. 
 
5 POPULATION 
5.1 
Patient population 
 
Adult patients with histologically or cytologically confirmed advanced or metastatic 
cholangiocarcinoma with FGFR2 gene fusions or translocations or other FGFR genetic 
alterations will be enrolled. Patients must have received at least one prior regimen 
containing gemcitabine with or without cisplatin for advanced/metastatic disease. Patients 
should have had evidence of progressive disease following their prior regimen or if prior 
treatment was discontinued due to toxicity must have continued evidence of measurable 
disease. 
 
Evidence of FGFR2 gene fusion or other FGFR genetic alterations must be documented 
through either institutional data or central laboratory testing (please refer to Section 7.1.1 
for further details). 
 
Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. Patients who do not initially meet all of the 
inclusion or exclusion criteria may be re-screened for consideration in the trial. If a 
patient is rescreened, the same patient ID number should be used (see Section 7.1.2.2). 
 
Only patients who have documented evidence of FGFR2 gene fusion or other FGFR 
genetic alterations will be allowed to enter screening. The investigator or designee must 
ensure that only patients who meet all the following inclusion and none of the exclusion 
criteria are offered treatment in the study. 


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5.2 
Inclusion criteria 
 
Patients eligible for inclusion into all cohorts of this study have to meet all of the 
following criteria, unless otherwise noted: 
 
1. Patients with histologically or cytologically confirmed cholangiocarcinoma at the 
time of diagnosis. Patients with cancers of the gallbladder or ampulla of Vater are not 
eligible. 
 
2. Written documentation of local laboratory or central laboratory determination of the 
following FGFR gene alterations from a sample collected before BGJ398 treatment: 
 
○ Cohort 1: FGFR2 gene fusions or translocations. 
 
○ Cohort 2: one of the following: 
 
a. FGFR1 fusions or translocations. 
 
b. FGFR3 fusions or translocations. 
 
c. FGFR1/2/3 mutation known to be an activating mutation and noted in 
Appendix 4 (Section 14.4; for mutations not listed in Appendix 4, enrollment 
may be allowed with written pre-approval of the QED Medical Monitor). 
 
○ Cohort 3: FGFR2 gene fusions or translocations. 
 
3. An archival tissue sample must be available with sufficient tumor for central FGFR 
gene alteration molecular testing if written documentation is provided from a local 
laboratory, unless agreed upon between QED Therapeutics and the Investigator. 
However, if an archival tissue sample is not available, a newly obtained (before start 
of treatment) tumor biopsy may be submitted instead. If written documentation of 
FGFR gene alteration in tumor tissue is available from the central laboratory, an 
additional tumor sample does not need to be submitted for central FGFR gene 
alteration molecular testing. Note: All enrolled patients should have determination of 
FGFR gene alteration by the central laboratory as confirmation of local laboratory 
testing, but this central confirmation is not required prior to enrollment in the study. 
 
4. Evidence of measurable disease according to RECIST Version 1.1. 
 
5. Patients must have received at least one prior regimen containing gemcitabine with or 
without cisplatin for advanced/metastatic disease. Patient should have had evidence 
of progressive disease following their prior regimen, or if prior treatment was 
discontinued due to toxicity must have continued evidence of measurable disease. 
 
6. Patients ≥ 18 years of age of either gender. 
 
7. ECOG performance status ≤ 1 (Patients with ECOG performance status of 2 may be 
considered on a case-by-case basis after discussion with QED Therapeutics). 


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8. Able to read and/or understand the details of the study and provide written evidence 
of informed consent as approved by IRB/EC. 
 
9. Recovery from adverse events of previous systemic anti-cancer therapies to baseline 
or Grade 1, except for: 
 
a. Alopecia 
 
b. Stable neuropathy of ≤ Grade 2 due to prior cancer therapy 
 
10. Able to swallow and retain oral medication. 
 
11. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
 
5.2.1 
Additional inclusion criteria for Cohort 3 
 
12. Documented prior treatment with FGFR inhibitor other than BGJ398/infigratinib. 
 
5.3 
Exclusion criteria 
 
Patients eligible for this study must not meet any of the following criteria: 
 
1. Prior or current treatment with a mitogen-activated protein kinase (MEK) inhibitor 
(all cohorts), BGJ398/infigratinib (all cohorts), or selective FGFR inhibitor (Cohorts 
1 and 2 only). 
 
2. Neurological symptoms related to underlying disease requiring increasing doses of 
corticosteroids. Note: Steroid use for management of CNS tumors is allowed but must 
be at a stable dose for at least 2 weeks preceding study entry. 
 
3. History of another primary malignancy 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. 
 
4. Any other medical condition that would, in the investigator’s judgment, prevent the 
patient’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures. 
 
5. Current evidence of corneal or retinal disorder/keratopathy including, but not limited 
to, bullous/band keratopathy, inflammation or ulceration, keratoconjunctivitis, 
confirmed by ophthalmic examination. 
 
6. History and/or current evidence of extensive tissue calcification including, but not 
limited to, the soft tissue, kidneys, intestine, myocardium, vascular system, and lung 
with the exception of calcified lymph nodes, minor pulmonary parenchymal 
calcifications, and asymptomatic coronary calcification. 


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7. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter 
the absorption of oral BGJ398 (eg, ulcerative diseases, uncontrolled nausea, vomiting, 
diarrhea, malabsorption syndrome, small bowel resection). 
 
8. Current evidence of endocrine alterations of calcium/phosphate homeostasis, eg, 
parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis 
etc. 
 
9. Treatment with any of the following anti-cancer therapies prior to the first dose of 
BGJ398 within the stated timeframes. 
 
• Cyclical chemotherapy (intravenous) within a period of time that is shorter than 
the cycle length used for that treatment (eg, 6 weeks for nitrosourea, mitomycin- 
C) 
 
• Biological therapy (eg, antibodies – including bevacizumab) within a period of 
time that is ≤ 5 t1/2 or ≤ 4 weeks, whichever is shorter, prior to starting study drug 
 
• Continuous or intermittent small molecule therapeutics within a period of time 
that is ≤ 5 t1/2 or ≤ 4 weeks (whichever is shorter) prior to starting study drug 
 
• Any other investigational agents within a period of time that is ≤ 5 t1/2 or less than 
the cycle length used for that treatment or ≤ 4 weeks (whichever is shortest) prior 
to starting study drug 
 
• Wide field radiotherapy (including therapeutic radioisotopes such as strontium 
89) ≤ 4 weeks or limited field radiation for palliation ≤ 2 weeks prior to starting 
study drug 
 
10. Patients who are currently receiving, or are planning to receive during participation in 
this study, treatment with agents that are known strong inducers or inhibitors of 
CYP3A4 and medications which increase serum phosphorus and/or calcium 
concentration are excluded. (Refer to Appendix 2 for list of prohibited medications). 
Patients are not permitted to receive enzyme-inducing anti-epileptic drugs 
 
11. Consumption of 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 
 
12. Insufficient bone marrow function 
 
• ANC < 1,000/mm3 [1.0 x 109/L] 
• Platelets < 75,000/mm3 [75 x 109/L] 
• Hemoglobin < 9.0 g/dL 
13. Insufficient hepatic and renal function 


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• Total bilirubin > 1.5x ULN (for patients with documented Gilbert syndrome, 
direct bilirubin ≤1.5x ULN and enrollment requires approval by the medical 
monitor) 
 
• AST/SGOT and ALT/SGPT > 2.5x ULN (AST and ALT > 5x ULN in the 
presence of liver metastases) 
 
• Serum creatinine > 1.5x ULN and a calculated (using the Cockcroft-Gault 
formula [Cockcroft 1976]) or measured creatinine clearance of < 45 mL/min 
 
14. Abnormal calcium or phosphorus: 
 
• Inorganic phosphorus outside of normal limits 
• Total serum calcium (can be corrected) outside of normal limits 
• Calcium-phosphorus product ≥55 mg2/dL2 
15. Clinically significant cardiac disease including any of the following: 
 
• Congestive heart failure requiring treatment (NYHA Grade ≥ 2), LVEF < 50% as 
determined by MUGA scan or ECHO, or uncontrolled hypertension (refer to 
WHOISH guidelines) 
 
• History or presence of clinically significant ventricular arrhythmias, atrial 
fibrillation, resting bradycardia, or conduction abnormality 
 
• Unstable angina pectoris or acute myocardial infarction ≤ 3 months prior to 
starting study drug 
 
• QTcF > 470 msec (males and females) 
• History of congenital long QT syndrome 
16. Pregnant or nursing (lactating) women, where pregnancy is defined as the state of a 
female after conception and until the termination of gestation, confirmed by a positive 
hCG laboratory test 
 
17. Women of child-bearing potential (WOCBP), defined as all women physiologically 
capable of becoming pregnant, unless they are using barrier contraception and a 
second form of highly effective contraception during dosing and for 3 months 
following the discontinuation of study treatment. 
 
WOCBP and males whose sexual partners are WOCBP must agree to use barrier 
contraception and a second form of highly effective contraception (Clinical Trials 
Facilitation Group 2014; see Appendix 5 [Section 14.5]) while receiving study drug 
and for 3 months following their last dose of study drug. Alternatively, total 
abstinence is also considered a highly effective contraception method when this is in 


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line with the preferred and usual lifestyle of the patient. Periodic abstinence (eg, 
calendar, ovulation, symptothermal, post-ovulation methods) and withdrawal are not 
acceptable methods of contraception. 
 
A woman is not of child-bearing potential if she has undergone surgical sterilization 
(total hysterectomy, or bilateral tubal ligation or bilateral oophorectomy at least 
6 weeks before taking study drug) or if she is postmenopausal and has had no 
menstrual bleeding of any kind including menstrual period, irregular bleeding, 
spotting, etc., for at least 12 months, with an appropriate clinical profile, and there is 
no other cause of amenorrhea (eg, hormonal therapy, prior chemotherapy). 
 
18. Sexually active males unless they 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 in 
this period. A condom is required to be used also by vasectomized men as well as 
during intercourse with a male partner in order to prevent delivery of the drug via 
seminal fluid. 
 
19. Have amylase or lipase >2.0 × ULN. 
 
20. Have any known hypersensitivity to calcium-lowering agents, infigratinib, or their 
excipients. 
 
6.1.1 
Additional exclusion criteria for Cohort 3 
 
21. Known existence of a V564F mutation in the FGFR2 gene. 
 
6 TREATMENT 
The investigational drug will be BGJ398 as an oral formulation (hard gelatin capsules). 
 
6.1 
Study treatment 
 
The pharmacist will dispense the correct number and dose strength of capsules to ensure 
that each patient receives sufficient drug until the next scheduled visit. 
 
6.1.1 
Dosing regimen 
 
Table 3: 
Dose and treatment schedule 
 
Study 
Pharmaceutical form 
and route of 
Frequency and/or 
treatment 
Formulation 
administration 
Dose 
Regimen 
BGJ398 
FMI I 
Hard gelatin capsule(s) for 125 mg 
Daily (3 weeks on, 
FMI III 
FMI IV 
oral use 
(administered as one 
100 mg capsule and 
one 25 mg capsule) 
1 week off schedule in 
28-day cycles) 
 
 


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6.1.1.1 
Instructions for administration of BGJ398 
 
• Patients should be instructed to take the daily dose of BGJ398 in the morning, at 
approximately the same time each day (24 ± 4 hour interval). Patients will take their 
first dose of infigratinib at the study center on Cycle 1 Day 1. On the days of PK 
sampling, patients should not take their study drug dose at home; patients should take 
their study drug with them to the investigative site where administration of BGJ398 
will be supervised and administration time recorded. On PK sampling days after 
Cycle 1 Day 1, the time of the previous infigratinib administration (ie, the prior day) 
before the pre-dose PK sample will be recorded in the eCRF. Administration may fall 
outside of the ±4 hour interval on the days of PK sampling. 
 
• Patients who initiate treatment as of the implementation of amendment 2 will begin 
treatment using the FMI III form of BGJ398; patients enrolled into Cohorts 2 and 3 
under amendment 4 will receive the FMI IV form of BGJ398. Patients who started 
treatment prior to the implementation of amendment 2 should continue to receive the 
formulation of BGJ398 that they received at the initiation of treatment until FMI IV is 
available at the study site. At that time all patients on study will receive FMI IV. 
 
• BGJ398 should be administered in the fasted state at least 1 hour before or 2 hours 
after a meal. 
 
• BGJ398 should be taken with a large glass of water (~250 mL) and consumed over as 
short a time as possible. Patients should be instructed to swallow the capsules whole 
and not chew them. 
 
• If the patient forgets to take the scheduled dose in the morning (other than on a day of 
PK sampling), he/she should not take the dose more than 4 hours after the usual time 
and should continue treatment the next day. Any such 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 the dosing of study drug, re-dosing is not permitted that 
same day. Dosing should resume the next day. If the vomiting occurs on full PK 
sampling days within the first 4 hours post-dosing, this event needs to be noted on the 
dose administration PK eCRF page, as well as on the adverse event page, as 
appropriate. 
 
• BGJ398 is characterized by pH-dependent solubility, and therefore, medicinal 
products that alter the pH of the upper gastro-intestinal tract may alter the solubility 
of BGJ398, 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. BGJ398 
should be dosed at least 2 hours before or 10 hours after dosing with a gastric 
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• Patients must avoid consuming grapefruits, grapefruit juice, grapefruit hybrids, 
pomegranates, star fruits, pomelos, Seville oranges, or products containing juice of 
these fruits, within 7 days prior to the first dose of study medication, through the end 
of study participation. This is due to a potential CYP3A4 interaction with study 
medication. Normal oranges and orange juice are allowed. 
 
• The investigator or responsible site personnel should instruct the patient to take the 
study drug exactly as prescribed to promote compliance. All dosages prescribed and 
dispensed to the patient and all dose changes or missed doses during the study must 
be recorded on the Dosage Administration Record eCRF. 
 
• Drug accountability must be performed on a regular basis. Patients will be instructed 
to return unused study drug to the site at the end of each cycle. The site personnel will 
ensure that the appropriate dose of each study drug is administered at each visit and 
will provide the patient with the correct amount of drug for subsequent dosing. 
 
6.1.2 
Ancillary treatments 
 
Phosphate-lowering treatment, including low phosphate diet and phosphate binding 
therapy such as sevelamer hydrochloride, should be implemented prophylactically with 
meals on the first day of study drug initiation and modified as clinically indicated 
throughout BGJ398 administration. Recommendations for treatment are provided in 
Table 5, but should be modified as per country or institutional guidelines. 
 
6.1.3 
Treatment duration 
 
All patients will receive BGJ398 daily on a three week on (21 days), one week off (7 
days) schedule in 28-day cycles. Patients may continue treatment with BGJ398 until the 
patient experiences unacceptable toxicity, disease progression, treatment is discontinued 
at the discretion of investigator or withdrawal of consent, or death. 
 
6.2 
Dose modifications 
 
6.2.1 
Dose modifications and dose delay 
 
For patients who do not tolerate the protocol-specified dosing schedule, dose adjustments 
are permitted in order to allow the patient to continue the study treatment. All dose 
modifications should be based on the worst preceding toxicity (Table 5, Table 6). Dosage 
changes must be recorded on the Dosage Administration Record CRF. 
 
The following guidelines should be applied. 
 
Each patient will be allowed 3 dose reductions according protocol-specified dose 
modifications for AEs. A QED medical monitor or designee approval is required for the 
third dose reduction (Table 4). 
 
Following resolution of toxicity to baseline or ≤ Grade 1, treatment is resumed at either 
the same or lower dose of study drug as per the criteria in Table 5. If treatment is 


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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 patient should have a second dose reduction. 
 
Patients who discontinue study treatment for a study related adverse event or an abnormal 
laboratory value must be followed as described in Section 6.2.2. 
 
Study drug must be permanently discontinued for a delay of >14 days and may only be 
restarted with written permission of a QED Therapeutics’ medical monitor if (1) the 
delay was not due to an AE that requires permanent study drug discontinuation as 
provided in Table 5, and (2) the patient has not met other criteria requiring study drug 
discontinuation in Section 7.1.4, and it is the Investigator’s opinion that no safety 
concerns are present. 
 
Table 4: 
Dose reduction table 
 
Dose reduction 
BGJ398 
Starting dose level 0 
125 mg 
Dose level -1 
100 mg 
Dose level -2 
75 mg 
Dose level -3 
50 mg a 
a 
Dose reduction to 50 mg requires QED Therapeutics medical monitor approval. Details are provided in the text 
above. 


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Table 5: 
Criteria for interruption and re-initiation of BGJ398 treatment 
 
Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
Cardiac disorders 
Cardiac - Prolonged QTcF interval 
Grade 1 and 2: QTcF ≥ 481 msec and ≤ 500 msec 
(asymptomatic) 
Maintain dose level of BGJ398 
Two additional electrocardiograms (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 for 2 additional cycles at the same frequency as in cycle 1, 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 as per the visit schedule. 
• 
If ECG assessments are still abnormal (QTcF ≥ 481 msec and ≤500 msec), then 
ECG monitoring must continue at the same frequency as in cycle 1 for all 
subsequent cycles. 
Grade 3: QTcF > 500 msec as identified on the ECG by the 
investigator 
Hold BGJ398. Two additional ECGs separated by at least 5 minutes should be 
performed to confirm the finding. If the finding is confirmed, monitor patient with 
hourly ECGs until the QTcF has returned to baseline and perform further monitoring 
as clinically indicated. 
• 
Exclude other causes of QTcF prolongation such as hypokalemia, 
hypomagnesaemia and decreased blood oxygenation. 
• 
Patients should receive appropriate electrolyte replacement and should not receive 
further BGJ398 until electrolytes are documented to be within normal limits. 
Once the QTcF prolongation has resolved, patients may be re-treated at one lower dose 
level at the investigator’s discretion 
Single ECG assessments should be performed for 2 additional cycles at the same 
frequency as in cycle 1 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 as per the visit schedule for subsequent cycles. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
• 
If ECG assessments are still abnormal (QTcF ≥ 481 msec and ≤500 msec), then 
ECG monitoring must continue at the same frequency as in cycle 1 or as clinically 
indicated, for all subsequent cycles 
Patients who experience recurrent QTcF ≥ 500msec after one dose reduction will be 
discontinued from study treatment. 
Grade 4: QTcF >500 or >60 msec change from baseline and Torsade 
de pointes or polymorphic ventricular tachycardia or signs/symptoms 
of serious arrhythmia 
Discontinue BGJ398. 
If QTcF >500 msec or >60 msec change from the baseline is observed, a plasma 
sample for determination of BGJ398 concentration should be obtained with the time of 
sample collection noted. 
Cardiac disorders - others 
Grade ≥ 3, or congestive heart failure ≥ 2 
Discontinue patient from study treatment. 
Investigations-Hematology 
Neutrophil count decreased (Neutropenia) 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1or baseline, then 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved between > 7 days and 14 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Grade 4 (ANC < 0.5 x 109/L) 
Hold dose of BGJ398 until resolved to CTCAE ≤ Grade 1, ↓ 1 dose level of BGJ398. 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L, single temperature of > 38.3°C or a 
sustained temperature of ≥ 38.0°C) 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then 
• 
If resolved within ≤ 7 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within 7 days discontinue patient from study drug treatment. 
Grade 4 
Discontinue patient from study treatment. 
Anemia 
Grade 3 (hemoglobin <8.0 mg/dL) 
Hold dose of BGJ398 until resolved or corrected to CTCAE Grade ≤ 1 or baseline, then 
maintain dose level 
Grade 4 
Hold dose of BGJ398 until resolved or corrected to CTCAE Grade ≤ 1 or baseline, then ↓ 
1 dose level 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
Platelet count decreased (Thrombocytopenia) 
Grade 3 (platelet < 50 - 25 x 109/L ) without Grade ≥2 bleeding 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved between > 7 days and 14 days, ↓ 1 dose level of BGJ398 
• 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Grade 3 (platelet < 50 - 25 x 109/L ) with Grade ≥2 bleeding or 
Grade 4 (platelet < 25 x 109/L ) 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline, then ↓ 1 dose 
level. 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Investigations – Renal 
Serum creatinine 
Creatinine clearance <45 mL/min (calculated or measured) 
Hold BGJ398 until creatinine clearance is ≥45 mL/min regardless of grade. 
Serum creatinine Grade 2 (≥1.5 - 3.0 x ULN or 1.5-3.0 × baseline) 
Hold dose of BGJ398 until resolved to Grade ≤1 or baseline: 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved between > 7 days and 14 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within ≤14 days, discontinue patient from study treatment. 
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. 
Serum creatinine Grade ≥ 3 (> 3.0 x ULN or >3 × baseline) 
Discontinue patient from study treatment. 
Investigations – Hepatic 
Blood bilirubin (for patients with Gilbert Syndrome, these dose 
modifications apply to changes in direct bilirubin only) 
Grade 2 (> 1.5 - 3.0 x ULN) 
Hold dose of study drug until resolved to CTCAE Grade ≤ 1 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If not resolved within ≤ 7 days, ↓ 1 dose level of BGJ398 
Grade ≥3 (> 3.0 x ULN) 
Discontinue patient from study treatment. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
Note: If CTCAE Grade 3 or 4 hyperbilirubinemia is due to hemolysis, then ↓ 1 dose 
level of BGJ398 and continue treatment at the discretion of the Investigator. 
AST or ALT 
Grade 3 (> 5.0 - 20.0 x ULN) without bilirubin elevation > 2.0 x 
ULN 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline 
• 
If resolved within ≤ 7 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within ≤ 7 days, discontinue patient from study treatment. 
Grade 4 (> 20.0 x ULN) without bilirubin elevation >2.0 x ULN 
Discontinue patient from study treatment. 
AST or ALT and Bilirubin 
AST or ALT > 3.0 – 5.0 x ULN and total bilirubin > 2.0 x ULN 
without liver metastasis or evidence of disease progression in the 
liver 
Hold dose of BGJ398 until both transaminases and bilirubin resolved to CTCAE 
Grade ≤ 1 or baseline 
• 
If resolved within ≤ 7 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within ≤ 7 days, discontinue patient from study treatment. 
AST or ALT > 5.0 x ULN and total bilirubin > 2.0 x ULN 
Discontinue patient from study treatment. 
Laboratory / Metabolic disorders 
Asymptomatic amylase and/or lipase elevation 
General Comment 
A CT scan or other imaging study to assess the pancreas, liver, and gallbladder should 
be performed as clinically indicated within 1 week of the first occurrence of any 
CTCAE ≥Grade 3 amylase and/or lipase. 
Grade 3 (> 2.0 - 5.0 x ULN) 
• 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 2. 
• 
↓ 1 dose level of BGJ398. 
• 
If not resolved within ≤14 days, discontinue patient from study treatment. 
For recurrent Grade 3 asymptomatic lipase or amylase elevation despite dose 
reduction, drug should be held and continuation of therapy should be discussed with 
the medical monitor following resolution to ≤ Grade 2. 
Grade 4 (>5.0 x ULN) 
For any Grade 4 asymptomatic lipase or amylase elevation, drug should be held and 
continuation of therapy should be discussed with the medical monitor following 
resolution to ≤ Grade 2. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
Hypophosphatemia 
Serum phosphorus <LLN-2.0 mg/dL (0.6 mmol/L) 
Maintain dose level of BGJ398; decrease or hold dose of phosphate binder and 
optimize standard diet or medical therapy as clinically indicated to increase phosphate 
level. 
Serum phosphorus <2.0-1.0 mg/dL (<0.6-0.3 mmol/L) 
• 
Hold dose of BGJ398 until resolved to >2.0 mg/dL (>0.6 mmol/L). 
• 
↓ 1 dose level of BGJ398. 
If not resolved within ≤14 days, discontinue patient from study drug. 
Serum phosphorus <1.0 mg/dL (<0.3 mmol/L) 
(life threatening consequences) 
Discontinue patient from study drug. 
Hyperphosphatemia 
Serum phosphorus > 5.5 – 7.5 mg/dL 
Maintain dose level of BGJ398 and optimize phosphate lowering therapy as clinically 
indicated 
Serum phosphorus > 7.5 mg/dL for more than 7 days despite 
maximal phosphate-lowering therapy Or, Single serum phosphorus 
> 9.0 mg/dL regardless of duration or dose of phosphate lowering 
therapy. 
(Optimize/maximize dose and schedule of phosphate lowering 
therapy in accordance with package insert, country or institutional 
guidelines.) 
Hold BGJ398 dose until resolved to serum phosphorus ≤ 5.5 mg/dL:Restart BGJ398 at 
the same dose level with maximal phosphate binder dosing if the patient did not 
receive maximal phosphate binder dosing for serum phosphorus > 7.0 mg/dL for > 7 
days. 
Reduce one dose level of BGJ398 if the patient had received maximal phosphate 
lowering therapy for serum phosphorus > 7.5 mg/dL for > 7 days or if patient had a 
one-time serum phosphorus of > 9.0 mg/dL. Restart BGJ398 with maximal phosphate 
binder dosing. 
It is recommended that phosphate binder dosing continues during BGJ398 dose 
interruptions for hyperphosphatemia and that serum phosphorus values be monitored 
frequently, e.g. every 2-3 days. 
Phosphate binder dosing should be held during the week off BGJ398 therapy each 
cycle (Days 22-28) and during BGJ398 dose interruptions for nonhyperphosphatemia 
adverse events. 
Serum phosphorus with life-threatening consequences; urgent 
intervention indicated (e.g., dialysis) 
Discontinue patient from study drug 
Hypercalcemia 
Serum calcium Grade 2 
Hold BGJ398 dose until resolved to Grade 1 or baseline: 
• 
if resolved within ≤ 7 days after suspending BGJ398, maintain dose level. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
• 
if resolved between > 7 days and 14 days after suspending BGJ398, ↓ 1 dose 
level. 
• 
if not resolved within ≤14 days, discontinue patient from study treatment. 
Serum calcium Grade ≥3 
Discontinue patient from the study treatment 
Nervous system disorders 
Neurotoxicity 
Grade 2 
Omit dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then ↓ 1 dose level of 
BGJ398. If not resolved within ≤14 days, discontinue patient from study drug. 
Grade ≥ 3 
Discontinue patient from study drug treatment 
GI disorders 
Pancreatitis 
Grade ≥ 2 
Discontinue patient from study drug treatment 
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 BGJ398, initiate anti-diarrheal treatment 
Grade 2 
• 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
• 
Optimize anti-diarrheal treatment. 
• 
For reoccurrence of diarrhea CTCAE Grade 2, hold dose of BGJ398 until 
resolved to CTCAE Grade ≤ 1, ↓ BGJ398 by 1 dose level 
Grade 3 
• 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
• 
Optimize anti-diarrheal treatment 
• 
↓ BGJ398 by 1 dose level 
• 
For reoccurrence of diarrhea CTCAE Grade 3, despite optimal antidiarrheal 
treatment, discontinue patient from study treatment. 
Grade 4 
Discontinue patient from study treatment. 
Vomiting 
Grade 2 not controlled by optimal anti-emetic therapy 
Hold BGJ398 doses until ≤ Grade 1, ↓ 1 dose level. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise specified) 
Dose Modifications any time during a cycle of therapy 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Grade 3 not controlled by optimal anti-emetic therapy or Grade 4 
Discontinue patient from study treatment. 
Eye Disorders (confirmed by ophthalmic examination) 
Retinal disorders 
Grade 2 central serous retinopathy and central serous retinopathy - 
like events 
Hold BGJ398 until resolved to ≤ Grade 1 and continue ophthalmic evaluation 
• 
If resolved within ≤ 14 days, ↓ BGJ398 by 1 dose level 
• 
If resolved after > 14 days, discontinue BGJ398 
Grade 3 central serous retinopathy and central serous retinopathy- 
like events and any other Grade 3 eye disorders 
Hold BGJ398 until resolved to Grade ≤ 1. 
• 
If resolved within ≤ 14 days, ↓ BGJ398 by 1 dose level 
• 
If resolved after > 14 days, discontinue BGJ398 
≥ Grade 1 retinal vein occlusion, Grade 4 central serous retinopathy 
and central serous retinopathy-like events, and Grade 4 other eye 
disorders 
Discontinue patient from study treatment. 
Other ocular/visual toxicity 
≥ Grade 3 
Hold BGJ398 until resolution to ≤ Grade 1 
• 
If resolution within ≤14 days, ↓ 1 dose level 
• 
If resolved after >14 days, discontinue BGJ398 
General disorders 
Fatigue 
Grade ≥3 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved after > 7 days, discontinue patient from study treatment. 
Other clinically significant AEs 
Grade 3 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then ↓ 1 dose level of 
BGJ398. 
If not resolved within ≤14 days, discontinue patient from study treatment. 
Grade 4 
Discontinue patient from study treatment. 
All dose modifications should be based on the worst preceding toxicity. Patients may have a third dose reduction only with approval of a QED Therapeutics’ 
medical monitor or designee. 


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6.2.2 
Follow-up for toxicities 
 
Patients whose treatment is interrupted or permanently discontinued due to an adverse 
event or clinically significant laboratory value, must be followed up at least once a week 
(or more frequently if required by institutional practices, or if clinically indicated) for 4 
weeks, and subsequently at 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. Clinical experts or specialists, such as ophthalmologist, 
endocrinologist, dermatologist, should be consulted as deemed necessary. Further 
guidelines and dose modifications for the management of specific study drug induced 
toxicities (hyperphosphatemia, diarrhea) are provided in Table 5. All patients must be 
followed up for adverse events and serious adverse events for 30 days following the last 
doses of BGJ398. 
 
6.2.3 
Anticipated risks and safety concerns for the study drug 
 
Eligibility criteria as well as specific dose modification and stopping rules are included in 
this protocol. Guidelines for prophylactic or supportive treatment for expected toxicities, 
including management of study-drug induced adverse events, i.e. hyperphosphatemia, 
renal toxicities are provided in Table 5. Refer to nonclinical toxicity and or clinical data 
found in the BGJ398 Investigator’s Brochure. 
 
Treatment of adverse events or laboratory abnormalities should follow the protocol where 
specified. If not specified in the protocol, treatment of AEs or laboratory abnormalities 
should be according to local institutional guidelines. 
 
6.3 
Concomitant medications 
 
The patient must notify the investigational sites about any new medications he/she takes 
after the start of the study drug. All medications (other than study drug) and significant 
non-drug therapies (including physical therapy, herbal/natural medications and blood 
transfusions) administered during the study must be listed on the Concomitant 
Medications eCRF page. All cancer medications/therapies given to the patient after the 
last dose of study drug must be recorded in the eCRF Cancer Medications/Therapies page 
until patient is off study. A concomitant medication is considered prohibited if it appears 
on any of the prohibited medication lists for any clinical pharmacology property of the 
drug (e.g. CYP, BCRP). 
 
6.3.1 
Permitted concomitant therapy 
 
Any palliative and supportive care for disease related symptoms, including; any 
medication for a concurrent medical condition are permitted, except as specifically 
prohibited below. 
 
Hematopoietic growth factors 
 
Hematopoietic growth factors (e.g. erythropoietin, G-colony stimulating factor (CSF) and 
GM-CSF) are not to be administered prophylactically or to be used to meet eligibility 


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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). 
 
Hormone replacement therapies 
 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as 
well as estrogen replacement hormone treatment. 
 
Management of Hyperphosphatemia 
 
Hyperphosphatemia is a recognized on-target effect of potent and selective inhibitors of 
the FGFR pathway. While on BGJ398, patients should avoid foods that are especially 
high in phosphate and, if possible, should restrict dietary phosphate to 600 – 800 mg/day. 
High-phosphate foods include dairy products; meats, nuts, and other high-protein foods; 
processed foods; and dark colas. 
 
Patients who have experienced hyperphosphatemia should take a phosphate binder such 
as sevelamer, sucroferric oxyhydroxide, lanthanum carbonate, ferric citrate, etc. within 
30 minutes of a meal on the day while taking BGJ398. Once the patient has had 
hyperphosphatemia, the patient should remain on a low phosphate diet, if possible, and 
take phosphate binder on the days BGJ398 is taken, even if the serum phosphorus is 
normalized. Unless otherwise specified by the local package insert or institutional 
practice, the following regimen should be used to manage hyperphosphatemia: 
 
• For serum phosphorus >5.5 – 7.5 mg/dL 
○ Start sevelamer 800 mg three times a day with meals 
 
○ Increase the dose of sevelamer up to 1200 mg every 8 hours 
 
• For serum phosphorus ≥7.5 mg/dL 
○ Increase the dose of sevelamer up to 1600 mg (2 tablets per meal) every 8 hours 
 
○ Consider adding acetazolamide two to three 250 mg tablets per day. 
 
During the BGJ398 cycle, patients do not need to be on a low phosphate diet or take a 
phosphate binder during their 1-week off period unless serum phosphorus is not 
normalized. Other dose modifications are provided in Table 5, but should be modified as 
per country or institutional practice. 
 
Management of Diarrhea 
 
Patients 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 patients may require concomitant treatment with 


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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 according to Table 5. 
 
Management of Bone Metastatic Disease 
 
Treatment of bone metastatic disease with symptomatic standard of care therapy 
according to institutional guidelines, including prophylactic treatment with 
bisphosphonates, palliative localized radiation therapy, and symptomatic treatment with 
steroids and pain medications is allowed. Initiation of other systemic anticancer therapy 
as described in Section 6.3.3 is not allowed and requires permanent discontinuation of 
study treatment. 
 
Management of Alopecia, Palmar-Plantar Erythrodysesthesia, Paronychia, 
and Stomatitis 
 
Recommendations for management (not required per protocol) of alopecia, palmar- 
plantar erythrodysesthesia syndrome, paronychia (adapted from Segaert 2005), and 
stomatitis (adapted from Rugo 2017) are provided in Table 6. These are guidelines only 
and institutional guidelines should be followed where applicable. 


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Table 6: 
Recommended Management of Alopecia, Palmar-Plantar 
Erythrodysesthesia Syndrome, Paronychia, and Stomatitis 
 
Alopecia 
Grade 1 
Continue study drug 
• 
Minoxidil 5% (OTC) solution or foam once daily to scalp 
Grade 2 
Continue study drug 
• 
Minoxidil 5% (OTC) solution or foam twice daily to scalp 
• 
Fluocinonide 0.05% solution daily to scalp 
Palmar-plantar erythrodysesthesia syndrome 
Grade 0/1 Continue study drug 
• 
Urea 20% or ammonium lactate 12% lotions BID to hands and feet 
Grade 2 
Continue study drug 
• 
Urea 20% or ammonium lactate 12% BID to hands and feet 
• 
Fluocinonide 0.05% cream BID to hands and feet 
Grade 3 
Hold study drug until resolved to Grade ≤1 
• 
Urea 20% or ammonium lactate 12% BID to hands and feet 
• 
Fluocinonide 0.05% cream BID to hands and feet 
Paronychia 
Grade 1 
Continue study drug 
• 
Clindamycin 1% solution around and under nails TID 
• 
Soak for 15 minutes daily in white vinegar in tap water (1:1) 
Grade 2 
Continue study drug 
• 
Obtain bacterial cultures to confirm sensitivity to antimicrobial 
• 
Cefadroxil 500 mg BID or TMP/SMX DS BID for 14 days 
• 
Soak for 15 minutes daily in white vinegar in tap water (1:1) 
• 
Dermatology consultation 
Grade 3 
Hold study drug until resolved to Grade ≤1 
• 
Obtain bacterial cultures to confirm sensitivity to antimicrobial 
• 
Cefadroxil 500 mg BID or TMP/SMX DS BID for 14 days 
• 
Dermatology consultation 
Stomatitis 
Grade 1 
Continue study drug 
• 
Dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5mL) TID. 
Grade 2 
Continue study drug 
• 
Dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5mL) TID 
Grade 3 
Hold study drug until resolved to Grade ≤1 
• 
Dexamethasone elixir 0.5 mg/mL swish and spit 1 teaspoon (5 mL) TID. 
• 
Clotrimazole 10 mg lozenges QD 
BID=2 times daily; OTC=over-the-counter; QD=once daily; TID=3 times daily; TMP/SMX 
DS=sulfamethoxazole and trimethoprim 
 
6.3.2 
Permitted concomitant therapy requiring caution and/or action 
 
Details for specific medications which require action and/or caution while on study are 
provided in Appendix 1. The rationale for these medications is provided below. 
 
Drugs that alter the pH of the GI tract 
 
BGJ398 is characterized by pH-dependent solubility, and therefore, medicinal products 
that alter the pH of the upper gastro-intestinal tract may alter the solubility of BGJ398, 
and limit bioavailability. These agents include, but are not limited to, proton pump 


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inhibitors (eg, omeprazole), H2-antagonists (eg, ranitidine) and antacids. If possible, 
proton pump inhibitors should be avoided due to their long gastric pH-lowering effect 
and replaced with H2-antagonists or antacids. Study drug should be taken ≥2 hours before 
or 10 hours after dosing with an acid-reducing agent. 
 
Substrates and inhibitors 
 
CYP3A inhibitors and inducers 
 
BGJ398 is a substrate of CYP3A4. Therefore moderate inhibitors and inducers should be 
used with caution if no other alternative is 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. 
 
Transporter substrates 
 
In vitro data show that BGJ398 is an inhibitor of BCRP (Breast Cancer Resistance 
Protein). Medications which are BCRP substrates must be monitored for potential 
toxicity and may require dose titration or reduction of the medication. 
 
Anti-emetics 
 
Anti-emetics are allowed for the treatment of nausea or vomiting. It is recommended to 
avoid using drugs that are known to cause QT prolongation. Note that some anti-emetics 
have a known risk for Torsade de Pointes, and therefore need to be used with caution. 
See Appendix 1 for list of drugs that need to be used with caution. Aprepitant is both a 
sensitive substrate and a moderate CYP3A4 inhibitor and should be used with caution if 
an alternative is not available. 
 
Medications with a possible or conditional risk of QT/QTc interval 
prolongation or torsade de pointes 
 
Preliminary data have shown that BGJ398 has no effect on cardiac conduction or ECG 
intervals (see current version of the BGJ398 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 patients should 
be carefully monitored. See Appendix 1 for list of drugs that need to be used with 
caution. Please note that the list might not be comprehensive. 
 
6.3.3 
Prohibited concomitant therapy 
 
Details for specific medications prohibited while on study are provided in Appendix 2. 
The rationale for the restricted medications is provided below. 


