Conditions: FGFR Gene Amplification FGFR1 Gene Amplification FGFR2 Gene Amplification FGFR2 Gene Mutation FGFR3 Gene Mutation Head and Neck Squamous Cell Carcinoma Human Papillomavirus Infection Recurrent Head and Neck Carcinoma Recurrent Nasopharynx Carcinoma Recurrent Oropharyngeal Squamous Cell Carcinoma
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 1
Healthy volunteers: no

Brief summary:
This phase IIa trial studies how well the experimental drug, BGJ398 (infigratinib), works in treating patients with fibroblast growth factor receptor (FGFR) 1-3 translocated, mutated, or amplified head and neck cancer that has returned after a period of improvement. BGJ398 may stop the growth of tumor cells by blocking some of the enzymes needed for cell growth.

Detailed description:

Arms:
arm 1: Patients receive BGJ398 (125 mg) by mouth once daily on a three weeks on, one week off schedule. Courses repeat every 28 days until disease progression or unacceptable toxicity.

Interventions: intervention 1: BGJ398
Intervention descriptions: intervention 1: Given by mouth (oral)

Protocol document:
Prot_SAP_000.pdf: 
 
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                                                                                                                                               Protocol No. 
 
Study Title:   
 
 
Phase IIa study of the efficacy of BGJ398 (infigratinib) in 
FGFR1-3 translocated, mutated, or amplified squamous 
cell carcinoma of the head and neck 
 
Institutional Study #: 
IRB14-1447 
Lead Investigator 
Name: 
Tanguy Y. Seiwert, MD 
Co-Principal 
Investigator 
Investigator Contact 
Information: 
Nicole Chau, MD (Dana-Farber Cancer Institute) 
 
The University of Chicago 
5841 S. Maryland Ave, MC 2115 
Chicago, IL 60637 USA 
Co-Investigators: 
Everett E. Vokes, MD 
Alexander Pearson, MD 
 
This study is being conducted by institutional members of the Personalized Cancer 
Care Consortium (PCCC), as well as additional sites. 
Version #: 
Initial Submission: 1/27/2016 
Amendment #1: 2/1/2017 
Amendment #2  3/23/2018 
 
 
 


 
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                                                                                                                                               Protocol No. 
Table of contents 
Table of contents ................................................................................................................. 2 
List of abbreviations ............................................................................................................ 5 
1 
Background .......................................................................................................................... 8 
1.1 
Overview of Disease to be studied .......................................................................... 8 
1.2 
Introduction to investigational treatment ................................................................. 8 
1.2.1 
Overview of BGJ398 (infigratinib) ......................................................... 8 
2 
Study purpose/rationale ..................................................................................................... 17 
3 
Objectives and endpoints ................................................................................................... 19 
3.1 
Primary Objectives ................................................................................................ 19 
3.2 
Secondary Objectives ............................................................................................ 19 
3.3 
Exploratory Objectives .......................................................................................... 20 
4 
Investigational plan ........................................................................................................... 21 
4.1 
Overview of Study Design and Schema ................................................................ 21 
4.2 
4.1.2   Methods of FGFR screening ....................................................................... 23 
4.3 
Treatment ............................................................................................................... 24 
4.4 
Definition of a treatment cycle .............................................................................. 24 
4.5 
Treatment duration ................................................................................................. 24 
4.6 
Treatment assignment/randomization .................................................................... 24 
4.7 
Rationale for the study design ............................................................................... 25 
5 
Population .......................................................................................................................... 25 
5.1 
Inclusion criteria .................................................................................................... 26 
5.2 
Exclusion criteria ................................................................................................... 27 
6 
Treatment ........................................................................................................................... 29 
6.1 
Treating the patient ................................................................................................ 30 
6.1.1 
Administration....................................................................................... 30 
6.1.2 
Instructions for Administration of BGJ398 (infigratinib) ..................... 30 
6.1.3 
Ancillary treatments with anti-emetics, phosphate lowering agents, 
anti-diarrheals, and growth factors ........................................................ 31 
6.1.4 
Dosing and treatment schedule ............................................................. 32 
6.1.5 
Dose modification and dose delay ........................................................ 32 
6.4 
Follow up for dose modifications/treatment interruptions .................................... 40 
6.5 
Concomitant therapy .............................................................................................. 40 
6.5.1 
Permitted concomitant therapy requiring caution and/or action ........... 41 
6.5.2 
Prohibited concomitant therapy ............................................................ 43 
6.6 
Criteria for removal from study ............................................................................. 44 
6.7 
Study drug(s) ......................................................................................................... 44 


 
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6.7.1 
Packaging and labeling ......................................................................... 44 
6.7.2 
Supply, receipt and storage ................................................................... 45 
6.7.3 
Drug compliance and accountability ..................................................... 45 
6.7.4 
Disposal and destruction ....................................................................... 45 
6.7.5 
Study drug discontinuation ................................................................... 45 
7 
Visit schedule and assessments ......................................................................................... 46 
7.1 
Study flow and visit schedule ................................................................................ 46 
7.2 
Screening Examination .......................................................................................... 48 
7.3 
Assessment types ................................................................................................... 49 
7.3.1 
Efficacy ................................................................................................. 49 
7.3.2 
Safety ..................................................................................................... 55 
7.3.3 
Pharmacokinetics .................................................................................. 55 
7.3.4 
Correlative Analysis .............................................................................. 56 
7.3.5 
Tumor Biopsies ..................................................................................... 56 
7.3.6 
Biopsy safety considerations ................................................................. 57 
8 
Data Reporting ................................................................................................................... 57 
9 
Registration Procedures ..................................................................................................... 57 
9.1 
General Guidelines ................................................................................................ 57 
9.2 
Registration Process ............................................................................................... 58 
10 Safety monitoring and reporting ........................................................................................ 59 
10.1 
Adverse Events ...................................................................................................... 59 
10.1.1 
Definitions and reporting ...................................................................... 59 
10.1.2 
Adverse event list .................................................................................. 59 
10.2 
Adverse Event Characteristics ............................................................................... 60 
10.3 
Adverse Event Definitions ..................................................................................... 60 
10.3.1 
Adverse Event ....................................................................................... 60 
10.3.2 
Serious Adverse Event .......................................................................... 61 
10.3.3 
Unexpected Events ................................................................................ 61 
10.3.4 
Adverse Reactions ................................................................................. 61 
10.4 
Adverse Event Reporting Requirements ............................................................... 62 
10.4.1 
Routine adverse event reporting ............................................................ 62 
10.4.2 
Serious adverse event reporting to the Coordinating Center ................ 62 
10.4.3 
Serious and Unexpected Adverse Event reporting by the 
Coordinating Center .............................................................................. 63 
10.4.4 
Reporting Requirements for the Institutional Review Board ................ 63 
10.4.5 
Novartis instructions for rapid notification of serious adverse 
events ..................................................................................................... 64 