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Other investigational and antineoplastic therapies 
 
Other investigational therapies must not be used while the patient is on the study 
treatment. Anticancer therapy (chemotherapy, biologic or radiation therapy, and surgery) 
other than the study treatment must not be given to patients while the patient is on the 
study medication. If such agents are required, then the patient must be discontinued from 
study treatment. The only exception is palliative localized radiation therapy for bone 
metastases with approval by QED Therapeutics’ medical monitor. 
 
CYP inhibitors 
 
Strong inhibitors of CYP3A4 such as the ones listed in Appendix 2 are prohibited 
because BGJ398 is a likely substrate of this isoenzyme. 
 
CYP inducers 
 
Strong inducers of CYP3A4 are prohibited because their usage may decrease the 
exposure of BGJ398. Therefore, agents such as those listed in Appendix 2 are prohibited. 
Please note that the list may not be exhaustive. 
 
Phosphorus and calcium 
 
Medications that increase the serum levels of phosphorus and/or calcium are prohibited. 
 
6.4 
Patient numbering, treatment assignment or randomization 
 
6.4.1 
Patient numbering 
 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned 
when the patient is first enrolled for screening and is retained as the primary identifier for 
the patient throughout his/her entire participation in the trial. The Subject No. consists of 
the Center Number (Center No.) (as assigned by QED Therapeutics to the investigative 
site) with a sequential patient number suffixed to it, so that each subject is numbered 
uniquely across the entire database. Upon signing the informed consent form, the patient 
is assigned to the next sequential Subject No. available to the investigator through the 
Oracle Clinical RDC interface. 
 
6.4.2 
Treatment assignment or randomization 
 
This is an open-label, single arm study. There will be no randomization required for this 
study. 
 
6.4.3 
Treatment blinding 
 
Treatment is not blinded in this study. 


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6.5 
Study drug preparation and dispensation 
 
The investigator or responsible site personnel must instruct the patient or caregiver to 
take the study drugs as per the protocol. Study drug(s) will be dispensed to the patient by 
authorized site personnel only. All dosages prescribed to the patient and all dose changes 
during the study must be recorded on the Dosage Administration Record CRF. 
 
BGJ398 will be supplied as hard gelatin capsules for oral use at dose strengths of 25 and 
100 mg. Excipients will include microcrystalline cellulose, lactose monohydrate, 
hypromellose 2910, crospovidone, colloidal silicon dioxide, magnesium stearate, and 
hard gelatin capsule. BGJ398 will be manufactured under Good Manufacturing Practice 
for investigational use. The color and appearance of the capsules are outlined below. 
 
Final market image version 3 (FMI III) formulation (Cohort 1): 
 
Physical 
Attribute 
Appearance 
(color) 
Size 3 Capsule: Swedish orange opaque cap and body filled 
with white to greyish powder (25 mg) 
Size 1 Capsule: Swedish orange opaque cap and body filled 
with white to greyish powder (100 mg) 
 
Final market image version 4 (FMI IV) formulation (all cohorts): 
 
Physical 
Attribute 
Appearance 
(color) 
Size 3 Capsule: White opaque body with gray opaque cap, 
imprinted with a green band on the body and a black band 
on the cap filled with white to greyish powder (25 mg) 
Size 1 Capsule: White opaque body with light orange 
opaque cap, imprinted with a green band on the body and a 
black band on the cap filled with white to greyish powder 
(100 mg) 
 
The FMI III formulation will be provided in 28-count bottles, and the FMI IV 
formulation will be provided in 21-count bottles. 
 
Patients who initially received FMI III will be switched over to FMI IV when FMI IV is 
available at the study site. 
 
The site pharmacist or designee will dispense the correct number and dose strength of 
capsules to ensure the patient receives sufficient drug for each 28-day treatment cycle. 
Study drug will be dispensed to the patient by authorized trained site personnel only. 
 
6.5.1 
Study drug packaging and labeling 
 
BGJ398 capsules are packaged in HDPE bottles with child resistant closures. 
Medication labels will be in the local language and comply with the legal requirements 
of each country. They will include storage conditions for the drug but no information 
about the patient. 


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6.5.2 
Drug supply and storage 
 
Study treatments must 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, the study treatment should be 
stored according to the instructions specified on the drug labels and in the Investigator’s 
Brochure. 
 
6.5.3 
Study drug compliance and accountability 
 
6.5.3.1 
Study drug compliance 
 
Compliance will be assessed by the investigator and/or study personnel at each patient 
visit and information provided by the patient and/or caregiver will be captured in the 
Drug Accountability Form. This information must be captured in the source document at 
each patient visit. 
 
On the day of a scheduled visit to the clinic, the patient will take the study drugs under 
the supervision of the Investigator or designee. The time of dose administrations on days 
when PK blood samples are drawn must be recorded in the Dosage Administration 
Record eCRF. 
 
6.5.3.2 
Study drug accountability 
 
The investigator or designee must maintain an accurate record of the shipment and 
dispensing of study treatment in a drug accountability log. Drug accountability will be 
noted by the field monitor during site visits and at the completion of the study. Patients 
will be asked to return all unused study treatment and packaging on a regular basis, at the 
end of the study or at the time of study treatment discontinuation. 
 
At study close-out, and, as appropriate during the course of the study, the investigator 
will provide access to all used and unused study treatment, packaging, drug labels, and a 
copy of the completed drug accountability log to the monitor. 
 
6.5.3.3 
Handling of other study treatment 
 
Not applicable. 
 
6.5.4 
Disposal and destruction 
 
The study drug can be destroyed at the site if permitted by local regulations. 
Alternatively, the study drug can be destroyed at a third-party depot. 


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7 VISIT SCHEDULE AND ASSESSMENTS 
7.1 
Study flow and visit schedule 
 
Table 7 lists all of the assessments and indicates with an “X” the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s 
source documentation. The table indicates which assessments produce data to be entered 
into the database (D) or remain in source documents only (S) (“Category” column). 
 
Molecular pre-screening assessments can be done any time prior to the initiation of the 
screening. 
 
• Baseline imaging assessments can be conducted within 28 days prior to 1st day of 
study treatment. 
 
• All other baseline/screening assessments must be performed within 21 days prior to 
1st treatment, except for the ophthalmic examination, which should be completed 
within 14 days prior to first treatment. 
 
• Baseline/screening assessments that are conducted within 3 days prior to 1st treatment 
can be used to satisfy the day 1 requirement. Every effort must be made to follow the 
schedule outlined in Table 7. 
 
For all visits, there is a ± 3-day window on assessments to take into account scheduling 
over weekends and holidays, if not explicitly specified otherwise. For post baseline 
imaging and ophthalmic assessments, a ±7 day window is allowed, except for the first 
post baseline assessment (+7 day window permitted). There are no visit windows for the 
trough PK sampling days (sparse PK sample group [Table 10]: Cycle 1 Days 2, 8, 15, and 
21; and extensive PK sample group [Table 11]: Cycle 1 Days 2 and 16). 
 
PK samples will be collected according to Table 10 or Table 11. Biomarker sampling 
will be conducted as outlined in Table 12. 
 
All assessments should be performed as outlined in Table 7 and as clinically indicated. 


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Table 7: 
Visit evaluation schedule for all cohorts 
 
Category 
Protocol Section 
Molecular Pre- 
screening 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30-day follow-up 
Disease 
Progression
follow-up 
every 
8 weeks 
Survival 
follow- 
up 
(every 4 
months 
after 
EOT) 
Study Period 
Screening 
Treatment 
EOT 
Follow-up 
Day of Cycle 
-21 to 
-1 
1 
2 
8 
15 
16 
21 
1 
15 
1 
15 
1 
15 
≤14 days of 
the decision to
discontinue 
the treatment 
Informed consent for molecular 
pre-screening if local data are 
not available 
D 
7.1.1 
X 
Pre-screening testing if local 
data are not available 
D 
7.1.1 
X 
Study Informed Consent (ICF) 
D 
7.1.2 
X 
Demography 
D 
7.1.2.3 
X 
X 
Inclusion/exclusion criteria 
D 5.2, 5.3, 
7.1.2 
X 
X 
Relevant medical history/current 
medical conditions 
D 
7.1.2.3 
X 
Diagnosis and extent of cancer 
D 
7.1.2.3 
X 
Prior antineoplastic therapy 
D 
7.1.2.3 
X 
Prior/concomitant medications 
D 
6.3 
X 
Continuous 
X 
X 
Physical examination 
S 
7.2.2.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Height 
D 
7.2.2.3 
X 
Weight 
D 
7.2.2.3 
X 
X 
X 
X 
X 
X 
Vital signs 
D 
7.2.2.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Performance status 
D 
7.2.2.4 
X 
X 
X 
X 
X 
X 
Ophthalmic assessment 
D 
7.2.2.5 
X 
X 
X 
X 
Xb 
X 
Hematology 
D 7.2.2.6.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Chemistry (predose) 
D 7.2.2.6.2 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Coagulation 
D 7.2.2.6.3 
X 
If clinically indicated 
Urinalysis (microscopic or 
macroscopic) 
D 7.2.2.6.4 
X 
If clinically indicated 
Pregnancy test 
D 7.2.2.6.5 
X 
X 
X 
X 
X 
X 


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Category 
Protocol Section 
Molecular Pre- 
screening 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30-day follow-up 
Disease 
Progression
follow-up 
every 
8 weeks 
Survival 
follow- 
up 
(every 4 
months 
after 
EOT) 
Study Period 
Screening 
Treatment 
EOT 
Follow-up 
Day of Cycle 
-21 to 
-1 
1 
2 
8 
15 
16 21 
1 
15 
1 
15 
1 
15 
≤14 days of 
the decision to
discontinue 
the treatment 
Tumor response per RECIST 1.1 D 
7.2.1 
X 
X 
Day 1 
of every
odd 
cycle 
X (if not done 
within 28 days 
prior) 
X (only for 
pts. who 
discontinue 
for any 
reason other 
than 
progression 
of disease 
Study drug administration 
D 
6.1 
Continuous on a 3 weeks on 1 week off schedulec 
12-lead ECG 
D 
7.2.2.7 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Cardiac imaging (ECHO or 
MUGA) 
D 
7.2.2.7 
X 
X 
X 
Adverse Events 
D 
8.1, 8.2 
Continuously throughout the study 
X 
Collection of archival paraffin 
blocks/slides or a newly 
obtained tumor sample AND 
pathology report 
D 
7.2.4.1 
X 
(if local 
data not 
available)
Xd 
Newly obtained tumor sample (if 
medically feasible) 
D 
7.2.4.2 
Xe 
X (upon disease progression)-optional 
Blood sample for assessment of 
circulating tumor DNA (cell free 
DNA) (all samples are predose) 
D 
7.2.4.3 
X 
X 
X 
Day 1 
of every
odd 
cycle 
X (if not done 
within 28 days 
prior) 
Blood for PK (sparse PK group) D 
7.2.3.1 
X 
X 
X 
X 
X 
X 
X 
X 
X 
Day 15 
Cycles 
4- 6 
Blood for PK (extensive PK 
group)f 
D 
7.2.3.1 
X 
X 
X 
X 
X 
X 
Day 1 
Cycles 
4-6 


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Category 
Protocol Section 
Molecular Pre- 
screening 
Screeninga 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30-day follow-up 
Disease 
Progression
follow-up 
every 
8 weeks 
Survival 
follow- 
up 
(every 4 
months 
after 
EOT) 
Study Period 
Screening 
Treatment 
EOT 
Follow-up 
Day of Cycle 
-21 to 
-1 
1 
2 
8 
15 
16 
21 
1 
15 
1 
15 
1 
15 
≤14 days of 
the decision to
discontinue 
the treatment 
Survival follow-up 
D 
7.1.6 
X 
Antineoplastic therapies since 
discontinuation of study 
treatment 
D 
7.1.4 
X 
X 
Disease progression follow-up 
D 
7.1.6 
X 
a Screening assessments are to be completed within 21 days prior to the first dose of treatment, except for the radiological tumor assessment, which can be 
performed within 28 days prior to the first dose, and the ophthalmic examination, which should be completed within 14 days prior to first treatment. 
b Ophthalmic assessments for subsequent cycles (ie, after C3D1) are to be completed at C7D1 and every 4 months after that (ie, C11D1, C15D1, C19D1, etc). 
c Study drug will be administered in the clinic on the following days (PK sampling days): 
Sparse PK sample group (Table 10): C1D1,2,8,15,21; and C2-6 D1 and D15. 
Extensive PK group (Table 11): C1D1,2,15,16; and C2-6 D1. 
d If written documentation of FGFR2 gene fusion or translocation is determined by a pre-existing test or local laboratory, archival tumor tissue from the same 
biopsy sample used to determine eligibility (or a new tumor biopsy collected before BGJ398 treatment) should be submitted to the central laboratory for 
confirmation testing within 14 days after the first treatment. Refer to the Laboratory Manual for the sample requirements and processing instructions for central 
laboratory testing. 
e Sample will not be collected if a fresh tumor sample has already been collected at baseline for the purpose of DNA sequencing. 
f The first 20 patients enrolled in Cohort 1 and treated with FMI III and all patients enrolled in either Cohort 2 or Cohort 3 and treated with FMI IV (amendment 
4) will follow the extensive PK sampling schedule. 


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7.1.1 
Molecular pre-screening 
 
Evidence of genetic alterations, including FGFR2 gene fusion or other FGFR genetic 
alterations, can be obtained from pre-existing analysis, local testing of samples at an 
institution-designated laboratory or an institution-designated sequencing facility, or 
through the submission of samples to a QED Therapeutics designated laboratory central 
facility for testing. When possible, pre-existing analysis by local testing should be 
performed using a clinically validated test in a CLIA-certified (or equivalent) laboratory. 
 
If local or central testing will be conducted to determine the molecular status of the 
tumor, potential patients will be asked to sign a pre-screening informed consent to allow 
for the collection and analysis of the sample. A pre-screening consent form is not needed 
if the molecular status of the tumor was previously determined. Written documentation of 
the local FGFR2 test result must be present in the source documentation for review by 
QED Therapeutics. 
 
For central FGFR molecular testing, the archival or newly obtained tumor sample will be 
sent to a QED Therapeutics designated lab and the results of the analysis will be 
communicated to the respective center. Upon positive determination that the sample 
submitted contains the required FGFR2 gene fusions or translocation (Cohorts 1 and 3), 
or FGFR1, 2, or 3 activating mutation or FGFR1 or 3 fusions or translocations 
(Cohort 2), the patient may sign the study’s main Informed Consent to begin screening 
procedures. 
 
Additional testing will be performed to evaluate other genetic alterations related to or 
thought to be related to cholangiocarcinoma. 
 
A copy of the corresponding pathology report for each set of slides/blocks should be sent 
to QED Therapeutics designated central laboratory. 
 
FGFR translocation/alterations status must be captured on the appropriate eCRF upon 
enrollment onto the study after the patient has signed the study’s main Informed Consent. 
 
The tumor blocks will be returned, if molecular pre-screening inclusion criteria are not 
met. 
 
7.1.2 
Screening 
 
The IRB/IEC study approved informed consent form (ICF) must be signed and dated 
before any study-specific screening procedure is performed. Procedures which are part 
of the clinical routine during the initial diagnostic work-up of the patient may be obtained 
before obtaining the ICF. A copy of the ICF must be given to the patient or to the person 
signing the form. The investigator or designee must record the date when the study 
informed consent was signed in the medical records of the patient. 
 
Patients will be evaluated against study inclusion and exclusion criteria and safety 
assessments. For details of assessments, refer to Table 7. Screening assessments must be 


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completed within 21 days prior to the first dose of treatment except for (1) the 
radiological tumor assessment, which should be performed within 28 days prior to the 
first dose, and (2) the ophthalmology examination, which should be completed within 
14 days prior to first dose. Screening assessments must be repeated if outside of 
screening windows. 
 
7.1.2.1 
Eligibility screening 
 
After a patient signs the study Informed Consent Form, the investigator or clinical site 
should determine patient eligibility. 
 
7.1.2.2 
Information to be collected for screen failures 
 
Patients who signed a molecular pre-screening ICF but are considered as ineligible after 
molecular screening, as well as patients who are found not eligible after signing the 
informed consent form to participate in the treatment phase of the study, will be 
considered as screening failures, and data will be handled in the same manner. The 
reason for not being started on study treatment will be entered on the screening phase 
disposition page. For all screening failure patients, demography, inclusion/exclusion and 
informed consent information along with the reason for screen failure will be collected. 
No other data will be entered in the database for patients who are screen failures, unless 
the patient experienced a Serious Adverse Event during the screening phase (see 
Section 8 for SAE reporting details). For molecular prescreening failures, only SAEs 
possibly related to a study procedure will be reported. 
 
7.1.2.3 
Patient demographics and other baseline characteristics 
 
Data to be collected will include general patient demographics, relevant medical history 
and current medical conditions, prior concomitant medications, diagnosis and extent of 
tumor, baseline tumor mutation status (FGFR gene fusions or translocation or other 
FGFR genetic alterations) and details on prior antineoplastic treatments. 
 
7.1.3 
Treatment period 
 
The treatment period commences on the first day of the first cycle of BGJ398 and ends 
after the last dose of BGJ398. 
 
During the study treatment period, patients will be regularly monitored to assess the 
safety and early anti-tumor activity of treatment. For purpose of scheduling and 
evaluations, a treatment cycle will consist of 28 days. 
 
During the treatment period, the patient is obliged to follow the investigators instructions 
with regards to contraception, concomitant medications and dosing regimen. There is no 
fixed duration; patients may continue treatment with the study drug until the development 
of an unacceptable toxicity that precludes any further treatment, disease progression, 
and/or treatment is discontinued at the discretion of the Investigator or by patient refusal. 
For details of assessments during the treatment period, refer to Table 7. 


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7.1.4 
Discontinuation of study treatment 
 
Patients may voluntarily discontinue from the study treatment for any reason at any time. 
If a patient decides to discontinue from the study treatment, the investigator should make 
a reasonable effort (e.g. telephone, e-mail, letter) to understand the primary reason for 
this decision and record this information in the patient’s chart and on the appropriate CRF 
pages. They may be considered withdrawn if they state an intention to withdraw, fail to 
return for visits, or become lost to follow-up for any other reason. 
 
Study treatment must be discontinued under the following circumstances: 
 
• Adverse events that lead to substantial changes in individual risk-benefit 
considerations 
 
• Dose delay of > 14 days from the intended day of the next scheduled dose, unless 
otherwise specified in Section 6.2.1, and approval by QED Therapeutics’ medical 
monitor 
 
• Pregnancy 
• Protocol deviation that results in a significant risk to the patient’s safety 
Patients who discontinue study treatment should NOT be considered withdrawn from the 
study. They should return for the assessments indicated in Table 7 (end of study 
treatment visit) and then enter the follow-up epoch. If they fail to return for these 
assessments for unknown reasons, every effort (e.g. telephone, email, letter) should be 
made to contact them as specified in Section 7.1.7 (Lost to follow-up). 
 
For patients who discontinue treatment for reasons other than documented disease 
progression, death, lost to follow-up, or withdrawal of consent, tumor assessments must 
continue to be performed every 8 weeks until documented disease progression, death, lost 
to follow-up, or withdrawal of consent. 
 
For patients who have documented radiographic disease progression and continue study 
treatment according to Section 6.2.1, no further imaging or transmittal of images for 
central imaging assessment is required. 
 
7.1.4.1 
Replacement policy 
 
No replacements will be needed. 
 
7.1.5 
Withdrawal of consent 
 
Patients may voluntarily withdraw consent to participate in the study for any reason at 
any time. Withdrawal of consent occurs only when a patient does not want to participate 
in the study any longer, and does not want any further visits or assessments, and does not 
want any further study related contact. 


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QED Therapeutics will continue to retain and use all research results that have already 
been collected for the study evaluation. All biological samples that have already been 
collected may be retained and analyzed at a later date (or as required by local 
regulations). 
 
If a patient withdraws consent, the investigator must make every effort (e.g. dates of 
telephone calls, e-mail, letter) to determine the primary reason for this decision and 
record this information. 
 
Study treatment must be discontinued and no further assessments conducted. 
 
Further attempts to contact the patient are not allowed unless safety findings require 
communication or follow-up. 
 
7.1.6 
Follow-up period 
 
Patients lost to follow-up should be recorded as such on the eCRF. For patients who are 
lost to follow-up, the Investigator should show "due diligence" by documenting in the 
source documents steps taken to contact the patient, e.g. dates of telephone calls, 
registered letters, etc. 
 
30-day safety follow-up period 
 
All patients must complete the safety follow-up assessments 30 days after the last dose of 
the study treatment. Information relating to antineoplastic therapies taken since 
discontinuation of study treatment and AEs (including concomitant medication taken for 
ongoing AEs) will be collected for 30 days after the last dose of the study treatment. 
 
All AEs suspected to be related to study drug should be followed up weekly, or as 
clinically indicated, until resolution or stability (see also Section 6.2.2). 
 
Disease progression follow-up period 
 
All patients enrolled in the study who discontinue study treatment for any reason other 
than disease progression will have a tumor assessment every 8 weeks (± 7 days) as 
detailed in Table 7, until disease progression or the initiation of subsequent anticancer 
therapies, or death, whichever occurs first. Any newly started antineoplastic therapies 
during the follow-up period must be recorded on the Antineoplastic therapy since 
discontinuation eCRF. 
 
Survival follow-up period 
 
All patients enrolled in the study will be followed for survival at least every 4 months 
after discontinuation of treatment. Survival follow-up will continue for up to 5 years or 
until all patients have discontinued study treatment or have died, withdrawn consent, or 
been lost to follow-up. 


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7.1.7 
Lost to follow-up 
 
For patients whose status is unclear because they fail to appear for study visits without 
stating an intention to withdraw consent, the investigator should show "due diligence" by 
contacting the patient, family or family physician as agreed in the informed consent and 
by documenting in the source documents steps taken to contact the patient (e.g. dates of 
telephone calls, emails, letters, etc.). A patient should not be considered lost to follow-up 
until due diligence has been completed. 
 
7.2 
Assessment types 
 
7.2.1 
Efficacy assessment 
 
Tumor response will be evaluated locally by the investigator according to the guideline 
(see Appendix 3) based on the Response Evaluation Criteria in Solid Tumors (RECIST) 
Version 1.1 (Eisenhauer 2009). Each patient will be evaluated for all potential sites of 
tumor lesions at screening/baseline and every 8 weeks after starting study treatment until 
disease progression. 
 
CT (Computed Tomography) /MRI (Magnetic Resonance Imaging) scans will be 
performed at baseline within 28 days before start of treatment and subsequently every 8 
weeks from treatment start until progression of disease. 
 
After baseline, the first assessment should be performed at Cycle 3 Day 1 (+7 day 
window) and all subsequent assessments should be performed within ±7 days of the 
scheduled day of assessment. The same method of assessment and the same technique 
should be used to characterize each individual and reported lesion at baseline and during 
follow-up. If a patient discontinues treatment for reasons other than radiological 
documentation of progression of disease, an efficacy assessment should be performed at 
the time of End of Treatment unless a CT/MRI for tumor measurement was performed 
≤ 4 weeks earlier. 
 
Chest, abdomen, and pelvis CT scans are required for all patients at baseline. If at 
baseline, a patient is known to have a contraindication to CT i.v. contrast media or 
develops a contraindication during the trial, a contrast-enhanced MRI (if possible) of 
chest, abdomen, and pelvis should be performed. CT/MRI of the brain should be 
performed if clinically indicated. 
 
For the patients with skeletal lesions suspected at baseline, whole-body bone imaging 
should be obtained either with a TC99 bone scan or alternatively a NaF CT/ MRI PET 
scan. Of note, the CT or MRI portion of the scan should only be substituted for the 
required chest, abdomen, and pelvic CT scans if the CT or MRI is of diagnostic quality 
and meets all requirements as described in the study imaging guide (ie, oral and IV 
contrast, slice thickness, and anatomic coverage). Post-baseline, if skeletal lesions were 
identified at baseline, which are not visible on the chest, abdomen or pelvis CT/MRI 
scan, bone imaging with either a TC99 bone scan or NaF CT/MRI PET is required at all 
post-baseline imaging timepoints (every 8 weeks). In all cases that post-baseline bone 


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imaging is required, the same modality that was used at screening should be used for all 
post-baseline imaging when possible. 
 
Partial Response (PR) and Complete Response (CR) should be confirmed by repeat 
assessments performed at least 4 weeks and no later than 6 weeks after the criteria for 
response are first met. 
 
PET/CT may be used only if it is of similar diagnostic quality as a CT performed without 
PET, including the utilization of oral and intravenous contrast media. While FDG-PET 
may complement CT scans in assessing progression per RECIST 1.1 (Appendix 3) FDG- 
PET assessments should be disregarded for this protocol. 
 
If possible, a single radiologist should perform all tumor response evaluations for an 
individual patient. 
 
Any lesion that has been previously treated with radiotherapy should be considered as a 
nontarget lesion. However, if a lesion previously treated with radiotherapy has clearly 
progressed since the radiotherapy, it can be considered as a target lesion. 
 
All radiological assessments obtained for patients enrolled in Cohort 1 will be sent to a 
QED Therapeutics designated central imaging CRO. The site manual provided by the 
designated imaging CRO will provide further details regarding image collection and 
central imaging assessment. 
 
7.2.2 
Safety and tolerability assessment 
 
Safety and tolerability assessments will include adverse event reporting and changes from 
baseline in laboratory parameters and vital signs. Tolerability will be assessed by the 
incidence of AEs leading to study drug delay or discontinuation. Safety will be monitored 
by assessing the procedures listed below as well as collecting of the adverse events at 
every visit. For details on AE collection and reporting, refer to Section 8. 
 
7.2.2.1 
Physical examination 
 
A complete physical examination must be performed as indicated in Table 7. 
 
Physical examination will be performed on the scheduled day, even if study treatment is 
being withheld. More frequent examinations may be performed at the discretion of the 
Investigator and if medically indicated. 
 
A complete physical examination will include the examination of general appearance, 
skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, back, 
lymph nodes, extremities, vascular and neurological. If indicated based on medical 
history and/or symptoms, rectal, external genitalia, breast, and pelvic exams will be 
performed. 
 
Information about the physical examination must be present in source documentation at 
the study site. Significant findings that are present prior to signing of informed consent 


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form for the study must be included in the Relevant Medical History/Current Medical 
Conditions page on the patient’s eCRF. Significant new findings that begin or worsen 
after informed consent for the study must be recorded on the AE eCRF. 
 
7.2.2.2 
Vital signs 
 
Vital signs (body temperature, pulse rate, blood pressure) must be performed in the same 
position, either sitting or supine, before dosing and as indicated in Table 7. 
Vital signs should be assessed on the scheduled day, even if study treatment is being 
withheld. More frequent examinations may be performed at the discretion of the 
Investigator and if medically indicated. 
 
7.2.2.3 
Height and weight 
 
Weight will be measured as indicated in Table 7. Height will be collected at screening 
only. More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated. 
 
7.2.2.4 
Performance status 
 
The ECOG performance status will be assessed as indicated in Table 8. Assessments of 
performance status will be performed on the scheduled day, even if study treatment is 
being withheld. 
 
Table 8: 
ECOG performance status 
 
Grade 
ECOG Status 
 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of 
a light or sedentary nature (eg, light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up 
and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking 
hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
 
 
7.2.2.5 
Ophthalmic assessments 
 
Ophthalmic examination will be performed by an ophthalmologist as indicated in Table 7 
(and with any new onset of visual disturbance). For post-baseline assessments, a ±7 day 
window is allowed, except for the first post-baseline assessment (+7 day window 
permitted). 
 
Assessments will include: visual acuity testing (including corrected distance acuity), slit 
lamp examination of the anterior eye segment, IOP, retinal OCT (required with 
amendment 5), and dilated fundoscopy (required with amendment 5). Additional 
examination methods such as specular microscopy and corneal pachymetry will be 
performed as clinically indicated. 


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Retinal OCT scan images may be collected centrally. 
 
7.2.2.6 
Laboratory evaluations 
 
Clinical laboratory analyses are to be performed by the local laboratory as indicated in 
Table 7 and Table 9. Laboratory tests will be collected and analyzed on the scheduled 
day, even if study treatment is being withheld. More frequent assessments may be 
performed at the discretion of the Investigator and if medically indicated, and should be 
recorded on the Unscheduled Visit eCRFs. 
 
At any time during the study, abnormal laboratory parameters which are clinically 
relevant (eg, require dose modification and/or interruption of study treatment, lead to 
clinical symptoms or signs, or require therapeutic intervention), whether specifically 
requested in the protocol or not, will be recorded on the Adverse Events eCRF page. 
Laboratory data will be summarized using the CTCAE (version 4.03). 
 
QED Therapeutics must be provided with a copy of the laboratory’s certification, and 
normal ranges for each parameter measured. In addition, if at any time a patient has 
laboratory parameters obtained from a different outside laboratory, QED Therapeutics 
must be provided with a copy of the certification and normal ranges for that laboratory. 
 
7.2.2.6.1 
Hematology 
 
Hematology tests are to be performed by the local laboratory according to the visit 
schedule outlined in Table 7. For details on the hematology panel refer to Table 9. 
 
7.2.2.6.2 
Clinical chemistry 
 
Clinical chemistry tests are to be performed by the local laboratory according to the visit 
schedule outlined in Table 7. For details on the biochemistry panel refer to Table 9. 
 
7.2.2.6.3 
Coagulation 
 
International normalized INR, pro-thrombin time (PT), partial thromboplastin time will 
be measured according to the visit schedule in Table 7 and Table 9. 
 
7.2.2.6.4 
Urinalysis 
 
Urinalysis includes dipstick analysis will be performed according to the visit schedule in 
Table 7 and Table 9. Microscopic urinalysis will be performed only if macroscopic 
urinalysis result is abnormal. 
 
7.2.2.6.5 
Pregnancy and assessments of fertility 
 
All WOCBP (pre-menopausal or less than 1 year after the onset of menopause) must have 
a serum pregnancy test (β-hCG) ≤ 72 hours before the first dose of study treatment. 
Additionally, a serum pregnancy test should be performed at Day 1 of each cycle and at 
the End of Treatment visit. 


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Table 9: 
Clinical laboratory parameters collection plan 
 
Test Category 
Test Name 
 
Hematology 
Hematocrit, Hemoglobin, Red blood cell count, Platelets, White blood cells, 
Differential (Basophils, Eosinophils, Lymphocytes, Monocytes, Neutrophils) 
Biochemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium (can be 
corrected), Chloride, Creatinine, Blood Urea Nitrogen (BUN), Potassium, Sodium, 
Magnesium, Phosphate. 
Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, Lipid profile (Total Cholesterol, 
Triglycerides), Total Protein, Urea, Uric Acid, Amylase, Lipase 
Urinalysis 
Macroscopic Panel (Dipstick) (Blood, Glucose, Ketones, pH, Protein, Specific 
Gravity). 
Microscopic Panel (Red Blood Cells, WBC) 
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), Partial 
thromboplastin time (PTT) 
Pregnancy Test 
Serum hCG at screening; day 1 of each cycle, EOT and other times points 
 
 
7.2.2.7 
Electrocardiograms and cardiac imaging 
 
ECG evaluations will be conducted centrally. For all patients prior to the first 
administration of BGJ398, a minimum of 3 sequential 12-lead ECGs, separated by at 
least 5-10 minutes, must be performed on Day 1 of Cycle 1. This is necessary to get an 
accurate baseline QTcF calculation. 12-lead ECGs are to be performed at the following 
time-points: 
 
• At screening and/or baseline 
• Cycle 1 Day 1: pre-dose, 2-hr post-dose, ± 15 min, and 4-hr post-dose ± 30 min 
(3 sequential) 
 
• Cycle 1 Days 2, 8 and 15: pre-dose and 2-hr post-dose, ± 15 min (3 sequential) 
• Cycle 1 Day 15: 4-hr post-dose ± 30 min (3 sequential) 
• Cycle 2 onwards, day 1 of every cycle: pre-dose (3 sequential) 
• At the end of treatment 
MUGA scans or echocardiogram to assess LVEF will be performed as outlined in 
Table 7, within the windows outlined in Section 7.1. A MUGA scan or echocardiogram 
will be performed at end of study treatment only if an assessment of LVEF has not been 
performed ≤14 days prior to study completion. 
 
Clinically significant ECG and cardiac imaging findings must be discussed with the QED 
Therapeutics Medical Monitor prior to enrolling the patient in the study. Clinically 
significant ECG and cardiac imaging abnormalities present prior to randomization should 
be reported on the Medical History eCRF page. Significant new findings post 


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randomization from initiation of study drug until 30 days after permanent discontinuation 
of study drug must be recorded as an AE on the AE eCRF. 
 
7.2.3 
Pharmacokinetics 
 
Blood samples for PK evaluation will be collected from all enrolled patients participating 
in the study. Time points of blood sample collection for PK are outlined in Table 10 and 
Table 11. 
 
On the days of pharmacokinetic sampling, patients should take their medication at the 
clinic immediately after the pre-dose sample is taken. Patients who forget and take their 
medication at home will be excluded from pharmacokinetic analysis for that day; they 
should not have blood samples collected. Complete dosing information, including the 
date and time of actual blood draw and time of the last study drug dose prior to the 
sampling, should be obtained on all sampling days and recorded on the appropriate blood 
collection eCRF. If any of the scheduled sampling times are missed or a sample is not 
drawn according to this schedule, the actual collection date and time will be recorded and 
the remaining samples will be collected on schedule whenever possible. 
 
If vomiting occurs within 4 hours following study-drug administration on the day of PK 
blood sampling, the time (using the 24-h clock) of vomiting should be recorded. No 
additional trial medication should be taken in an effort to replace the material that has 
been vomited. The occurrence and frequency of any vomiting during a treatment cycle 
must be noted in the Adverse Events eCRF. If vomiting occurs after taking the drug no 
re-dosing of the patient is allowed before the next schedule dose. 
 
If any of the following events occurs, an unscheduled PK samples should be collected: 
 
• If a patient treated with investigational drug experiences an AE that results in an 
unscheduled visit or fits the criteria of a SAE, as determined by the investigator. 
 
• Whenever an ECG with a QTcF change from baseline > 60 ms or a new absolute 
QTcF ≥ 501ms result is known, an unscheduled blood samples should be collected to 
assess concentrations of BGJ398 and its metabolites. The exact time of sample 
collection should be noted in the eCRF. 
 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
 
At the specified time points detailed in Table 10 or Table 11, as appropriate, 3 mL of 
blood (per sample) will be collected for the measurement of plasma concentrations of 
BGJ398 and its metabolites. 
 
The first 20 patients enrolled in Cohort 1 and treated with FMI III, and all patients 
enrolled in Cohort 2 and Cohort 3 and treated with FMI IV, will follow the PK sampling 
schedule outlined in Table 11. 
 
All blood samples will be taken by central line, direct venipuncture, or an indwelling 
cannula inserted in a forearm vein. Complete instructions for sampling processing, 


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handling and shipment will be provided in the Laboratory Manual. Residual plasma 
samples from this study may also be used for exploratory analysis to further characterize 
the PK of BGJ398 and/or its metabolites. This may include using leftover samples for 
protein binding analysis or metabolite profiling (eg, other metabolites and markers for 
metabolic enzyme activity such as 4- beta hydroxyl cholesterol levels), if there is 
sufficient sample remaining. 
 
Table 10: 
Pharmacokinetic blood collection time points for patients 
(applicable for patients enrolled under amendment 1 and 
patients on sparse PK sample group) 
 
Cycle 
Day 
Scheduled time point 
relative to dosing 
Dose reference 
identification 
(DRID) No. 
(BGJ398) 
PK Sample No. 
(BGJ398) 
Sample 
volume (mL) 
1 
1 
Pre-dosea 
101 
101 
3 
1 
1 
2 hrs (±15 min) postdose 
101 
102 
3 
1 
1 
4 hrs (±30 min) postdose 
101 
301 
3 
1 
2 
Pre-dosea (24 h post day 1 
dose ± 120 min) 
102, 12* 
103 
3 
1 
2 
2 hrs (±15 min) post dose 
102 
104 
3 
1 
2 
4 hrs (±30 min) postdose 
102 
302 
3 
1 
8 
Pre-dosea (24 h post day 7 
dose ± 120 min) 
103, 13* 
105 
3 
1 
8 
2 hrs (±15 min) postdose 
103 
106 
3 
1 
8 
4 hrs (±30 min) postdose 
103 
303 
3 
1 
15 
Pre-dosea (24 h post day 14 
dose ± 120 min) 
104, 14* 
107 
3 
1 
15 
2 hrs (±15 min) post dose 
104 
108 
3 
1 
15 
4 hrs (±30 min) post dose 
104 
304 
3 
1 
21 
Pre-dosea (24 h post day 20 
dose ± 120 min) 
105, 15* 
109 
3 
2 
1 
Pre-dosea 
106 
110 
3 
2 
15 
Pre-dosea 
106 
305 
3 
2 
15 
4 hrs (±30 min) post dose 
106 
306 
3 
3 
1 
Pre-dosea 
107 
111 
3 
3 
15 
Pre-dosea 
107 
307 
3 
3 
15 
4 hrs (±30 min) post dose 
107 
308 
3 
4 
15 
Pre-dosea 
108 
309 
3 
4 
15 
4 hrs (±30 min) post dose 
108 
310 
3 
5 
15 
Pre-dosea 
109 
311 
3 
5 
15 
4 hrs (±30 min) post dose 
109 
312 
3 
6 
15 
Pre-dosea 
110 
313 
3 
6 
15 
4 hrs (±30 min) post dose 
110 
314 
3 
Unscheduled: PK samples 
NA 
NA 
related to a QTcF change from NA 
1001+ 
3 
baseline > 60 ms and a new 
absolute QTcF >= 501 ms 
NA 
NA 
Unscheduled Anytime 
NA 
1051+ 
3 
 
Note: 
Patients enrolled under amendment 1 and patients on the sparse PK sample group enrolled before 
amendment 4 did not have Cycles 1-3 samples taken 4 hours post dose or Cycles 4-6 samples. 
a 
Take PK sample immediately prior to the next administration of BGJ398 
* 
Dose reference ID (DRID) corresponds to previous days dosing time 


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Table 11: Pharmacokinetic blood collection time points for patients (for 
first 20 patients treated with FMI III [Cohort 1] and all patients 
treated with FMI IV [Cohort 2 and 3]: extensive PK group) 
 
Cycle 
Day 
Scheduled time point 
relative to dosing 
Dose reference 
identification 
(DRID) No. 
(BGJ398) 
PK Sample No. 
(BGJ398) 
Sample 
volume 
(mL) 
1 
1 
Pre-dosea 
201b/301c/401d 
201/301/401 
3 
1 
1 
0.5 hr post dose ± 10 min 
201/301/401 
202/302/402 
3 
1 
1 
1 hr post dose ± 10 min 
201/301/401 
203/303/403 
3 
1 
1 
2 hr post dose ± 15 min 
201/301/401 
204/304/404 
3 
1 
1 
3 hr post dose ± 30 min 
201/301/401 
205/305/405 
3 
1 
1 
4 hr post dose ± 30 min 
201/301/401 
206/306/406 
3 
1 
1 
6 hr post dose ± 30 min 
201/301/401 
207/307/407 
3 
1 
1 
8 hr post dose ± 60 min 
201/301/401 
208/308/408 
3 
1 
2 
Pre-dosea (24 hr post day 1 
202, 201*/302, 
a209/309/409 
3 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
a 
Take PK sample immediately prior to the administration of BGJ398, applicable to Cohorts 1-3 
b 
Dose reference ID starting with 2 (e.g 201) refers to patients dosed in Cohort 1. 
c 
Dose reference ID starting with 3 (e.g 301) refers to patients dosed in Cohort 2. 
d 
Dose reference ID starting with 4 (e.g 401) refers to patients dosed in Cohort 3. 
* 
Dose reference ID (DRID) corresponds to previous days dosing time 
 
7.2.3.2 
Analytical method 
 
Plasma concentrations of BGJ398 and its active metabolites (BHS697, BQR917, and 
CQM157) will be measured using a validated liquid chromatography-tandem mass 
1 
15 
dose ± 120 min) 
Predosea 
301*/402, 401* 
203, 203*/303, 
a210/310/ 410 
3 
303*/ 403, 403* 
1 
15 
0.5 hr post dose ± 10 min 
203/303/403 
211/311/411 
3 
1 
15 
1 hr post dose ± 10 min 
203/303/403 
212/312/412 
3 
1 
15 
2 hr post dose ± 15 min 
203/303/403 
213/313/413 
3 
1 
15 
3 hr post dose ± 30 min 
203/303/403 
214/314/414 
3 
1 
15 
4 hr post dose ± 30 min 
203/303/403 
215/315/415 
3 
1 
15 
6 hr post dose ± 30 min 
203/303/403 
216/316/416 
3 
1 
15 
8 hr post dose ± 60 min 
203/303/403 
217/317/417 
3 
1 
16 
Pre-dosea (24 hr post dose 
204, 203*/304, 
a218//318/418 
3 
2 
1 
± 120 min) 
Pre-dosea 
303*/404, 403* 
205, 205*/305, 
a219/319/419 
3 
3 
1 
Pre-dosea 
305*/ 405, 405* 
206, 206*/306, 
a220/320/420 
3 
4 
1 
Pre-dosea 
306*/ 406, 406* 
207, 207*/307, 
a221/321/421 
3 
5 
1 
Pre-dosea 
307*/407, 407* 
208, 208*/308, 
a222/322/422 
3 
6 
1 
Pre-dosea 
308*/ 408, 408* 
209, 209*/309, 
a223/323/423 
3 
309*/ 409, 409* 
Unscheduled: PK samples 
NA 
NA 
related to a QTcF change 
from baseline > 60 ms and a NA 
2001+/3001/4001 
3 
new absolute QTcF ≥ 501 ms 
NA 
NA 
Unscheduled Anytime 
NA 
2051+/3051/4051 
3 


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spectrometry (LC-MS/MS) assay with a lower limit of quantification (LLOQ) of 
approximately 1.0 ng/mL. Concentrations below the LLOQ will be reported as 0 ng/mL 
and missing samples will be labeled accordingly. Study samples may be reanalyzed at 
other QED Therapeutics approved facilities for the determination of long term stability or 
cross-check between QED Therapeutics approved laboratories. These additional 
investigations are not considered part of this study and, as such, the results of any such 
analysis will not be included in the final report. 
 
7.2.4 
Biomarkers 
 
BGJ398 biomarker assessments are required to confirm patient eligibility and potentially 
aid in understanding the effects of BGJ398 treatment on molecular markers of disease 
and FGFR pathway regulation as related to clinical outcome. 
 
For all cohorts, written documentation of local laboratory or central laboratory 
determination of FGFR gene alterations from tissue collected before BGJ398 treatment is 
required. 
 
For Cohort 1 and Cohort 2: 
 
• If eligibility is determined by pre-existing test results or pre-screening by a local 
laboratory, then tumor tissue sample must be sent to the central laboratory for 
confirmation of the FGFR genetic alteration. The tumor tissue sent for confirmatory 
testing should be from the same biopsy sample that was used to determine eligibility. 
 
• If an archival tissue sample is not available, a new tumor biopsy must be obtained 
before BGJ398 treatment. Refer to the Laboratory Manual for additional details on 
the amount of tumor tissue required for testing by the central laboratory. 
 
• If written documentation of FGFR genetic alteration in tumor tissue is available from 
the central laboratory, an additional tumor sample does not need to be submitted for 
central molecular testing. 
 
For Cohort 3, written documentation of the FGFR2 gene fusion from a clinically- 
validated test on a sample (tumor tissue or cell-free DNA from blood) collected after 
treatment with the prior FGFR inhibitor is highly recommended. If written documentation 
is not available, a tumor sample collected after treatment with the prior FGFR inhibitor 
may be submitted to the central laboratory but is not required for enrollment. 
 
QED Therapeutics designated lab(s) will be used for processing of all tumor samples 
collected. The central laboratory will provide kits to collect and ship these samples to 
QED Therapeutics designated lab(s) for analysis. Details on the collections, shipment of 
samples are provided to investigators in the laboratory manual. 
 
While the goal of the biomarker assessments is to provide supportive data for the clinical 
study, there may be circumstances when a decision is made to stop a collection, or not 
perform or discontinue an analysis due to either practical or strategic reasons (eg, 
inadequate sample number, issues related to the quality of the sample or issues related to 


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the assay that preclude analysis, impossibility to perform correlative analyses, etc.). 
Therefore, depending on the results obtained during the study, sample collection analysis 
may be omitted at the discretion of QED Therapeutics. 
 
Table 12: 
Biomarker sample collection plan 
 
Sample Type 
Tissue Amount 
Visit 
Time point 
Archival tumor tissue 
and corresponding 
pathology report (to 
determine patient’s 
FGFR status)a 
OR 
Newly obtained tumor 
sample 
A tumor block is 
preferred or a minimum 
of 15-20 slides 
Molecular pre-screening 
for central testing 
Requires Molecular 
prescreening ICF 
Any time prior to starting 
study-specific screening 
procedure (patient must 
have required genetic 
alteration in order to start 
screening) 
 
Archival tumor tissue 
and a corresponding 
pathology reportb 
OR 
Newly obtained tumor 
sample if archival 
sample is not available 
(highly recommended 
for Cohort 3). 
A tumor block is 
preferred or a minimum 
of 15-20 slides. 
Screening 
Day -28 up to day -1 
Optional-Newly 
obtained tumor sample 
(if feasible) 
Tumor tissue (formalin 
fixed paraffin 
embedded) 11-20 
unstained slides 
For patients who have 
had a response upon 
disease progression 
Upon disease progression 
Blood (plasma) for 
circulating tumor DNA 
(cell free DNA) 
assessment b 
~ 10.0mL 
Screening/ baseline, 
C2D1, day 1 of every 
odd numbered cycle and 
at progression/ end of 
treatment (should be 
taken prior to biopsy 
procedure) 
Circulating tumor DNA 
assessment 
 
 
a 
Only needed if pre-screening is done by the QED Therapeutics designated lab 
b 
Only if not submitted to the central laboratory for FGFR molecular pre-screening 
 
7.2.4.1 
Archived tumor samples 
 
Collection of an archival tumor sample (tissue blocks or 11-20 unstained slides) is 
mandatory and will be collected from all patients at screening if a sample was not 
submitted to the central laboratory for FGFR molecular prescreening. A corresponding 
pathology report should be included along with the archival sample. If an archival tumor 
sample is not available, a newly obtained tumor sample should be obtained and provided 
as a formalin-fixed, paraffin-embedded block. Archival or newly obtained tumor samples 
will be used to explore mechanisms of resistance to cancer treatment through analysis of 
next generation DNA sequencing data from tumor samples at baseline and after the 


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development of disease progression (whenever available). Additional archival sample 
may be requested if the original sample sent is of insufficient quantity or quality to 
complete the planned analysis. 
 
The sample collection must be captured on the appropriate eCRF and requisition page(s). 
Detailed instructions for the collection, handling, labeling, and shipment of samples are 
outlined in the CRO Laboratory Manuals. 
 
7.2.4.2 
Newly obtained tumor samples 
 
A newly obtained tumor sample should be collected at progression (end of treatment) for 
patients if safe and feasible, as it will provide a unique opportunity to investigate the 
potential mechanisms of resistance to BGJ398. This will be performed using a 
combination of genomic, transcriptomic and proteomic technology, which may include 
profiling of mutation, amplification and/or modification in DNA, RNA, or protein levels 
in tumor tissue. 
 
The sample collection must be captured on the appropriate eCRF and requisition page(s). 
Detailed instructions for the collection, handling, labeling, and shipment of samples are 
outlined in the CRO Laboratory Manuals. 
 
7.2.4.3 
Exploratory biomarkers- cell free DNA assessment 
 
Blood (approximately 10 ml) will be collected at screening, Cycle 2 Day 1, day 1 of 
every odd numbered cycle at the time of response assessment scans, and at the time of 
disease progression (EOT). These samples will be used for analysis of cell-free DNA to 
explore whether genetic alterations found in tumor samples may also be observed in 
blood, and if any alterations found are predictive of response and/or associated with 
development of resistance. 
 
Detailed instructions for the collection, handling and shipment of samples are outlined in 
the [CBGJ398X2204 Laboratory Manual]. 
 
7.2.4.4 
Optional additional exploratory biomarker assessments using the 
remaining biomarker samples 
 
Patients will have the opportunity to consent to use of their remaining samples (tissue, 
tumor DNA, or blood) for additional research related to BGJ398, cancer or other study 
treatments. This may also include research to help develop ways to detect, monitor or 
treat cancer. A decision to perform such exploratory biomarker research studies would be 
based on outcome data or from new scientific findings related to the drug class or disease, 
as well as reagent and assay availability. 
 
Remaining tissue and cell free DNA samples may be subjected to genetic testing (DNA, 
RNA, protein) to profile genetic alterations in these samples. The investigators and 
patients will not receive the results from future research. The biological samples will be 
coded with a unique number that links the samples to the study patient in the study 
database as part of de-identification of the samples. 


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The samples may be stored under QED Therapeutics’ control or by its authorized agents. 
The samples will be stored up to 15 years. The period of time that data derived from 
future research may be used is not specified and these data may be used indefinitely. The 
data may be shared with Health Authorities worldwide, at medical meetings, or in 
medical publications. Participation is optional for patients to have their tissue and blood 
used in future research. Patients can request that QED Therapeutics not use their stored 
samples for future research, to the extent that they have not already used the sample, and 
to the extent that they are able to locate the sample after it has been de-identified. Patients 
who fail prescreening or fail screening will not have their samples stored for future 
research. 
 
8 SAFETY MONITORING AND REPORTING 
8.1 
Adverse events 
 
8.1.1 
Definition and reporting 
 
An adverse event is defined as the appearance of (or worsening of any pre-existing) 
undesirable sign(s), symptom(s), or medical condition(s) that occur after patient’s signed 
informed consent has been obtained. (Adverse events that occur before a patient signs the 
informed consent are recorded on the Medical History/Current Medical Conditions 
eCRF.) Adverse events that occur after informed consent is signed and prior to initiation 
of study treatment will only be captured if they meet the definition of serious adverse 
events and are reported to be causally related with study procedures (eg, an invasive 
procedure such as biopsy). All other adverse events occurring after informed consent is 
signed prior to initiation of study treatment should be recorded as medical history. 
Adverse event monitoring and recording should be continued for at least 30 days 
following the last dose of study treatment. 
 
For patients who sign the molecular pre-screening ICF, AEs which occur after signature 
of this consent will only be captured if they meet the definition of serious as outlined in 
Section 8.2 and are reported to be causally related with study procedures (e.g. an invasive 
procedure such as biopsy). 
 
Patients with known FGFR2 gene fusions or other FGFR genetic alteration status will 
only sign the main study ICF and AE collection for these patients will start from the time 
of signing the main ICF. 
 
Adverse events (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 Adverse Event. 
 
Adverse events will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse 
event, the severity of mild, moderate, severe, and life-threatening, corresponding to 
Grades 1 - 4, will be used. CTCAE Grade 5 (death) will not be used in this study. Rather, 


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if the patient dies while on study, the death will be captured on the End of Treatment 
disposition eCRF. If the patient dies while in follow-up, the death will be captured on the 
End of Study disposition eCRF and if the patient dies post-follow-up and is being 
followed for survival, their death will be captured on the Survival Follow-up eCRF. 
The occurrence of adverse events should be sought by non-directive questioning of the 
patient during the screening process after signing informed consent and at each visit 
during the study. Adverse events also may be detected when they are volunteered by the 
patient during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be 
evaluated to determine: 
 
1. The severity grade (CTCAE Grade 1-4) 
 
2. Its duration (start and end dates) 
 
3. Its relationship to study drug (reasonable possibility that AE is related: No, Yes) 
 
4. Action taken with respect to study treatment (none, dose adjusted, temporarily 
interrupted, permanently discontinued, unknown, not applicable) 
 
5. Whether medication or therapy was given (no concomitant medication/non-drug 
therapy given, concomitant medication/non-drug therapy given) 
 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequelae, fatal, unknown) 
 
7. Whether it is serious, where a Serious Adverse Event (SAE) is defined as in 
Section 8.2.1. 
 
Unlike routine safety assessments, SAEs are monitored continuously and have 
special reporting requirements; see Section 8.2. 
 
All adverse events should be treated appropriately. Such treatment may include changes 
in study drug treatment including possible interruption or discontinuation, starting or 
stopping concomitant treatments, changes in the frequency or nature of assessments, 
hospitalization, or any other medically required intervention. If a concomitant medication 
or non-drug therapy is given, this action should be recorded on the Adverse Event eCRF. 
 
Once an adverse event is detected, it should be followed until its resolution or until it is 
judged to be permanent, and assessment should be made at each visit (or more frequently, 
if necessary) of any changes in severity, the suspected relationship to the study treatment, 
the interventions required to treat it, and the outcome. 
 
Information about common side effects already known about the investigational drug can 
be found in the Investigator’s Brochure or will be communicated between IB updates in 
the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 


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8.1.1.1 
AE reporting of overdose of BGJ398 
 
Overdose of BGJ398 is to be reported as an AE when drug is administered or taken at a 
dose ≥200 mg and the overdose is associated with signs or symptoms. Overdose should 
follow the same reporting requirements as SAEs. 
 
8.1.1.2 
Hy’s Law 
 
Additionally, potential drug induced liver injury that meets the following criteria 
(elevation of bilirubin and ALT/AST that meet Hy’s Law criteria [FDA Guidance for 
Industry 2009]): 
 
• Treatment-emergent ALT or AST >3 × baseline value in combination with total 
bilirubin ≥2 × ULN (of which ≥35% is direct bilirubin) 
 
• Treatment-emergent ALT or AST >3 × baseline value in combination with clinical 
jaundice. 
 
and is suspected or confirmed drug-induced liver injury, according to Hy’s law criteria, 
requires reporting as an SAE. 
 
8.1.1.3 
Progression of underlying malignancy should be reported as AE 
only in special circumstances 
 
Progression of underlying malignancy is not reported as an adverse event if it is 
clearly consistent with the suspected progression of the underlying cancer as defined by 
RECIST criteria, or other criteria as determined by protocol. Hospitalization solely due to 
the progression of underlying malignancy should NOT be reported as a serious adverse 
event. Clinical symptoms of progression may be reported as adverse events 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 patients. In this situation, progression is 
evident in the patient’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 adverse event being due only to the disease under 
study, it should be reported as an AE or SAE. 
 
8.1.2 
Laboratory test abnormality 
 
Abnormal laboratory values or test results occurring after informed consent constitute 
adverse events only if they induce clinical signs or symptoms, are considered clinically 


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significant, require therapy (eg, hematologic abnormality that requires transfusion or 
hematological stem cell support), or require changes in study medication(s).Laboratory 
abnormalities that constitute an Adverse event in their own right should be recorded on 
the Adverse Events eCRF. Whenever possible, a diagnosis, rather than a symptom should 
be provided (e.g. anemia instead of low hemoglobin). Laboratory abnormalities that meet 
the criteria for Adverse Events should be followed until they have returned to normal or 
an adequate explanation of the abnormality is found. When an abnormal laboratory or test 
result corresponds to a sign/symptom of an already reported adverse event, it is not 
necessary to separately record the lab/test result as an additional event. 
 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not 
be reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE v4.0 does not 
automatically indicate a SAE unless it meets the definition of serious as defined below 
and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality 
may be required by the protocol and is still, by definition, an adverse event. 
 
8.2 
Serious adverse events 
 
8.2.1 
Definitions 
 
Serious adverse event (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 patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
 
• Requires inpatient hospitalization or prolongation of existing hospitalization, unless 
hospitalization is for: 
 
a. Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
 
b. 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 
 
c. Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
 
d. Social reasons and respite care in the absence of any deterioration in the patient’s 
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In addition, any suspected transmission of an infectious agent via a medicinal product 
will be considered an SAE at study centers in the EU. 
 
Progression of underlying malignancy is not reported as an adverse event if it is clearly 
consistent with the suspected progression of the underlying cancer as defined by RECIST 
criteria, or other criteria as determined by protocol. Hospitalization due solely to the 
progression of underlying malignancy should NOT be reported as a serious adverse 
event. 
 
Clinical symptoms of progression may be reported as adverse events 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 patients. In this situation, progression is 
evident in the patient’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 adverse event being due only to the disease under 
study, it should be reported as an AE or SAE. 
 
8.2.2 
Reporting 
 
For patients whose FGFR2 gene fusions or other FGFR genetic alteration status is 
unknown, SAE collection will start upon signing the molecular pre-screening ICF. SAEs 
will only be reported if the event is suspected to be causally related to a study procedure 
as assessed by the investigator (e.g. an invasive procedure such as biopsy). SAEs will be 
followed until resolution or until clinically relevant improvement or stabilization. If the 
main ICF is not signed (molecular screen failure), SAE collection ends 30 days after the 
last study related procedure. If the main ICF is signed, SAE collection is as below. 
 
Patients with known FGFR2 gene fusions or translocations/other FGFR genetic alteration 
status who do not sign the molecular pre-screening ICF, SAE collection starts at the time 
of signing main study informed consent regardless of whether the patient is found to be a 
screen failure. 
 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after 
the patient has provided informed consent and until at least 30 days after the patient has 
stopped study treatment must be reported to Covance Safety (email: 
SAEintake@covance.com; FAX: 1-888-726-8416) within 24 hours of learning of its 
occurrence. Any SAEs experienced after this 30 days period should only be reported to 
Covance Safety if the investigator suspects a causal relationship to the study treatment. 
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 


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occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
 
Information about all SAEs is collected and recorded on the Serious Adverse Event 
Report Form; all applicable sections of the form must be completed in order to provide a 
clinically thorough report. The investigator must assess and record the relationship of 
each SAE to each specific study treatment (if there is more than one study treatment), 
complete the SAE Report Form in English, and submit the completed form within 24 
hours to Covance Safety (email: SAEintake@covance.com; FAX: 1-888-726-8416). 
Detailed instructions regarding the submission process and requirements for signatures 
are to be found in the investigator folder provided to each site. 
 
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, whether 
the blind was broken or not, and whether the patient continued or withdrew from study 
participation. 
 
If the SAE is not previously documented in the Investigator’s Brochure or Package Insert 
(new occurrence) and is thought to be related to the study treatment, a Covance Safety 
associate may urgently require further information from the investigator for Health 
Authority reporting. Covance Safety may need to issue an Investigator Notification (IN), 
to inform all investigators involved in any study with the same drug that this SAE has 
been reported. Suspected Unexpected Serious Adverse Reactions (SUSARs) will be 
collected and reported to the competent authorities and relevant ethics committees in 
accordance with Directive 2001/20/EC or as per national regulatory requirements in 
participating countries. 
 
8.3 
Emergency blinding of treatment assignment 
 
Not applicable. 
 
8.4 
Pregnancies 
 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment 
(and for 30 days after the last study drug dose) must be reported to Covance Safety 
(email: SAEintake@covance.com; FAX: 1-888-726-8416) within 24 hours of learning of 
its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of the birth, and the presence or absence of 
any birth defects, congenital abnormalities, or maternal and/or newborn complications. 
 
Pregnancy of a patient or partner of a male patient should be entered on the Pregnancy 
Notification CRF and reported by the investigator to Covance Safety (email: 
SAEintake@covance.com; FAX: +1-888-726-8416). Pregnancy follow-up should be 
documented on a paper Pregnancy Follow-up Form and reported to Covance Safety as 
above. Any SAE experienced during pregnancy must be reported on the SAE Report 
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Pregnancy outcomes must be collected for the female partners of any males who took 
study treatment in this study. Consent to report information regarding these pregnancy 
outcomes should be obtained from the mother. 
 
8.5 
Warning and precautions 
 
No evidence available at the time of this writing indicated that special warnings or 
precautions were appropriate, other than those noted in the current Investigator’s 
Brochure. Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be 
included in the patient informed consent and should be discussed with the patient during 
the study as needed. 
 
8.6 
Data monitoring committee 
 
A Data Monitoring Committee (DMC) will not be in place for this trial: a DMC is 
considered not feasible due to the short duration of the study. However, measures are put 
in place for monitoring the safety of the patients participating in this part of the study: 
 
• Prompt review of safety data and constant monitoring for emerging safety signals by 
participating study sites and QED Therapeutics Personnel. As for any other study 
conducted by QED Therapeutics, any SUSAR and/or new safety signals will be 
promptly communicated to all participating investigators and Health Authorities. 
 
In lieu of a DMC, regular teleconferences with investigators will be held for reviewing 
reported safety data during the trial. 
 
8.7 
Steering committee 
 
Not applicable. 
 
9 DATA COLLECTION AND MANAGEMENT 
9.1 
Data confidentiality 
 
All records identifying the patient will be kept confidential and, in accordance with the 
applicable laws and/or regulations, will not be made publicly available. 
 
Patient names will not be supplied to the sponsor. Only the subject number will be 
recorded on the eCRF. If the patient name appears on any other document or trial 
materials, then that information must be redacted before a copy of the document is 
supplied to the sponsor. Trial data stored on a computer will be stored in accordance with 
local data protection laws and regulations. Patients will be informed in writing that 
representatives of the sponsor, Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB), or regulatory authorities may inspect 
their medical records to verify the information collected, and that all personal information 
made available for inspection will be handled in strictest confidence and in accordance 
with local data protection laws and regulations. 


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If the results of the trial are published, the patients’ identity will remain confidential. 
 
The investigator will maintain a list to enable patients’ records to be identified in 
accordance with applicable laws and regulations. 
 
The data collection system for this study uses built-in security features to encrypt all data 
for transmission in both directions, preventing unauthorized access to confidential 
participant information. Access to the system will be controlled by a sequence of 
individually assigned user identification codes and passwords, made available only to 
authorized personnel who have completed prerequisite training. 
 
Either year of birth or exact date of birth (depending on local privacy regulations) will be 
recorded to establish that the patient satisfies protocol age requirements and to enable 
appropriate age-related normal ranges to be used in assessing laboratory test results. 
 
9.2 
Site monitoring 
 
Before study initiation, at a site initiation visit or at an investigator’s meeting, QED 
Therapeutics personnel (or designated CRO) will review the protocol and CRFs with the 
investigators and their staff. During the study, the field monitor will visit the site 
regularly to check the completeness of patient records, the accuracy of entries on the 
CRFs, the adherence to the protocol and to Good Clinical Practice, the progress of 
enrollment, and to ensure that study treatment is being stored, dispensed, and accounted 
for according to specifications. Key study personnel must be available to assist the field 
monitor during these visits. 
 
The investigator must maintain source documents for each patient in the study, consisting 
of case and visit notes (hospital or clinic medical records) containing demographic and 
medical information, laboratory data, electrocardiograms, and the results of any other 
tests or assessments. All information recorded on CRFs must be traceable to source 
documents in the patient's file. The investigator must also keep the original signed 
informed consent form (a signed copy is given to the patient). 
 
The investigator must give the monitor access to all relevant source documents to 
confirm their consistency with the CRF entries. QED Therapeutics monitoring standards 
require full verification for the presence of informed consent, adherence to the 
inclusion/exclusion criteria and documentation of SAEs. Additional checks of the 
consistency of the source data with the CRFs are performed according to the study- 
specific monitoring plan. 
 
9.3 
Data collection 
 
The designated investigator staff will enter the data required by the protocol into the 
Electronic Case Report Forms (eCRF). The eCRFs have been built using fully validated 
secure web-enabled software that conforms to 21 CFR Part 11 requirements. the 
investigator and site staff will not be given access to the EDC system until they have been 
trained. Automatic validation programs check for data discrepancies in the eCRFs and, 
allow modification or verification of the entered data by the investigator staff. 


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The Principal Investigator is responsible for assuring that the data entered into eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
 
PK and biomarker (blood and tissue) samples obtained during the course of the study will 
be collected from the Investigator sites and analyzed by a QED Therapeutics designated 
laboratory, contracted central laboratories, or local laboratories. ECG data collected 
during the study will be reviewed and processed centrally by a specialist CRO. 
Designated investigational site staff will enter the information required by the protocol 
into the appropriate eCRF and/or designated laboratory requisition forms. Field monitors 
will review the eCRFs and laboratory paper requisition forms for accuracy and 
completeness and instruct site personnel to make any required corrections or additions. 
One copy of the requisition form will be forwarded to each analytical laboratory with the 
respective sample(s) by the field monitor or by the designated investigational site staff; 
and one copy will be retained at the investigational site. 
 
9.4 
Database management and quality control 
 
For studies using eCRFs, QED Therapeutics personnel (or designated CRO) will review 
the data entered by investigational staff for completeness and accuracy. Electronic data 
queries stating the nature of the problem and requesting clarification will be created for 
discrepancies and missing values and sent to the investigational site via the EDC system. 
Designated investigator site staff are required to respond promptly to queries and to make 
any necessary changes to the data. 
 
Concomitant treatments and prior medications entered into the database will be coded 
using the WHO Drug Reference List, which employs the Anatomical Therapeutic 
Chemical classification system. Medical history/current medical conditions and adverse 
events will be coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
 
PK, and biomarker samples and ECG data will be processed centrally and the results will 
be sent electronically to QED Therapeutics (or a designated CRO). 
 
The occurrence of any protocol violations will be determined. Once the data has been 
verified to be complete and accurate, the database will be declared locked and made 
available for data analysis. Appropriate QED authorization is required prior to making 
any database changes to locked data. 
 
After database lock, the investigator will receive a CD-ROM or paper copies of the 
patient data for archiving at the investigational site. 
 
10 STATISTICAL METHODS AND DATA ANALYSIS 
Data will be analyzed by QED Therapeutics and/or designated CRO. Any data analysis 
carried out independently by the investigator must be submitted to QED Therapeutics 
before publication or presentation. 


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It is planned that the data from participating centers in this protocol will be combined, so 
that an adequate number of patients will be available for analysis. Data will be 
summarized with respect to demographic and baseline characteristics, efficacy and safety 
observations and measurements and all relevant PK and PD measurements. Categorical 
data will be presented as frequencies and percentages. For continuous data, mean, 
standard deviation, median, 25th and 75th percentiles, minimum, and maximum will be 
presented. 
 
In general, analyses will be done by cohort with subanalyses by formulation (FMI I, III, 
or IV) or fusion status as appropriate unless otherwise specified. 
 
Two formal interim analyses for Cohort 1 are described in Section 10.7. The primary 
analysis for Cohort 1 will be conducted when all patients in Cohort 1 have the potential to 
be followed for at least 10 months after their initial exposure to study treatment. 
 
For Cohorts 2 and 3, review of data will be performed after a total of 15 patients in either 
Cohort 2 or 3 have been treated with FMI IV for at least one cycle. Primary analysis will 
be conducted when all patients in the cohorts have the potential to be followed for at least 
10 months after their initial exposure to study treatment. 
 
For Cohort 3, one formal interim analysis will be conducted after the first 10 dosed 
patients in this cohort have the potential to complete their second scheduled scans 
(approximately 16 weeks from their first dose) to determine if the cohort will be 
expanded. 
 
The additional data for patients continuing to receive BGJ398 and for patients who 
remain in safety or survival follow-up beyond the cut-off point for the primary analyses, 
as allowed by the protocol, will be summarized in a final CSR that will be prepared at the 
end of the study. In the final CSR, analyses will be done for each cohort. For exploratory 
purposes, for patients enrolled in Cohort 1 who do not have FGFR2 fusions or 
translocations, data may be combined and summarized with Cohort 2. 
 
10.1 
Analysis sets 
 
10.1.1 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all patients who received at least one dose of 
BGJ398. The FAS will be used for all listings of raw data. Unless otherwise specified, the 
FAS will be the default analysis set used for all analyses. 
 
10.1.2 
Interim Efficacy Analysis Set 1 for Cohort 1 
 
The Interim Efficacy Analysis Set 1 for Cohort 1 includes all patients with planned 
extensive PK sample collection (regardless of whether extensive PK samples were 
actually collected) and all patients enrolled prior to amendment 2. Unless otherwise 
specified, the Interim Efficacy Analysis Set 1 will be used as the primary efficacy 
analysis set for the first formal interim analysis for Cohort 1 after amendment 3. Patients 


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will be classified according to their baseline genetic status (FGFR2 gene fusions or 
translocations only vs other FGFR genetic alterations). 
 
10.1.3 
Interim Analysis Set 2 for Cohort 1 
 
The Interim Analysis Set 2 for Cohort 1 includes patients in Cohort 1 with FGFR2 gene 
fusions or translocations who have received at least one dose of BGJ398. Interim 
Analysis Set 2 for Cohort 1 will be used as the primary analysis set for the second formal 
interim analysis for Cohort 1 after amendment 3. 
 
10.1.4 
Sensitivity Analysis Set for Cohort 1 
 
The Sensitivity Analysis Set for Cohort 1 includes patients with FGFR2 gene fusions or 
translocations who received BGJ398 at the time of the first formal interim analysis and 
patients who have disease progression according to central imaging review or ended 
treatment by the cutoff date for the second formal interim analysis for Cohort 1 after 
amendment 3. The cutoff date for the second formal interim analysis is planned so that all 
the patients with FGFR2 gene fusions or translocations who received BGJ398 at the time 
of the first formal interim analysis have 10 months follow-up after their initial exposure 
to BGJ398. The Sensitivity Analysis Set for Cohort 1 will be used for supportive 
sensitivity analyses for the second formal interim analysis for Cohort 1. 
 
10.1.5 
Interim Analysis Set for Cohort 3 
 
The Interim Analysis Set for Cohort 3 will include the first 10 dosed patients who have 
the potential to complete second scheduled scan. 
 
10.1.6 
Per-Protocol Set 
 
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS who are 
compliant with requirements of the Clinical Study Protocol (CSP) in the following ways: 
 
• Patient had an adequate tumor assessment at baseline 
• Patient is evaluable for efficacy 
• Patient had no CSR-reportable protocol deviations that may affect efficacy 
evaluation. 
 
Patients will be evaluable for efficacy if they have at least one response assessed 
differently from ‘unknown’ or ‘not assessed’ as per RECIST v1.1. All CSR-reportable 
protocol deviations leading to exclusion from the PPS will be provided in a listing. 
 
10.1.7 
Pharmacokinetic analysis set 
 
The Pharmacokinetic analysis set (PAS) includes all patients who (a) receive the planned 
treatment, (b) provide at least one evaluable PK concentration, and (c) do not vomit 
within 4 hours after the dosing of BGJ398. 


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Detailed definition of PAS will be described in the statistical analysis plan (SAP). 
Patients will be removed from the estimation of certain PK parameters on an individual 
basis depending on the number of available blood samples and whether the PK 
parameters can be reliably estimated based on the available blood samples. These 
patients will be identified at the time of the analyses. 
 
10.2 
Patient demographics/other baseline characteristics 
 
Demographic and other baseline data will be listed by patient and summarized 
descriptively. 
 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
 
10.3.1 
Study treatment 
 
The actual dose and duration in days of BGJ398 treatment and the relative dose intensity 
(computed as the ratio of actual cumulative dose and planned cumulative dose), will be 
listed and summarized by means of descriptive statistics. 
 
10.3.2 
Concomitant therapies 
 
Concomitant medications and significant non-drug therapies prior to and after the start of 
the study drug treatment will be listed by patient and summarized by ATC (anatomical 
therapeutic chemical classification system) term by means of contingency tables. 
 
10.3.3 
Compliance 
 
Compliance to the protocol will be assessed by the number and proportion of patients 
with CSR-reportable protocol deviations. These will be identified prior to database lock 
and will be listed and summarized. Compliance to the study drug will be assessed by the 
number of dose reductions and dose interruptions, see Section 10.5.2.6. 
 
10.4 
Primary objective 
 
10.4.1 
Variable 
 
For Cohort 1, the primary objective of the study is to assess the efficacy of BGJ398 using 
overall response assessed by central imaging review. 
 
Overall response rate (ORR) is defined as the proportion of patients with a best overall 
response of Complete Response (CR) or Partial Response (PR), as per RECIST 
version 1.1 (Appendix 3). 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
 
It is assumed that the number of responses follow a binomial distribution. 


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The estimated ORR per central imaging review along with the 95% binomial exact CI 
will be provided. 
 
10.4.3 
Handling of missing values/censoring/discontinuations 
 
Disposition including the reason for discontinuation from study treatment will be 
summarized and listed, along with dates of first and last study treatment, duration of 
exposure to BGJ398 and date of discontinuation for each patient. 
 
Missing data will simply be noted as missing on appropriate listings. 
 
The handling of censoring for time to event endpoints and completely/partial missing 
dates will be described in SAP. 
 
10.5 
Secondary objectives 
 
This section describes analyses of secondary objectives for Cohort 1. The same variables 
will be analyzed for Cohorts 2 and 3 as exploratory, so this section also applies to 
analyses of those variables/endpoints (Section 3). 
 
10.5.1 
Secondary efficacy objectives and variables 
Overall survival 
Overall Survival (OS) is defined as the time from the date of start of treatment to the date 
of death due to any cause. The survival time for patients without documentation of death 
prior to the data cutoff, will be censored at the last date the patient was known to be alive 
prior to the cutoff date. Survival time for patients with no post-baseline survival 
information will be censored at the date of start of treatment. 
 
OS will be analyzed using the Kaplan-Meier (K-M) method. Survival rate at 4, 6, 8, 12, 
18 and 24 months and median OS will be estimated along with 95% confidence intervals 
using the K-M method. 
 
Progression Free Survival 
 
Progression free survival (PFS) is defined as the date of the start of treatment to the date 
of the event defined as the first documented progression or death due to any cause. If 
patient has not had an event, progression- free-survival will be censored according to 
details described in the SAP. K-M analysis of PFS will be provided. 
 
For Cohorts 2 and 3, the percentage of patients who are progression-free at the second 
scheduled scan (approximately 16 weeks from treatment initiation) or later will be 
analyzed using 95% exact binomial confidence interval. Patients who do not have scans 
to show that they are progression-free at the second scheduled scan or later will be 
considered as not benefiting from the study treatment. Sensitivity analysis will be done 
by estimating PFS >16 weeks using K-M estimate. 


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Overall Response Rate (ORR) 
 
ORR (based on overall response assessed by the investigator) will be estimated with 95% 
binomial exact confidence interval. 
 
Best Overall Response and Disease Control Rate 
 
Overall lesion assessments will be listed by patient. Best overall response (BOR) will be 
summarized by the proportion of patients having a best overall response of PR, CR, SD, 
or PD. Disease control rate will be summarized presenting the combined proportion of 
patients having a BOR of CR, PR, or SD. The estimates will be presented along with 
corresponding 95% binomial exact confidence intervals. These analyses will be 
conducted for the central imaging assessment and for the investigator assessment as 
specified by cohort (Section 3). 
 
10.5.2 
Safety objectives and variables 
 
10.5.2.1 
Analysis set and grouping for the analyses 
 
For all safety analyses, the safety analysis set will be used. 
 
The overall observation period will be divided into three mutually exclusive segments: 
 
1. Pre-treatment period: from day of patient’s informed consent to the day before first 
dose of study medication 
 
2. On-treatment period: from day of first dose of study medication to 90 days after last 
dose of study medication 
 
3. Post-treatment period: starting at day 31 after last dose of study medication. 
 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period 
cannot be made, then the respective data will be assigned to the on-treatment period. 
 
10.5.2.2 
Adverse events (AEs) 
 
Summary tables for adverse events (AEs) have to include only AEs that started or 
worsened during the on-treatment period, the treatment-emergent AEs. However, all 
safety data (including those from the pre and post-treatment periods) will be listed and 
treatment-emergent are to be flagged. 
 
The incidence of treatment-emergent adverse events (new or worsening from baseline) 
will be summarized by system organ class and or preferred term, severity (based on 
CTCAE grades), type of adverse event, relationship to study treatment. 
 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient 
and tabulated. 


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Adverse events of special interest (AESI) will be considered. Each AESI consists of one 
or more well-defined safety events which are similar in nature and for which there is a 
specific clinical interest in connection with the study treatment(s). 
 
For each specified AESI, number and percentage of patients with at least one event 
within the AESI will be reported. 
 
10.5.2.3 
Laboratory abnormalities 
 
For laboratory tests covered by the Common Terminology Criteria for Adverse Events 
(CTCAE) version CTCAE v4.03, Grade 1 or higher will be assigned per CTCAE v4.03. 
Grade 0 will be assigned for all non-missing values not graded as 1 or higher. Grade 5 
will not be used. 
 