 
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10.5 
Pregnancies ............................................................................................................ 64 
10.6 
Duration of Follow up ........................................................................................... 64 
11 Statistical methods and data analysis ................................................................................ 65 
11.1 
Sample size calculation .......................................................................................... 65 
12 Ethical considerations and administrative procedures ...................................................... 66 
12.1 
Ethics and good clinical practice ........................................................................... 66 
12.2 
Discontinuation of the study .................................................................................. 67 
12.3 
Publication of results ............................................................................................. 67 
12.4 
Disclosure and confidentiality ............................................................................... 67 
12.5 
Declaration of Helsinki .......................................................................................... 67 
13 Study Management and Regulatory Affairs ...................................................................... 67 
13.1 
Multicenter guidelines ........................................................................................... 67 
13.2 
Institutional Review Board (IRB) Approval and Consent ..................................... 68 
13.3 
Food and Drug Administration (FDA) Approval .................................................. 69 
13.4 
Required Documentation ....................................................................................... 69 
13.5 
Data and Safety Monitoring ................................................................................... 70 
13.6 
Auditing ................................................................................................................. 71 
13.7 
Amendments to the Protocol ................................................................................. 71 
13.8 
Annual IRB Renewals, Continuing Review and Final Reports ............................. 72 
13.9 
Record Retention ................................................................................................... 72 
13.10 Obligations of Study Site Investigators ................................................................. 72 
14 Appendices ........................................................................................................................ 74 
14.1 
Appendix A: Performance Status Criteria ............................................................. 74 
14.2 
Appendix B:  Multicenter Guidelines .................................................................... 75 
14.3 
Appendix C: Tissue Sample Collection Form ....................................................... 76 
14.4 
Appendix D: Tumor Response Assessment RECIST 1.1 ...................................... 77 
14.5 
Appendix E: Drug Accountability - Sample Medication Diary ............................ 79 
15 References ......................................................................................................................... 81 
 
 
 


 
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List of abbreviations 
ADME 
Absorption, distribution, metabolism, and excretion 
AE 
Adverse Event 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolute Neutrophil Count 
AST 
BCRP 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
Breast cancer resistance protein 
BID 
bis in diem/twice a day 
CK 
Creatine Phosphokinase 
Cmax 
Maximum (peak) concentration of drug 
Cmin 
CapSeq 
CCTO 
CHGC 
Minimum (peak) concentration of drug 
University of Chicago’s DNA and RNA based genetic profiling assay  
University of Chicago Comprehensive Cancer Center Clinical Trials Office 
University of Chicago HNC Genomics Cohort 
CR 
Complete Response 
CTC 
Common Toxicity Criteria 
CTCAE 
Common Terminology Criteria Adverse Events 
DLT 
Dose Limiting Toxicity  
DoR 
Duration of tumor Response 
DMC 
Data Monitoring Committee 
DS&E 
Drug Safety and Epidemiology 
EC 
Ethics committee 
ECG 
EGFR 
Electrocardiogram 
Epidermal Growth Factor Receptor 
EORTC 
European Organization for Research and Treatment of Cancer 
EOT 
End of Treatment 
FAS 
FDA 
Full Analysis Set 
Food and Drug Administration 
FFPE 
FGFR 
Formalin-Fixed Paraffin-Embedded 
Fibroblast Growth Factor Receptor 
GCP 
Good Clinical Practice 
Hgb 
HNC 
HNSCC 
HPV 
Hemoglobin 
Head and Neck Cancer 
Head and Neck Squamous Cell Carcinoma 
Human Papilloma Virus 
IB 
Investigator’s Brochure 
ICF 
Informed Consent Form 
ICH 
International Conference of Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LLOQ 
MTD 
ORR  
PCR 
Lower limit of quantification 
Maximum Tolerated Dose 
Objective Response Rate 
Polymerase Chain Reaction 
PD 
Pharmacodynamics 


 
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PFS 
Progression Free Survival 
PK 
Pharmacokinetics 
QD 
Quaque die/ once a day 
REB 
Research Ethics Board 
RECIST 
Response Criteria in Solid Tumors 
SAE 
SCC 
Serious Adverse Event 
Squamous Cell Carcinoma 
SD 
Stable Disease 
SGOT 
Serum glutamic oxaloacetic transaminase; aspartate aminotransferase; AST 
SGPT 
Serum glutamic pyruvic transaminase; alanine aminotransferase; ALT 
SUSAR 
TCGA 
UCCCC 
WBC 
Serious and Unexpected Suspected Adverse Reaction 
The Cancer Genome Atlas 
University of Chicago Comprehensive Cancer Center 
White Blood cells 
WHO 
World Health Organization 
 
 
 
 


 
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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Control drug 
A study treatment used as a comparator to reduce assessment bias, 
preserve blinding of investigational drug, assess internal study validity, 
and/or evaluate comparative effects of the investigational drug 
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 testing 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 
Medication number 
A unique identifier on the label of each study treatment package which is 
linked to one of the treatment groups of a study.  
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Subject Number (Subject No.) 
A unique identifying number assigned to each patient/healthy volunteer 
who enrolls in the study 
Phase 
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 
Randomization number 
A unique treatment identification code assigned to each randomized 
patient, corresponding to a specific treatment arm assignment 
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 non-investigational 
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 
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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1 
Background  
1.1 
Overview of Disease to be studied 
 
Head and Neck squamous cell carcinoma (HNSCC) is the 6th most common cause of cancer 
death worldwide with more than 600,000 annual cases. In the United States alone, there are 
over 40,000 new HNSCC cases and 11,000 deaths per year. HNSCC results in significant 
morbidity because major vital functions such as nutrition, respiration and communication 
are impaired.  
 
Approximately two thirds of patients with HNSCC will present with locoregional disease 
and despite aggressive local therapy, close to than half will succumb to recurrent and/or 
metastatic disease. If untreated, the median survival of patients with metastatic disease is 
dismal and on the order of 4 months (Bentzen 2005; Ang, Berkey et al. 2002). 
 