For laboratory tests where grades are not defined by CTCAE, results will be categorized 
as low/normal/high based on laboratory normal ranges. 
 
The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
 
• Shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• For laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst 
on-treatment value. 
 
In addition to the tables and listings mentioned above, other exploratory analyses, for 
example figures plotting time course of raw or change in laboratory tests over time or box 
plots might be specified in the SAP. 
 
10.5.2.4 
Other safety data 
 
Data from other tests (eg, electrocardiogram, LVEF, or ophthalmic assessments) will be 
listed, notable values will be flagged. Any statistical tests performed to explore the data 
will be used only to highlight any interesting comparisons that may warrant further 
consideration. Additionally, the following outputs will be produced: 
 
ECG 
 
• Shift table baseline to worst on-treatment result for overall assessments 
• Listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
 
• Table with frequency/percentage of patients with abnormal vital signs. 


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• Table with descriptive statistics at baseline, one or several post-baseline time points 
and change from baseline to this/these post-baseline time points. 
 
10.5.2.5 
Supportive analyses for secondary objectives 
 
Not applicable. 
 
10.5.2.6 
Tolerability 
 
Tolerability of study drug will be assessed by summarizing the number of dose 
interruptions and dose reductions. Reasons for dose interruption and dose reductions will 
be listed by patient and summarized. Cumulative dose, dose intensity and relative dose 
intensity of BGJ398 will be summarized. Categories for relative dose intensity of 
BGJ398 will be specified as ≤0.5, >0.5 - ≤0.75, >0.75 - ≤0.9, >0.9 - ≤1.0 and >1.0. The 
number and proportion of patients within each category will be presented. 
 
10.5.3 
Pharmacokinetics 
 
Patients treated with FMI I and some patients treated with FMI III (sparse PK group) will 
have limited PK collected as indicated in Table 10. For these patients, only trough and 2- 
hr or 4-hr plasma concentration data will be available. No PK parameters can be 
calculated for these patients. 
 
A secondary objective of this study is to characterize the single and multiple doses PK of 
BGJ398 FMI III and FMI IV formulations. Data as per Table 11 will be available for 
about 20 patients treated with FMI III and for all patients enrolled in either Cohort 2 or 
Cohort 3 and treated with FMI IV. For these patients, PK parameters as listed in 
Table 13, may be determined from PK profiles after the first dose on Day 1 of Cycle 1 
and Day 15 of Cycle 1 after repeated daily dosing using non-compartmental method(s) of 
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Table 13: 
Non-compartmental pharmacokinetic parameters 
 
Term 
Definition 
 
Cmax 
Maximum observed plasma concentration after drug administration [mass x volume-1] 
Ctrough 
Measured concentration at the end of a dosing interval (taken directly before next 
administration) [mass x volume-1] 
Tmax 
Time to reach Cmax [time] 
AUC24 
Area under the concentration-time curve from 0 to 24 hours [mass x time x volume-1] 
T1/2 
Elimination half-life associated with the terminal slope (lambda_z) of a semi- 
logarithmic concentration-time curve [time] 
AUCinf 
Area under the concentration-time curve from 0 to infinity [mass x time x volume-1] 
CL/F 
Apparent clearance [dose/AUC] 
Vz/F 
Apparent volume of distribution [dose/AUC x lambda_z] 
Racc 
Accumulation ratio calculated as AUC0-24 of C1D15/AUC0-24 of C1D1 and Cmax of 
C1D15/Cmax of C1D1 
 
 
 
10.5.3.1 
Data handling principles 
 
All concentrations below the lower limit of quantification (LLOQ) or missing data will 
be labeled as such in the concentration data listings. Concentrations below the LLOQ will 
be treated as zero in summary statistics. 
 
10.5.3.2 
Data analysis principles 
 
Exploratory PK analysis may be conducted based on preliminary data prior to data base 
lock, and nominal time and dose information may be used. 
 
PK data generated from this study may be used in conjunction with PK data from other 
clinical studies for population PK and PK/PD assessment. These assessments will be 
reported separately. If possible, exploratory comparisons will be made to historical 
pharmacokinetic data. Available PK data from this study may be modeled using a 
population pharmacokinetic data analysis approach in order to characterize the population 
pharmacokinetics of BGJ398. Any population PK data generated will be reported 
separate from the CSR. If feasible, exploratory PK and PK/PD analysis may be 
performed, using appropriate methods, to elucidate concentration-response (efficacy 
and/or biomarkers) and/or concentration-toxicity relationships. These analyses will be 
defined in a stand-alone analysis plan document(s), as appropriate, prior to clinical 
database lock. 
 
Descriptive graphical plots of individual and mean plasma concentration (per treatment) 
along with its time course will be generated. Further graphical exploratory analysis will 
be carried out if deemed appropriate. 


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Analysis will be done separately for the 3 formulations. In addition, analyses that require 
derived PK parameters will be applicable to patients treated with FMI III and FMI IV 
who are expected to provide extensive PK blood samples as indicated in Table 11. 
 
10.5.3.2.1 
Analysis sets 
 
Only PK blood samples with the date and time and for which the last prior dose dates and 
times are adequately recorded will be included in the PK analyses. Samples taken from 
patients who vomited within 4 hours of dosing will be excluded from the analysis. The 
PAS will be used. 
 
10.5.3.2.2 
Basic tables, Figures and Listings 
 
The PK concentration and PK (when available for patients treated with FMI III or FMI 
IV), will be summarized and listed using relevant statistics by formulation, and study day. 
Descriptive statistics (mean, SD, CV% or median [range]) will be presented. When a 
geometric mean is presented, it will be stated as such. Only median values and ranges 
will be presented for Tmax. 
 
Graphical plots of individual and mean plasma concentration-time data will be generated 
for BGJ398 and its metabolites. This graphical presentation will be applicable to patients 
who are treated with FMI III or FMI IV and have PK profile collected as per Table 11. 
 
Median, minimum and maximum will be calculated based on collected samples. All 
analyses will refer to BGJ398 and its metabolites. BGJ398 and its metabolites 
concentration vs time data will be reported. Exploratory PK analysis may be conducted 
based on preliminary data prior to data base lock and nominal time and dose information 
may be used. 
 
10.5.4 
Resource utilization 
 
Not applicable. 
 
10.5.5 
Patient-reported outcomes 
 
Not applicable. 
 
10.6 
Exploratory objectives 
 
The details of the statistical analyses described in this section or any additional statistical 
analyses for the exploratory objectives may be a stand-alone analysis plan document, as 
appropriate. The results from the analyses, if conducted, may be reported separate from 
the CSR. 


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10.6.1 
Biomarkers 
 
DNA sequencing will be performed in order to detect changes from baseline in molecular 
and proteomic profiles in tumor tissue from patients who have progressed through 
treatment with BGJ398 using available paired biopsies. 
 
Genetic alterations data will be available from the analysis of cell free tumor DNA and 
will be summarized and will be used for concordance analysis of baseline data and 
correlation analysis with markers with response and/or resistance. 
 
10.6.1.1 
Outline of the data analysis 
 
PD markers collected in the clinical database will be analyzed by QED Therapeutics or 
designated CRO. Since this clinical trial was not designed to address specific hypotheses 
related to patient pre-selection or PD markers, the analysis of this data should be viewed 
as exploratory and hypotheses generating. Analytical results from such analyses may be 
used to generate additional hypotheses that must then be verified with data derived from 
subsequent clinical trials. No adjustment for multiple comparisons is planned. 
 
If the number of samples is inadequate to perform a rigorous data analysis, then the 
available data will only be listed. Additional analyses that may be performed after the 
completion of the end-of-study clinical study report will be documented in separate 
reports. These analyses may include but are not limited to the meta-analysis of data from 
this study combined with data from other studies or the analysis of patient pre-selection 
or PD markers generated from samples collected during the study but analyzed after the 
database lock and completion of the clinical study report. 
 
10.6.1.2 
Data handling principles 
 
All measurements below their respective LLOQs or missing data will be labeled as such 
in the concentration data listings. Measurements below the LLOQ will be treated as zero 
in summary statistics. Change from baseline analyses will only be performed on patients 
with measurable samples and pre- and post-treatment time points. 
 
10.6.1.3 
Data analysis principles 
 
10.6.1.3.1 
Analysis sets 
 
The FAS will be used for all analyses unless otherwise specified. The number of patients 
with measurable samples will be identified in the summaries and relevant proportions 
will be calculated against this number of patients. 
 
10.6.1.3.2 
Basic tables, figures and listings 
 
Change from baseline for markers measured pre and post baseline to assess the effect on 
FGFR pathway will be listed by patient and may be summarized by means of descriptive 
statistics. 


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Correlation of baseline amplification status of FGFR or mutation status and clinical 
antitumor activity outcome will be summarized and may be explored graphically. 
 
Individual CA19-9 serum levels (or change from baseline) will be listed as well as 
presented as line plots over time. If enough data is available, statistical analysis will be 
performed in order to assess the relationship between anti-tumor activity (BOR and OS) 
and CA19-9 levels (or change from baseline). 
 
Patient’s FGFR2 gene fusion status in DNA from non-tumor tissue (cell free DNA data) 
will be listed and compared to the FGFR2 gene fusion status in tumor tissue at baseline; a 
contingency table will be presented. Genetic alterations detected in cell free tumor DNA 
will be summarized and presented graphically for patients with both baseline and post- 
baseline samples. If there is enough data, change from baseline expression levels will be 
correlated with efficacy data. Further exploratory analyses will be performed if feasible. 
 
10.6.1.3.3 
Advanced analysis methods 
 
Any advance analyses e.g. to assess potential correlation between baseline molecular 
status and clinical response, will be defined in a stand-alone analysis plan document, as 
appropriate. 
 
10.6.2 
Objectives for Cohorts 2 and 3 
 
The variables for the exploratory objectives for Cohorts 2 and 3 are defined and analyzed 
as described in the previous sections, as applicable. 
 
10.7 
Interim analysis 
 
Safety and efficacy data will be continuously monitored by QED Therapeutics in 
conjunction with the investigators for decision-making purposes. Please refer to 
Section 4.2 on the timing of the interim analysis. 
 
Specifically, two formal interim analyses are planned for Cohort 1 after amendment 3: 
 
• The first formal interim analysis for Cohort 1 was conducted when all patients in the 
Interim Efficacy Analysis Set 1 had been followed for at least 10 months after their 
initial exposure to BGJ398. Primary efficacy analyses were conducted for the Interim 
Efficacy Analysis Set 1, and key efficacy analyses were repeated for the Full Analysis 
Set. Safety analyses were conducted on the Full Analysis Set. 
 
• The second formal interim analysis for Cohort 1 is planned when all patients who 
received BGJ398 at the time of the first formal interim analysis after amendment 3 
have at least 10 months follow-up after their initial exposure to BGJ398. For this 
interim analysis, the primary analyses will be conducted on the Interim Analysis Set 2 
for Cohort 1. The Sensitivity Analysis Set for Cohort 1 will be used for supportive 
sensitivity analyses. 


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For Cohort 3, a formal interim analysis will be conducted when the first dosed 10 patients 
in Cohort 3 have the potential to complete the second scheduled scan. This is to 
determine if an additional 10 patients will be added to Cohort 3. 
 
10.8 
Sample size calculation 
 
10.8.1 
Cohort 1 
 
At the time of the first formal interim analysis after amendment 3, the Interim Efficacy 
Analysis Set 1 will include 72 patients with FGFR2 gene fusions or translocations. The 
half-width of the exact 95% confidence interval for ORR will not exceed 12%. 
 
With at least 106 patients with FGFR2 gene fusions or translocations, the half-width of 
the exact 95% confidence interval width of ORR will not exceed 10%. 
 
10.8.2 
Cohorts 2 and 3 
 
In Cohorts 2 and 3, patients who are progression-free at the second scheduled scan 
(approximately 16 weeks from treatment initiation) or later will be considered to be 
benefiting from study treatment. If the lower bound of the patients who are progression- 
free at the second scheduled scan (approximately 16 weeks) or later excludes 20%, the 
treatment will be considered as benefiting the patients. 
 
For Cohort 2, the percentage of patients who are progression-free at the second scheduled 
scan (approximately 16 weeks) or later will be estimated with 95% exact confidence 
interval. There will be approximately 20 patients in total. A sample size of 20 will result 
in the exact 95% confidence interval half width of less than 23%. Patients who withdraw 
from the study for any reason before the second scheduled scan will be considered as not 
benefiting from study treatment. Sensitivity analysis will be conducted using the K-M 
method to estimate PFS >16 weeks. 
 
Table 14 provides some examples of CIs corresponding to observed numbers of patients 
considered to have benefited from treatment. For example, if 9 of 20 patients are 
progression-free at the second scheduled scan or later, then the lower bound of the 95% 
exact confidence interval (CI) will exclude 20%. 
 
In Cohort 3, the same definition of benefit rate as for Cohort 2 (the percentage of patients 
who are progression-free at the second scheduled scan [approximately 16 weeks] or later) 
will be applied. The benefit rate will be estimated with 95% exact confidence interval. 
The planned enrollment for Cohort 3 is a maximum of 20 patients. With 20 patients, the 
exact 95% confidence interval half width is <23%. One interim analysis is planned when 
10 patients have been dosed and have the potential to be followed up for response for at 
least 2 scheduled scans. If at the interim analysis, ≥4 patients are progression-free at the 
second scheduled scan (after approximately 16 weeks) or later, the cohort will continue to 
enroll the additional 10 patients; otherwise, enrollment will stop at 10 patients. If ≤20% 
patients are benefiting from the study treatment, there is <12.1% chance that the decision 
after the interim analysis will lead to continuing enrollment. 


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The percentage of patients considered to have benefited from treatment will be estimated 
with 95% exact binomial CI. If all 20 patients are enrolled, the exact 95% CI half width 
will not exceed 23%. Table 14 provides some examples of CIs corresponding to observed 
numbers of patients considered to have benefited from treatment. At the final analysis, if 
9 of 20 patients who are progression-free at the second scheduled scan or later, the lower 
bound of the 95% exact CI will exclude 20%. 
 
Table 14: 
95% CI examples corresponding to observed numbers of 
patients considered to have benefited from treatment 
(Cohorts 2 and 3) 
 
Number of patients considered to have 
benefited from treatment 
95% Exact CI 
4 
(0.057, 0.437) 
8 
(0.191, 0.640) 
9 
(0.231, 0.685) 
10 
(0.272, 0.728) 
12 
(0.361, 0.809) 
CI: confidence interval; PFS: progression-free survival 
 
10.9 
Power for analysis of key secondary variables 
 
Not applicable. 
 
11 ETHICAL CONSIDERATIONS AND ADMINISTRATIVE 
PROCEDURES 
11.1 
Regulatory and ethical compliance 
 
This clinical study was designed, shall be implemented and reported in accordance with 
the ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable 
local regulations (including European Directive 2001/20/EC and US Code of Federal 
Regulations Title 21), and with the ethical principles laid down in the Declaration of 
Helsinki. 
 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
 
The protocol and the proposed informed consent form must be reviewed and approved by 
a properly constituted Institutional Review Board/Independent Ethics 
Committee/Research Ethics Board (IRB/IEC/REB) before study start. Prior to study start, 
the investigator is required to sign a protocol signature page confirming his/her 
agreement to conduct the study in accordance with these documents and all of the 
instructions and procedures found in this protocol and to give access to all relevant data 
and records to QED Therapeutics monitors, auditors, QED Therapeutics Clinical Quality 
Assurance representatives, designated agents of QED Therapeutics, IRBs/IECs/REBs and 
regulatory authorities as required. 


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11.3 
Informed consent procedures 
 
Eligible patients may only be included in the study after providing written (witnessed, 
where required by law or regulation), IRB/IEC/REB-approved informed consent 
 
Informed consent must be obtained before conducting any study-specific procedures (i.e. 
all of the procedures described in the protocol). Study patients will be informed in writing 
and orally before the start of the study about the nature and scope of the planned study 
procedures, in particular about the possible benefits and risks of participating in the 
study. Consent will be documented by signature on the ICF. The process of obtaining 
informed consent should be documented in the patient source documents. The date when 
a patient’s Informed Consent was actually obtained will be captured in their CRFs. 
 
QED Therapeutics will provide to investigators, in a separate document, a proposed 
informed consent form (ICF) that is considered appropriate for this study and complies 
with the ICH GCP E6 guideline, regulatory requirements. Any changes to this ICF 
suggested by the investigator must be agreed to by QED Therapeutics before submission 
to the IRB/IEC/REB, and a copy of the approved version must be provided to the QED 
Therapeutics monitor after IRB/IEC/REB approval. 
 
Women of child bearing potential should be informed that taking the study medication 
may involve unknown risks to the fetus if pregnancy were to occur during the study and 
agree that in order to participate in the study they must adhere to the contraception 
requirement for the duration of the study. If there is any question that the patient will not 
reliably comply, they should not be entered in the study. 
 
11.4 
Discontinuation of the study 
 
QED Therapeutics reserves the right to discontinue this study under the conditions 
specified in the clinical study agreement. Specific conditions for terminating the study are 
outlined in Publication of study protocol and results 
 
QED Therapeutics assures that the key design elements of this protocol will be posted in 
a publicly accessible database such as clinicaltrials.gov. In addition, upon study 
completion and finalization of the study report the results of this study will be either 
submitted for publication and/or posted in a publicly accessible database of clinical study 
results. 
 
11.5 
Publication of study protocol and results 
 
QED Therapeutics is committed to following high ethical standards for reporting study 
results for its innovative medicine, including the timely communication and publication 
of clinical trial results, whatever their outcome. QED Therapeutics assures that the key 
design elements of this protocol will be posted on the publicly accessible database, e.g. 
www.clinicaltrials.gov before study start. In addition, results of interventional clinical 
trials will be posted publically per local regulations. 


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QED Therapeutics follows the ICMJE authorship guidelines (www.icmje.org) and other 
specific guidelines of the journal or congress to which the publication will be submitted 
Authors will not receive remuneration for their writing of a publication, either directly 
from QED Therapeutics or through the professional medical writing agency. Author(s) 
may be requested to present poster or oral presentation at scientific congress; however, 
there will be no honorarium provided for such presentations. 
 
As part of its commitment to full transparency in publications, QED Therapeutics 
supports the full disclosure of all funding sources for the study and publications, as well 
as any actual and potential conflicts of interest of financial and non-financial nature by all 
authors, including medical writing/editorial support, if applicable. 
 
11.6 
Study documentation, record keeping and retention of documents 
 
Each participating site will maintain appropriate medical and research records for this 
trial, in compliance with Section 4.9 of the ICH E6 GCP, and regulatory and institutional 
requirements for the protection of confidentiality of subjects. As part of participating in a 
QED Therapeutics-sponsored study, each site will permit authorized representatives of 
the sponsor(s) and regulatory agencies to examine (and when required by applicable law, 
to copy) clinical records for the purposes of quality assurance reviews, audits and 
evaluation of the study safety and progress. 
 
Source data are all information, original records of clinical findings, observations, or 
other activities in a clinical trial necessary for the reconstruction and evaluation of the 
trial. Examples of these original documents and data records include, but are not limited 
to, hospital records, clinical and office charts, laboratory notes, memoranda, subjects’ 
diaries or evaluation checklists, pharmacy dispensing records, recorded data from 
automated 
 
instruments, copies or transcriptions certified after verification as being accurate and 
complete, microfiches, photographic negatives, microfilm or magnetic media, x-rays, and 
subject files and records kept at the pharmacy, at the laboratories, and medico-technical 
departments involved in the clinical trial. 
 
Data collection is the responsibility of the clinical trial staff at the site under the 
supervision of the site Principal Investigator. The study case report form (CRF) is the 
primary data collection instrument for the study. The investigator should ensure the 
accuracy, completeness, legibility, and timeliness of the data reported in the CRFs and all 
other required reports. Data reported on the CRF, that are derived from source 
documents, should be consistent with the source documents or the discrepancies should 
be explained. All data requested on the CRF must be recorded. Any missing data must be 
explained. Any change or correction to a paper CRF should be dated, initialed, and 
explained (if necessary) and should not obscure the original entry. For electronic CRFs an 
audit trail will be maintained by the system. The investigator should retain records of the 
changes and corrections to paper CRFs. 


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The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial (ICH E6 Section 8) and as required by 
applicable regulations and/or guidelines. The investigator/institution should take 
measures to prevent accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less 
than fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides 
written permission to dispose of them or, requires their retention for an additional period 
of time because of applicable laws, regulations and/or guidelines 
 
11.7 
Confidentiality of study documents and patient records 
 
The investigator must ensure pseudonymization of the patients by replacing names with 
the study-specific subject identification number; patients must not be identified by names 
in any documents submitted to QED Therapeutics. Signed informed consent forms and 
patient enrollment log must be kept strictly confidential to enable patient identification at 
the site. The names of study patients and all other confidential information are subject to 
medical confidentiality and the provisions of the General Data Protection Regulation 
(GDPR) and other applicable regulations or laws. Patient data may only be passed on in 
pseudonymized form beyond the study center. Third parties do not have access to original 
documents. 
 
11.8 
Audits and inspections 
 
Source data/documents must be available for inspection by QED Therapeutics or 
designee or Health Authorities. 
 
11.9 
Financial disclosures 
 
Financial disclosures should be provided by study personnel who are directly involved in 
the treatment or evaluation of patients at the site - prior to study start. 
 
12 PROTOCOL ADHERENCE 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under 
no circumstances should the investigator contact QED Therapeutics or its agents, if any, 
monitoring the study to request approval of a protocol deviation, as no authorized 
deviations are permitted. If the investigator feels a protocol deviation would improve the 
conduct of the study this must be considered a protocol amendment, and unless such an 
amendment is agreed upon by QED Therapeutics and approved by the IRB/IEC/REB it 
cannot be implemented. All significant protocol deviations will be recorded and reported 
in the CSR. 
 
12.1 
Amendments to the protocol 
 
Any change or addition to the protocol can only be made in a written protocol 
amendment that must be approved by QED Therapeutics, Health Authorities where 
required, and the IRB/IEC/REB. 


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Only amendments that are required for patient safety may be implemented prior to 
IRB/IEC/REB approval. Notwithstanding the need for approval of formal protocol 
amendments, the investigator is expected to take any immediate action required for the 
safety of any patient included in this study, even if this action represents a deviation from 
the protocol. In such cases, QED Therapeutics should be notified of this action and the 
IRB/IEC at the site should be informed according to local regulations (e.g. UK requires 
the notification of urgent safety measures within 3 days) but not later than 10 working 
days. 


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13 REFERENCES (AVAILABLE UPON REQUEST) 
Alpini, G, Prall, R, LaRusso, NF (2001). The pathobiology of biliary epithelia. The Liver 
Biology & Pathobiology, 4E: pp 421-435. 
American Cancer Society. (2012). Bile duct cancer (cholangiocarcinoma). Retrieved 
from cancer.org/acs/groups/cid/documents/webcontent/003084-pdf.pdf. 
Arai Y, Totoki Y, Hosoda F, et al (2013) FGFR2 tyrosine kinase fusions define a unique 
molecular subtype of cholangiocarcinoma. Hepatology. 2013 Oct 9. doi: 
10.1002/hep.26890 
 
Clinical Trials Facilitation Group. Recommendations related to contraception and 
pregnancy testing in clinical trials. 2014. Retrieved from 
http://www.hma.eu/fileadmin/dateien/Human_Medicines/01- 
About_HMA/Working_Groups/CTFG/2014_09_HMA_CTFG_Contraception.pdf . 
Accessed 03 October 2018. 
 
Cockcroft DW, Gault MH. Prediction of creatinine clearance from serum creatinine. 
Nephron. 1976;16(1):31-41. 
Eisenhauer EA, Therasse P, Bogaerts J, Schwartz LH, Sargent D, Ford R, et al (2009) 
New response evaluation criteria in solid tumours: revised RECIST guideline (version 
1.1). Eur J Cancer. Jan;45(2):228-47. 
FDA Guidance for Industry: Clinical drug interaction studies — Study design, data 
analysis, and clinical implications. 2017. Retrieved from 
https://www.fda.gov/downloads/drugs/guidances/ucm292362.pdf. Accessed 07 April 
2019. 
FDA Guidance for Industry: Drug-induced liver injury: Premarketing clinical evaluation. 
2009. Retrieved from 
https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guid 
ances/UCM174090.pdf. Accessed 10 April 2019. 
 
Flockhart DA. Drug Interactions: Cytochrome P450 Drug Interaction Table. Indiana 
University School of Medicine (2007). https://drug-interactions.medicine.iu.edu. 
Accessed 30 July 2019. 
Guagnano V, Kauffmann A, Wöhrle S, et al (2012) FGFR genetic alterations predict for 
sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov; 2(12):1118- 
33. 
 
Helsten T, Elkin S, Arthur E, Tomson BN, Carter J, Kurzrock R. The FGFR landscape in 
cancer: analysis of 4,853 tumors by next-generation sequencing. Clin Cancer Res; 22(1); 
259–267. 2015 AACR. 
Jiao Y, Pawlik T, Anders R, et al (2013) Exome sequencing identifies frequent 
inactivating mutations in BAP1, ARID1A and PBRM1 in intrahepatic 
cholangiocarcinomas. Nature Genetics 45,1470–1473 


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Konecny GE, Kolarova T, O'Brien NA, et al (2013) Activity of the Fibroblast Growth 
Factor Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial 
Cancer Cells. Mol Cancer Ther; Epub 2013 Feb 26. 
Patel T. (2002) Worldwide trends in mortality from biliary tract malignancies. BMC 
Cancer. 2002; 2:10. 
 
Rugo HS, Seneviratne L, Beck JT, Glaspy JA, Peguero JA, Pluard TJ, et al. Prevention of 
everolimus-related stomatitis in women with hormone receptor-positive, HER2-negative 
metastatic breast cancer using dexamethasone mouthwash (SWISH): a single-arm, phase 
2 trial. Lancet Oncol. 2017;18(5):654–662. 
 
Segaert S, Van Cutsem E. Clinical signs, pathophysiology and management of skin 
toxicity during therapy with epidermal growth factor receptor inhibitors. Ann Oncol. 
2005;16:1425–1433. 
Sirica, A. E. (2005). Cholangiocarcinoma: molecular targeting strategies for 
chemoprevention and therapy. Hepatology Vol 41, Issue 1 (Jan 2005), pp 5-15. 
Therasse P, Arbuck SG, Eisenhauer EA, Wanders J, Kaplan RS, Rubinstein L, et al. New 
guidelines to evaluate the response to treatment in solid tumors. European Organization 
for Research and Treatment of Cancer, National Cancer Institute of the United States, 
National Cancer Institute of Canada. J Natl Cancer Inst. 2000;92(3):205–216. 
Valle J, Wasan H, Palmer D, et al (2010) Cisplatin plus gemcitabine versus gemcitabine 
for biliary tract cancer. N Engl J Med 2010;362:1273-81. 
Wesche J, Haglund K, Haugsten E (2011) Fibroblast growth factors and their receptors in 
cancer. Biochem. J. (2011) 437, 199–213 
Wu Y, Su F, Kalyana-Sundaram S, et al (2013) Identification of Targetable FGFR Gene 
Fusions in Diverse Cancers. Cancer Discov; 3(6); 1–12. 


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14 APPENDICES 
14.1 
Appendix 1: List of concomitant medications 
 
In general, the use of any concomitant medication deemed necessary for the care of the 
patient is permitted in this study, except as specifically prohibited below. Combination 
administration of study drugs could result in drug-drug interactions (DDI) that could 
potentially lead to reduced activity or enhanced toxicity of the concomitant medication 
and/or BGJ398. 
 
The following lists in Table 15 are based on the Indiana University School of Medicine’s 
“Clinically Relevant” Table (Flockhart Table™; Flockhart 2007) and supplemented with 
the FDA Draft guidance and the online database Drugbank.ca. Note: this may not be an 
exhaustive list of medications, investigator should use this list as a guide. 
 
Table 15: 
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, H2 antagonists (eg, ranitidine), proton-pump inhibitors 
(eg, omeprazole) 
Medications that have possible 
risk of TdP/QT prolongation 
alfuzosin, amantadine, atazanavir, chloral hydrate, clozapine, 
dolasetron, eribulin, famotidine, felbamate, fingolimod, 
foscarnet, fosphenytoin, gatifloxacin, gemifloxacin, 
granisertron, iloperidone, indapamide, isradipine, lapatinib, 
lithium, moexipril, nicardipine, nilotinib, octreotide, ofloxacin, 
oxytocin, paliperidone, pasireotide, quetiapine, ranolazine, 
risperidone, roxithromycin, sertindole, sunitinib, tamoxifen, 
tizanidine, vardenafil, venlafaxine, ziprasidone 
Medications that have 
conditional risk of TdP/QT 
prolongation 
amitriptyline, amisulpride, ciprofloxacin, clomipramine, 
desipramine, diphenhydramine, doxepin, fluoxetine, 
galantamine, imipramine, nortriptyline, paroxetine, 
protriptyline, sertraline, solifenacin, trazodone, trimethoprim- 
sulfa, trimipramine 


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Category 
Drug Names 
Medications with established 
potential for QT prolongation 
or TdP 
amiodarone, anagrelide, arsenic trioxide, astemizole (off US 
market), azithromycin, bepridil (off US market), chloroquine, 
chlorpromazine, cisapride (off US market), citalopram, 
clarithromycin, cocaine, disopyramide, dofetilide, 
domperidone (not on US market), dronedarone, droperidol, 
erythromycin, escitalopram, flecainide, halofantrine, 
haloperidol, ibutilide, levofloxacin, levomethadyl (off US 
market), mesoridazine (off US market), methadone, 
moxifloxacin, ondansetron, pentamidine, pimozide, probucol 
(off US market), procainamide (oral off US market), 
quinidine, sevoflurane, sotalol, sparfloxacin (off US market), 
sulpiride (not on US market), terfenadine (off US market), 
thioridazine, vandetanib 
BCRP substrates 
atorvastatin, irinotecan, methotrexate, rosuvastatin, simvastatin, 
sulfasalazine, topotecan 
Abbreviations: BCRP, breast cancer resistance protein; CYP, cytochrome p; FDA, Food and Drug 
Administration; GI, gastrointestinal; TdP, Torsades de Pointes 
a BGJ398 should be dosed at least 2 hours before or 10 hours after dosing with a gastric protection agent. 
b If possible, proton pump inhibitors should be avoided due to their long pharmacodynamic effect and 
replaced with H2 antagonists or antacids. 
Sources: FDA Guidance for Industry, 2017; Flockhart 2007; drugbank.ca. 


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14.2 
Appendix 2: List of prohibited medications 
 
Table 16: 
List of prohibited medications and substances while on study 
 
Category 
Drug name 
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) 


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14.3 
Appendix 3: Guidelines for assessments of response 
 
14.3.1 
Introduction 
 
The purpose of this document is to provide the working definitions and rules necessary 
for a consistent and efficient analysis of efficacy for oncology studies in solid tumors. 
This document is based on the RECIST criteria for tumor responses (Therasse 2000) and 
the revised RECIST 1.1 guidelines (Eisenhauer 2009). 
 
14.3.2 
Disease measurability 
 
In order to evaluate tumors throughout a study, definitions of measurability are required 
in order to classify lesions appropriately at baseline. In defining measurability, a 
distinction also needs to be made between nodal lesions (pathological lymph nodes) and 
non-nodal lesions. 
 
• Measurable disease - the presence of at least one measurable nodal or non-nodal 
lesion. If the measurable disease is restricted to a solitary lesion, its neoplastic nature 
should be confirmed by cytology/histology. 
 
Measurable lesions (both nodal and non-nodal) 
 
• Measurable non-nodal - As a rule of thumb, the minimum size of a measurable non- 
nodal target lesion at baseline should be no less than double the slice thickness or 
10mm whichever is greater - e.g. the minimum non-nodal lesion size for CT/MRI 
with 5mm cuts will be 10 mm, for 8 mm contiguous cuts the minimum size will be 16 
mm. 
 
• Lytic bone lesions or mixed lytic-blastic lesions with identifiable soft tissue 
components that can be evaluated by CT/MRI, can be considered as measurable 
lesions, if the soft tissue component meets the definition of measurability. 
 
• Measurable nodal lesions (i.e. lymph nodes) - Lymph nodes ≥15 mm in short axis 
can be considered for selection as target lesions. Lymph nodes measuring ≥10 mm 
and <15 mm are considered non-measurable. Lymph nodes smaller than 10 mm in 
short axis at baseline, regardless of the slice thickness, are normal and not considered 
indicative of disease. 
 
Cystic lesions: 
 
• Lesions that meet the criteria for radiographically defined simple cysts (ie, spherical 
structure with a thin, non-irregular, non-nodular and non-enhancing wall, no 
septations, and low CT density [water-like] content) should not be considered as 
malignant lesions (neither measurable nor non-measurable) since they are, by 
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• ‘Cystic lesions’ thought to represent cystic metastases can be considered as 
measurable lesions, if they meet the definition of measurability described above. 
However, if noncystic lesions are present in the same patient, these are preferred for 
selection as target lesions. 
 
• Non-measurable lesions - all other lesions are considered non-measurable, including 
small lesions (e.g. longest diameter <10 mm with CT/MRI or pathological lymph 
nodes with ≥ 10 to < 15 mm short axis), as well as truly non-measurable lesions eg, 
blastic bone lesions, leptomeningeal disease, ascites, pleural/pericardial effusion, 
inflammatory breast disease, lymphangitis cutis/pulmonis, abdominal 
masses/abdominal organomegaly identified by physical exam that is not measurable 
by reproducible imaging techniques. 
 
14.3.3 
Methods of tumor measurement - general guidelines 
In this document, the term “contrast” refers to intravenous (i.v.) contrast. 
The following considerations are to be made when evaluating the tumor: 
• All measurements should be taken and recorded in metric notation (mm), using a 
ruler or calipers. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 4 weeks before the beginning of 
the treatment. 
 
• Imaging-based evaluation is preferred to evaluation by clinical examination when 
both methods have been used to assess the antitumor effect of a treatment. 
 
• For optimal evaluation of patients, the same methods of assessment and technique 
should be used to characterize each identified and reported lesion at baseline and 
during followup. Contrast-enhanced CT of chest, abdomen and pelvis should 
preferably be performed using a 5 mm slice thickness with a contiguous 
reconstruction algorithm. CT/MRI scan slice thickness should not exceed 8 mm cuts 
using a contiguous reconstruction algorithm. If, at baseline, a patient is known to have 
a medical contraindication to CT contrast or develops a contraindication during the 
trial, the following change in imaging modality will be accepted for follow-up: a non- 
contrast CT of chest (MRI not recommended due to respiratory artifacts) plus 
contrast-enhanced MRI of abdomen and pelvis. 
 
• A change in methodology can be defined as either a change in contrast use (e.g. 
keeping the same technique, like CT, but switching from with to without contrast use 
or vice-versa, regardless of the justification for the change) or a change in technique 
(e.g. from CT to MRI, or vice-versa), or a change in any other imaging modality. A 
change in methodology will result by default in a UNK overall lesion response 
assessment. However, another response assessment than the QED Therapeutics 
calculated UNK response may be accepted from the investigator or the central 
blinded reviewer if a definitive response assessment can be justified, based on the 
available information. 


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• FDG-PET: can complement CT scans in assessing progression (particularly possible 
for ‘new’ disease). New lesions on the basis of FDG-PET imaging can be identified 
according to the following algorithm: 
 
○ Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
 
○ No FDG-PET at baseline with a positive FDG-PET at follow-up: 
 
• If the positive FDG-PET at follow-up corresponds to a new site of disease confirmed 
by CT, this is PD. 
 
• If the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT are needed to determine if there is truly progression 
occurring at that Site (if so, the date of PD will be the date of the initial abnormal CT 
scan). 
 
• If the positive FDG-PET at follow-up corresponds to a pre-existing site of disease on 
CT that is not progressing on the basis of the anatomic images, this is not PD. 
 
• Chest x-ray: Lesions on chest x-ray are acceptable as measurable lesions when they 
are clearly defined and surrounded by aerated lung. However, CT is preferable. 
 
• Ultrasound: When the primary endpoint of the study is overall response evaluation, 
ultrasound (US) should not be used to measure tumor lesions. It is, however, a 
possible alternative to clinical measurements of superficial palpable lymph nodes, 
subcutaneous lesions and thyroid nodules. US might also be useful to confirm the 
complete disappearance of superficial lesions usually assessed by clinical 
examination. 
 
• Endoscopy and laparoscopy: The utilization of endoscopy and laparoscopy for 
objective tumor evaluation has not yet been fully and widely validated. Their uses in 
this specific context require sophisticated equipment and a high level of expertise that 
may only be available in some centers. Therefore, the utilization of such techniques 
for objective tumor response should be restricted to validation purposes in specialized 
centers. However, such techniques can be useful in confirming complete pathological 
response when biopsies are obtained. 
 
• Tumor markers: Tumor markers alone cannot be used to assess response. However, 
some disease specific and more validated tumor markers (e.g. CA-125 for ovarian 
cancer, PSA for prostate cancer, alpha-FP, LDH and Beta-hCG for testicular cancer) 
can be integrated as non-target disease. If markers are initially above the upper 
normal limit they must normalize for a patient to be considered in complete clinical 
response when all lesions have disappeared. 
 
• Cytology and histology: Cytology and histology can be used to differentiate between 
PR and CR in rare cases (ie, after treatment to differentiate between residual benign 


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lesions and residual malignant lesions in tumor types such as germ cell tumors). 
Cytologic confirmation of neoplastic nature of any effusion that appears or worsens 
during treatment is required when the measurable tumor has met the criteria for 
response or stable disease. Under such circumstances, the cytologic examination of 
the fluid collected will permit differentiation between response and stable disease (an 
effusion may be a side effect of the treatment) or progressive disease (if the neoplastic 
origin of the fluid is confirmed). 
 
• Clinical examination: Clinical lesions will only be considered measurable when they 
are superficial (ie, skin nodules and palpable lymph nodes). For the case of skin 
lesions, documentation by color photography, including a ruler to estimate the size of 
the lesion, is recommended. 
 