In patients with recurrent or metastatic HNSCC, therapeutic options are usually palliative 
consisting of systemic chemotherapy and the EGFR inhibitor cetuximab in the first-line 
treatment setting (Vermorken et al. 2007; Vermorken et al. 2008). Median survival is 
estimated at 10.1 months using a combination of cisplatin/5-FU/cetuximab. Cytotoxic 
chemotherapy can have significant toxicities, consisting of bone marrow suppression, 
nausea/vomiting, rash, hand-foot syndrome, and many others.  Better therapeutic options are 
necessary. Second line treatment options include methotrexate, taxanes, or clinical trials. 
Targeted therapies after the failure of cetuximab are generally considered inactive, e.g. use 
of sorafenib in a clinical trial resulted in a response rate of ≤5% (Williamson et al. 2010, de 
Souza et al 2012), and generally a drug with ≤5% response rate is not considered 
active/worthy of further study.  
1.2 
Introduction to investigational treatment 
1.2.1 
Overview of BGJ398 (infigratinib) 
BGJ398 (infigratinib) is an orally bioavailable, potent and selective inhibitor of the fibroblast 
growth factor receptors (FGFRs). The FGFR family of receptor tyrosine kinases (RTKs) 
consists of four members (FGF-R1, FGF-R2, FGF-R3, FGF-R4), which serve as the high 
affinity receptors for 22 FGF ligands. These are pleiotropic growth factors that control cell 
proliferation, migration, angiogenesis, apoptosis and differentiation and are involved in both 
developmental and adult tissue homeostasis. More recently, cancer epidemiological and 
molecular studies have reported various genetic alterations including gene amplifications, 
mutations and chromosomal translocations, as well as aberrant protein expression for this 
family of RTKs and ligands. Further, their link to cancer dependence has been established 
preclinically by means of loss of function approaches. Preclinical research studies have shown 
that BGJ398 selectively suppresses FGFR signaling and proliferation in cancer cells with FGFR 
dependency and also the tumor growth of mouse and rat xenograft models associated with 
aberrant FGFRs expression/activation. On this basis, targeted inhibition of FGFRs can be 
exploited for therapeutic gain. 


 
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BGJ398 (infigratinib) belongs to the pyrimidinyl aryl urea chemical class and its chemical name 
is 
3-(2,6-Dichloro-3,5-dimethoxyphenyl)-1-{6-[4-(4-ethyl-1-piperazin-1-yl)phenylamino]-
pyrimidinyl-4-yl}-1-methylurea phosphate(1:1).   
Please refer to the Investigator’s Brochure for additional information on BGJ398 (infigratinib). 
1.2.1.1 
Non-clinical experience 
At the cellular level, BGJ398 (infigratinib) selectively inhibits the kinase activity of FGFR1 
FGFR2, FGFR3, and FGFR 4 as measured by inhibition of receptor autophosphorylation with 
IC50 values of 3 – 7 nM for FGFR1, FGFR2 and FGFR3, and 168 nM for FGFR4. In cellular 
kinase selectivity assays using a panel of BaF3 cell lines rendered IL-3 independent by various 
tyrosine kinases, the most potently inhibited kinase, in addition to the FGFRs were VEGFR2 
and FLT1 with IC50s of 1510 nM and 1591 nM, respectively. 
Consistent with inhibition of FGFR autophosphorylation, BGJ398 (infigratinib) inhibits FGFR 
downstream signaling and proliferation of human cancer cell lines harboring genetic alterations 
of the FGFRs. These include, among others, lung and breast cancer cell lines with FGFR1 gene 
amplification, gastric cancer with FGFR2 gene amplification, endometrial cancer with FGFR2 
mutations and bladder cancer with FGFR3 mutations or FGFR3 translocations (Wesche, 2011). 
In line with its cellular activity, BGJ398 (infigratinib) shows anti-tumor activity in multiple 
models bearing FGFR genetic alterations (Guagnano, 2012; Konecny, 2013).   
In vivo, BGJ398 significantly inhibits growth of tumors in a dose-dependent manner in 
various mouse and rat xenograft subcutaneous or orthotopic models. These include models of 
bladder cancer (RT112, MGHU3), multiple myeloma (KMS11), endometrial cancer 
(AN3CA), and gastric cancer (SNU16). The dose ranges needed to induce tumor growth 
inhibition; stasis and regression are well tolerated based on body weight monitoring. In vivo 
pharmacokinetic/pharmacodynamic (PK/PD) analyses of tumor tissues and blood biomarkers 
show a good correlation between the given dose, AUC in plasma and tumor tissues, the 
effects. on the FGFR pathway as measured by the phosphorylation status of FRS2 and MAPK 
activation and the antitumor activity.  
Please refer to the Investigator’s Brochure for additional information on BGJ398 (infigratinib). 
 
1.2.1.1.1 Animal drug metabolism and pharmacokinetics 
In all species tested, BGJ398 (infigratinib) 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 (infigratinib) is widely 
distributed to tissues in the rat and has a high affinity to melanin containing tissues. In vitro 
hepatic systems metabolize BGJ398 (infigratinib) predominantly to 2 pharmacologically active 
metabolites: BHS697 and BQR917. Biotransformation of BGJ398 (infigratinib) 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 (infigratinib) is primarily a CYP3A4 substrate.  


 
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BGJ398 (infigratinib) 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 (infigratinib) is also a time dependent inhibitor of 
CYP3A4 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). 
Please refer to the Investigator’s Brochure for additional information on BGJ398 (infigratinib). 
 
1.2.1.1.2 Preclinical Safety  
BGJ398 showed no evidence of genotoxicity (in vitro and in vivo) and no evidence of 
phototoxicity in a 3T3 photo-cytotoxicity test. In vitro safety pharmacology assessment of 
BGJ398 revealed a potential for QTc prolongation.  
In repeated dose (oral gavage; up to 13 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 and dogs. These effects were deemed to be on-target effects mediated by 
pharmacological inhibition of FGFR.  
In rat toxicity studies, ophthalmoscopic examination revealed increased severity of mainly 
bilateral corneal opacity during the treatment period. This finding showed a trend towards 
reversibility. The ophthalmoscopic finding of cornea opacity correlated histopathologically 
with cornea thinning/keratopathy, mineralization and meibomian gland atrophy which likewise 
showed a trend towards reversibility.  
In the 13-week rat toxicity study, besides the cornea thinning, additional effects on the 
epithelium (thinning or degeneration) were reported mainly for the tongue, nasal cavity and 
incisors (non-growing teeth such as the molar teeth were not affected). In the 13-week dog 
toxicity study only, atrophy of the meibomian and sebaceous gland was reported. In rat and dog 
13-week toxicity study, a change in the coat appearance (denoted by relatively longer hair/fur) 
was noted. This finding did not show any microscopic correlate.  
Please refer to the Investigator’s Brochure for additional information on BGJ398 (infigratinib). 
 


 
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1.2.1.1.3 Pharmacology and toxicology 
BGJ398 (infigratinib) 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 (infigratinib) 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 (infigratinib) 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 (infigratinib) treatment consisting 
of irreversible, slight corneal opacity in dose-dependent incidence, as assessed by in vivo 
ophthalmology, associated with reversible, diffuse epithelial keratopathy at the highest dose of 
10 mg/kg. In the 4-week GLP oral toxicity study in rats, the severely toxic dose in 10% (STD10) 
was considered to be at 10 mg/kg/day which resulted in premature death in one (1/30) animal. 
Doses of 20 mg/kg/day in rats did lead to vasculopathy associated with morbidity after 6 
administrations. In dogs, the highest non-severely toxic dose was considered to be at 10 
mg/kg/day leading to 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 
 
BGJ398 is being evaluated in the following studies:  
 Two phase I studies (BGJ398X1101 and BGJ398X2101)   
 Three phase II studies (CBGJ398X2201, CBGJ398X2204, and CBGJ398XUS04)   
 One phase Ib study that is evaluating BGJ398 in combination with the PI3K alpha 
specific inhibitor BYL719 (BGJ398X2102).   (Not referenced here  See 
investigator brochure) 
 Four healthy volunteer studies, CBGJ398X2103, CBGJ398X2105 CBGJ398A2104 
and CBGJ398X2106 have been conducted.  (Not referenced here  See investigator 
brochure) 
1.2.1.2.1 Clinical safety 
 
CBGJ398X1101  


 
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The purpose of this first in human study is to evaluate safety and to determine the MTD of 
BGJ398 in the Japanese population. As of the September 4, 2015 cutoff date for this clinical 
database, nine patients were enrolled to two dose escalation cohorts, 50 mg BGJ398 (N=4) and 
100 mg BGJ398 (N=2) and one safety run-in cohort in the Chinese population 100 BGJ398 
(N=3). No dose limiting toxicities (DLTs) have been reported.  
CBGJ398X2101  
As of data cut-off date January 30, 2017, 208 patients have received at least one dose of BGJ398. 
Forty-three patients were enrolled to dose escalation cohorts and 165 patients to dose expansion 
arms.  
Enrollment to the dose escalation cohorts was as follows: 5mg [N=3], 10mg [N=3], 20mg [N=4], 
40mg [N=6], 60mg [N=3], 100mg [N=6], 50 mg bid [N=4], 125mg [N=8], and 150mg [N=6]. 
MTD was identified to be 125 mg qd on a continuous dosing schedule.  
This document (090095af89ea165c in docbase CREDI_EH) has been digitally signed with 
external signatures using Entrust PKI. Signatures manifested as of 12/5/2017 4:30:52 PM, 
signing status at this time: Completed (1 of 1 signatures) Approved for report publication by 
Sharma Neelesh in East Hanover at Tue, 05 Dec 2017 11:30:30 AM EST  
Dose expansion consists of 4 arms enrolling different patient populations on two different 
dosing schedules at 125 mg (daily or 3 weeks on/1 week off in 28-day cycles). Arm 1 [N=28] 
enrolled FGFR1-amplified advanced or metastatic squamous NSCLC with FGFR1 
amplification on the continuous dosing schedule. Arm 2 [N=21] enrolled advanced solid 
malignancies with any FGFR mutation or amplification dosed continuously. Arm 3 [N=49] 
enrolled advanced solid malignancies with any FGFR genetic alteration, mutation, or 
amplification on the 3 weeks on/1 week off dosing schedule. Arm 4 [N=67] enrolled advanced 
or metastatic urothelial cell carcinoma (UCC) with FGFR3 mutation or gene fusion on the 3 
weeks on/1 week off dosing schedule.  
The 3 weeks on/1 week off schedule was implemented based on observations of the timing and 
duration of drug interruptions during Cycle 1 necessitated by episodes of hyperphosphatemia. 
The data for continuous dosing before the alternative regimen was introduced indicated that the 
median time to drug interruption was 22 days and the median duration of the interruption was 
7 days.  
At the time of data cutoff, 11 patients were still receiving study medication. Of the 197 patients 
who have discontinued from the study, 145 discontinued treatment due to progression of disease, 
30 discontinued due to adverse events, 6 died while on study, 14 discontinued due to withdrawal 
of consent, 1 due to administrative problems, and 1 due to lost to follow-up.  
Adverse events  


 
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The treatment emergent adverse events as of the cutoff date of January 30, 2017, regardless of 
BGJ398 relationship, that occurred in 20% or more of patients are: hyperphosphatemia, 65.4%, 
constipation (39.9%), decreased appetite (37.5%), fatigue (36.1%), stomatitis (34.1%), nausea 
(32.2%), blood creatinine increased/hypercreatininaemia (29.8%), diarrhea (28.4%), alopecia 
(26.4%), dry mouth (24.5%), vomiting (21.6%), and anemia, 20.7%, (Table 5-14). 
Approximately 59percent of patients (122/208) experienced at least one grade 3 or 4 event 
regardless of the relationship to BGJ398, (Table 5-15). Grade 3 or 4 events that occurred in at 
least 5% of patients were lipase increased (6.7%) and alanine aminotransferase increased (5.3%). 
Overall, most adverse events reported have been mild to moderate in severity, reversible, and 
unrelated to BGJ398.  
Four DLTs occurred in four patients enrolled in the dose escalation part of the study. The MTD 
as determined by DLT was based on the following events.  
 One grade 3 event of AST/ALT elevation was reported in the 100mg cohort.   
 One patient enrolled to the 125 mg cohort experienced hyperphosphatemia for 
greater than  14 days despite adequate therapy that resulted in study drug 
interruption.   
 Two patients enrolled to the 150 mg cohort experienced DLTs. One patient 
experienced grade 1 corneal toxicity. The second patient experienced grade 3 
AST/ALT elevations, which led to study treatment interruption and dose reduction. 
  