14.3.4 
Baseline documentation of target and non-target lesions 
 
For the evaluation of lesions at baseline and throughout the study, the lesions are 
classified at baseline as either target or non-target lesions: 
 
• Target lesions: All measurable lesions (nodal and non-nodal) up to a maximum of 
five lesions in total (and a maximum of two lesions per organ), representative of all 
involved organs should be identified as target lesions and recorded and measured at 
baseline. Target lesions should be selected on the basis of their size (lesions with the 
longest diameter) and their suitability for accurate repeated measurements (either by 
imaging techniques or clinically). Each target lesion must be uniquely and 
sequentially numbered on the CRF (even if it resides in the same organ). 
 
Minimum target lesion size at baseline 
 
• Non-nodal target: Non-nodal target lesions identified by methods for which slice 
thickness is not applicable (e.g. clinical examination, photography) should be at least 
10 mm in longest diameter. See Section 14.3.2. 
 
• Nodal target: See Section 14.3.9. 
A sum of diameters (long axis for non-nodal lesions, short axis for nodal) for all target 
lesions will be calculated and reported as the baseline sum of diameters (SOD). The 
baseline sum of diameters will be used as reference by which to characterize the objective 
tumor response. Each target lesion identified at baseline must be followed at each 
subsequent evaluation and documented on eCRF. 
 
• Non-target lesions: All other lesions are considered non-target lesions, i.e. lesions 
not fulfilling the criteria for target lesions at baseline. Presence or absence or 
worsening of non-target lesions should be assessed throughout the study; 
measurements of these lesions are not required. Multiple non-target lesions involved 
in the same organ can be assessed as a group and recorded as a single item (i.e. 
multiple liver metastases). Each non-target lesion identified at baseline must be 
followed at each subsequent evaluation and documented on eCRF. 


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14.3.5 
Follow-up evaluation of target and non-target lesions 
 
To assess tumor response, the sum of diameters for all target lesions will be calculated (at 
baseline and throughout the study). At each assessment response is evaluated first 
separately for the target (Table 17) and non-target lesions (Table 18) identified at 
baseline. These evaluations are then used to calculate the overall lesion response 
considering both the target and non-target lesions together (Table 19) as well as the 
presence or absence of new lesions. 
 
14.3.6 
Follow-up and recording of lesions 
 
At each visit and for each lesion the actual date of the scan or procedure which was used 
for the evaluation of each specific lesion should be recorded. This applies to target and 
non-target lesions as well as new lesions that are detected. At the assessment visit all of 
the separate lesion evaluation data are examined by the investigator in order to derive the 
overall visit response. Therefore, all such data applicable to a particular visit should be 
associated with the same assessment number. 
 
14.3.7 
Non-nodal lesions 
 
Following treatment, lesions may have longest diameter measurements smaller than the 
image reconstruction interval. Lesions smaller than twice the reconstruction interval are 
subject to substantial “partial volume” effects (ie, size may be underestimated because of 
the distance of the cut from the longest diameter; such lesions may appear to have 
responded or progressed on subsequent examinations, when, in fact, they remain the 
same size). 
 
If the lesion has completely disappeared, the lesion size should be reported as 0 mm. 
 
Measurements of non-nodal target lesions that become 5 mm or less in longest diameter 
are likely to be non-reproducible. Therefore, it is recommended to report a default value 
of 5 mm, instead of the actual measurement. This default value is derived from the 5 mm 
CT slice thickness (but should not be changed with varying CT slice thickness). Actual 
measurement should be given for all lesions larger than 5 mm in longest diameter 
irrespective of slice thickness/reconstruction interval. 
 
In other cases where the lesion cannot be reliably measured for reasons other than its size 
(eg, borders of the lesion are confounded by neighboring anatomical structures), no 
measurement should be entered and the lesion cannot be evaluated. 
 
14.3.8 
Nodal lesions 
 
A nodal lesion less than 10 mm in size by short axis is considered normal. Lymph nodes 
are not expected to disappear completely, so a “non-zero size” will always persist. 
 
Measurements of nodal target lesions that become 5 mm or less in short axis are likely to 
be non-reproducible. Therefore, it is recommended to report a default value of 5 mm, 
instead of the actual measurement. This default value is derived from the 5 mm CT slice 


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thickness (but should not be changed with varying CT slice thickness). Actual 
measurement should be given for all lesions larger than 5 mm in short axis irrespective of 
slice thickness/reconstruction interval. 
 
However, once a target nodal lesion shrinks to less than 10 mm in its short axis, it will be 
considered normal for response purpose determination. The lymph node measurements 
will continue to be recorded to allow the values to be included in the sum of diameters for 
target lesions, which may be required subsequently for response determination. 
 
14.3.9 
Determination of target lesion response 
Table 17:  Response criteria for target lesions 
Response Criteria 
Evaluation of target lesions 
Complete Response (CR): 
Disappearance of all non-nodal target lesions. In addition, any pathological 
lymph nodes assigned as target lesions must have a reduction in short axis to < 
10 mm 1 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameter of all target lesions, taking as 
reference the baseline sum of diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target lesions, 
taking as reference the smallest sum of diameter of all target lesions recorded at 
or after baseline. In addition to the relative increase of 20%, the sum must also 
demonstrate an absolute increase of at least 5 mm.2 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR or CR nor an increase in lesions 
which would qualify for PD. 
 
Unknown (UNK) 
Progression has not been documented and one or more target lesions have not 
been assessed or have been assessed using a different method than baseline.3 
1 
SOD for CR may not be zero when nodal lesions are part of target lesions 
2 
Following an initial CR, a PD cannot be assigned if all non-nodal target lesions are still not present and 
all nodal lesions are <10 mm in size. In this case, the target lesion response is CR 
3 
Methodology change; See Section 14.3.4. 
 
 
Notes on target lesion response 
 
Reappearance of lesions: If the lesion appears at the same anatomical location where a 
target lesion had previously disappeared, it is advised that the time point of lesion 
disappearance (ie, the “0 mm” recording) be re-evaluated to make sure that the lesion was 
not actually present and/or not visualized for technical reasons in this previous 
assessment. If it is not possible to change the 0 value, then the investigator/radiologist has 
to decide between the following three possibilities: 
 
• The lesion is a new lesion, in which case the overall tumor assessment will be 
considered as progressive disease 


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• The lesion is clearly a reappearance of a previously disappeared lesion, in which case 
the size of the lesion has to be entered in the CRF and the tumor assessment will 
remain based on the sum of tumor measurements as presented in Table 17 above (ie, a 
PD will be determined if there is at least 20% increase in the sum of diameters of all 
measured target lesions, taking as reference the smallest sum of diameters of all target 
lesions recorded at or after baseline with at least 5 mm increase in the absolute sum of 
the diameters). Proper documentation should be available to support this decision. 
This applies to patients who have not achieved target response of CR. For patients 
who have achieved CR, please refer to last bullet in this section. 
 
• For those patients who have only one target lesion at baseline, the reappearance of the 
target lesion which disappeared previously, even if still small, is considered a PD. 
 
• Missing measurements: In cases where measurements are missing for one or more 
target lesions it is sometimes still possible to assign PD based on the measurements of 
the remaining lesions. For example, if the sum of diameters for 5 target lesions at 
baseline is 100 mm at baseline and the sum of diameters for 3 of those lesions at a 
post-baseline visit is 140 mm (with data for 2 other lesions missing) then a PD should 
be assigned. However, in other cases where a PD cannot definitely be attributed, the 
target lesion response would be UNK. 
 
• Nodal lesion decrease to normal size: When nodal disease is included in the sum of 
target lesions and the nodes decrease to “normal” size they should still have a 
measurement recorded on scans. This measurement should be reported even when the 
nodes are normal in order not to overstate progression should it be based on increase 
in the size of nodes. 
 
• Lesions split: In some circumstances, disease that is measurable as a target lesion at 
baseline and appears to be one mass can split to become two or more smaller sub- 
lesions. When this occurs, the diameters (long axis - non-nodal lesion, short axis - 
nodal lesions) of the two split lesions should be added together and the sum recorded 
in the diameter field on the case report form under the original lesion number. This 
value will be included in the sum of diameters when deriving target lesion response. 
The individual split lesions will not be considered as new lesions, and will not 
automatically trigger a PD designation. 
 
• Lesions coalesced: Conversely, it is also possible that two or more lesions which 
were distinctly separate at baseline become confluent at subsequent visits. When this 
occurs a plane between the original lesions may be maintained that would aid in 
obtaining diameter measurements of each individual lesion. If the lesions have truly 
coalesced such that they are no longer separable, the maximal diameters (long axis - 
non-nodal lesion, short axis nodal lesions) of the “merged lesion” should be used 
when calculating the sum of diameters for target lesions. On the case report form, the 
diameter of the “merged lesion” should be recorded for the size of one of the original 
lesions while a size of “0”mm should be entered for the remaining lesion numbers 
which have coalesced. 


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• The measurements for nodal lesions, even if less than 10 mm in size, will contribute 
to the calculation of target lesion response in the usual way with slight modifications. 
 
○ Since lesions less than 10 mm are considered normal, a CR for target lesion 
response should be assigned when all nodal target lesions shrink to less than 10 
mm and all non-nodal target lesions have disappeared. 
 
○ Once a CR target lesion response has been assigned a CR will continue to be 
appropriate (in the absence of missing data) until progression of target lesions. 
 
○ Following a CR, a PD can subsequently only be assigned for target lesion 
response if either a non-nodal target lesion “reappears” or if any single nodal 
lesion is at least 10 mm and there is at least 20% increase in sum of the diameters 
of all nodal target lesions relative to nadir with at least 5 mm increase in the 
absolute sum of the diameters. 
 
14.3.10 
Determination of non-target lesion response 
Table 18:  Response criteria for non-target lesions 
Response Criteria 
Evaluation of non-target lesions 
Complete Response (CR): 
Disappearance of all non-target lesions. In addition, all lymph nodes assigned 
a non-target lesions must be non-pathological in size (< 10 mm short axis) 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions.1 
Non-CR/Non-PD: 
Neither CR nor PD 
Unknown (UNK) 
Progression has not been documented and one or more non-target lesions 
have not been assessed or have been assessed using a different method than 
baseline. 
 
1 
Although a clear progression of non-target lesions only is exceptional, in such circumstances, the 
opinion of the treating physician does prevail and the progression status should be confirmed later on 
by the review panel (or study chair). 
 
Notes on non-target lesion response 
 
• The response for non-target lesions is CR only if all non-target non-nodal lesions 
which were evaluated at baseline are now all absent and with all non-target nodal 
lesions returned to normal size (i.e. < 10 mm). If any of the non-target lesions are still 
present, or there are any abnormal nodal lesions (i.e. ≥ 10 mm) the response can only 
be ‘NonCR/Non-PD’ unless any of the lesions was not assessed (in which case 
response is UNK) or there is unequivocal progression of the non-target lesions (in 
which case response is PD). 
 
• Unequivocal progression: To achieve “unequivocal progression” on the basis of non- 
target disease there must be an overall level of substantial worsening in non-target 
disease such that, even in presence of CR, PR or SD in target disease, the overall 
tumor burden has increased sufficiently to merit discontinuation of therapy. A modest 


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“increase” in the size of one or more non-target lesions is usually not sufficient to 
qualify for unequivocal progression status. The designation of overall progression 
solely on the basis of change in non-target disease in the face of CR, PR or SD of 
target disease is therefore expected to be rare. In order for a PD to be assigned on the 
basis of non-target lesions, the increase in the extent of the disease must be 
substantial even in cases where there is no measurable disease at baseline. If there is 
unequivocal progression of non-target lesion(s), then at least one of the non-target 
lesions must be assigned a status of “Worsened”. Where possible, similar rules to 
those described in Section 14.3.10 (Determination of target lesion response) for 
assigning PD following a CR for the non-target lesion response in the presence of 
non-target lesions nodal lesions should be applied. 
 
14.3.11 
New lesions 
 
The appearance of a new lesion is always associated with Progressive Disease (PD) and 
has to be recorded as a new lesion in the New Lesion CRF page. 
 
• If a new lesion is equivocal, for example because of its small size, continued therapy 
and follow-up evaluation will clarify if it represents truly new disease. If repeat scans 
confirm there is definitely a new lesion, then progression should be declared using the 
date of the first observation of the lesion. 
 
• If new disease is observed in a region which was not scanned at baseline or where 
the particular baseline scan is not available for some reason, then this should be 
considered as a PD. The one exception to this is when there are no baseline scans at 
all available for a patient in which case the response should be UNK, as for any of 
this patient's assessment (see Section 14.3.13). 
 
• A lymph node is considered as a “new lesion” and, therefore, indicative of 
progressive disease if the short axis increases in size to ≥10 mm for the first time in 
the study plus 5 mm absolute increase. 
FDG-PET: can complement CT scans in assessing progression (particularly possible 
for ‘new’ disease). See Section 14.3.4. 
 
14.3.12 
Evaluation of overall lesion response 
 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as shown below 
in Table 19. 


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Table 19:     Overall lesion response at each assessment 
 
Target lesions 
Non-target lesions 
New Lesions 
Overall lesion 
response 
CR 
CR 
No 
CR1 
CR 
Non-CR/Non-PD 
No 
PR2 
CR 
UNK 
No 
PR 
PR 
Non-PD and not UNK 
No 
PR1, 2 
SD 
Non-PD and not UNK 
No 
SD1 
UNK 
Non-PD 
No 
UNK1 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 
This overall lesion response also applies when there are no non-target lesions identified at baseline. 
2 
Unconfirmed PR will be considered SD for analysis purposes. If there are no baseline scans available 
at all, then the overall lesion response at each assessment should be considered Unknown (UNK). 
 
If the evaluation of any of the target lesions identified at baseline could not be made 
during follow-up, the overall status must be ‘unknown’ unless progression was seen. 
 
In some circumstances it may be difficult to distinguish residual disease from normal 
tissue. When the evaluation of complete response depends on this determination, it is 
recommended that the residual lesion be investigated (fine needle aspirate/biopsy) to 
confirm the CR. 


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14.4 
Appendix 4: FGFR1/2/3 Allowed Mutations (Known Activating 
Mutations) 
 
Patients who have a mutation listed below meet the inclusion criterion 2c. 
 
 
FGFR Mutation 
Functional Effect 
FGFR1 N546K 
Activating 
FGFR1 K656E 
Activating 
FGFR2 S252W 
Activating 
FGFR2 P253R 
Activating 
FGFR2 A315T 
Activating 
FGFR2 Y375C 
Activating 
FGFR2 C382R 
Activating 
FGFR2 N549K 
Activating 
FGFR2 K659E 
Activating 
FGFR3 R248C 
Activating 
FGFR3 S249C 
Activating 
FGFR3 G370C 
Activating 
FGFR3 S371C 
Activating 
FGFR3 Y373C 
Activating 
FGFR3 G380R 
Activating 
FGFR3 K650E 
Activating 
FGFR3 K650M 
Activating 
Sources: Helsten 2015, data on file. 


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14.5 
Appendix 5: List of Highly Effective Methods of Contraception 
 
The following is from the Clinical Trials Facilitation Group 2014 (Section 4.1). 
 
Methods that can achieve a failure rate of less than 1% per year when used consistently 
and correctly are considered as highly effective birth control methods. Such methods 
include: 
 
• combined (estrogen and progestogen containing) hormonal contraception associated 
with inhibition of ovulation 1: 
○ oral 
 
○ intravaginal 
 
○ transdermal 
 
• progestogen-only hormonal contraception associated with inhibition of ovulation 1: 
○ oral 
 
○ injectable 
 
○ implantable 2 
• intrauterine device (IUD) 2 
• intrauterine hormone-releasing system (IUS) 2 
• bilateral tubal occlusion 2 
• vasectomised partner 2,3 
• sexual abstinence 4 
 
 
1 Hormonal contraception may be susceptible to interaction with the IMP, which may reduce the efficacy 
of the contraception method (see Clinical Trials Facilitation Group 2014, section 4.3). 
2 Contraception methods that in the context of this guidance are considered to have low user dependency. 
3 Vasectomised partner is a highly effective birth control method provided that partner is the sole sexual 
partner of the WOCBP trial participant and that the vasectomised partner has received medical 
assessment of the surgical success. 
4 In the context of this guidance sexual abstinence is considered a highly effective method only if defined 
as refraining from heterosexual intercourse during the entire period of risk associated with the study 
treatments. The reliability of sexual abstinence needs to be evaluated in relation to the duration of the 
clinical trial and the preferred and usual lifestyle of the subject. 

SAP_001.pdf: 
Infigratinib (BGJ398) 
QED Therapeutics 
 
Property of QED Therapeutics 
For business use only 
May not be used, divulged, published, or otherwise disclosed 
without the consent of QED Therapeutics 
Clinical Development 
INFIGRATINIB 
Protocol CBGJ398X2204 Version 6 (Amendment 5) 
 
A phase II multicenter, single arm study of oral BGJ398 in adult patients with 
advanced or metastatic cholangiocarcinoma with FGFR2 gene fusions or 
other FGFR genetic alterations who failed or are intolerant to platinum-based 
chemotherapy 
STATISTICAL ANALYSIS PLAN (SAP) 
Amendment 2 
 
 
Author: 
 
Version: 
V3.0 (13 May 2020) 
 
Supersedes: 
V2.0 (26 March 2020) 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
PI 


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TABLE OF CONTENTS 
STATISTICAL ANALYSIS PLAN (SAP) ................................................................................. 1 
SUMMARY OF CHANGES (V1.0) ............................................................................................ 4 
SUMMARY OF CHANGES (V2.0, AMENDMENT 1) ............................................................ 7 
SUMMARY OF CHANGES (V3.0, AMENDMENT 2) .......................................................... 10 
LIST OF ABBREVIATIONS .................................................................................................... 11 
1 
INTRODUCTION ............................................................................................................... 12 
1.1 
Study Design .................................................................................................................... 12 
1.2 
Study Objectives and Endpoints .................................................................................... 15 
2 
STATISTICAL METHODS ............................................................................................... 16 
2.1 
Data Analysis General Information .............................................................................. 16 
2.1.1 
General Definitions ................................................................................................... 17 
2.2 
Analysis Sets .................................................................................................................... 19 
2.2.1 
Full Analysis Set ........................................................................................................ 19 
2.2.2 
Interim Efficacy Analysis Set 1 for Cohort 1 ......................................................... 20 
2.2.3 
Interim Analysis Set 2 for Cohort 1 ........................................................................ 20 
2.2.4 
Sensitivity Analysis Set for Cohort 1 ....................................................................... 20 
2.2.5 
Interim Analysis Set for Cohort 3 ........................................................................... 20 
2.2.6 
Per-Protocol Set ........................................................................................................ 21 
2.2.7 
Pharmacokinetic analysis set ................................................................................... 21 
2.2.8 
Subgroups of interest ................................................................................................ 21 
2.3 
Subject Disposition, Demographics and Other Baseline Characteristics .................. 22 
2.3.1 
Subject disposition .................................................................................................... 22 
2.3.2 
Demographics ............................................................................................................ 22 
2.3.3 
Medical History ......................................................................................................... 22 
2.3.4 
Prior Antineoplastic Therapy .................................................................................. 22 
2.3.5 
Diagnosis and Extent of Cancer ............................................................................... 23 
2.4 
Protocol Deviations ......................................................................................................... 23 
2.5 
Treatments (Study Treatment, Concomitant Therapies, Compliance) ..................... 23 
2.5.1 
Study Treatment ....................................................................................................... 23 
2.5.2 
Prior, Concomitant and Post Therapies ................................................................. 25 
2.5.3 
Compliance ................................................................................................................ 25 
2.6 
Analysis of the primary objective .................................................................................. 25 
2.6.1 
Variable ...................................................................................................................... 25 
2.6.2 
Statistical Hypothesis, Model, and Method of Analysis ........................................ 26 
2.7 
Analysis of Secondary Objective(s) ............................................................................... 26 
2.7.1 
Secondary Efficacy Objectives ................................................................................. 26 
2.7.2 
Safety Objectives ....................................................................................................... 28 
2.7.3 
Other Safety Data ..................................................................................................... 34 
2.7.4 
Pharmacokinetics ...................................................................................................... 37 
2.8 
Exploratory Analyses ...................................................................................................... 39 
2.8.1 
Biomarkers ................................................................................................................ 40 
2.9 
Interim Analysis .............................................................................................................. 41 
3 
SAMPLE SIZE CALCULATION ...................................................................................... 42 
3.1 
Cohort 1 ........................................................................................................................... 42 


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3.2 
Cohort 2 and Cohort 3 .................................................................................................... 42 
4 
CHANGE TO PROTOCOL SPECIFIED ANALYSES ................................................... 43 
5 
APPENDIX ........................................................................................................................... 43 
5.1 
Imputation Rules ............................................................................................................. 43 
5.1.1 
AE, CM, and Safety Assessment Date Imputation ................................................ 43 
5.1.2 
Death Date Imputation ............................................................................................. 44 
5.2 
Table of Adverse Events of Special Interest, Search Strategies, and 
Rationales for Sponsor-Defined Search Strategies ...................................................... 45 
5.3 
AESI: Calcium-Phosphate Homeostasis – Hypercalcaemia, 
Hyperphosphataemia, and Hypophosphataemia ......................................................... 46 
5.4 
AESI: Eye Disorder of Central Serous Retinopathy/Retinal Pigment 
Epithelium Detachment .................................................................................................. 46 
5.5 
AESI: Pathological Fracture .......................................................................................... 47 
5.6 
AESI: Tissue Calcification ............................................................................................. 48 
5.7 
AESI: Vascular/intravascular Mineralization ............................................................. 49 
5.8 
AESI: Eye Disorder: SOC Eye Disorders (Excluding 9 PTs Used to 
Characterize CSR/RPED) .............................................................................................. 50 
5.9 
Minimum Critical Toxicities .......................................................................................... 59 
5.10 
CYP3A4 Inhibitors and Inducers .................................................................................. 60 
5.11 
Phosphate Binders .......................................................................................................... 63 
6 
REFERENCE ....................................................................................................................... 63 
 
LIST OF TABLES 
Table 1: 
Objectives and Related Endpoints for Cohort 1 and Overall Study .............. 15 
Table 2: 
Objectives and Related Endpoints for Cohort 2 and 3 .................................... 16 
Table 3: 
Dose and Treatment Schedule ........................................................................... 17 
Table 4: 
Example of Laboratory Parameters for Which CTCAE Grades are 
Defined ................................................................................................................. 34 
Table 5: 
Examples of Laboratory Parameters (Without CTCAE Grades) for 
Which Lab Reference Ranges Are Defined ...................................................... 34 
Table 6: 
Criteria for Notable Vital Sign Values .............................................................. 37 
Table 7: 
Non-compartmental Pharmacokinetic Parameters ......................................... 38 
Table 8: 
95% CI Examples Corresponding to Observed Numbers of Subjects 
Considered to Have Benefited From Treatment (Cohorts 2 and 3) ............... 43 
Table 9: 
Imputation of Start Dates (AE, CM) ................................................................. 43 
Table 10: 
Imputation of End Dates (AE, CM) .................................................................. 44 
Table 11: 
Table of Minimal Critical Toxicities and SMQ Search Strategies ................. 60 
LIST OF FIGURES 
Figure 1: 
Study Design (Applied to Protocol Version 6 (Amendment 5)) ...................... 14 


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SUMMARY OF CHANGES (V1.0) 
This Summary of Change summarized the change of the Statistical Analysis Plan for Study 
CBGJ398X2204 based on the SAP developed by Novartis dated on 09-Nov-2017. 
 
Rationale for Change 
 
The primary purpose of the changes is to: 
 
• Revise the SAP to be consistent with the Protocol Version 5 (Amendment 4) (24-Apr-2019) 
• Clarify some statistical analysis details 
Major Changes 
 
Global changes 
 
• Editorial and format changes 
• Change the term of ‘patient’ to ‘subject’ as appropriate 
• Change the term of ‘BGJ398’ to infigratinib as appropriate 
• Change the term of FMI v1 and FMI v3 to FMI I and FMI III, respectively 
• Update the Protocol table/section numberings cited in this SAP to match with the 
corresponding tables/sections in the protocol 
 
• Remove all the analyses related to the Bayesian approaches. 
Changes to specific sections 
 
• Title page: update SAP version set to Final V1.0 and update the date 
• Study design, Study objectives and endpoints: updated to match with the protocol amendment 
4 (24-Apr-2019) 
 
• Data analysis general information: updated to match with the protocol on the scope and 
timing for the interim, primary and final analyses 
 
• Investigational drug and study treatment: updated to match with the protocol on the 
introduction of new formulation of FMI IV; indicate that the analysis by 
treatment/formulation is determined by formulation a subject first received if a subject 
switches formulation during the study as required per the Protocol 
 
• Analysis sets: clarify how analysis will be organized within Full Analysis Set (by treatment, 
by FGFR2 fusion/translocations status, etc); remove the Safety Set since it is overlapped with 


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the Full Analysis Set; clarify the definition of Per-Protocol Set; remove the section of Patient 
Classification; add Interim Analysis Set for Cohort 1 and Interim Analysis Set for Cohort 3; 
remove the section of Withdrawal of Informed Consent since it is not an analysis set; provide 
details on Subgroup of interest 
 
• Subject disposition: clarify the summaries which will be provided for subject disposition. 
• Demographic: The category of ‘18 - <65 years, 65 - <85 years and ≥ 85 years’ is replaced 
with ‘<65 years vs >= 65 years’ 
 
• Prior antineoplastic therapy: clarify the summaries which will be provided for prior 
antineoplastic therapy 
 
• Protocol deviations: clarify the categories of protocol deviations 
• Study Treatment: indicate that no study treatment permanent discontinuation will be 
discussed in this section; remove several sections which provide too detailed programming 
specification; clarify the definition of treatment duration and relative dose intensity; specify 
that no summary will be provided for planned dose intensity and actual dose intensity; simply 
the algorithm for the summary of dose reductions and interruptions 
 
• Prior, concomitant and post therapies: specify only on-treatment concomitant medication 
will be summarized; no general listing for concomitant will be provided. 
 
• Compliance: the category of ‘< 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1’ is 
replaced with ‘< =0.5, > 0.5 - <= 0.75, > 0.75 - <= 0.9, > 0.9 - <= 1.0 and >1.0’ 
 
• Analysis of the primary objective: specify that ORR per central review imaging will be the 
primary endpoint; clarify the timing for the interim and primary analysis for Cohort 1; delete 
all the analyses using Bayesian approaches; delete the subsection of Supportive analyses 
 
• Analysis of secondary objective(s): update to be consistent with the Protocol Amendment 4; 
add the description on best tumor burden change; provide details on the PFS censoring 
specification; provide the details on PFS sensitivity analysis; introduce the definition of PFS 
> 16 weeks for Cohort 2 and Cohort 3; 
 
• Safety objectives: specify ‘In general, summary will be provided only for the on-treatment 
safety assessments, which are the assessments occurring or taken during the on-treatment 
period’ 
 
• Adverse Events: emphasize that only TEAEs will be summarized; removed the summary 
tables related to TEAEs leading to study discontinuation; added some summary tables for 
TEAE; add the description of Adverse Events of Special Interest for this study 
 
• Laboratory data: minor update on Table 2-3 and 2-4 and indicate the laboratory tests in those 
two tables are just examples; clarify the details on how laboratory data will be analyzed 


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• Other safety data: Add sections on Ophthalmologic assessment and Left ventricular ejection 
fraction (LVEF); clarify the analyses of ECG and cardiac imaging data and vital signs and 
ECOG performance status; for tolerability, the category of ‘<0.5, ≥0.5 - <0.75, ≥0.75 - <0.9, 
≥0.9 - <1.1 and ≥1.1’ is replaced with ‘<=0.5, >0.5 - <=0.75, >0.75 - <=0.9, >0.9 - <=1.0 and 
>1.0’ 
 
• Pharmacokinetics: update to indicate FMI IV will be used; Clarify that the sections on the 
PK analysis is intended to provide general principle for the PK analysis. Additional details of 
the analysis approaches will be provided in a separate PK analysis plan 
 
• Exploratory analyses: indicate that the exploratory analyses will be conducted if there are 
sufficient data available 
 
• Interim Analysis: specify the interim analysis for Cohort 1 and the interim analysis for 
Cohort 3 
 
• Sample size calculation: update the rationale for Cohort 1 sample size based estimation 
precision (the Bayesian approach is removed); add the rationale for Cohort 2 and Cohort 3 
sample size 
 
• Imputation rules: Clarify the imputation rules for AE and CM start/end partial/complete 
missing date and the scope of the application of the imputation rules 


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SUMMARY OF CHANGES (V2.0, Amendment 1) 
This Summary of Change summarized the change of the Statistical Analysis Plan Version 2.0 for 
Study CBGJ398X2204 from Version 1.0 (29 May 2019). 
 
Rationale for Change 
 
The primary purpose of the changes is to: 
 
• Revise the SAP to be consistent with the Protocol Version 6 (Amendment 5) (15-Jan-2020) 
Global Changes 
• Change the term of ‘BGJ398’ to infigratinib as appropriate 
Description of Changes 
 
• Title page: update SAP version and date and the corresponding protocol version and date 
• Approval signature page: removed and a separate signature page will be used for approval 
• List of Abbreviations: Add CSR/RPED 
• 1 Introduction: update the corresponding protocol version and date 
• 1.1 Study design: update to match with the current protocol 
• Table 1-1: update to match the protocol 
• Figure 1-1: replace with the one in the current protocol and the main change is from ‘Cohort 
1: ~120 patients, 108 with FGFR2’ to ‘Cohort 1: ~120 patients, 106 with FGFR2’ 
 
• 2.1 Data Analysis General Information: replace ‘QED personnel’ with ‘QED Therapeutics’; 
indicate that one additional interim analysis will be added for Cohort 1; add details of the 
data review for Cohort 2 and Cohort 3 
 
• 2.1.1.1 Investigational Drug and Study Treatment: add ‘if subjects without FGFR2 
fusion/translocation are included in the analysis’ to clarify analysis details since only subjects 
with FGFR2 fusion/translocation will be included for the second formal interim analysis for 
Cohort 1. 
 
• 2.2 Analysis Sets: update analysis sets used for the analyses mainly due to the change of 
adding the second interim analysis for Cohort 1 
 
• 2.2.8 Subgroups of Interest: clarify the subgroups related to CYP3A4 inhibitors 


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• 2.3.3 Medical History: indicates a summary table of medical history will be provided instead 
of a listing. 
 
• 2.4 Protocol Deviation: add ‘Unless otherwise specified’ since FAS will not be used for the 
second interim analysis for Cohort 1 after amendment 3 
 
• 2.6 Analysis of Primary Objective: remove ‘using FAS, or Interim Efficacy Analysis Set for 
Cohort 1’ since different analysis sets will be used for different interim/primary/final 
analyses 
 
• Best Overall Response and Disease Control in 2.7.1: add ‘as specified by Cohort (Section 
2.1)’ 
 
• 2.7.2 Safety Objectives: clarify the analysis sets which will be used for safety summary and 
listings. 
 
• Deaths in 2.7.2.1.2: remove ‘for the full analysis set’ since the details on which analysis sets 
should be used for death listings have been clarified in the section of ‘Safety Objective’ 
 
• Adverse Events of Special Interest in 2.7.2.1.2: to match the program wide definition: update 
the adverse events of special interest; add the section for ‘Minimum Critical Toxicities’; add 
the section of ‘phosphate binders medication’ 
 
• 2.7.2.2.1 CTC Grading for Laboratory Parameters: add details to clarify how grade 0 will be 
assigned. 
 
• 2.7.2.2.1 Imputation Rules: clarify the algorithm of corrected calcium 
• 2.7.2.2.3. Data Analysis: add ‘as discussed in Minimum Critical Toxicities in Section 
2.7.2.1.2’ to provide analysis reference 
 
• Table 2-3 Example of Laboratory Parameters for Which CTCAE Grades are Defined: update 
the table to be consistent with the analysis approaches 
 
• Table 2-4 Examples of Laboratory Parameters (Without CTCAE Grades) for Which Lab 
Reference Ranges are Defined: update the table to be consistent with the analysis approaches 
 
• 2.7.3 Other Safety Data: add a paragraph to provide overall guidance on the analysis 
• 2.7.3.4 Vital Signs and ECOG Performance Status: clarify the summary of ECOG 
• 2.7.4 Pharmacokinetics: replace “pre-dose and 2-hr post-dose” with “trough and 2-hour or 4- 
hour”; change ‘Table 9 of CSP Amendment 4’ to ‘Table 10 of CSP Amendment 5’ 
 
• 2.7.4.3 Analysis Sets: Details added to match with the protocol 
• 2.7.4.4 Basic Tables, Figures and Listings: Details added to match with the protocol 


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• Table 2-6 Non-compartmental pharmacokinetic parameters: update the table to match the 
protocol amendment 5 
 
• 3.8.1.3.1 Analysis Sets: the section numbering is corrected to be 2.8.1.3.1; add ‘unless 
otherwise specified’ 
 
• 2.9 Interim Analysis: update the details of the interim analyses to match with the protocol 
amendment 5 
 
• 3.1 Cohort 1: Two subjects who were considered previously as FGFR2 fusion/translocation 
subjects do not actually have FGFR2 fusion/translocation. Therefore, the number ‘74’ is 
changed to ‘72’ and ‘108’ is changed to ‘106’ 
 
• 5 Appendix: Add the following contents 
• Table of Adverse Events of Special Interest, Search Strategies, and Rationales for Sponsor- 
Defined Search Strategies 
 
• AESI: Calcium-phosphate homeostasis – hypercalcaemia, hyperphosphataemia and 
hypophosphataemia 
 
• AESI: Eye Disorder of Central Serious Retinopathy/Retinal Pigment Epithelium Detachment 
• AESI: Pathological Fracture 
• AESI: Tissue Calcification 
• AESI: Vascular Calcification / Mineralization 
• AESI: Eye Disorder: SOC Eye Disorders (Excluding 9 PTs Used to Characterize 
CSR/RPED) 
 
• Minimum Critical Toxicities 
• CYP3A4 Inhibitors and Inducers 
• Phosphate Binders 
• 6 Reference: add one more reference 


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PI 
 
SUMMARY OF CHANGES (V3.0, Amendment 2) 
This Summary of Changes summarized the change of the Statistical Analysis Plan Version 3.0 
for Study CBGJ398X2204 from Version 2.0 (26 March 2020). 
 
Rationale for Change 
 
The primary purpose of the changes is to: 
 
• More precisely specify analysis methods for overall response rate (ORR), time to response 
(TTR), and duration of response (DOR). 
 
Description of Changes 
 
• Title page: updated SAP version, amendment number, and date; replaced 
with 
 
• Summary of Changes: Added version and amendment numbers for clarity, as appropriate. 
• Section 2.6.1: Added paragraph to specify analysis methods. 
• Section 2.6.2: Removed the last sentence (related to Section 2.6.1 change above). 
• Section 2.7.1: Added paragraph to specify analysis methods and deleted last sentence. 
• Throughout: Reformatted to be in the current QED template and style guide, including 
revising table and figure numbers, adding appropriate headings to appear in the Table of 
Contents (eg, List of Abbreviations, Summary of Changes), completing the List of 
Abbreviations, defining abbreviations on first use only, appropriately referring to sections, 
and other minor editorial/administrative changes. 
PI 


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LIST OF ABBREVIATIONS 
AE 
adverse event 
AESI 
adverse event of special interest 
ATC 
Anatomical Therapeutic Chemical 
AUC 
area under the curve 
bid 
bis in diem/twice a day 
BLQ 
below the limit of quantitation 
BOR 
best overall response 
cfDNA 
cell-free DNA 
CI 
confidence interval 
CR 
complete response 
CSR 
Clinical Study report 
CSR/RPED 
central serious retinopathy/retinal pigment epithelium detachment 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria for Adverse Events 
DOR 
duration of response 
FAS 
full analysis set 
eCRF 
electronic Case Report Form 
LVEF 
left ventricular ejection fraction 
MedDRA 
Medical Dictionary for Drug Regulatory Affairs 
NCI 
National Cancer Institute 
o.d. 
once daily 
ORR 
overall response rate 
OS 
overall survival 
PD 
pharmacodynamics 
PFS 
progression-free survival 
PK 
pharmacokinetics 
PPS 
per-protocol set 
PR 
partial response 
PT 
Preferred Term 
qd 
qua’que di’e / once a day 
RECIST 
Response Evaluation Criteria in Solid Tumors 
SAE 
serious adverse event 
SAP 
Statistical Analysis Plan 
SD 
standard deviation 
SOC 
System Organ Class 
SMQ 
Standardized MedDRA Queries 
TEAE 
treatment-emergent adverse event 
TFLs 
tables, figures, listings 
TTR 
time to response 
WHO 
World Health Organization 


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1 INTRODUCTION 
This Statistical Analysis Plan (SAP) provides detailed statistical methodology for the analysis of 
data from study CBGJ398X2204 that will be presented in the Clinical Study Report (CSR). The 
output shells (in-text and post-text) accompanying this document can be found in the Tables, 
Figures and Listings (TFL) shells document. The specifications for derived variable and datasets 
can be found in the ADaM Reviewer's Guide. This version of the SAP is based on the Clinical 
Study Protocol (CSP) CBGJ398X2204 Version 6 (Amendment 5) dated on 15-Jan-2020. 
 
All changes to the planned analysis described in this document required before or after database 
lock will be made through an amendment or addendum, respectively. Note that obvious 
corrections will be made at the time of analysis to address minor formatting or spelling mistakes 
present in the TFL shells document without the need to amend. 
 
The SAP, TFL shells, and ADaM Reviewer's Guide documents may also serve as a reference for 
the creation of any outputs required outside of the CSR, eg, IB updates, abstracts, posters, 
presentations, manuscripts, and management updates. Data used for these analyses will have a 
status aligned to the database lock guidance. 
 
The purpose of sections 1.1 to 1.2 is to make the SAP a standalone document and to be more 
specific on endpoints as required. No clinical background information needs to be included, as 
this is already provided in the CSP; only information relevant to the analyses is to be included. 
 