 
CBGJ398X2204  
This study is designed to evaluate the efficacy of BGJ398 when administered as a single agent 
to patients with advanced or metastatic cholangiocarcinoma with FGFR2 gene 
fusions/translocations or other FGFR genetic alterations. The treatment dose of BGJ398 is 125 
mg q.d. for the first 3 weeks (21days) of a 28-day cycle, followed by a 7 day break. The dosing 
regimen for BGJ398 was chosen based on data obtained from the CBGJ398X2101study.  
As of June 01, 2017, 63 patients have been treated which included fifty patients with FGFR2 
fusions and thirteen patients with other FGFR alterations.  
Adverse Events  
Table 5-20 lists the treatment emergent adverse events that have been reported for the 
CBGJ398X2204 study. The most commonly reported treatment emergent adverse event of any 
grade was hyperphosphatemia, reported in 82.5% of patients. Other frequently reported adverse 
event include fatigue (49.2%), constipation (41.3%), stomatitis (38.1%), alopecia (38.1%), 
dysgeusia (31.7%), blood creatinine increased (27.0%), hypophosphatemia (27.0%), nausea  
(27.0%), diarrhea (25.4%), dry eye (25.4%), arthralgia (23.8%), dry mouth (23.8%), dry skin 
(23.8%), palmar plantar erythrodysesthesia syndrome (23.8%), aspartate aminotransferase 
increased 
(22.0%), 
decreased 
appetite 
(20.6%), 
hypercalcemia 
(20.6%), 
alanine 
aminotransferase increased (19.0%), vision blurred (19.0%), anemia (17.5%), dyspepsia 
(17.5%), vomiting (17.5%), weight decreased (17.5%), epistaxis (17.5%), onychomadesis 
(17.5%), myalgia (17.5%), pain in extremity (16.1%) and cough (16.1%).  


 
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Forty one of 63 patients (65.1%) experienced at least one grade 3 or 4 event regardless of the 
relationship to BGJ398, Table 5-20. Grade 3 or 4 events that occurred in at least 5% of patients 
were hyperphosphatemia (15.9%), hypophosphatemia (6.3%), hyponatremia (12.7%), lipase 
increased (7.9%), and stomatitis (7.9%).  
Twenty nine of 63 patients (46.0%) experienced at least one grade 3 or 4 suspected to be related 
to BGJ398, Table 5-21. Grade 3 or 4 events that occurred in at least 5% of patients were 
hyperphosphatemia (15.9%) and stomatitis (7.9%).  
Overall, most adverse events reported have been mild to moderate in severity, reversible, and 
unrelated to BGJ398.  
 
CBGJ398XUS04  
This is a phase II, open label study to determine the efficacy and safety of single agent BGJ398 
in patients with a diagnosis of solid tumors or hematological malignancies that have been pre- 
identified (prior to study consent) to have FGFR genetic alterations and whose disease has 
progressed on or after standard treatment. The treatment dose of BGJ398 is 125 mg q.d. on a 3 
week on (21 day) /1 week off (7 day) schedule. This dose level and regimen was selected based 
on experiences from the CBGJ398X2101 trial.  
As of October 5, 2017, 85 patients have been treated on this study. The study is closed to 
enrollment.  
Adverse events  
The most commonly reported treatment emergent adverse event of any grade regardless of 
BGJ398 relationship was hyperphosphatemia, occurring in 48% of patients. Other frequently 
reported treatment emergent adverse events include fatigue (45%), nausea (29%), constipation 
(28%), diarrhoea (23%), dry mouth (22%), stomatitis (22%), blood creatinine increased (21%), 
decreased appetite (21%), dysgeusia (20%), blood phosphorus increased (19%), vomiting 
(17%), abdominal pain (15%), alopecia (15%), dehydration (15%), dry eye (15%), urinary tract 
infection (15%), weight decreased (15%), mucosal inflammation (14%), dyspnoea (13%), 
hypomagnesaemia (13%), aspartate aminotransferase increased (12%), anaemia 10)%), blood 
alkaline phosphatase increased (10%), hyponatraemia (10%), pain in extremity (10%) and 
pyrexia (10%).  
Grade 3 or 4 events that occurred in at least 5% of patients were hyperphosphatemia (8%) 
fatigue (8%) and nausea (5%). Overall, most adverse events reported have been mild to 
moderate in severity, reversible, and unrelated to BGJ398.  
 
 
Please refer to the Investigator Brochure for additional information on BGJ398 (infigratinib). 
1.2.1.2.2 Preliminary efficacy of BGJ398 (infigratinib) 
CBGJ398X2101  


 
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Preliminary antitumor efficacy has been shown in patients treated at ≥ 100 mg in squamous 
NSCLC and urothelial carcinoma with FGFR genetic alterations. As of 15 May 2015, 4/36 
patients with NSCLC and 3/8 patients with urothelial carcinoma achieved PR (Nogova L et al 
JCO 2017). In addition, as of 1 Mar 2016, of 37 evaluable patients in a dedicated arm for 
urothelial carcinoma, 12 achieved PR, and 1 achieved CR (Pal et al ASCO 2016).  
CBGJ398X2102  
Preliminary anti-tumor activity has been detected in patients treated at doses of ≥100 mg of 
BGJ398 in combination with 300 mg BYL719. This activity has been detected in patients with 
the following tumor types; bladder, breast, ovarian, and head and neck.  
CBGJ398X2204  
Preliminary antitumor activity has been observed in cholangiocarcinoma patients harboring 
FGFR2 fusion or other FGFR genetic alteration treated with 125mg BGJ398 on 3 weeks on, 1 
week off schedule. Of the 63 patients enrolled to the BGJ398X2204 study, there were 59 
patients evaluable for efficacy (with valid baseline and at least one valid post-baseline 
assessment). Out of these 59 patients, 15 (23.8%) patients had BOR of confirmed partial 
response and 33 (52.4%) experienced BOR of stable disease. Therefore, the primary endpoint 
of investigator-assessed ORR (confirmed responses only) is 23.8%. Disease control rate is 76.2% 
(48 patients). Additionally, out of the 33 patients who achieved stable disease, 4 patients 
achieved PR in one scan (did not have subsequent scan confirming the PR). The median PFS is 
estimated at 6.7 months (95% CI: 4.8-7.6 months). Of the 63 patients,49 (77.8%) had a PFS 
event (4 deaths and 45 patients progressed as per RECIST). (Javle M et al JCO 2018) 
 
1.2.1.2.3 Conclusion of safety and efficacy in humans 
 
Preliminary data obtained from the CBGJ398X2101 first in human trial indicate that the main 
safety findings in patients treated with BGJ398 (infigratinib) were as expected based on the 
preclinical studies: The on-target effects on calcium-phosphate homeostasis result in the 
observed increases in calcium, phosphorus, and creatinine, and not associated with clinical 
symptoms. In general, the increases have been mild to moderate in severity and manageable 
and reversible upon interruption or discontinuation of BGJ398 administration.  
Ocular adverse events are frequent, but generally mild to moderate in severity and reversible. 
Corneal or retinal adverse events are recognized on ophthalmologic evaluations.  
No effect of BGJ398 (infigratinib) on ECG intervals, including QTc has been noted. Reversible 
and largely asymptomatic decreases in LVEF have been noted in patients enrolled on study as 
measured by serial TTE or MUGA scans.  
The preliminary efficacy signals were observed in multiple patients including patients with 
squamous cell histology. 
 
 


 
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1.2.1.2.4 Clinical pharmacokinetics 
The pharmacokinetics (PK) of BGJ398 (infigratinib) and active metabolites have been 
evaluated following single and repeat daily doses in the ongoing phase 1 study (CBGJ398 
(infigratinib)X2101).   
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.   
Following a single dose, median Tmax was approximately 2-3 hours.  The mean AUC0-24 on 
Day 1 increased approximately 9 fold from 20 to 150 mg.  A 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 (infigratinib), PK parameters on Day 28 should be viewed with caution.  The inter-
patient variability was high for BGJ398 (infigratinib).  When dosed at 125 mg with a schedule 
of 3 weeks on, 1 week off, the mean Cmax and AUC0-24 were 230 ng/mL (n=12) and 3492.9 
ng*hr/mL, (n=10), respectively at day 15. The coefficient of variation for Cmax and AUC0-24 
ranged from approximately 50 – 75% and higher variability was observed while estimating 
secondary pharmacokinetic parameters like clearance and volume of distribution.   
Concentration data from active metabolites BHS697 (desethyl metabolite) and BQR917 (N-
oxide) was available across all cohorts.  CQM157 (aniline metabolite) was analyzed in a few 
patients following Amendment 6 of the BGJ398 (infigratinib)X2101 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 
(infigratinib) varied across patients (3% -300%).  CQM157 (N=4) did not appear to accumulate 
on daily dosing, whereas accumulation was observed for BGJ398 (infigratinib) and metabolites 
BHS697 and BQR917. 
Please refer to Investigator’s Brochure for more details.  
 
 
 
 
 
 
 


 
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2 
Study purpose/rationale 
Head and neck cancer (HNC) is the 6th most common cancer worldwide (~50,000 cases/year 
in the US; 60,000 cases/year in Europe).  Once recurrent or metastatic, head and neck cancer 
carries a poor prognosis with a median survival of only 6-10 months (Vermorken et al. 2008; 
Seiwert et al. 2008).  Cetuximab is the only approved targeted therapy for this disease and 
the response rate is 13% (Vermorken et al. 2007; Seiwert et al. 2012).  Better treatments are 
needed. 
 
Over the past decade, it has become clear that HPV-related (HPV (+)) head and neck cancer 
represents a distinct epidemiologic, molecular, pathologic, and clinical entity.  In recent years, 
HNSCC, in particular, oropharyngeal cancer, has shown a sharp increase in incidence related 
to oncogenic HPV16 infections (Marur et al. 2010).  These cancers arise almost exclusively in 
the oropharynx (base of tongue and tonsil) for reasons that have not yet been identified, and 
tend to affect younger patients, appear to metastasize early to regional lymph nodes, and carry 
better prognosis than “classic” smoking and alcohol related, HPV (-) HNSCC (Marur et al. 
2010).  Interestingly, up to 70% of oropharyngeal cancers in several developed countries, 
including the US, is felt to be HPV-related (Chaturvedi et al. 2011).  HPV has also been detected 
in smaller subsets of laryngeal and oral cavity cancers, though these estimates are closer to 10% 
(Halec et al. 2013).  HPV origin of HNSCC in individual patients can be established by direct 
assessment of HPV based on detection of HPV DNA or RNA (i.e. in situ hybridization or PCR).  
However, more frequently, p16 immunohistochemistry can serve as a surrogate marker for 
oropharyngeal cancers, albeit concerns about accuracy have been voiced (Vokes et al. 2013).   
 
Along with the classification of HNC into HPV (+) and HPV (-) diseases, the head and neck 
cancer (HNC) genome has been defined in several cohorts.  The Cancer Genome Atlas (TCGA) 
sequenced tumor samples from 279 patients with HNC containing primarily HPV (-) tumors 
(87%) while the University of Chicago HNC Genomics cohort (CHGC) analyzed tumor samples 
from 134 patients with a large HPV (+) cohort (41%).  While HPV (+) and HPV (-) HNSCC 
are genetically distinct tumors, with HPV negative HNSCC paralleling the genomic landscape 
of lung squamous cell carcinoma and HPV (+) HNSCC resembling cervical carcinoma (Hayes 
et al 2013), both large cohorts confirm fibroblast growth factor receptor (FGFR) as an emerging 
target for HNC.   
 
With the changing epidemiology of head and neck cancers and the rise of HPV-related (HPV 
(+)) HNSCC largely in developed countries, it is becoming increasingly important to recognize 
HPV (+) and HPV (-) HNSCC as two distinct tumor types, which may have differential response 
to targeted therapeutics.  Interestingly, one of the most common potentially targetable 
aberration in both HPV (-) and HPV (+) SCCHN are alterations in the fibroblast growth factor 
receptor family, with the spectrum of alterations being distinct in both subtypes of HNSCC. 
 


 
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Fibroblast growth factor receptor plays an important role in cancer and is an emerging treatment 
target for lung, bladder, and other cancer types.  Data from the University of Chicago HNC 
Genomics cohort show FGFR2-3 mutations in HPV (+) head and neck cancer at rates of 15% 
in our cohort – and 8% in the TCGA cohort.  Most of these mutations are canonical/predicted 
driver mutations (six S249C FGFR3 mutations (validated by Sanger sequencing in the CHGC 
cohort), as well as two N569K/D FGFR2 mutations also in our cohort).  Pre-clinically, the 
multikinase inhibitor ponatinib, which does inhibit FGFR1-4 has demonstrated in vitro and in 
vivo single agent clinical activity against such driver mutations (Wu et al. 2013). 
 