1.1 
Study Design 
 
This is a multi-center, open label, phase II study evaluating infigratinib anti-tumor activity in 
advanced or metastatic cholangiocarcinoma patients with FGFR genetic alterations. All patients 
will receive infigratinib once daily on a three week on (21 days), 1 week off (7 days) schedule in 
28-day cycles. Approximately 120 patients in total will be enrolled into Cohort 1 on the study. 
As of Amendment 2, only patients with advanced or metastatic cholangiocarcinoma with FGFR 
gene fusions/translocation will be enrolled into Cohort 1. As of Amendment 4, two new cohorts, 
Cohort 2 and Cohort 3, were added to this study. Cohort 2 is planned to enroll approximately 
20 patients with FGFR genetic alterations other than FGFR2 gene fusions or translocations and 
Cohort 3 is planned to enroll up to approximately 20 patients with FGFR2 gene fusions or 
translocations who have received a prior FGFR inhibitor other than infigratinib. According to 
Amendment 2, the final market image version 3 (FMI III) formulation of infigratinib replaced 
FMI I. According to amendment 4, the final market image version 4 (FMI IV) formulation of 
infigratinib will be used for patients in Cohort 2 and 3. Patients who started treatment prior to the 
implementation of amendment 2 should continue to receive the formulation of infigratinib that 
they received at the initiation of treatment until FMI IV is available at the study site. 
Pharmacokinetics, safety, and tolerability data from all available patients enrolled in either 
Cohort 2 or Cohort 3 treated with FMI IV up to the end of cycle 1 of treatment will be assessed 
and compared with the historical data from patients treated with FMI III. 


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In order to assess the antitumor activity of infigratinib, patients in all cohorts will be evaluated 
for tumor response radiographically every 8 weeks until disease progression or discontinuation 
from study using RECIST 1.1 criteria. 


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All Patients 
Diagnosis of advanced or metastatic cholangiocarcinoma (N=up to approx. 160 patients) 
FGFR2 gene fusions or translocations / other FGFR genetic alterations 
Progression after cisplatin-and gemcitabine-containing regimen for advanced disease or 
gemcitabine-containing regimen for those who are considered intolerant to cisplatin 
Molecular prescreening (local or central) for FGFR2 gene fusions or translocations/other 
FGFR genetic alterations 
Cohort 1: ~120 patients, 106 with FGFR2 gene fusions or translocations 
Cohort 2: ~20 patients with FGFR genetic alterations other than FGFR2 
gene fusions or translocations 
Cohort 3: Up to ~20 patients with FGFR2 gene fusions or translocations 
who have received a prior FGFR inhibitor 
Screen patients per eligibility criteria (within 21 days of first infigratinib dose)a 
Continue treatment until disease 
progression, unacceptable toxicity, 
withdrawal of consent or death 
CT/MRI every 8 weeks and response 
evaluation according to RECIST 1.1 
Follow-up: Patients permanently discontinuing infigratinib therapy will have visits following 
the End of treatment visit at: 
30-day safety follow-up period (30 days after the last dose of infigratinib) – All patients 
Disease progression follow-up: tumor assessment every 8 weeks – For patients who 
discontinue for any reason other than disease progression, until disease progression or 
the initiation of subsequent anticancer therapy or death, whichever occurs first 
Survival follow-up: every 4 months after discontinuation of study treatment. Survival follow- 
up period for the study will continue for 5 years or until all patients have discontinued study 
treatment or have died, withdrawn consent, or been lost to follow-up – All patients 
End of treatment visit within 14 days of the decision to discontinue treatment 
 
Figure 1: 
Study Design (Applied to Protocol Version 6 (Amendment 5)) 
 
 
 
 
 
 
 
 
 
 
a 
Screening assessments are to be completed within 21 days prior to the first dose of treatment, except 
for the radiological tumor assessment, which can be performed within 28 days prior to the first dose. 
infigratinib: 125 mg qd oral 
28-day cycle (3 weeks on, 1 week off) 


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1.2 
Study Objectives and Endpoints 
 
Objectives and related endpoints are described in Table 1 below. 
 
Table 1: 
Objectives and Related Endpoints for Cohort 1 and Overall Study 
 
Objective 
Endpoint 
 
Primary (Cohort 1) 
To evaluate the efficacy of single agent infigratinib in 
Overall response rate (ORR) assessed by central imaging 
patients with advanced or metastatic cholangiocarcinoma review as per RECIST v1.1 
with FGFR2 gene fusions/translocations or other FGFR 
genetic alterations 
Secondary 
Cohort 1: To further evaluate the efficacy of single agent 
infigratinib 
 
 
 
Cohort 1: To characterize the safety and tolerability of 
single agent infigratinib 
 
Overall study: 
To determine selected trough and 2-hr or 4-hr plasma 
concentrations of infigratinib and its metabolites 
To characterize the pharmacokinetic profile of 
infigratinib FMI III and FMI IV formulations 
 
Exploratory (Overall Study) 
To assess markers that may correlate with genetic 
alterations in tumor tissue at baseline, predictions of 
response and/or resistance (e.g. gene mutations, 
amplifications, deletion and/or altered protein expression 
or activation) 
Overall response rate assessed by investigator; 
progression free survival, best overall response, and 
disease control rate assessed by investigator and by 
central imaging review as per RECIST 1.1; and overall 
survival 
Safety: Type, frequency, and severity of AEs and SAEs; 
Tolerability: dose interruptions, reductions and dose 
intensity 
 
Selected trough and 2-hr or 4-hr plasma concentration 
profile and derived PK parameters of infigratinib and its 
metabolites 
For FMI III and FMI IV: Plasma concentration profile 
and derived PK parameters of FMI III and FMI IV 
 
DNA sequencing of paired biopsies (tumor tissue) from 
patients who progressed and analysis of cell free tumor 
DNA 
 
Serial serum CA19-9 levels 
 
 


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Table 2: 
Objectives and Related Endpoints for Cohort 2 and 3 
 
Exploratory Objectives 
Endpoint 
To characterize the safety and tolerability of infigratinib 
in patients with advanced or metastatic 
cholangiocarcinoma with… 
Cohort 2: …FGFR genetic alterations other than 
FGFR2 gene fusions or translocations 
Cohort 3: …FGFR2 gene fusions or translocations 
who have received prior FGFR inhibitors 
To evaluate the efficacy of single agent infigratinib in 
Safety: Type, frequency, and severity of AEs and SAEs; 
Tolerability: dose interruptions, reductions, and dose 
intensity 
 
 
 
 
Progression free survival, overall response, best overall 
patients with advanced or metastatic cholangiocarcinoma response, response onset, and disease control assessed by 
with… 
Cohort 2: …FGFR genetic alterations other than 
FGFR2 gene fusions or translocations 
Cohort 3: …FGFR2 gene fusions or translocations 
who have received prior FGFR inhibitors 
investigator as per RECIST v1.1, and overall survival 
 
 
 
2 STATISTICAL METHODS 
2.1 
Data Analysis General Information 
 
Study data will be analyzed by QED Therapeutics and/or designated CRO(s) using the most 
updated SAS® version in the statistical computing environment. PK parameters will be 
calculated using non-compartmental methods available in Phoenix WinNonlin version 7.0 or 
higher. 
 
Two formal interim analyses for Cohort 1 are planned after Amendment 3 as described in 
Section 2.9. The first formal interim analysis will include all patients in Cohort 1 who receive 
study treatment before the interim analysis cutoff date. The efficacy analysis for the first formal 
interim analysis for Cohort 1 will be focused on the population as described in Section 2.2.2 
below. The second formal interim analysis will be conducted on all the subjects with FGFR2 
fusions or translocations in Cohort 1. The primary analysis for Cohort 1 will be conducted when 
all patients in Cohort 1 have the potential to be followed for at least 10 months after their initial 
exposure to study treatment. For the interim and primary analyses for Cohort 1, patients will be 
grouped by fusion status (if subjects without FGFR2 fusions or translocations are included) and 
formulation. Here, the formulation refers to the first formulation a subject received if a subject 
switched formulation during the study as described in Section 1.1. 
 
For Cohorts 2 and 3, review of data will be performed after a total of 15 patients in either 
Cohort 2 or 3 have been treated with FMI IV for at least one cycle. Primary analysis will be 
conducted when all patients in the cohorts have the potential to be followed for at least 
10 months after their initial exposure to study treatment. Additionally, for Cohort 3, one interim 
analysis will be conducted after the first 10 dosed patients in this cohort have the potential to 
complete their second scheduled scans (approximately 16 weeks from their first dose) to 
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The additional data for patients continuing to receive study treatment or remain in study past the 
data cutoff date of the primary analysis, as allowed by the protocol, will be reported in a final 
CSR that will be prepared at the end of the study. In the final CSR, analyses will be done for 
each cohort, for patients enrolled in Cohort 1 who do not have FGFR2 fusions or translocations, 
data may be combined and summarized with Cohort 2. 
 
Data from participating centers in this study protocol will be combined, so that an adequate 
number of patients will be available for analysis. No center effect will be assessed. The data will 
be summarized with respect to demographic and baseline characteristics, efficacy observations 
and measurements, safety observations and measurements, and all relevant pharmacokinetic 
(PK) and pharmacodynamics (PD) measurements using descriptive statistics (n, mean, standard 
deviation, median, minimum, and maximum) for quantitative data and contingency tables 
(frequencies and percentages) for qualitative data. 
 
Additional data for which there is a separate informed consent, eg, PK, biomarker etc., collected 
in the clinical database without having obtained that consent will not be included in the analysis. 
 
Qualitative data (eg, gender, race, etc.) will be summarized by means of contingency tables; a 
missing category will be included as applicable. Percentages will be calculated using the number 
of patients in the relevant population or subgroup as the denominator. 
 
Quantitative data (eg, age, body weight, etc.) will be summarized by appropriate descriptive 
statistics (ie, mean, standard deviation, median, Q1, Q3, minimum, and maximum). 
 
2.1.1 
General Definitions 
 
2.1.1.1 
Investigational Drug and Study Treatment 
 
Investigational drug will refer to infigratinib as an oral formulation. The terms investigational 
drug and study drug/treatment are used interchangeably. For consistency across studies, the term 
study treatment will be used throughout this document. 
 
Table 3: 
Dose and Treatment Schedule 
 
Study 
treatment 
Formulation 
Pharmaceutical form and 
route of administration 
Dose 
Frequency and/or 
Regimen 
infigratinib 
FMI I 
Capsule(s) for oral use 
125 mg (administered 
Daily (3 weeks on, 1 
FMI III 
FMI IV 
as one 100 mg capsule 
and one 25 mg 
capsule) 
week off schedule in 
28-day cycles) 
 
 
 
A treatment is defined by the dose formulation (FMI I, FMI III and FMI IV). The treatment 
formulation is determined by the formulation a subject first received if a subject switches 
formulation during the study as described in Section 1.1. 
 
Unless otherwise specified, all efficacy related analyses will be done separately for all patients, 
patients with baseline FGFR2 gene fusion/translocation, and patients with other FGFR genomic 


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alterations if subjects without FGFR2 fusion/translocation are included in the analysis. In 
addition, within patients who had baseline FGFR2 gene fusion/translocation, the data will be 
summarized by treatment. Unless otherwise specified, for all other analyses, including safety, 
disposition, demographic/baseline disease characteristics, study drug exposure and 
prior/concomitant/post therapy related analyses, will be done separately for all subjects, all 
subjects by FGFR status (FGFR2 gene fusion/translocation vs. other FGFR genomic alterations) 
if subjects without FGFR2 fusion/translocation are included in the analysis, and all subjects by 
treatment. 
 
Note that reporting by treatment is equivalent to reporting by formulation, and “by treatment” 
will be used throughout this document. 
 
2.1.1.2 
Date of First/Last Administration of Study Treatment 
 
In the single agent arm, the date of first (last) administration of study treatment is derived as the 
first (last) date when a non-zero dose of infigratinib was administered and recorded on the 
Dosage Administration Record (DAR) eCRF. If a subject has not ended treatment at data cut-off 
date for an analysis, the subject is considered ongoing at the last dosing record. 
 
2.1.1.3 
Study Day 
 
The study day for safety assessments (eg, adverse event onset, laboratory abnormality 
occurrence, vital sign measurement, dose interruption, etc.) that are after the start of study 
treatment will be calculated as the difference between the date of the event (onset date of an 
event, assessment date etc.) and the start of study treatment plus 1. The first day of study 
treatment is therefore study Day 1. Example: if start of study treatment is on 05-Jan-2014 and 
start date of an adverse event is on 09-Jan-2014 then the study day of the adverse event onset is 
5. For safety assessments before start of study treatment, the study day is negative and derived by 
(date of event – start date of study treatment). For example: if start of study treatment is on 05- 
Jan-2014 and date of lab measurement is on 02-Jan-2014 then the study day of the laboratory 
abnormality is -3. Note, the day of start of study treatment is Day 1, and the day before the date 
of first study treatment is Day –1, not Day 0. 
 
2.1.1.4 
Baseline 
 
Baseline is the result of an investigation describing the “true” state of the subject before start of 
study treatment administration. 
 
For safety evaluations, the last available assessment on or before the date of start of study 
treatment is taken as “baseline” assessment. In case time of assessment and time of treatment 
start is captured (eg, pre-dose ECG), the last available assessment before the treatment start 
date/time is used for baseline. 
 
For safety parameters (eg, ECGs or vital signs), where study requires multiple replicates per time 
point, the average of these measurements would be calculated for baseline (if not already 
available in the database). 


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In rare cases where multiple measurements meet the baseline definition, with no further flag or 
label that can identify the chronological order, then the following rule should be applied: If 
values are from central and local laboratories, the value from central assessment should be 
considered as baseline; if multiple values are from the same laboratory (local or central) or 
collected for ECGs or vital signs, then the average value should be considered as baseline while 
for the grade of laboratory tests the worst grade will be considered as baseline. For this study, 
safety laboratory testing is per local site laboratory. 
 
If subjects have no value as defined above, the baseline result will be missing. 
 
2.1.1.5 
On-treatment Assessment/Event and Observation Periods 
 
The overall observation period will be divided into three mutually exclusive segments: 
 
pre-treatment period: from day of subject’s first informed consent to the day before first 
administration of study treatment 
 
on-treatment period: from date of first administration of study treatment to 30 days after date of 
last actual administration of any study treatment (including start and stop date). 
 
post-treatment period: starting at Day 31 after last administration of study treatment in the single 
arm. 
 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 
 
Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (eg, change from 
baseline summaries). In addition, a separate summary for death including on-treatment and post 
treatment deaths will be provided. Summary tables for adverse events (AEs) will summarize only 
on-treatment events, with a start date during the on-treatment period (treatment-emergent AEs). 
 
2.1.1.6 
Handling of Missing Values/Censoring 
 
Subjects who are of unknown clinical response or not assessed will be treated as nonresponders 
in the analyses of overall response rate (ORR). 
 
Subjects who haven’t experienced the specified event at the time of analysis will have time-to- 
event data (eg, progression-free survival, overall survival, etc.) censored at the time of last 
measurement prior to the data cut-off point used in the report. 
 
2.2 
Analysis Sets 
 
2.2.1 
Full Analysis Set 
 
The Full Analysis Set (FAS) includes all subjects who received at least one dose of infigratinib. 
Unless otherwise specified, all the analyses will be done separately for each cohort. 


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Unless otherwise specified, all the analyses will be conducted on FAS. All efficacy related 
analyses will be done separately for all subjects, subjects with baseline FGFR2 gene fusions or 
translocations and subjects with only other FGFR genomic alterations. In addition, for subjects 
with baseline FGFR2 gene fusions or translocations, the data will be summarized by treatment 
(formulation FMI I vs FMI III vs FMI IV). The analyses, including safety, disposition, 
demographic/baseline disease characteristics, study drug exposure and prior/concomitant/post 
therapy related analyses, will be done separately for all subjects, all subjects by FGFR status 
(FGFR2 gene fusion/translocation vs. only other FGFR genomic alterations) and all subjects by 
treatment. 
 
Unless otherwise specified, the FAS will be used for all listings of raw data. 
 
2.2.2 
Interim Efficacy Analysis Set 1 for Cohort 1 
 
The Interim Efficacy Analysis Set 1 for Cohort 1 includes all subjects with planned extensive PK 
sample collection in Cohort 1 (regardless of whether extensive PK samples were actually 
collected) and all patients enrolled prior to Amendment 2. Unless otherwise specified, the 
Interim Efficacy Analysis Set 1 will be used as the primary efficacy analysis set for the first 
formal interim analysis for Cohort 1 after Amendment 3. Patients will be classified according to 
their baseline genetic status (FGFR2 gene fusions or translocations vs only other FGFR genetic 
alterations). 
 
2.2.3 
Interim Analysis Set 2 for Cohort 1 
 
The Interim Analysis Set 2 for Cohort 1 includes patients in Cohort 1 with FGFR2 gene fusions 
or translocations who have received at least one dose of infigratinib. Interim Analysis Set 2 for 
Cohort 1 will be used as the primary analysis set for the second formal interim analysis for 
Cohort 1 after Amendment 3. 
 
2.2.4 
Sensitivity Analysis Set for Cohort 1 
 
The Sensitivity Analysis Set for Cohort 1 includes patients with FGFR2 gene fusions or 
translocations who received infigratinib at the time of the first formal interim analysis and 
patients who have disease progression according to central imaging review or ended treatment by 
the cutoff date for the second formal interim analysis for Cohort 1 after Amendment 3. The 
cutoff date for the second formal interim analysis is planned so that all the patients with FGFR2 
gene fusions or translocations who received infigratinib at the time of the first formal interim 
analysis have 10 months follow-up after their initial exposure to infigratinib. The Sensitivity 
Analysis Set for Cohort 1 will be used for supportive sensitivity analyses for the second formal 
interim analysis for Cohort 1. Some analyses, including summary of demographic, baseline 
characteristics and disposition, and some key efficacy and safety analyses, will be repeated on 
the Sensitivity Analysis Set. 
 
2.2.5 
Interim Analysis Set for Cohort 3 
The Interim Analysis Set for Cohort 3 will include the first 10 dosed subjects who have the 
potential to complete second scheduled post baseline scan. 


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2.2.6 
Per-Protocol Set 
 
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS who are compliant 
with requirements of the CSP in the following ways: 
• Patient had an adequate tumor assessment at baseline 
• Patient is evaluable for efficacy 
• Patient had no CSR-reportable protocol deviations that may affect efficacy evaluation. 
Subjects will be evaluable for efficacy if they have at least one post-baseline response assessed 
differently from ‘unknown’ or ‘not assessed’ as per RECIST v1.1. All CSR-reportable protocol 
deviations leading to exclusion from the PPS will be provided in a listing. 
 
If more than 10% of FAS subjects were excluded from PPS, key efficacy analysis may be 
repeated on PPS. 
 
2.2.7 
Pharmacokinetic analysis set 
 
The Pharmacokinetic analysis set (PAS) includes all patients who (a) receive the planned 
treatment, (b) provide at least one evaluable PK concentration, and (c) do not vomit within 
4 hours after the dosing of infigratinib. 
 
Subjects will be removed from the estimation of certain PK parameters on an individual basis 
depending on the number of available blood samples and whether the PK parameters can be 
reliably estimated based on the available blood samples. These patients will be identified at the 
time of the analyses. 
 
2.2.8 
Subgroups of interest 
 
The summaries of the efficacy variables may be repeated for the following subgroups: 
• Lines of prior therapy (<=1 vs >1) 
• Gender (male vs female) 
• Age >=65 vs <65 
• Region (North America vs Western Europe vs Asia) 
Summaries for TEAEs will be repeated for the following subgroups: 
• Gender (male vs female) 
• Age group (>=65 vs <65) 
• Region group (North America vs Western Europe vs Asia) 
• BMI (<18.5 vs. >=18.5) 
• Subjects who received strong CYP3A4 inhibitors vs moderate CYP3A4 inhibitors vs none 
(Section 5.10) 


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• Subjects who received strong CYP3A4 inducers vs moderate CYP3A4 inducers vs none 
(Section 5.10) 
 
The list of strong CYP3A4 inhibitors and inducers is documented in Section 5.10. 
 
2.3 
Subject Disposition, Demographics and Other Baseline Characteristics 
 
Unless noted otherwise, summaries and listings described in this section will be based on the 
FAS. 
 
2.3.1 
Subject disposition 
 
The following will be tabulated: 
• Number (%) of patients treated; 
• Number (%) of patients who are still on-treatment at the time of cut-off; 
• Number (%) of patients who discontinued treatment and primary reasons for discontinuation. 
A listing of disposition will be produced. 
2.3.2 
Demographics 
 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data, eg, gender, age groups:<65 years vs ≥65 years, race, ECOG performance 
status, will be summarized by frequency counts and percentages; the number and percentage of 
patients with missing data will be provided. Continuous data, eg, age, weight, height will be 
summarized by descriptive statistics (N, mean, median, standard deviation, Q1, Q3, minimum 
and maximum). 
 
2.3.3 
Medical History 
 
Summary of medical history will be provided by SOC and PT, using the Medical Dictionary for 
Regulatory Activities (MedDRA) (version 21.0 or later) terminology available at the time of 
reporting. 
 
2.3.4 
Prior Antineoplastic Therapy 
 
The number (%) of patients who received any prior anti-neoplastic medication, radiotherapy or 
surgery will be summarized. The summary will include only the prior antineoplastic therapy after 
or on the date of the initial diagnosis of cholangiocarcinoma. 
 
The summary of prior anti-neoplastic medications will include the total number of regimens 
(note: there can be more than one medication per regimen) and the total number of lines 
(excluding adjuvant or neoadjuvant regimens), setting at last treatment, best response at last 
treatment (defined to be the best response during the last treatment regimens recorded), best 
response during treatment with gemcitabine and cisplatin. For this analysis, gemcitabine and 
gemcitabine hydrochloride will be grouped to define prior treatment with gemcitabine. Prior 


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antineoplastic medications will also be summarized by Anatomical Therapeutic Chemical (ATC) 
class, and preferred term. The summary of the efficacy endpoints, including response 
assessment, duration of response and time to progression, on the 1st line of gemcitabine base 
therapy will also be provided. 
 
The summary of prior anti-neoplastic radiotherapy will include the total number of subjects who 
received prior anti-neoplastic radiotherapy, the radiotherapy locations, (including all locations 
recorded for each patient), setting at last radiotherapy. 
 
The summary of prior anti-neoplastic surgery will include the time (in months) between the last 
surgery (non-biopsy procedure) to start of study treatment, procedure at last surgery and residual 
disease at last surgery. 
 
2.3.5 
Diagnosis and Extent of Cancer 
 
The summary and listing of diagnosis and extent of cancer (disease history) will include primary 
site of cancer, details of tumor histology/cytology, histologic grade, stage at initial diagnosis, 
time (in months) since initial diagnosis of primary site to treatment start, time (in months) from 
initial diagnosis to first recurrence/relapse, time (in months) since most recent recurrence/relapse 
to treatment start, current extent of disease (metastatic sites). 
 
2.4 
Protocol Deviations 
 
Unless otherwise specified, the FAS will be used for the protocol deviation summary tables and 
listing. The number (%) of patients with any CSR-reportable protocol deviation will be tabulated 
by the deviation category as listed below: 
 
• Subject enrolled and did not satisfy the entry criteria 
• Subject developed study/treatment withdrawal criteria during the study, but was not 
withdrawn 
• Subject received the wrong treatment or incorrect dose 
• Subject took a prohibited concomitant medication 
• Major procedural or other GCP deviation that potentially affects patient safety or efficacy 
data interpretation 
 
2.5 
Treatments (Study Treatment, Concomitant Therapies, Compliance) 
 
2.5.1 
Study Treatment 
 
Unless otherwise specified, the full analysis set will be used for all summaries and listings of 
study treatment. 


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2.5.1.1 
Data Analysis 
 
Duration of exposure, actual cumulative dose, relative dose intensity (RDI) will be summarized 
in the full analysis set. Duration of exposure will be categorized into time intervals; frequency 
counts and percentages will be presented for the number (%) of subjects in each interval. The 
number (%) of subjects who have dose reductions or interruptions, and the reasons, will be 
summarized by treatment. 
 
Subject level listings of all doses administered on treatment along with dose change reasons will 
be produced. 
 
2.5.1.2 
Duration of Exposure to Study Treatment 
 
Duration of exposure (day) = (end date of infigratinib) – (start date of infigratinib) + 1, 
 
End date of infigratinib refers to the end date of last non-zero dose record with the exception for 
subjects who are still on treatment. For subjects who are still on treatment, the end date of 
infigratinib refers to the end date of last dose record. 
 
Then, 
Duration of exposure (month) = Duration of exposure (day) / 30.4375. 
 
The duration of exposure to study treatment will be determined by the number of months 
exposed to infigratinib. Duration of exposure will be summarized using descriptive statistics. 
 
Summary of duration of exposure of study drug will include categorical summaries (based on 
clinically meaningful time intervals) and continuous summaries (ie, mean, standard deviation 
etc.) using appropriate units of time. 
 
2.5.1.3 
Cumulative Dose 
 
Cumulative dose of study treatment is defined as the total dose given during the study treatment 
exposure and will be summarized. 
 
The planned cumulative dose for study treatment refers to the total planned dose as per the 
protocol up to the last date of investigational drug administration. The actual cumulative dose 
refers to the total actual dose administered, over the duration for which the subject is on the study 
treatment as documented in the Dose Administration eCRF. 
 
2.5.1.4 
Relative Dose Intensity 
 
Relative dose intensity (RDI) is defined as the ratio of actual cumulative dose to the planned 
cumulative dose. For example, a subject take study drug from day 1 to day 21 at 125 mg/day; 
then from day 29 to day 30 at 100mg/day, and end treatment afterward. The cumulative actual 
dose =21*125+100*2=2825 mg; the planned cumulative dose =21*125+125*2=2875 mg. The 
relative dose intensity = 2825/2875=98.3%. 


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RDI will be summarized. Summary of RDI will include categorical summaries based on the 
following categories: ≤0.5, >0.5 - ≤0.75, >0.75 - ≤0.9, >0.9 - ≤1.0 and >1.0. 
 
2.5.1.5 
Dose Reductions, Interruptions 
 
The number of subjects who have dose reductions, or interruptions, and the reasons, will be 
summarized separately for the study treatment. 
 
Dose reductions will be summarized by the lowest non-zero dose level. Note that planned 1 week 
off in dosing schedule will not be collected or counted as dose interruption. 
 
The corresponding fields ‘Reason for dose change/dose interrupted’ and ‘Reason for permanent 
discontinuation’ will be used to summarize the reasons. 
 
2.5.2 
Prior, Concomitant and Post Therapies 
 
Concomitant therapies are defined as any medications (excluding study treatment, prior 
antineoplastic treatments) and significant non-drug therapies (including physical therapy and 
blood transfusions) administered in the study and are recorded in the Prior and Concomitant 
Medications eCRF. These therapies will be coded using the WHO Drug Reference Listing 
(WHO DRL) dictionary that employs the WHO Anatomical Therapeutic Chemical (WHO ATC) 
classification system. Only on-treatment (treatment-emergent) concomitant medication (CM) 
will be summarized. On-treatment (treatment-emergent) concomitant medication refers to the 
concomitant medication taken on or after the first administration day of study drug and up to last 
study administration day of study drug +30 days. Some groups of concomitant medication may 
also be summary separately, for example, phosphate-binders. 
 
The imputation of a concomitant medication start date and end date will follow the same 
conventions as for an AE start date if needed for analyses. 
 
The post antineoplastic medication will be listed. 
 
Prior, concomitant and post therapies may be listed as needed. 
 
2.5.3 
Compliance 
 
Compliance to the study treatment will be summarized in terms of the RDI or percentage of 
patients who took a predefined percentage of the number of prescribed. The predefined RDI 
categories are ≤0.5, >0.5 - ≤0.75, >0.75 - ≤0.9, >0.9 - ≤1.0 and >1.0. The number and proportion 
of patients falling in each category will be presented. Details are provided in Section 2.5.1. 
 
2.6 
Analysis of the primary objective 
 
2.6.1 
Variable 
 
For Cohort 1, the primary objective of the study is to assess anti-tumor activity of infigratinib 
using overall response rate assessed by central imaging review. 


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Best overall response (BOR) is the best overall response a subject ever achieves during the study 
prior to any subsequent anti-cancer therapy. Overall response rate (ORR) is defined as the 
proportion of patients with a best overall response of confirmed Complete Response (CR) or 
Partial Response (PR), as per RECIST version 1.1, among the corresponding analysis set. 
 
ORR (central imaging assessment) is the primary efficacy endpoint, and its analysis consists of a 
Clopper-Pearson 95% CI accompanied by a characterization of time to response (TTR) and 
duration of response (DOR) to allow for a more complete characterization of the beneficial effect 
Infigratinib may have in the principal analysis population. The Brookmeyer-Crowley method 
will be used to construct the 95% CI for each of TTR and DOR. 
 
2.6.2 
Statistical Hypothesis, Model, and Method of Analysis 
 
For Cohort 1, the primary analysis of the primary endpoint (ORR assessed by central imaging 
review) should occur when all subjects in Cohort 1 have the potential to be followed for at least 
10 months after their initial exposure to study treatment. The formal interim analysis for 
Cohort 1 will be conducted when all patients in the interim efficacy analysis set have been 
followed for at least 10 months after their initial exposure to the study treatment. Any confirmed 
PR or CR until the data cut-off date and any subsequent anti-cancer therapy will be considered as 
a responder for ORR, irrespective of when it occurred. 
 
2.7 
Analysis of Secondary Objective(s) 
 
This section describes analyses of secondary objectives for Cohort 1. The same endpoints will be 
analyzed for Cohorts 2 and 3 as exploratory, so the approaches described in this section also 
apply to Cohort 2 and 3. 
 
2.7.1 
Secondary Efficacy Objectives 
 
Overall Response Rate Per Investigator 
 
ORR per investigator is among the secondary endpoints. The estimated ORR will be presented 
with the corresponding 95% confidence interval based on exact binomial distribution using the 
corresponding analysis set. 
 
Overall Survival 
 
Overall Survival (OS) is defined as the time from the date of start of treatment to the date of 
death due to any cause. The survival time for subjects without documentation of death prior to 
the data cutoff will be censored at the last date the subject was known to be alive prior to the 
cutoff date. Survival time for subjects with no post-baseline survival information will be 
censored at the date of start of treatment. 
 
OS will be analyzed using the Kaplan-Meier method. Survival rate at 4, 6, 8, 12, 18, 24 months 
(and every 6 months thereafter as reported in database) with median OS will be estimated along 
with 95% confidence intervals. 


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Progression Free Survival 
 
Progression free survival (PFS) is defined as the date of the start of treatment to the date of the 
event defined as the first documented progression or death due to any cause, whichever is earlier. 
If subject has not had an event, progression-free-survival is censored at date of last valid tumor 
assessment or start of study treatment if there is no valid tumor assessment available. For 
subjects who had an event after two or more missed visits, the subject will be censored at the last 
adequate tumor assessment. The PFS analyses will be done based on central and local 
assessments separately. Kaplan-Meier analysis of PFS will be provided. 
 
The primary PFS will be derived based on all the tumor assessments and death including any 
after a subsequent anti-cancer therapy. A sensitivity analysis will also be conducted on PFS 
excluding the tumor assessments and death after any subsequent anti-cancer therapies. If the 
event (the first progressive disease or death) is after a subsequent anti-cancer therapy, the PFS 
for the sensitivity analysis will be censored at the last valid tumor assessment prior to all 
subsequent anti-tumor therapies or first dose date if there is no valid tumor assessment prior to 
all subsequent anti-tumor therapies. 
 
For Cohorts 2 and 3, the percentage of subjects who are progression-free at the second scheduled 
scan (approximately 16 weeks from treatment initiation) or later will be analyzed using 95% 
exact binomial confidence interval. Patients who do not have scans to show that they are 
progression-free at the second scheduled scan or later will be considered as not benefiting from 
the study treatment. Sensitivity analysis will be done by estimating PFS >16 weeks using K-M 
estimate. 
 
Best Overall Response and Disease Control Rate 
 
Overall lesion assessments will be listed by subject. BOR will be summarized for the rate of best 
overall response of progressive disease, stable disease, confirmed partial response (PR), and 
confirmed complete response (CR) separately; it will also summarized for the Disease Control 
Rate which are the proportion of subjects having respectively a best overall response of 
confirmed PR or CR, or stable disease. The estimates will be presented along with the 
corresponding 95% exact confidence interval. Best overall response will be provided for 
investigator assessment and central assessment as specified by cohort (Section 1.2). In addition, 
the concordance of best overall response based on central assessment and local assessment will 
be assessed. 
 
Best tumor burden change (maximum tumor burden reduction from baseline or minimum tumor 
burden increase from baseline if tumor burden has never reduced prior to any anti-cancer 
therapy) will be presented graphically. 
 
Response Onset and Duration of Response 
 
Response onset will be estimated using Kaplan-Meier product limit method to analyze TTR 
based on ORR central imaging assessment. The Brookmeyer-Crowley method will be used to 
construct the 95% CI for TTR. DOR will be further summarized by length of exposure to 


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infigratinib using the following exposure cut-off lengths: at least 6 months, at least 9 months, at 
least 12 months. 
 
Response onset and duration of response (DOR) will be summarized for confirmed responders 
only, based on local and central assessments separately. Response onset is defined as the time 
from the first study drug administration date to the initial response date. DOR is defined as the 
time from the initial response to the date of the event defined as the first documented progression 
or death due to any cause, whichever is earlier. The same event/censoring rule applied to PFS 
will be applied to DOR. 
 
2.7.2 
Safety Objectives 
 
The FAS will be used for summaries and listings of safety data except for the second formal 
interim analysis for Cohort 1 after amendment 3 where the Interim Analysis Set 2 for Cohort 1 
will be used. In general, summaries will be provided only for the on-treatment safety 
assessments, which are the assessments occurring or taken during the on-treatment period. 
 
2.7.2.1 
Adverse Events (AEs) 
 
2.7.2.1.1 
Data Handling 
 
Adverse events will be coded using the Medical Dictionary for Regulatory Activities (MedDRA) 
version 21.0 and assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03, respectively. 
 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by defining a 5-point scale generally corresponding to 
mild, moderate, severe, life threatening, and death. This grading system inherently places a value 
on the importance of an event, although there is not necessarily proportionality among grades (a 
Grade 2 is not necessarily twice as bad as a Grade 1). 
 
If CTCAE grading does not exist for an AE, Grades 1, 2, 3, or 4 corresponding to the severity of 
mild, moderate, severe, and life-threatening, respectively, will be used. CTCAE Grade 5 (death) 
will not be used in this study. Death information will be collected on the “Death” eCRF pages. 
 
2.7.2.1.2 
Data Analysis 
 
AE Summaries 
 
AE summaries will include all AEs occurring during on-treatment period, i.e. treatment emergent 
AEs. Treatment emergent AEs (TEAEs) include all AEs that started on or after the first 
administration day of study treatment and up to last study administration day of study treatment 
+30 days. All AEs collected in the AE (e)CRF page will be listed along with the information 
collected on those AEs, eg, AE relationship to study drug, AE outcome, etc. Treatment-emergent 
AEs will be flagged in the listings. 


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TEAEs will be summarized by number and percentage of subjects having at least one TEAE, 
having at least one TEAE in each primary system organ class (SOC) and for each preferred term 
(PT) using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
 
In TEAE summaries the primary system organ class will be presented alphabetically, and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency in FAS. The following TEAE summaries will 
be produced by treatment and by FGFR2 fusion/translocation status: 
• Overview of TEAEs and deaths (number and % of subjects who died from fatal TEAE, 
number and % of subjects with any TEAE, any treatment emergent serious AE, any TEAE 
leading to dose reductions/interruptions, TEAE leading to discontinuation of study treatment) 
• All TEAEs by SOC and PT and worst grade 
• Treatment related TEAEs by SOC and PT and worst grade 
• Grade 3 or 4 TEAEs by SOC and PT and worst grade 
• Treatment emergent serious AEs (SAEs) by SOC and PT and worst grade 
• Treatment emergent serious treatment-related AEs by SOC and PT and worst grade 
• TEAE with fatal outcome by SOC and PT and worst grade 
• TEAE leading to study treatment discontinuation by SOC, PT and grade 
• TEAE leading to dose interruption/adjustment by SOC, PT and grade 
• TEAE leading to treatment discontinuation by SOC and PT and worst grade 
• TEAE requiring additional medication or therapies by SOC and PT and worst grade 
• All TEAEs by PT by descending order of frequency 
• Treatment related TEAEs by PT by descending order of frequency 
• All TEAEs occurred in ≥10% subjects by PT by descending order of frequency 
• Grade 3 or 4 TEAEs by PT by descending order of frequency 
• Treatment related Grade 3 or 4 TEAEs by PT by descending order of frequency 
• Treatment emergent serious AEs (SAEs) by PT by descending order of frequency 
• Treatment emergent serious treatment-related AEs by PT by descending order of frequency 
• TEAE leading to treatment discontinuation by PT by descending order of frequency 
• TEAE requiring additional medication or therapies by descending order of frequency 


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The following listings will be produced: 
• All adverse events 
• All serious adverse events 
Deaths 
 
Primary reason for on-treatment, post-treatment and all deaths will be summarized for the full 
analysis set. Treatment-emergent AE with fatal outcome will be summarized by SOC and PT. 
On-treatment death will also be summarized by SOC and PT. 
 
All deaths will be listed and on-treatment death will be flagged. 
 
Adverse Events of Special Interest 
 
Adverse events of special interest (AESI) will be considered. Each AESI consists of one or more 
well-defined safety events which are similar in nature and for which there is a specific clinical 
interest in connection with the study treatment(s) (Section 5.2 to Section 5.8). For each specified 
AESI, number and percentage of patients with at least one event within the AESI will be 
reported. The following AESI will be considered for this study: 
 
• Calcium phosphate homeostasis, including the subcategories of hypercalcemia, 
hyperphosphatemia, and hypophosphatemia 
• Eye disorder 
• Central Serious Retinopathy/Retinal Pigment Epithelium Detachment (CSR/RPED) 
• Cardiac disorder 
• Acute pancreatitis 
• Tissue calcification 
• Pathological fracture 
• Vascular calcification/mineralization 
For each AESI (or its subcategory), the overall summary of the characteristics will be provided. 
In addition, each AESI will also be summarized by subcategory (as applicable), preferred term 
and worst grade. The current search strategy for each AESI is documented in Section 5.2. 
 
Minimum Critical Toxicities 
 
Minimal critical toxicities are toxicities that should always be explicitly considered during the 
planning for the development of every new medicinal product (Section 5.9). Analyses of these 
are based on FDA guidance as applicable (ie, Drug Induced Liver Injury using Hy's Law per 
FDA guidance). 