While the prevalence of FGFR2-3 mutations in HPV (-) HNSCC is lower (4% in HNC TCGA), 
FGFR1 amplification has been demonstrated in 10% of HPV (-) head and neck cancer in the 
TCGA cohort, interestingly primarily in laryngeal cancers (Vermorken et al. 2008).  FGFR1 
amplifications have also been reported in oral carcinoma (Freier et al. 2007).  More recently, 
autocrine signaling loops involving FGFR2 and FGFR1 have been reported in HNC cell lines 
(Marshall et al. 2011).  As investigators have used varying definitions of gene amplification, 
we prefer to adopt copy number ≥ 6 as a standard definition of high level amplification, which 
seems to be most predictive of response to therapy, with copy number assessed through next 
generation sequencing. 
 
Furthermore, the HNC-TCGA data has reported three TACC3-FGFR3 translocations, two in 
HPV (+) (incidence of ~5% in HPV (+)) tumors), with a slightly different breakpoint from 
bladder/lung SCC, as well as a functionally unclear FGFR1 translocation (Hayes et al. 2013).  
Cell lines harboring FGFR3 fusion proteins have exhibited exquisite susceptibility to 
pharmacologic inhibition in vitro and in vivo (Wu et al. 2013).  As the FGFR3 breakpoint can 
occur with different partner proteins, we utilize RNA based detection to avoid interrogation of 
large intronic areas.  At the University of Chicago we have established a next generation 
sequencing based genetic profiling assay (comparable to Foundation One assay) that includes 
detection of TACC3-FGFR3 translocations. In summary: 
 
FGFR1: 
FGFR1 amplification has been demonstrated in 10% of HPV (-) head and 
neck cancer in the TCGA cohort primarily in laryngeal cancers.  FGFR1 amplifications have 
also been reported in oral carcinoma. More recently, autocrine signaling loops involving 
FGFR2 and FGFR1 have been reported in HNC cell lines.   
FGFR2-3: 
Data from the University of Chicago HNC Genomics cohort show FGFR2-3 
mutations in HPV (+) head and neck cancer at rates of 15% in our cohort – and 8% in the 
TCGA cohort.  Most of these mutations are canonical/predicted driver mutations (six S249C 
FGFR3 mutations (validated by Sanger sequencing), N569K/D FGFR2 mutations in our 
cohort).  Pre-clinically, the multikinase inhibitor ponatinib has demonstrated in vitro and in 
vivo single agent clinical activity against such driver mutations. 
FGFR3: 
The HNC-TCGA data has reported three TACC3-FGFR3 mutations, with a 
slightly different breakpoint from bladder/lung SCC, as well as a functionally unclear 
FGFR1 translocation.  Cell lines harboring FGFR3 fusion proteins have exhibited exquisite 
susceptibility to pharmacologic inhibition in vitro and in vivo. 


 
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Oncogenic translocations involving FGFR3, and recurrent FGFR3 and FGFR2 mutations 
have been reported in >10% of HPV (+) tumors, while HPV (-) tumors have a ~10% rate of 
FGFR1 amplification and ~5% rate of FGFR2/3 mutations.  In brief, while the spectrum of 
alterations seems to be distinct in both subtypes of HNSCC, fibroblast growth factor receptor 
(FGFR) emerges as a targetable pathway in both HPV (+) and HPV (-) HNSCC. 
Unlike cancers in which genetic aberrations correlate with activity of certain targeted agents, 
there are currently no such therapies approved for squamous cell carcinomas including 
HNSCC.  While cetuximab is approved both upfront in combination with radiation or in the 
recurrent/metastatic disease setting, there are no biomarkers to predict response to therapy 
(Vermorken et al. 2008).  Based on the literature from the Cancer Genome Atlas as well as 
our Chicago HNC Genome cohort, we propose to assess the oral specific and potent pan-
FGFR inhibitor BGJ398 (infigratinib) in patients with head and neck cancer with a focus on 
FGFR relevant biomarkers that hold potential to identify patients who will benefit from 
therapy with BGJ398 (infigratinib). 
This study analyses a novel pathway and attempts to establish fibroblast growth factor 
receptor (FGFR) as a targetable pathway in HPV (+) and HPV (-) FGFR1-3 translocated, 
mutated, or amplified squamous cell carcinoma of the head and neck. 
3 
Objectives and endpoints 
3.1 
Primary Objectives 
 
 
Objective 
Endpoint/Analysis 
Primary 
Assess efficacy of BGJ398 (infigratinib) in FGFR 
altered HNSCC 
 
Objective Response Rate 
(RECIST 1.1) (complete or 
partial response) 
3.2 
Secondary Objectives 
 
 
Objective 
Endpoint/Analysis 
Secondary 
Assess safety and tolerability of BGJ398 
(infigratinib) in patients with Head and Neck 
Cancer 
 
AE / SAE 
Secondary 
Assess duration of response, progression free 
and overall survival 
DOR / PFS* / OS** 
*Progression-free survival [days] = date of progression (or of death if no earlier progression) –
date of randomization +1 
 


 
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*Progression-free survival (censored) [days] = date of last adequate assessment per RECIST 
1.1 with negative imaging before patient withdrawal of consent or start of new therapy – date 
of randomization +1 
 
**Overall survival [days] = date of death – date of randomization +1 
 
Trial termination is synonymous with off study / end of treatment. 
 
3.3 
Exploratory Objectives 
 
 
Objective 
Endpoint/Analysis 
Exploratory Determine mechanisms of resistance to FGFR 
inhibition at disease progression  
Genomic profiling of pre- 
response tumor tissue and 
comparison with acquired 
resistance 
tumor 
specimen 
Exploratory Assess efficacy of BGJ398 (infigratinib) in 
relation to specific genetic aberrations in FGFR 
altered 
HNSCC 
(i.e. 
FGFR3-TACC3 
translocation, 
FGFR1 
high 
copy 
number/amplification, FGFR2 mutation, FGFR3 
mutation) 
 
Response 
Rate 
in 
subgroups of patients (as 
defined by certain genetic 
changes in FGFR1-3) 
Exploratory Efficacy by HPV status 
Descriptive response rate 
in both HPV(+) and HPV(-) 
patients. 
 