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Minimal critical toxicities to be analyzed under this statistical analysis plan include the following 
categories: 
• Cardiac toxicity including QT prolongation and other ECG abnormalities 
• Hepatotoxicity 
• Nephrotoxicity 
• Hematologic toxicity 
Subject incidence of TEAEs indicative of potential cases of the toxicities will be summarized for 
each of the categories. 
 
For hepatotoxicity, in addition, abnormalities in liver function tests will be summarized. Subject 
incidence of the following will be provided: 
• 3×-, 5×-, 10×-, and 20× upper limit of normal (ULN) elevations of aspartate aminotransferase 
(AST) and/or alanine aminotransferase (ALT). 
• Any elevations of bilirubin; elevated total bilirubin to ≥2×ULN. 
• Any elevations of alkaline phosphatase (ALP) >1.5×ULN. 
• Elevation of “ALT or AST” (>3×ULN) accompanied by elevated total bilirubin (>1.5×ULN, 
>2×ULN) and ALP <2×ULN. 
 
In addition, a listing of potential Hy’s Law cases identified will be provided. Potential 
hepatotoxicity is identified by the Hy’s Law (FDA Guidance for Industry Drug Induced Liver 
Injury: Pre-marketing Clinical Evaluation, July 2009) as: ALT or AST >3.0×ULN; total bilirubin 
≥2.0×ULN, ALP <2.0×ULN; and no other confounding factors including preexisting or acute 
liver disease. 
 
For cardiac toxicity, ECG findings will also be summarized as specified in Section 2.7.3.3. 
 
Phosphate Binder Medication 
 
Number of subjects who have taken phosphate binder medication (Section 5.11) and the types of 
medication will be summarized by the formulation. Of these patients who have taken phosphate 
binder, number (percentage) of subjects who had a Grade 3/4 hypophosphatemia AE (including 
preferred terms hypophosphatemia and blood phosphorus decrease) will be summarized. 
 
2.7.2.2 
Laboratory Data 
 
2.7.2.2.1 
CTC Grading for Laboratory Parameters 
 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of laboratory 
CTC grades will be based on the observed laboratory values only; clinical assessments will not 
be taken into account. 


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For laboratory tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher for 
CTCAE parameters that are unidirectional. For CTCAE parameters that are bidirectional non- 
gradable values which are beyond the normal range will be left missing while Grade 0 will be 
assigned to the value within the normal range. Grade 5 is not applicable. 
 
2.7.2.2.2 
Imputation Rules 
 
CTC grading for blood differentials is based on absolute values. 
 
If laboratory values are provided as ‘<X’ (ie, below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X. 
 
The following rules will be applied to derive the WBC differential counts when only percentages 
are available for a xxx differential 
 
xxx count = (WBC count) * (xxx %value / 100) 
 
Corrected calcium can be derived using the reported total calcium value and albumin at the same 
assessment. The adjustment is done on calcium where albumin is less than 40 g/L and doesn’t 
adjust when albumin ≥40 g/L because it can lead to underestimation. The formula for adjustment 
based on SI unit is: 
 
When Albumin ≥40 g/L, then Corrected Calcium (mmol/L) = Calcium (mmol/l); 
 
When non-missing Albumin <40 g/L, Corrected Calcium (mmol/L) = Calcium (mmol/L) + 0.02 
× (40-Albumin(g/L)) 
 
In the formula above, SI unit mmol/L and g/L for Calcium and Albumin are used, respectively. 
The normal range of corrected calcium is same as the calcium’s. 
 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium are as defined in the previous section. 
 
2.7.2.2.3 
Data Analysis 
 
The laboratory summaries will include all assessments available for the lab parameter collected 
no later than 30 days after the last study treatment administration date. Laboratory parameters for 
hematology and blood chemistry will be summarized at baseline, each post-baseline visit (based 
on the visit schedule defined in the protocol along with a window), the maximum and minimum 
observed post-baseline values, and last observed value, along with the change from baseline. 


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For laboratory tests where grades are defined by CTCAE 4.03: 
• Worst post-baseline CTCAE grade (regardless of the baseline status). Each subject will be 
counted only once for the worst grade observed post-baseline. 
• Shift tables using CTCAE 4.03 grades to compare baseline to the worst on-treatment value 
For laboratory tests where grades are not defined by CTCAE 4.03, the summary will be based on 
normal range: 
• Worst post-baseline abnormal value (regardless of the baseline status). Each subject will be 
counted only once for the high/low category. 
• Shift tables to compare baseline to worst on-treatment values using the low/normal/high/ 
(low and high) 
 
For laboratory tests that are graded for both low and high directions, the shift tables and 
summary of post-baseline abnormal results will be done separately and labeled by direction. 
 
As discussed in ‘Minimum Critical Toxicities’ in Section 2.7.2.1.2, incidence of potential drug- 
induced liver injury based AST, ALT, TBL, ALP will be presented and potential Hy’s law cases 
will also be listed. 
 
Table 4 provides an example of laboratory parameters for which CTCAE grades are defined, 
Table 5 provides an example of laboratory parameters for which shift tables were based upon the 
local lab normal range 


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Table 4: 
Example of Laboratory Parameters for Which CTCAE Grades are Defined 
 
Hematology and Coagulation 
Biochemistry 
White Blood Cells (WBC) 
↑ 
↓ 
Creatinine 
↑ 
Hemoglobin 
↑ 
↓ 
Sodium 
↑ 
↓ 
Platelets counts 
↓ 
Potassium 
↑ 
↓ 
Absolute Neutrophils 
↓ 
Corrected Calcium 
↑ 
↓ 
Absolute Lymphocytes 
↑ 
↓ 
Magnesium 
↑ 
↓ 
APTT 
↑ 
Albumin 
↓ 
INR 
↑ 
AST (SGOT) 
↑ 
ALT (SGPT) 
↑ 
Total Bilirubin 
↑ 
Phosphate 
↓ 
amylase 
↑ 
lipase 
↑ 
Alkaline phosphatase 
↑ 
Total Cholesterol 
↑ 
Triglycerides 
↑ 
Urate 
↑ 
↑ Indicates that CTC grade increases as the parameter increases. 
↓ Indicates that CTC grade increases as the parameter decreases. 
 
Table 5: 
Examples of Laboratory Parameters (Without CTCAE Grades) for Which 
Lab Reference Ranges Are Defined 
 
Hematology and Coagulation 
Biochemistry 
 
Prothrombin time (PT) 
Blood urea nitrogen (BUN) 
Hematocrit 
Urea 
Absolute Basophils, 
Total protein 
Absolute Eosinophils 
Direct Bilirubin 
Absolute Monocytes 
Indirect Bilirubin 
Chloride 
Red Blood Cells (RBC) 
 
 
 
2.7.3 
Other Safety Data 
 
The FAS will be used for summaries and listings of other safety data discussed in this section 
except for the second formal interim analysis for Cohort 1 after Amendment 3 where the Interim 


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Analysis Set 2 for Cohort 1 will be used. In general, summaries will be provided only for the on- 
treatment safety assessments, which are the assessments occurring or taken during the on- 
treatment period. 
 
2.7.3.1 
Ophthalmologic Assessment 
 
Both visual acuity score (logMAR) and tonometry will be summarized at baseline, each post- 
baseline visit (based on the visit schedule defined in the protocol along with a window), the 
maximum and minimum observed post-baseline values, and last observed value, along with the 
change from baseline. 
 
Along with the summary described above, the number (percentage) of clinically significant 
changes in visual acuity score (logMAR) will be also summarized: 
• <0.1 logMAR 
• 0.1 - <0.2 logMAR 
• 0.2 - <0.3 logMAR 
• ≥0.3 logMAR 
In addition, the number (percentage) of clinically significant values in tonometry will be 
summarized by visit: 
• ≤21 mmHg 
• >21 mmHg 
Number (%) of clinically significant abnormalities will also be summarized by visit for slit lamp, 
OCT, and fundoscopy exams. 
 
2.7.3.2 
Left Ventricular Ejection Fraction 
 
Left ventricular ejection fraction (LVEF) will be summarized for baseline, each post-baseline 
visit (based on the scheduled defined in the protocol along with a window), minimum post- 
baseline, along with the changes from baseline. Shift tables of the minimum post-baseline LVEF 
(<40%, 40% to 50%, ≥50%) with baseline LVEF status (≥50%, <50%) will be provided. 
Clinically significant changes of LVEF defined below will also be presented: 
 
1. Absolute decrease from baseline >10% but <20% and LVEF ≥40% to <50% 
 
2. Absolute decrease from baseline ≥20% and LVEF ≥20% to <40% 
 
3. LVEF <20% 
 
2.7.3.3 
ECG and Cardiac Imaging Data 
 
The ECG analysis will be performed on all subjects who have received at least one dose of 
infigratinib with the baseline and at least one on-treatment post-baseline ECG assessment. 


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The average of the ECG parameters at each assessment should be used in the analyses. 12-lead 
ECGs including PR, QRS, QT, QTcF, QTcB, and HR intervals will be obtained central/local for 
each subject during the study. ECG data will be read and interpreted centrally. The ECG 
summaries will include all assessments available for the ECG parameter collected no later than 
30 days after the last study treatment administration date. 
 
ECG parameters will be summarized at baseline, each post-baseline visit (based on the nominal 
visit as collected from eCRF), the maximum and minimum observed post-baseline values, and 
last observed value, along with the change from baseline. For the maximum/minimum/last 
observed value, both scheduled and unscheduled assessments will be considered. 
 
The number and percentage of subjects with notable ECG values will be presented. 
• QT 
○ New value of >500 ms 
• QT, or QTcF 
○ New value of >450 ms 
○ New value of >480 ms 
○ New value of >500 ms 
○ Increase from baseline of >30 ms to ≤60 ms 
○ Increase from baseline of >60 ms 
• HR 
○ Increase from baseline >25% and to a value >100 bpm 
○ Decrease from baseline >25% and to a value <50 bpm 
• PR 
○ Increase from baseline >25% and to a value >200 ms 
• QRS 
○ Increase from baseline >25% and to a value >100 ms 
 
A listing of all ECG assessments will be produced and notable values will be flagged. In the 
listing, the on-treatment assessments will be flagged. In addition, a shift table baseline to worst 
on-treatment result for overall assessments will also be produced. 
 
In addition to the ECG analysis in CSR, a separate report on cardiac safety evaluation including 
QTc/PK modeling will be provided, based on a separate cardiac safety analysis plan. 
 
2.7.3.4 
Vital Signs and ECOG Performance Status 
 
ECOG performance status will be summarized at baseline, each post-baseline visit (based on the 
visit schedule defined in the protocol along with a window), and the last observed value. 


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Vital sign assessments are performed in order to characterize basic body function. The following 
parameters were collected: height (cm), weight (kg), body temperature (°C), pulse rate (beats per 
minute), systolic and diastolic blood pressure (mmHg). 
 
Vital signs (except height) collected during on-treatment will also be summarized using the same 
approach as for ECOG. The number and percentage of subjects with notable vital sign values 
(high/low) will be presented. 
 
Table 6: 
Criteria for Notable Vital Sign Values 
 
Vital sign (unit) 
Notable high value 
Notable low value 
Systolic blood pressure (mmHg) 
≥180 and increase from baseline of 
≥20 
Diastolic blood pressure (mmHg) 
≥105 and increase from baseline of 
≥15 
Pulse rate (bpm) 
≥100 and increase from baseline of 
>25% 
≤90 and decrease from baseline of 
≥20 
≤50 and decrease from baseline of 
≥15 
≤50 and decrease from baseline of 
>25% 
Body temperature (°C) 
≥39.1 
-- 
 
 
 
2.7.3.5 
Supportive Analyses for Secondary Objectives 
 
Not applicable. 
 
2.7.3.6 
Tolerability 
 
Tolerability of study drug will be assessed by summarizing the number of dose interruptions and 
dose reductions. Reasons for dose interruption and dose reductions will be listed by subject and 
summarized. Cumulative dose, dose intensity and relative dose intensity of infigratinib will be 
listed by subject and summarized. Categories for relative dose intensity of infigratinib will be 
specified as ≤0.5, >0.5 - ≤0.75, >0.75 - ≤0.9, >0.9 - ≤1.0, and >1.0. The number and proportion 
of subjects within each category will be presented. 
 
2.7.4 
Pharmacokinetics 
 
Subjects treated with FMI I and some subjects treated with FMI III (sparse PK group) will have 
limited PK collected as indicated in Table 10 of CSP Amendment 5. For these subjects, only 
trough and 2-hr or 4-hr plasma concentration data will be collected. No PK parameters can be 
calculated for these subjects, but the concentration data may be used in the population PK 
modeling. 
 
A secondary objective of this study is to characterize the single and multiple doses PK of 
infigratinib FMI III and FMI IV formulations. Data as per Table 11 of CSP Amendment 5 will be 
available for about 20 subjects treated with FMI III and for all subjects enrolled in either 
Cohort 2 or Cohort 3 and treated with FMI IV. For these subjects, PK parameters as listed in 
Table 7, may be determined from PK profiles after the first dose on Day 1 of Cycle 1 and Day 15 


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of Cycle 1 after repeated daily dosing using non-compartmental method(s) of WinNonlin 
(Pharsight, Mountain View, CA). 
 
The sections below on the PK analysis are intended to provide general principle for the PK 
analysis. Additional details of the analysis approaches will be provided in a separate PK analysis 
plan. 
 
Table 7: 
Non-compartmental Pharmacokinetic Parameters 
 
Term 
Definition 
 
Cmax 
Maximum observed plasma concentration after drug administration [mass × volume-1] 
Ctrough 
Measured concentration at the end of a dosing interval (taken directly before next 
administration) [mass × volume-1] 
Tmax 
Time to reach Cmax [time] 
AUC0-24 
Area under the concentration-time curve from 0 to 24 hours [mass × time × volume-1] 
T1/2 
Elimination half-life associated with the terminal slope (lambda_z) of a semi-logarithmic 
concentration-time curve [time] 
AUCinf 
Area under the concentration-time curve from 0 to infinity [mass × time × volume-1] 
CL/F 
Apparent clearance [dose/AUC] 
Vz/F 
Apparent volume of distribution [dose/AUC × lambda_z] 
Racc 
Accumulation ratio calculated as AUC0-24 of C1D15/AUC0-24 of C1D1 and Cmax of C1D15/ 
Cmax of C1D1 
 
 
 
2.7.4.1 
Data Handling Principles 
 
Only PK blood samples with the date and time and for which the last prior dose dates and times 
are adequately recorded will be included in the PK analyses. Missing concentration values will 
be reported as is in data listings. Missing values for any PK parameters or concentrations will not 
be imputed and will be treated as missing. Below the limit of quantitation (BLQ) values will be 
displayed in the listings as is. BLQ values will be treated as zero for the calculation of the 
geometric means and geometric CV%. 
 
At the time of analysis, concentration data from subjects may be removed from the estimation of 
certain PK parameters depending on the number of available blood samples, concomitant 
medications, vomiting, etc. Specific time points might be removed from the analysis set if 
technical issues with the sample are reported (eg, sampling issues, missing information). These 
data points will be identified at the time of analysis 
 
2.7.4.2 
Data Analysis Principles 
 
Exploratory PK analysis may be conducted based on preliminary data prior to data base lock, and 
nominal time and dose information may be used. 


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PK data generated from this study may be used in conjunction with PK data from other clinical 
studies for population PK and PK/PD assessment. These assessments will be reported separately. 
If possible, exploratory comparisons will be made to historical pharmacokinetic data. Available 
PK data from this study may be modeled using a population pharmacokinetic data analysis 
approach in order to characterize the population pharmacokinetics of infigratinib. Any 
population PK data generated will be reported separate from the CSR. 
 
All analyses will refer to infigratinib and its metabolites. Infigratinib and its metabolites 
concentration vs time data will be reported. 
 
Analysis will be done separately for the three formulations. In addition, analyses that require 
derived PK parameters will be applicable to subjects treated with FMI III and FMI IV who have 
provided PK parameters based on extensive PK sampling as indicated in Table 11 of CSP 
Amendment 5. 
 
2.7.4.3 
Analysis Sets 
 
Only PK blood samples with the date and time and for which the last prior dose dates and times 
are adequately recorded will be included in the PK analyses. Samples taken from patients who 
vomited within 4 hours of dosing will be excluded from the analysis. The PAS will be used. 
 
2.7.4.4 
Basic Tables, Figures, and Listings 
 
The PK concentration and PK parameters (when available for subjects treated with FMI III or 
FMI IV), will be summarized and listed using relevant statistics by treatment, and study day. 
Descriptive statistics (mean, SD, CV%, geometric mean, geometric CV%, median, and range) 
will be presented. Median, minimum and maximum will be calculated based on collected 
samples. When a geometric mean is presented, it will be stated as such. Only median values and 
ranges will be presented for Tmax. 
 
Graphical plots of individual and mean plasma concentration-time data will be generated for 
infigratinib and its metabolites. This graphical presentation will be applicable to subjects who are 
treated with FMI III and have PK profile collected as per Table 11 of CSP Amendment 5. 
Further graphical exploratory analysis will be carried out if deemed appropriate. 
 
Median, minimum and maximum will be calculated based on collected samples. All analyses 
will refer to infigratinib and its metabolites. Infigratinib and its metabolites concentration vs time 
data will be reported. Exploratory PK analysis may be conducted based on preliminary data prior 
to data base lock and nominal time and dose information may be used. 
 
2.8 
Exploratory Analyses 
 
The exploratory analyses described below will be conducted if there are sufficient data available. 


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2.8.1 
Biomarkers 
 
Sequencing analyses of cell-free DNA (cfDNA) isolated from the plasma of a subset of subjects 
who have progressed through treatment with Infigratinib are performed in order to detect genetic 
alterations from baseline. 
 
2.8.1.1 
Outline of the Data Analysis 
 
Since the clinical trial was not designed to address specific hypotheses related to subject pre- 
selection or resistance markers, the analysis of this data should be viewed as exploratory. 
Analytical results from such analyses may be used to generate additional hypotheses that must 
then be verified with data derived from subsequent clinical trials. No adjustment for multiple 
comparisons is planned. 
 
If the number of samples is inadequate to perform a rigorous data analysis, then the available 
data will only be listed. Additional analyses that may be performed after the completion of the 
end-of-study clinical study report will be documented in separate reports. These analyses may 
include but are not limited to the meta-analysis of data from this study combined with data from 
other studies or the analysis of subject pre-selection or PD markers generated from samples 
collected during the study but analyzed after the database lock and completion of the clinical 
study report. Any additional data analysis will be described in an addendum of the SAP or in a 
stand-alone analysis plan document, as appropriate. 
 
2.8.1.2 
Data Handling Principles 
 
All measurements below their respective LLOQs or missing data will be labeled as such in the 
concentration data listings. Measurements below the LLOQ will be treated as zero in summary 
statistics. Change from baseline analyses will only be performed on subjects with measurable 
samples and pre- and post-treatment time points. 
 
2.8.1.3 
Data Analysis Principles 
 
2.8.1.3.1 
Analysis Sets 
 
The FAS will be used for all analyses unless otherwise specified. The number of subjects with 
measurable samples will be identified in the summaries and relevant proportions will be 
calculated against this number of subjects. 
 
2.8.1.3.2 
Basic Tables, Figures, and Listings 
 
Change from baseline for markers measured pre and post baseline to assess the effect on FGFR 
pathway will be listed by subject and may be summarized by means of descriptive statistics. 
 
Individual CA19-9 serum levels (or change from baseline) will be listed as well as presented as 
line plots over time. If enough data is available, statistical analysis will be performed in order to 
assess the relationship between anti-tumor activity (BOR and OS) and CA19-9 levels (or change 


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from baseline). Best percent change in the sum of longest tumor diameters and the percent 
change in CA19-9 concentration from baseline will be plotted together in a bar graph. 
 
Subject’s FGFR2 gene fusion status in DNA from non-tumor tissue (cell free DNA data) will be 
listed and compared to the FGFR2 gene fusion status in tumor tissue at baseline; a contingency 
table will be presented. Genetic alterations detected in cell free tumor DNA will be summarized 
and presented graphically for subjects with both baseline and post-baseline samples. If there is 
enough data, change from baseline expression levels will be correlated with efficacy data. 
Further exploratory analyses will be performed if feasible. 
 
2.9 
Interim Analysis 
 
Safety and efficacy data will be continuously monitored by QED Therapeutics in conjunction 
with the investigators for decision-making purposes. 
 
For Cohort 1, one analysis was performed before Amendment 2 based on the 61 patients enrolled 
in the study (30 Jun 2016). Protocol amendment 2 restricted enrollment to patients with FGFR2 
fusions or translocations, and the formulation was changed from FMI I to FMI III. 
 
After 20 subjects had been treated with FMI III (for at least one cycle) based on Amendment 2, a 
comprehensive review of all relevant data such as PK, safety, dose interruptions/reductions, and 
available efficacy was performed. PK, safety, and tolerability data from the first 20 subjects 
treated with FMI III up to the end of cycle 1 of treatment were assessed and compared with the 
historical data from subjects treated with FMI I. Upon review of the data, it was decided to 
continue dosing all subsequent patients treated with FMI III at 125 mg on a 3 weeks on, 1 week 
off schedule. 
 
In addition, two formal interim analyses for Cohort 1 are planned after Amendment 3: 
 
• The first formal interim analysis for Cohort 1 was conducted when all patients in the Interim 
Efficacy Analysis Set 1 have been followed for at least 10 months after their initial exposure 
to the study treatment. This interim analysis will be done using only patients in Cohort 1. 
Efficacy analysis for this interim analysis will be based on the Interim Efficacy Analysis 
Set 1 and some key efficacy analyses may be repeated in the FAS. All the other analyses will 
be conducted on FAS unless otherwise specified. 
 
• The second will be conducted when all the patients who received infigratinib at the time of 
the first formal interim analysis have at least 10 months follow-up after their initial exposure 
to infigratinib. 
 
Additionally, for Cohorts 2 and 3, review of data will be performed after a total of 15 patients in 
either Cohort 2 or 3 have been treated with FMI IV for at least one cycle. A formal interim 
analysis will be conducted for Cohort 3 when the first dosed 10 patients in Cohort 3 have the 
potential to complete the second scheduled scan. This interim analysis will only include data 
from Cohort 3. This is to determine if an additional 10 patients will be added to Cohort 3. 


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3 SAMPLE SIZE CALCULATION 
3.1 
Cohort 1 
 
At the time of the first formal interim analysis after amendment 3, the interim efficacy analysis 
set 1 will include 72 patients with FGFR2 gene fusions or translocations. The half-width of the 
exact 95% confidence interval for ORR will not exceed 12%. 
 
With at least 106 subjects with FGFR2 gene fusions or translocation will result in the exact 95% 
confidence interval half-width of ORR less than 10%. 
 
3.2 
Cohort 2 and Cohort 3 
 
In Cohorts 2 and 3, patients who are progression-free at the second scheduled post-baseline scan 
(approximately 16 weeks from treatment initiation) or later will be considered to be benefiting 
from study treatment. If the lower bound of the patients who are progression-free at the second 
scheduled post-baseline scan (approximately 16 weeks) or later excludes 20%, the treatment will 
be considered as benefiting the patients. 
 
For Cohort 2, the percentage of patients who are progression-free at the second scheduled post- 
baseline scan (approximately 16 weeks) or later will be estimated with 95% exact confidence 
interval. There will be approximately 20 patients in total. A sample size of 20 will result in the 
exact 95% confidence interval half width of less than 23%. Patients who withdraw from the 
study for any reason before the second scheduled scan will be considered as not benefiting from 
study treatment. Sensitivity analysis will be conducted using the K-M method to estimate PFS 
>16 weeks. 
 
Table 8 provides some examples of CIs corresponding to observed numbers of patients 
considered to have benefited from treatment. For example, if 9 of 20 patients are progression- 
free at the second scheduled post-baseline scan or later, then the lower bound of the 95% exact 
confidence interval (CI) will exclude 20%. 
 
In Cohort 3, the same definition of benefit rate as for Cohort 2 (the percentage of patients who 
are progression-free at the second scheduled post-baseline scan [approximately 16 weeks] or 
later) will be applied. The benefit rate will be estimated with 95% exact confidence interval. The 
planned enrollment for Cohort 3 is a maximum of 20 patients. With 20 patients, the exact 95% 
confidence interval half width is <23%. One interim analysis is planned when 10 patients have 
been dosed and have the potential to be followed up for response for at least 2 scheduled post- 
baseline scans. If at the interim analysis, ≥4 patients are progression-free at the second scheduled 
post-baseline scan (after approximately 16 weeks) or later, the cohort will continue to enroll the 
additional 10 patients; otherwise, enrollment will stop at 10 patients. If ≤20% patients are 
benefiting from the study treatment, there is <12.1% chance that the decision after the interim 
analysis will lead to continuing enrollment. 
 
The percentage of patients considered to have benefited from treatment will be estimated with 
95% exact binomial CI. If all 20 patients are enrolled, the exact 95% CI half width will not 
exceed 23%. Table 8 provides some examples of CIs corresponding to observed numbers of 


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subjects considered to have benefited from treatment. At the final analysis, if 9 of 20 subjects 
who are progression-free at the second scheduled post-baseline scan or later, the lower bound of 
the 95% exact CI will exclude 20%. 
 
Table 8: 
95% CI Examples Corresponding to Observed Numbers of Subjects 
Considered to Have Benefited From Treatment (Cohorts 2 and 3) 
 
Number of subjects considered to have benefited 
from treatment 
95% Exact CI 
4 
(0.057, 0.437) 
8 
(0.191, 0.640) 
9 
(0.231, 0.685) 
10 
(0.272, 0.728) 
12 
(0.361, 0.809) 
CI=confidence interval 
 
4 CHANGE TO PROTOCOL SPECIFIED ANALYSES 
None. 
 
5 APPENDIX 
5.1 
Imputation Rules 
 
5.1.1 
AE, CM, and Safety Assessment Date Imputation 
 
Table 9: 
Imputation of Start Dates (AE, CM) 
 
Missing Element 
Rule 
day, month, and year 
• 
No imputation will be done 
day, month 
• 
No imputation will be done 
day 
• 
If available month and year = month and year of study treatment start date then 
○ 
If stop date contains a full date and stop date is earlier than study treatment 
start date then set start date= 01MONYYYY. 
○ 
Else set start date = study treatment start date. 
• 
If available month and year > month and year of study treatment start date then 
01MONYYYY 
• 
If available month and year < month year of study treatment start date then 
01MONYYYY 


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Table 10: 
Imputation of End Dates (AE, CM) 
 
Subject 
EOT (Y/N) Missing Element 
Rule 
(*= min (last treatment date plus 30 days, death date, cut-off date, 
withdrawal of consent date)) 
N 
day, month, and 
year 
• 
Data cutoff date 
Y 
day, month, and 
year 
• 
Completely missing end dates will be imputed by the end date of the on- 
treatment period* 
day, month 
• 
If partial end date contains year only, set end date = earliest of 31DecYYYY 
or end date of the on-treatment period * 
day 
• 
If partial end date contains month and year, set end date = earliest of last day 
of the month or end date of the on-treatment period* 
 
Any AEs and CMs with partial/missing dates will be displayed as such in the data listings. 
 
There should be no cases where AE or CM end dates are partial missing (year is available but 
month or day or both are missing) if a subject has not ended study treatment (EOT). The above 
imputations are only used for the calculation of time to and duration of AEs and concomitant 
medications. 
 
5.1.2 
Death Date Imputation 
 
If day is missing, then impute to the 1st of the month unless last known to be alive date is greater 
than the 1st of the month, in that case, set the death date to the last known to be alive date. 


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5.2 
Table of Adverse Events of Special Interest, Search Strategies, and Rationales for 
Sponsor-Defined Search Strategies 
 
Adverse Event of Special Interest 
Search Strategy 
Calcium-phosphate homeostasis1 
• 
Hypercalcaemia 
• 
Hyperphosphataemia 
• 
Hypophosphataemia 
Sponsor-defined grouped PTs 
Eye disorder2 
Sponsored-defined PTs in SOC Eye disorder: 
CSR/RPED 
Eye disorder other than RPED 
Central serous retinopathy/retinal pigment epithelium 
detachment (CSR/RPED)3 
Subset of PTs from SOC Eye disorders 
Cardiac disorder* 
Cardiac failure SMQ [narrow, broad] 
Myocardial infarction SMQ [narrow, broad] 
Other ischaemic heart disease SMQ [narrow, broad] 
Cardiac arrhythmia terms, nonspecific SMQ [narrow] 
Bradyarrhythmia terms, nonspecific SMQ [narrow] 
Tachyarrhythmia terms, nonspecific SMQ [narrow] 
Arrhythmia related investigations, signs and symptoms 
SMQ [narrow, broad] 
Acute pancreatitis 
Acute pancreatitis SMQ [narrow, broad] 
Pathological fracture4 
Sponsor-defined PTs 
Tissue calcification5 
Sponsor-defined PTs 
Vascular/intravascular mineralization6 
Sponsor-defined Grouped PTs 
* 
Note: SMQs relating to Torsade de Pointes / QT prolongation and cardiac arrhythmias are part of Minimum 
Critical Toxicity: Cardiac toxicity Rationales for Sponsor-defined grouped terms: 
1 
Sponsor-defined PTs capture the medical concept of hypercalcaemia, hyperphosphataemia, and 
hypophosphataemia. No SMQs available for these terms. 
2 
Sponsor-defined PTs in the SOC Eye Disorders, including 9 PTs used to characterize CSR/RPED, broadly 
capture eye related events. No SMQ available for this medical concept. 
3 
A narrow subset of PTs from SOC Eye Disorder (as selected by an ophthalmologist) are grouped to capture the 
medical concept of RPED. No SMQ available for this medical concept. 
4 
Sponsor-defined PTs include PTs with ‘fracture’, which capture the broad medical concept of fractures, 
recognizing that any fracture could be pathological in nature for the population under study. No SMQ 
available for this medical concept. 
5 
Sponsor-defined PTs include PTs with ‘calcification’ and ‘calcinosis’ which capture the broad medical 
concept of tissue calcification. No SMQ available for this medical concept. 
6 
Sponsor-defined PTs include PTs with targeted root words (athero, arterio, and sclerosis) and words (arterial, 
artery, calcification, insufficiency, mineralization, peripheral, and venous) with medical judgement to refine on 
terms which capture the broad medical concept of vascular calcification/mineralization. No SMQ available for 
this medical concept. 


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5.3 
AESI: Calcium-Phosphate Homeostasis – Hypercalcaemia, Hyperphosphataemia, 
and Hypophosphataemia 
 
AESI 
Sponsor-Defined Grouped PTs 
Hypercalcaemia 
Adjusted calcium increased 
Blood calcium abnormal 
Blood calcium increased 
Calcium ionised abnormal 
Calcium ionised increased 
Calcium phosphate product increased 
Hypercalcaemia 
Hyperphosphataemia 
Blood phosphorus abnormal 
Blood phosphorus increased 
Hyperphosphataemia 
Hypophosphataemia 
Blood phosphorus decreased 
Hypophosphataemia 
 
5.4 
AESI: Eye Disorder of Central Serous Retinopathy/Retinal Pigment Epithelium 
Detachment 
 
AESI of Eye disorder is characterized by PTs from SOC Eye disorders. CSR/RPED terms are 
listed below and remaining eye disorders (excluding PTs used to characterize CSR/RPED) are 
listed in Section 5.8. 
 
AESI 
Sponsor-Defined Grouped PTs 
Central serous retinopathy/retinal pigment 
epithelium detachment (CSR/RPED) 
Chorioretinopathy 
Detachment of macular retinal pigment epithelium 
Detachment of retinal pigment epithelium 
Macular detachment 
Retinal detachment 
Serous retinal detachment 
Subretinal fluid 
MEK inhibitor-associated serous retinopathy 
Retinopathy 


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5.5 
AESI: Pathological Fracture 
 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Fracture 
Fracture nonunion 
Osteochondral fracture 
Acetabulum fracture 
Fracture of clavicle due to birth 
trauma 
Osteophyte fracture 
Ankle fracture 
Fracture of penis 
Osteoporotic fracture 
Atypical femur fracture 
Fracture pain 
Patella fracture 
Atypical fracture 
Fracture reduction 
Pathological fracture 
Avulsion fracture 
Fracture treatment 
Pelvic fracture 
Cervical vertebral fracture 
Fractured coccyx 
Periprosthetic fracture 
Chance fracture 
Fractured ischium 
Pseudofracture 
Clavicle fracture 
Fractured maxilla elevation 
Pubis fracture 
Closed fracture manipulation 
Fractured sacrum 
Radius fracture 
Comminuted fracture 
Fractured skull depressed 
Rib fracture 
Complicated fracture 
Fractured zygomatic arch elevation 
Sacroiliac fracture 
Compression fracture 
Greenstick fracture 
Scapula fracture 
Costal cartilage fracture 
Hand fracture 
Skull fracture 
Craniofacial fracture 
Hip fracture 
Skull fractured base 
Elevation skull fracture 
Humerus fracture 
Spinal compression fracture 
Epiphyseal fracture 
Ilium fracture 
Spinal fracture 
External fixation of fracture 
Impacted fracture 
Spinal fusion fracture 
Facial bones fracture 
Internal fixation of fracture 
Sternal fracture 
Femoral neck fracture 
Jaw fracture 
Stress fracture 
Femur fracture 
Limb fracture 
Subchondral insufficiency fracture 
Fibula fracture 
Lisfranc fracture 
Surgical fixation of rib fracture 
Foot fracture 
Loss of anatomical alignment after 
fracture reduction 
Thoracic vertebral fracture 
Forearm fracture 
Lower limb fracture 
Tibia fracture 
Fracture blisters 
Lumbar vertebral fracture 
Tooth fracture 
Fracture debridement 
Metaphyseal corner fracture 
Torus fracture 
Fracture delayed union 
Multiple fractures 
Traumatic fracture 
Fracture displacement 
Open fracture 
Ulna fracture 
Fracture infection 
Open reduction of fracture 
Upper limb fracture 
Fracture malunion 
Open reduction of spinal fracture 
Wrist fracture 


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5.6 
AESI: Tissue Calcification 
 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Administration site calcification 
Infusion site calcification 
Splenic calcification 
Adrenal calcification 
Injection site calcification 
Tendon calcification 
Application site calcification 
Intervertebral disc calcification 
Thyroid calcification 
Articular calcification 
Intestinal calcification 
Tracheal calcification 
Bladder wall calcification 
Ligament calcification 
Vaccination site calcification 
Bone decalcification 
Lymph node calcification 
Calcinosis 
Breast calcifications 
Medical device site calcification 
Chondrocalcinosis 
Bursa calcification 
Myocardial calcification 
Chondrocalcinosis pyrophosphate 
Calcification metastatic 
Ovarian calcification 
Gastric mucosal calcinosis 
Calcification of muscle 
Pancreatic calcification 
Nephrocalcinosis 
Catheter site calcification 
Pericardial calcification 
Cerebral calcification 
Pleural calcification 
Cutaneous calcification 
Postoperative heterotopic 
calcification 
Dystrophic calcification 
Primary familial brain calcification 
Hepatic calcification 
Prostatic calcification 
Implant site calcification 
Pulmonary calcification 


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5.7 
AESI: Vascular/intravascular Mineralization 
 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Sponsor-Defined Grouped PTs 
Acute vascular insufficiency of 
intestine 
Coeliac artery occlusion 
Peripheral artery restenosis 
Aortic arteriosclerosis 
Coeliac artery stenosis 
Peripheral artery stenosis 
Aortic valve calcification 
Coronary artery disease 
Peripheral vascular disorder 
Arterial insufficiency 
Coronary artery insufficiency 
Precerebral arteriosclerosis 
Arterial insufficiency coronary 
Coronary artery occlusion 
Precerebral artery occlusion 
Arterial insufficiency peripheral 
Coronary artery reocclusion 
Pulmonary artery occlusion 
Arteriosclerosis 
Coronary artery restenosis 
Pulmonary artery stenosis 
Arteriosclerosis coronary artery 
Coronary artery stenosis 
Pulmonary valve calcification 
Arteriosclerotic retinopathy 
Heart valve calcification 
Renal arteriosclerosis 
Atherosclerotic plaque rupture 
Hepatic artery flow decreased 
Renal artery arteriosclerosis 
Basilar artery occlusion 
Hepatic artery occlusion 
Renal artery occlusion 
Basilar artery stenosis 
Hepatic artery stenosis 
Renal artery restenosis 
Basilar insufficiency 
Iliac artery disease 
Renal artery stenosis 
Brachiocephalic arteriosclerosis 
Iliac artery occlusion 
Retinal artery occlusion 
Brachiocephalic artery occlusion 
Inner ear vascular insufficiency 
Retinal artery stenosis 
Brachiocephalic artery stenosis 
Insufficiency cerebrovascular 
Splenic artery stenosis 
Carotid arteriosclerosis 
Insufficiency coronary artery 
Subclavian artery occlusion 
Carotid artery insufficiency 
Intraoperative cerebral artery 
occlusion 
Subclavian artery stenosis 
Carotid artery occlusion 
Mesenteric arteriosclerosis 
Tricuspid valve calcification 
Carotid artery restenosis 
Mesenteric artery stenosis 
Unspecified vascular insufficiency of 
intestine 
Carotid artery stenosis 
Mesenteric vascular insufficiency 
Vascular calcification 
Cerebellar artery occlusion 
Microvascular coronary artery 
disease 
Vascular insufficiency 
Cerebral arteriosclerosis 
Mitral valve calcification 
Vascular insufficiency of intestine 
Cerebral artery occlusion 
Penile artery occlusion 
Vascular insufficiency of intestine, 
unspecified 
Cerebral artery restenosis 
Peripheral arterial occlusive disease 
Vertebral artery occlusion 
Cerebral artery stenosis 
Peripheral arterial reocclusion 
Vertebral artery stenosis 
Cerebrovascular insufficiency 
Peripheral artery occlusion 
Vertebrobasilar insufficiency 
Chronic vascular insufficiency of 
intestine 


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5.8 
AESI: Eye Disorder: SOC Eye Disorders (Excluding 9 PTs Used to Characterize 
CSR/RPED) 
 
There are two subcategories in the eye disorder AESI summary table, one for CSR/RPED which 
included 9 PTs described in Section 5.4, the other is Eye Disorder SOC Other than CSR/RPED 
which included the remaining eye disorders not included in CSR/RPED section and are 
described in this section. 
 
SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Abnormal sensation in eye 
Exfoliation syndrome 
Ocular ischaemic syndrome 
Abscess of eyelid 
Exophthalmos 
Ocular lymphoma 
Acanthamoeba keratitis 
Exophthalmos congenital 
Ocular myasthenia 
Accommodation disorder 
Exposure keratitis 
Ocular neoplasm 
Acquired corneal dystrophy 
Extraocular muscle disorder 
Ocular pemphigoid 
Acquired epiblepharon 
Extraocular muscle paresis 
Ocular procedural complication 
Acquired lenticonus 
Extraocular retinoblastoma 
Ocular retrobulbar haemorrhage 
Acquired pigmented retinopathy 
Exudative retinopathy 
Ocular rosacea 
Acute haemorrhagic conjunctivitis 
Eye abscess 
Ocular sarcoidosis 
Acute macular outer retinopathy 
Eye allergy 
Ocular surface disease 
Acute myopia 
Eye anterior chamber congenital 
anomaly 
Ocular toxicity 
Acute zonal occult outer retinopathy Eye burns 
Ocular vascular disorder 
Adenoviral conjunctivitis 
Eye colour change 
Ocular vasculitis 
Age-related macular degeneration 
Eye complication associated with 
device 
Oculocerebrorenal syndrome 
AIDS retinopathy 
Eye contusion 
Oculodentodigital dysplasia 
Allergic keratitis 
Eye degenerative disorder 
Oculoglandular syndrome 
Alstroem syndrome 
Eye discharge 
Oculogyric crisis 
Altered visual depth perception 
Eye disorder 
Oculomucocutaneous syndrome 
Amaurosis 
Eye haemangioma 
Oculopharyngeal dystrophy 
Amaurosis fugax 
Eye haematoma 
Oculorespiratory syndrome 
Amblyopia 
Eye haemorrhage 
Onchocerciasis 
Amblyopia alcohol 
Eye infection 
Open angle glaucoma 
Amblyopia congenital 
Eye infection bacterial 
Open globe injury 
Amblyopia strabismic 
Eye infection chlamydial 
Ophthalmia neonatorum 
Amblyopia tobacco 
Eye infection fungal 
Ophthalmia nodosa 
Angle closure glaucoma 
Eye infection gonococcal 
Ophthalmic herpes simplex 
Aniridia 
Eye infection helminthic 
Ophthalmic herpes zoster 
Aniseikonia 
Eye infection intraocular 
Ophthalmic vein thrombosis 
Anisometropia 
Eye infection staphylococcal 
Ophthalmoplegia 
Anomaly of orbit, congenital 
Eye infection syphilitic 
Ophthalmoplegic migraine 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Anophthalmos 
Eye infection toxoplasmal 
Opitz-G/BBB syndrome 
Anterior capsule contraction 
Eye infection viral 
Opsoclonus myoclonus 
Anterior chamber angle 
neovascularisation 
Eye inflammation 
Optic atrophy 
Anterior chamber cell 
Eye injury 
Optic disc disorder 
Anterior chamber cleavage syndrome Eye irritation 
Optic disc drusen 
Anterior chamber collapse 
Eye laser scar 
Optic disc haemorrhage 
Anterior chamber crystallisation 
Eye luxation 
Optic disc hyperaemia 
Anterior chamber degeneration 
Eye movement disorder 
Optic disc pit 
Anterior chamber disorder 
Eye muscle entrapment 
Optic disc telangiectasia 
Anterior chamber fibrin 
Eye naevus 
Optic disc vascular disorder 
Anterior chamber flare 
Eye oedema 
Optic discs blurred 
Anterior chamber inflammation 
Eye opacity 
Optic glioma 
Anterior chamber opacity 
Eye pain 
Optic ischaemic neuropathy 
Anterior chamber pigmentation 
Eye paraesthesia 
Optic nerve compression 
Anterior segment ischaemia 
Eye pruritus 
Optic nerve cupping 
Antimetropia 
Eye swelling 
Optic nerve disorder 
Aphakia 
Eye symptom 
Optic nerve hypoplasia 
Aphakia congenital 
Eye ulcer 
Optic nerve infarction 
Aqueous fibrin 
Eyeball avulsion 
Optic nerve injury 
Aqueous humour leakage 
Eyelash changes 
Optic nerve neoplasm 
Arcus lipoides 
Eyelash discolouration 
Optic nerve sheath haemorrhage 
Argyll-Robertson pupils 
Eyelash hyperpigmentation 
Optic neuritis 
Arteriosclerotic retinopathy 
Eyelash hypopigmentation 
Optic neuritis meningococcal 
Asthenopia 
Eyelash injury 
Optic neuropathy 
Astigmatism 
Eyelash thickening 
Optic pathway injury 
Atopic cataract 
Eyelid bleeding 
Orbit atrophy 
Atopic keratoconjunctivitis 
Eyelid boil 
Orbital apex syndrome 
Atrophy of globe 
Eyelid contusion 
Orbital compartment syndrome 
Autoimmune retinopathy 
Eyelid cyst 
Orbital cyst 
Autoimmune uveitis 
Eyelid degenerative disorder 
Orbital granuloma 
Bacterial blepharitis 
Eyelid disorder 
Orbital infection 
Bacterial dacryocystitis 
Eyelid erosion 
Orbital myositis 
Bacterial iritis 
Eyelid exfoliation 
Orbital oedema 
Balint's syndrome 
Eyelid folliculitis 
Oscillopsia 
Basal cell naevus syndrome 
Eyelid function disorder 
Osteoporosis-pseudoglioma 
syndrome 
Basedow's disease 
Eyelid haemangioma 
Ota's naevus 
Behcet's syndrome 
Eyelid haematoma 
Overwear syndrome 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Bell's phenomenon 
Eyelid infection 
Panophthalmitis 
Benign neoplasm of choroid 
Eyelid injury 
Papilloedema 
Benign neoplasm of conjunctiva 
Eyelid irritation 
Papilloma conjunctival 
Benign neoplasm of cornea 
Eyelid margin crusting 
Papillophlebitis 
Benign neoplasm of eye 
Eyelid myoclonus 
Paralytic lagophthalmos 
Benign neoplasm of eyelid 
Eyelid naevus 
Paraneoplastic retinopathy 
Benign neoplasm of lacrimal duct 
Eyelid oedema 
Parinaud syndrome 
Benign neoplasm of lacrimal gland 
Eyelid pain 
Parophthalmia 
Benign neoplasm of optic nerve 
Eyelid ptosis 
Pars plana cyst 
Benign neoplasm of orbit 
Eyelid ptosis congenital 
Pathologic myopia 
Benign neoplasm of retina 
Eyelid rash 
Periorbital abscess 
Bickerstaff's encephalitis 
Eyelid retraction 
Periorbital cellulitis 
Binocular eye movement disorder 
Eyelid sensory disorder 
Periorbital disorder 
Birdshot chorioretinopathy 
Eyelid skin dryness 
Periorbital fat atrophy 
Blau syndrome 
Eyelid thickening 
Periorbital fat herniation 
Blebitis 
Eyelid tumour 
Periorbital haematoma 
Blepharal papilloma 
Eyelid vascular disorder 
Periorbital haemorrhage 
Blepharal pigmentation 
Eyelid vellus hair changes 
Periorbital infection 
Blepharitis 
Eyelids pruritus 
Periorbital inflammation 
Blepharitis allergic 
Faciodigitogenital dysplasia 
Periorbital oedema 
Blepharochalasis 
Fat adherence syndrome 
Persistent corneal epithelial defect 
Blepharophimosis 
Fibrin deposition on lens 
postoperative 
Persistent pupillary membrane 
Blepharophimosis congenital 
Filariasis 
PHACES syndrome 
Blepharospasm 
Flat anterior chamber of eye 
Phacolytic glaucoma 
Blepharosynechia 
Floppy eyelid syndrome 
Phakomatosis 
Blindness 
Floppy iris syndrome 
Photoelectric conjunctivitis 
Blindness congenital 
Foreign body in eye 
Photokeratitis 
Blindness cortical 
Foreign body sensation in eyes 
Photophobia 
Blindness day 
Foster-Kennedy Syndrome 
Photopsia 
Blindness hysterical 
Fraser syndrome 
Pigment dispersion syndrome 
Blindness transient 
Fuchs' syndrome 
Pigmentary glaucoma 
Blindness traumatic 
Fungal retinitis 
Pinguecula 
Blindness unilateral 
Gaze palsy 
Pingueculitis 
Bloch-Sulzberger syndrome 
Giant papillary conjunctivitis 
Polypoidal choroidal vasculopathy 
Borderline glaucoma 
Glare 
Post measles blindness 
Bowman's membrane disorder 
Glassy eyes 
Posterior capsule opacification 
Bowman's membrane injury 
Glaucoma 
Posterior capsule rupture 
Brow ptosis 
Glaucoma traumatic 
Posterior segment of eye anomaly 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Candida endophthalmitis 
Glaucomatocyclitic crises 
Posterior segment of eye anomaly 
congenital 
Candida retinitis 
Glaucomatous optic disc atrophy 
Presbyopia 
CANVAS syndrome 
Graft versus host disease in eye 
Presumed ocular histoplasmosis 
syndrome 
Capsular block syndrome 
Growth of eyelashes 
Progressive external ophthalmoplegia 
Carcinoma in situ of eye 
Haemangioma of retina 
Prominent epicanthal folds 
Cataract 
Halo vision 
Prostaglandin analogue 
periorbitopathy 
Cataract congenital 
Heerfordt's syndrome 
Protozoal corneal ulcer 
Cataract cortical 
Hemianopia 
Pseudo-blepharoptosis 
Cataract diabetic 
Hemianopia heteronymous 
Pseudoendophthalmitis 
Cataract nuclear 
Hemianopia homonymous 
Pseudomyopia 
Cataract operation complication 
Hepato-lenticular degeneration 
Pseudopapilloedema 
Cataract subcapsular 
Hereditary choroidal dystrophy 
Pseudophakic bullous keratopathy 
Cataract traumatic 
Hereditary optic atrophy 
Pseudophakic glaucoma 
Cavernous sinus syndrome 
Hereditary retinal dystrophy 
Pseudophakodonesis 
Cellulitis orbital 
Hermansky-Pudlak syndrome 
Pseudopterygium 
Chalazion 
Herpes ophthalmic 
Pseudostrabismus 
CHARGE syndrome 
Herpes simplex necrotising 
retinopathy 
Pseudoxanthoma elasticum 
Charles Bonnet syndrome 
Herpes simplex virus conjunctivitis 
neonatal 
Psychogenic visual disorder 
Chemical burns of eye 
Herpes zoster necrotising retinopathy Pterygium 
Chemical eye injury 
Heterochromia iridis 
Punctate keratitis 
Chemical iritis 
Heteronymous diplopia 
Pupil fixed 
Chiasma syndrome 
Heterophoria 
Pupillary block 
Chloropsia 
Hippus 
Pupillary deformity 
Cholesterolosis bulbi 
Holmes-Adie pupil 
Pupillary disorder 
Chorioretinal atrophy 
Homonymous diplopia 
Pupillary reflex impaired 
Chorioretinal degeneration 
congenital 
Hordeolum 
Pupillotonia 
Chorioretinal disorder 
Horner's syndrome 
Pupils unequal 
Chorioretinal folds 
Hyalosis asteroid 
Purtscher retinopathy 
Chorioretinal scar 
Hypermetropia 
Quadrantanopia 
Chorioretinitis 
Hypertelorism of orbit 
Radiation cataract 
Choroid melanoma 
Hyphaema 
Radiation corneal injury 
Choroid neoplasm 
Hypoaesthesia eye 
Radiation retinopathy 
Choroid tubercles 
Hypopigmentation of eyelid 
Raymond-Cestan syndrome 
Choroidal coloboma 
Hypopyon 
Recession of chamber angle of eye 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Choroidal detachment 
Hypotelorism of orbit 
Refraction disorder 
Choroidal dystrophy 
Hypotony of eye 
Refractive amblyopia 
Choroidal effusion 
Idiopathic orbital inflammation 
Retinal aneurysm 
Choroidal haemangioma 
IIIrd nerve disorder 
Retinal aneurysm rupture 
Choroidal haematoma 
IIIrd nerve injury 
Retinal anomaly congenital 
Choroidal haemorrhage 
IIIrd nerve paralysis 
Retinal arteriovenous malformation 
Choroidal infarction 
IIIrd nerve paresis 
Retinal artery embolism 
Choroidal neovascularisation 
Immune recovery uveitis 
Retinal artery occlusion 
Choroidal rupture 
Inclusion conjunctivitis 
Retinal artery spasm 
Choroidal sclerosis 
Inclusion conjunctivitis neonatal 
Retinal artery stenosis 
Choroiditis 
Infectious crystalline keratopathy 
Retinal artery thrombosis 
Chromatopsia 
Infectious iridocyclitis 
Retinal collateral vessels 
Ciliary body degeneration 
Infective corneal ulcer 
Retinal coloboma 
Ciliary body disorder 
Infective episcleritis 
Retinal cyst 
Ciliary body haemorrhage 
Infective iritis 
Retinal degeneration 
Ciliary hyperaemia 
Infective keratitis 
Retinal depigmentation 
Ciliary muscle spasm 
Infective scleritis 
Retinal deposits 
Ciliary zonular dehiscence 
Infective uveitis 
Retinal disorder 
Closed globe injury 
Inflammation of lacrimal passage 
Retinal drusen 
Cockayne's syndrome 
Injury corneal 
Retinal dystrophy 
Cogan's syndrome 
Injury of conjunctiva 
Retinal exudates 
Cohen syndrome 
Intra-ocular injection complication 
Retinal fibrosis 
Coloboma 
Intraocular haematoma 
Retinal haemorrhage 
Colour blindness 
Intraocular melanoma 
Retinal infarction 
Colour blindness acquired 
Iridocele 
Retinal infiltrates 
Commotio retinae 
Iridocorneal endothelial syndrome 
Retinal injury 
Computer vision syndrome 
Iridocyclitis 
Retinal ischaemia 
Congenital astigmatism 
Iridodialysis 
Retinal melanocytoma 
Congenital choroidal anomaly 
Iridodonesis 
Retinal melanoma 
Congenital corneal anomaly 
Iridoplegia 
Retinal migraine 
Congenital epiblepharon 
Iridoschisis 
Retinal neoplasm 
Congenital eye disorder 
Iris adhesions 
Retinal neovascularisation 
Congenital eye naevus 
Iris atrophy 
Retinal oedema 
Congenital eyelid malformation 
Iris bombe 
Retinal pallor 
Congenital Horner's syndrome 
Iris coloboma 
Retinal perivascular sheathing 
Congenital iris anomaly 
Iris convex 
Retinal phototoxicity 
Congenital lacrimal gland anomaly 
Iris cyst 
Retinal pigment epithelial tear 
Congenital lacrimal passage anomaly Iris disorder 
Retinal pigment epitheliopathy 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Congenital lenticonus 
Iris exfoliation 
Retinal pigmentation 
Congenital myopia 
Iris haemorrhage 
Retinal scar 
Congenital night blindness 
Iris hyperpigmentation 
Retinal tear 
Congenital nystagmus 
Iris hypopigmentation 
Retinal telangiectasia 
Congenital oculomotor apraxia 
Iris incarceration 
Retinal thickening 
Congenital optic nerve anomaly 
Iris injury 
Retinal toxicity 
Congenital retinoblastoma 
Iris melanoma 
Retinal vascular disorder 
Congenital scleral disorder 
Iris neoplasm 
Retinal vascular occlusion 
Congenital trichomegaly 
Iris neovascularisation 
Retinal vascular thrombosis 
Congenital visual acuity reduced 
Iris transillumination defect 
Retinal vasculitis 
Congenital vitreous anomaly 
Iris vascular disorder 
Retinal vein occlusion 
Conjunctival abrasion 
Iritis 
Retinal vein thrombosis 
Conjunctival adhesion 
Irlen syndrome 
Retinal vessel avulsion 
Conjunctival bleb 
IRVAN syndrome 
Retinal white without pressure 
Conjunctival cyst 
IVth nerve disorder 
Retinitis 
Conjunctival degeneration 
IVth nerve injury 
Retinitis histoplasma 
Conjunctival deposit 
IVth nerve paralysis 
Retinitis pigmentosa 
Conjunctival discolouration 
Kayser-Fleischer ring 
Retinitis viral 
Conjunctival disorder 
Kearns-Sayre syndrome 
Retinoblastoma 
Conjunctival erosion 
Keratic precipitates 
Retinopathy congenital 
Conjunctival filtering bleb leak 
Keratitis 
Retinopathy haemorrhagic 
Conjunctival follicles 
Keratitis bacterial 
Retinopathy hypertensive 
Conjunctival granuloma 
Keratitis fungal 
Retinopathy hyperviscosity 
Conjunctival haemorrhage 
Keratitis interstitial 
Retinopathy of prematurity 
Conjunctival hyperaemia 
Keratitis sclerosing 
Retinopathy proliferative 
Conjunctival irritation 
Keratitis viral 
Retinopathy sickle cell 
Conjunctival laceration 
Keratitis-ichthyosis-deafness 
syndrome 
Retinopathy solar 
Conjunctival lymphangiectasia 
Keratoconjunctivitis measles 
Retinoschisis 
Conjunctival melanoma 
Keratoconus 
Retinoschisis congenital 
Conjunctival neoplasm 
Keratomalacia 
Retro-orbital neoplasm 
Conjunctival oedema 
Keratopathy 
Rhegmatogenous retinal detachment 
Conjunctival opacity 
Keratorhexis 
Rheumatoid scleritis 
Conjunctival pallor 
Keratosis gonococcal 
Romana's sign 
Conjunctival pigmentation 
Keratouveitis 
Ross syndrome 
Conjunctival primary acquired 
melanosis 
Koeppe nodules 
Saccadic eye movement 
Conjunctival retraction 
Lacrimal atrophy 
Schlemm's canal obstruction 
Conjunctival scar 
Lacrimal cyst 
Scintillating scotoma 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Conjunctival telangiectasia 
Lacrimal disorder 
Scleral cyst 
Conjunctival ulcer 
Lacrimal duct neoplasm 
Scleral degeneration 
Conjunctival vascular disorder 
Lacrimal duct pigmentation 
Scleral deposits 
Conjunctivalisation 
Lacrimal fistula 
Scleral discolouration 
Conjunctivitis 
Lacrimal gland abscess 
Scleral disorder 
Conjunctivitis allergic 
Lacrimal gland enlargement 
Scleral haemorrhage 
Conjunctivitis bacterial 
Lacrimal haemorrhage 
Scleral hyperaemia 
Conjunctivitis chlamydial 
Lacrimal mucocoele 
Scleral oedema 
Conjunctivitis fungal 
Lacrimal passage granuloma 
Scleral pigmentation 
Conjunctivitis gonococcal neonatal 
Lacrimal punctum agenesis 
Scleral thinning 
Conjunctivitis tuberculous 
Lacrimal punctum enlarged 
Scleritis 
Conjunctivitis viral 
Lacrimal sac cellulitis 
Scleritis allergic 
Conjunctivochalasis 
Lacrimal structural disorder 
Scleromalacia 
Contact lens acute red eye 
Lacrimal structure injury 
Seasonal allergy 
Contact lens intolerance 
Lacrimation decreased 
Septo-optic dysplasia 
Corectopia 
Lacrimation disorder 
Silent sinus syndrome 
Cornea verticillata 
Lacrimation increased 
Sjogren's syndrome 
Corneal abrasion 
Lagophthalmos 
Slipped extraocular muscle 
Corneal abscess 
Laurence-Moon-Bardet-Biedl 
syndrome 
Spherophakia 
Corneal bleeding 
Leber's congenital amaurosis 
Spontaneous hyphaema 
Corneal cyst 
Lecithin-cholesterol acyltransferase 
deficiency 
Staphylococcal blepharitis 
Corneal decompensation 
Lens abnormality, congenital 
Staphyloma 
Corneal defect 
Lens discolouration 
Stargardt's disease 
Corneal degeneration 
Lens dislocation 
Stickler's syndrome 
Corneal deposits 
Lens disorder 
Strabismus 
Corneal disorder 
Lenticular injury 
Strabismus congenital 
Corneal dystrophy 
Lenticular opacities 
Sturge-Weber syndrome 
Corneal endothelial cell loss 
Lenticular pigmentation 
Subacute myelo-opticoneuropathy 
Corneal endotheliitis 
Leukaemic retinopathy 
Subconjunctival cyst 
Corneal epithelial microcysts 
Leukocoria 
Subretinal fibrosis 
Corneal epithelial wrinkling 
Lid lag 
Subretinal haematoma 
Corneal epithelium defect 
Lid margin discharge 
Sudden visual loss 
Corneal erosion 
Lid sulcus deepened 
Superficial injury of eye 
Corneal exfoliation 
Ligneous conjunctivitis 
Superior corneal epithelial arcuate 
lesion 
Corneal flap complication 
Limbal stem cell deficiency 
Superior limbic keratoconjunctivitis 
Corneal graft rejection 
Limbal swelling 
Susac's syndrome 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Corneal hypertrophy 
Lipaemia retinalis 
Swollen tear duct 
Corneal infection 
Lipodermoid tumour 
Symblepharon 
Corneal infiltrates 
Loss of visual contrast sensitivity 
Sympathetic ophthalmia 
Corneal irritation 
Macrocornea 
Tear discolouration 
Corneal lesion 
Macular cyst 
Temporal arteritis 
Corneal leukoma 
Macular degeneration 
Tenon's cyst 
Corneal neovascularisation 
Macular dystrophy congenital 
Terrien's marginal degeneration 
Corneal oedema 
Macular fibrosis 
Thermal burns of eye 
Corneal opacity 
Macular hole 
Thyrotoxic crisis 
Corneal opacity congenital 
Macular ischaemia 
Tilted disc syndrome 
Corneal perforation 
Macular oedema 
Tolosa-Hunt syndrome 
Corneal pigmentation 
Macular opacity 
Toxic anterior segment syndrome 
Corneal scar 
Macular pigmentation 
Toxic cataract 
Corneal staphyloma 
Macular pseudohole 
Toxic optic neuropathy 
Corneal striae 
Macular rupture 
Toxocariasis 
Corneal thickening 
Macular scar 
Trachoma 
Corneal thinning 
Macular vasospasm 
Tractional retinal detachment 
Corneal touch 
Maculopathy 
Traumatic iritis 
Corneal warpage 
Madarosis 
Trichiasis 
Corneoconjunctival intraepithelial 
neoplasia 
MAGIC syndrome 
Trichomegaly 
Cortical visual impairment 
Malignant exophthalmos 
Triple A syndrome 
Cri du Chat syndrome 
Malignant glaucoma 
Trisomy 13 
Crocodile tears syndrome 
Malignant melanoma of eyelid 
Trisomy 22 
Cryptophthalmos 
Malignant neoplasm of choroid 
Tuberculosis of eye 
Cutaneous horn of eyelid 
Malignant neoplasm of conjunctiva 
Tubulointerstitial nephritis and 
uveitis syndrome 
Cyanopsia 
Malignant neoplasm of cornea 
Tunnel vision 
Cyclitic membrane 
Malignant neoplasm of eye 
Uhthoff's phenomenon 
Cyclitis 
Malignant neoplasm of eyelid 
Ulcerative keratitis 
Cyclopia 
Malignant neoplasm of lacrimal duct Usher's syndrome 
Cycloplegia 
Malignant neoplasm of lacrimal 
gland 
Uveal prolapse 
Cystic eyeball, congenital 
Malignant neoplasm of orbit 
Uveitic glaucoma 
Cystoid macular oedema 
Malignant neoplasm of retina 
Uveitis 
Cytomegalovirus chorioretinitis 
Marcus Gunn syndrome 
Uveitis-glaucoma-hyphaema 
syndrome 
Dacryoadenitis acquired 
Marfan's syndrome 
Varicella keratitis 
Dacryocanaliculitis 
Meibomian gland discharge 
Venous stasis retinopathy 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Dacryocystitis 
Meibomian gland dysfunction 
Vernal keratoconjunctivitis 
Dacryolith 
Meibomianitis 
Vestibular nystagmus 
Dacryostenosis acquired 
Metallosis of globe 
Viral corneal ulcer 
Dacryostenosis congenital 
Metamorphopsia 
Viral keratouveitis 
Dark circles under eyes 
Metastases to eye 
Viral uveitis 
Deep anterior chamber of the eye 
Metastatic ocular melanoma 
Vision abnormal neonatal 
Deformity of orbit 
Microcornea 
Vision blurred 
Delayed dark adaptation 
Microphthalmos 
Visual acuity reduced 
Delayed light adaptation 
Microvascular cranial nerve palsy 
Visual acuity reduced transiently 
Delayed visual maturation 
Mikulicz's disease 
Visual brightness 
Dellen 
Mikulicz's syndrome 
Visual cortex atrophy 
Deposit eye 
Millard-Gubler syndrome 
Visual field defect 
Detached Descemet's membrane 
Miller Fisher syndrome 
Visual impairment 
Developmental glaucoma 
Miosis 
Visual pathway disorder 
Diabetic blindness 
Mittendorf dot 
Visual perseveration 
Diabetic eye disease 
Morning glory syndrome 
Visual snow syndrome 
Diabetic glaucoma 
Mycotic corneal ulcer 
Vitamin A deficiency eye disorder 
Diabetic keratopathy 
Mycotic endophthalmitis 
Vitamin A deficiency related 
conjunctival disorder 
Diabetic ophthalmoplegia 
Mydriasis 
Vitamin A deficiency related corneal 
disorder 
Diabetic retinal oedema 
MYH9-related disease 
VIth nerve disorder 
Diabetic retinopathy 
Myopia 
VIth nerve injury 
Diabetic uveitis 
Myopic chorioretinal degeneration 
VIth nerve paralysis 
Diffuse lamellar keratitis 
Myopic disc 
VIth nerve paresis 
Diffuse uveal melanocytic 
proliferation 
Narrow anterior chamber angle 
Vitreal cells 
Diplopia 
Necrotising herpetic retinopathy 
Vitreomacular interface abnormal 
Disorder of globe 
Necrotising retinitis 
Vitreous abscess 
Disorder of orbit 
Necrotising scleritis 
Vitreous adhesions 
Distichiasis 
Neoplasm of cornea unspecified 
malignancy 
Vitreous cyst 
Dry age-related macular degeneration Neoplasm of orbit 
Vitreous degeneration 
Dry eye 
Neovascular age-related macular 
degeneration 
Vitreous detachment 
Duane's syndrome 
Neurologic neglect syndrome 
Vitreous disorder 
Dyschromatopsia 
Neurological eyelid disorder 
Vitreous fibrin 
Dysmetropsia 
Neuromyelitis optica pseudo relapse 
Vitreous floaters 
Eales' disease 
Neuromyelitis optica spectrum 
disorder 
Vitreous haematoma 


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SOC Eye Disorders 
SOC Eye Disorders 
SOC Eye Disorders 
Eccentric fixation 
Neuropathy, ataxia, retinitis 
pigmentosa syndrome 
Vitreous haemorrhage 
Ectropion 
Neurotrophic keratopathy 
Vitreous haze 
Ectropion uveae 
Nictitating spasm 
Vitreous injury 
Eczema eyelids 
Night blindness 
Vitreous loss 
Emanuel syndrome 
Non-infectious endophthalmitis 
Vitreous opacities 
Endocrine ophthalmopathy 
Noninfective chorioretinitis 
Vitreous prolapse 
Endophthalmitis 
Noninfective conjunctivitis 
Vitritis 
Enophthalmos 
Noninfective retinitis 
Vogt-Koyanagi-Harada syndrome 
Enophthalmos traumatic 
Normal tension glaucoma 
Waardenburg syndrome 
Entropion 
Norrie's disease 
Wagner's disease 
Entropion congenital 
Nystagmus 
Weill-Marchesani syndrome 
Episcleral hyperaemia 
Ocular albinism 
Wildervanck syndrome 
Episcleritis 
Ocular cancer metastatic 
Winchester syndrome 
Erythema of eyelid 
Ocular discomfort 
Wolfram syndrome 
Erythropsia 
Ocular dysmetria 
Wyburn Mason's syndrome 
Eversion of lacrimal punctum 
Ocular fistula 
Xanthopsia 
Excessive eye blinking 
Ocular haemangiopericytoma 
Xerophthalmia 
Excessive ocular convergence 
Ocular hyperaemia 
Zika virus associated ocular birth 
defect 
Exfoliation glaucoma 
Ocular hypertension 
Ocular icterus 
 
 
5.9 
Minimum Critical Toxicities 
 
Minimum Critical Toxicity search strategies are per SMQs and utilize MedDRA 21.0. As SMQs 
are standardized lists of PTs per MedDRA version, the individual SMQ PTs are not enumerated 
further within this document. The search strategies described below will be used to identify cases 
for analysis purposes and are not intended to be used to calculate frequencies of adverse drug 
reactions. 


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Table 11: 
Table of Minimal Critical Toxicities and SMQ Search Strategies 
 
Minimal Critical Toxicity 
Search Strategy 
Hepatotoxicity 
• 
Biliary system related investigations, signs, and symptoms SMQ [narrow, broad] 
• 
Cholestasis and jaundice of hepatic origin SMQ [narrow, broad] 
• 
Hepatic failure, fibrosis and cirrhosis and other liver damage-related conditions 
SMQ [narrow, broad] 
• 
Hepatitis, non-infectious SMQ [narrow, broad] 
• 
Liver related investigations, signs and symptoms SMQ [narrow, broad] 
Cardiac Toxicity 
• 
Torsade de Pointes / QT prolongation SMQ [narrow, broad] 
Nephrotoxicity 
• 
Acute renal failure SMQ [narrow, broad] 
Haematologic Toxicities 
• 
Haematopoietic cytopenias affecting more than one type of blood cell SMQ 
[narrow, broad] 
• 
Haematopoietic erythropenia SMQ [narrow, broad] 
• 
Haematopoietic leukopenia SMQ [narrow, broad] 
• 
Haematopoietic thrombocytopenia SMQ [narrow, broad] 
 
5.10 
CYP3A4 Inhibitors and Inducers 
 
The list of CYP3A4 inducers and inhibitors are retrieved from the Drug Bank (Wishart 2017). 
Terms are coded based on WHODrug Enhanced + Herbals (HD/DDE) Mar2018 B3 global. 
 
The coded concomitant medications which contained below preferred terms will be marked 
according to type (inhibitor/inducer)) and category (moderate/strong) with the exception that 
medication administered through topical, optic or aural routes will not be considered as inducers 
or inhibitors. 
 
Type 
Category 
Preferred Name/Generic Name Type 
Category 
Preferred Term 
Inhibitor Moderate 
AMIODARONE 
Inducer 
Moderate 
AVASIMIBE 
Inhibitor Moderate 
AMPRENAVIR 
Inducer 
Moderate 
BEXAROTENE 
Inhibitor Moderate 
ANASTROZOLE 
Inducer 
Moderate 
BOSENTAN 
Inhibitor Moderate 
APREPITANT 
Inducer 
Moderate 
DABRAFENIB 
Inhibitor Moderate 
BARNIDIPINE 
Inducer 
Moderate 
EFAVIRENZ 
Inhibitor Moderate 
BENIDIPINE 
Inducer 
Moderate 
ETRAVIRINE 
Inhibitor Moderate 
CLOBAZAM 
Inducer 
Moderate 
MIFEPRISTONE 
Inhibitor Moderate 
CLOZAPINE 
Inducer 
Moderate 
MODAFINIL 
Inhibitor Moderate 
CRIZOTINIB 
Inducer 
Moderate 
NAFCILLIN 
Inhibitor Moderate 
DANAZOL 
Inducer 
Strong 
APALUTAMIDE 
Inhibitor Moderate 
DESVENLAFAXINE 
Inducer 
Strong 
CARBAMAZEPINE 
Inhibitor Moderate 
DILTIAZEM 
Inducer 
Strong 
DEXAMETHASONE 
Inhibitor Moderate 
DIMETHYL SULFOXIDE 
Inducer 
Strong 
ENZALUTAMIDE 
Inhibitor Moderate 
DRONEDARONE 
Inducer 
Strong 
FOSPHENYTOIN 
Inhibitor Moderate 
ERYTHROMYCIN 
Inducer 
Strong 
LUMACAFTOR 


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Type 
Category 
Preferred Name/Generic Name Type 
Category 
Preferred Term 
Inhibitor Moderate 
FLUCONAZOLE 
Inducer 
Strong 
MIDOSTAURIN 
Inhibitor Moderate 
FLUVOXAMINE 
Inducer 
Strong 
MITOTANE 
Inhibitor Moderate 
FOSAMPRENAVIR 
Inducer 
Strong 
NEVIRAPINE 
Inhibitor Moderate 
FOSNETUPITANT 
Inducer 
Strong 
OXCARBAZEPINE 
Inhibitor Moderate 
FUSIDIC ACID 
Inducer 
Strong 
PENTOBARBITAL 
Inhibitor Moderate 
HALOPERIDOL 
Inducer 
Strong 
PHENOBARBITAL 
Inhibitor Moderate 
IMATINIB 
Inducer 
Strong 
PHENYTOIN 
Inhibitor Moderate 
INDALPINE 
Inducer 
Strong 
PRIMIDONE 
Inhibitor Moderate 
ISAVUCONAZOLE 
Inducer 
Strong 
RIFAMPICIN 
Inhibitor Moderate 
ISAVUCONAZONIUM 
Inducer 
Strong 
RIFAMYCIN 
Inhibitor Moderate 
ISONIAZID 
Inducer 
Strong 
RIFAXIMIN 
Inhibitor Moderate 
ISRADIPINE 
Inducer 
Strong 
RIMEXOLONE 
Inhibitor Moderate 
LINAGLIPTIN 
Inducer 
Strong 
HYPERICUM PERFORATUM 
Inhibitor Moderate 
LOVASTATIN 
Inducer 
Strong 
GLUCOCORTICOIDS 
Inhibitor Moderate 
LULICONAZOLE 
Inhibitor Moderate 
MICONAZOLE 
Inhibitor Moderate 
MIFEPRISTONE 
Inhibitor Moderate 
MILNACIPRAN 
Inhibitor Moderate 
NETUPITANT 
Inhibitor Moderate 
NICARDIPINE 
Inhibitor Moderate 
NILVADIPINE 
Inhibitor Moderate 
PAROXETINE 
Inhibitor Moderate 
PRIMAQUINE 
Inhibitor Moderate 
RISPERIDONE 
Inhibitor Moderate 
SERTRALINE 
Inhibitor Moderate 
SIMEPREVIR 
Inhibitor Moderate 
TIOCONAZOLE 
Inhibitor Moderate 
VENETOCLAX 
Inhibitor Moderate 
VENLAFAXINE 
Inhibitor Moderate 
VERAPAMIL 
Inhibitor Moderate 
ZIMELDINE 
Inhibitor Moderate 
ZIPRASIDONE 
Inhibitor Strong 
ATAZANAVIR 
Inhibitor Strong 
BOCEPREVIR 
Inhibitor Strong 
CLARITHROMYCIN 
Inhibitor Strong 
CLOTRIMAZOLE 
Inhibitor Strong 
COBICISTAT 
Inhibitor Strong 
CONIVAPTAN 


Infigratinib (BGJ398) 
CBGJ398X2204 Statistical Analysis Plan V3.0 
13 May 2020 
QED Therapeutics 
Confidential 
Page 62 
 
 
 
 
Type 
Category 
Preferred Name/Generic Name Type 
Category 
Preferred Term 
Inhibitor Strong 
CURCUMIN 
Inhibitor Strong 
DANOPREVIR 
Inhibitor Strong 
DARUNAVIR 
Inhibitor Strong 
DELAVIRDINE 
Inhibitor Strong 
DILTIAZEM 
Inhibitor Strong 
ECONAZOLE 
Inhibitor Strong 
EFAVIRENZ 
Inhibitor Strong 
ELVITEGRAVIR 
Inhibitor Strong 
ERGOTAMINE 
Inhibitor Strong 
IDELALISIB 
Inhibitor Strong 
INDINAVIR 
Inhibitor Strong 
ITRACONAZOLE 
Inhibitor Strong 
KETOCONAZOLE 
Inhibitor Strong 
LOPERAMIDE 
Inhibitor Strong 
LOPINAVIR 
Inhibitor Strong 
MIBEFRADIL 
Inhibitor Strong 
MIDOSTAURIN 
Inhibitor Strong 
NALOXONE 
Inhibitor Strong 
NEFAZODONE 
Inhibitor Strong 
NELFINAVIR 
Inhibitor Strong 
NILOTINIB 
Inhibitor Strong 
POSACONAZOLE 
Inhibitor Strong 
RIBOCICLIB 
Inhibitor Strong 
RITONAVIR 
Inhibitor Strong 
SAQUINAVIR 
Inhibitor Strong 
STIRIPENTOL 
Inhibitor Strong 
TELAPREVIR 
Inhibitor Strong 
TELITHROMYCIN 
Inhibitor Strong 
TERFENADINE 
Inhibitor Strong 
TIPRANAVIR 
Inhibitor Strong 
TROLEANDOMYCIN 
Inhibitor Strong 
VORICONAZOLE 


Infigratinib (BGJ398) 
CBGJ398X2204 Statistical Analysis Plan V3.0 
13 May 2020 
QED Therapeutics 
Confidential 
Page 63 
 
 
 
 
5.11 
Phosphate Binders 
 
All terms in the search strategy are based on WHODrug Enhanced + Herbals (HD/DDE) 
Mar2018 B3 Global. 
 
Preferred Name/Generic Name 
Preferred Name/Generic Name 
Preferred Name/Generic Name 
CALCIUM CARBONATE 
SEVELAMER HYDROCHLORIDE 
ALUMINUM HYDROXIDE 
CALCIUM POLYSTYRENE 
SULFONATE 
SUCROFERRIC OXYHYDROXIDE 
SEVELAMER 
FERRIC CITRATE 
SEVELAMER CARBONATE 
LANTHANUM CARBONATE 
 
6 REFERENCE 
Clinical Trial Protocol CBGJ398X2204 Version 6 (Amendment 5), Dated on 15-Jan-2020 
 
Wishart DS, Feunang YD, Guo AC, Lo EJ, Marcu A, Grant JR, et al. DrugBank 5.0: a major 
update to the DrugBank database for 2018. Nucleic Acids Res. 2018 Jan 4;46(D1):D1074- 
D1082.