Overall, we hypothesize that: 
 
1) BGJ398 (infigratinib) will have clinical activity in FGFR altered HNSCC 
2) BGJ398 (infigratinib) will demonstrate clinical activity in FGFR altered HNSCC 
3) BGJ398 (infigratinib) will demonstrate clinical activity in all FGFR subgroups (i.e. 
FGFR1 high copy number/amplification, FGFR2 mutation, FGFR3 mutation, FGFR3 
translocation) 
4) Re-biopsy of patients who demonstrate initial response, followed by subsequent disease 
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4 
Investigational plan 
 
Definitions 
 
Cycle 
A 4-week period of treatment with study medication BGJ398 (infigratinib) 
End of treatment (EOT) visit 
Clinic visit/assessment within 14 days of permanent termination of trial 
drug intake 
End of post treatment follow-up 
Clinic visit/assessment at Day 28 ± 8 days after the EOT visit 
4.1 
Overview of Study Design and Schema 
Open label single arm study in FGFR altered HNSCC.  There is no dose escalation; we will 
employ the established phase II dose. 
Intervention Status:  Interventional  
Study Phase:  Phase IIa 
 
 


 
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NB: In order to allow a representative sampling of genetic aberrations each type of genetic 
aberration should be represented and enrollment for other genetic aberrations can be 
limited (see inclusion criteria). Such adjustments can be made by the Lead Investigator 
via a memo.   
 
This phase IIa proof-of-concept trial will be an open-label single arm study in multiple centers 
through the University of Chicago personliazed cancer care Consortium (PCCC), in which all 
eligible patients with histologically-confirmed recurrent/metastatic HNSCC and FGFR 
alteration will receive BGJ398 (infigratinib) at 125 mg PO daily.  Patients with FGFR1-3 high 
level amplification, mutation, or translocation will be included.   
 
 
 
4.1.1   FGFR aberration (pre-screening) 
 
In order for patient to be eligible one of the following genetic aberrations need to be present in 
the tumor: 
-           FGFR1 amplification, FGFR1 somatic mutations, FGFR1 translocations. 
-           FGFR2 somatic mutations, FGFR2 translocations, FGFR2 amplification. 
-           FGFR3 somatic mutations, FGFR3 translocations, FGFR3 amplification. 
 
NB: In order to allow a representative sampling of genetic aberrations each type of genetic 
aberration should be represented and enrollment for other genetic aberrations can be 
limited (see inclusion criteria). Such adjustments can be made by the Lead Investigator 
via a memo.   
 
A number of next generation sequencing based tests are acceptable including Foundation One 
based testing, academic center CLIA laboratory based testing (e.g. DFCI Profile, University of 
Chicago large and small mutation and/or translocation panels, others). Additional commercial 
tests, and tests using other methodologies in a CLIA laboratory are potentially acceptable, but 
should 
be 
confirmed 
by 
the 
Lead 
Investigator 
prior 
to 
use 
(Dr. 
Seiwert, 
tseiwert@medicine.bsd.uchicago.edu, 773-702-2452)  
 
Testing is not part of this study, but the University of Chicago does offer limited testing for 
outside centers and centralized genomic profiling/prescreening can be offered through the U 
Chicago molecular pathologic laboratory.  Please contact Dr. Tanguy Seiwert if requesting Univ. 
of Chicago molecular analysis/testing. 
 
Each cycle is 4 weeks.  CT scans will be obtained every 2 cycles.   This study will enroll 15 
HPV (+) and 15 HPV (-) patients with HNSCC and FGFR alterations.   
 


 
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Primary objective will be objective response rate (ORR; complete or partial response) of 
BGJ398 (infigratinib) in FGFR altered HPV (-) and HPV (+) SCCHN (Simon Two Stage 
Design).  As genomic profiling will be used as a prescreening tool to identify FGFR altered 
tumors, an exploratory objective will be to assess efficacy of BGJ398 (infigratinib) in relation 
to specific genetic aberrations in HPV (+) and HPV (-) FGFR altered HNSCC (i.e. FGFR3-
TACC3 translocation, FGFR1 high copy number/amplification, FGFR2 mutation, FGFR3 
mutation).  Please refer to statistical considerations, methods, and data analysis in Section 11. 
 
In responders who subsequently demonstrate disease progression (acquired resistance), 
mandatory tissue biopsy will be performed and genomic profiling of pre-treatment tissue will 
be compared to genomic profiling of acquired resistance tumor to explore mechanisms of 
acquired resistance to FGFR inhibition.  Primary (and secondary/exploratory) endpoints will be 
assessed through RECIST 1.1 defined response rate. 
 
4.2 
4.1.2   Methods of FGFR screening 
 
This trial requires screening for FGFR aberration prior to patient trial enrollment.   
Both DNA and RNA based assay that detect FGFR1-3 mutation, amplification, and 
translocations are acceptable.   
 
FGFR1-3 aberrations can be determined by any next generation sequencing based assay prior 
to enrolling a patient on study. Alternative assays may be acceptable (e.g. FISH, Sanger 
Sequencing, qPCR) after discussion with the Lead Investigator (Dr. Seiwert). Commercial 
assays as well as academic assays will be acceptable if done in a CLIA laboratory. 
 
In case a patient tumor is not already characterized, characterization is available via the 
University of Chicago. A separate (non-study related) consent form is provided to perform 
FGFR testing. This pre-screening is NOT considered enrollment on the actual trial. 
 
The following genetic aberrations will be screened for: 
- 
FGFR1 amplification, FGFR1 somatic mutations, FGFR1 translocations. 
- 
FGFR2 somatic mutations, FGFR2 translocations, FGFR2 amplification 
- 
FGFR3 somatic mutations, FGFR3 translocations, FGFR3 amplification 
 
Other genetic FGF/FGFR pathway aberrations may be acceptable should such genetic changes 
be observed to emerge and require approval per the Lead Investigator for enrollment (e.g. FGF 
amplification). 
Should one genetic aberration be overrepresented in one or both of the arms, the Lead 
Investigator (Dr. Seiwert) may decide to restrict enrollment of such patients. A 
notification/memo will be sent out to all participating investigators should such a restriction on 
enrollment be implemented (see inclusion criteria). 
 


 
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4.1.3      Investigational treatment, other study treatment, study treatment, 
supportive treatment 
 
The investigational study drug used in this trial is BGJ398 (infigratinib), which is supplied as 
capsules. 
 
 
4.3 
Treatment 
 
Treatment   
Arm/Cohort 
# of Pts 
Planned 
Type of Study 
Drug 
Compound 
(specify brand 
or generic) 
Min 
Dose 
and 
unit 
Max 
Dose 
and 
unit 
Frequency  Admin 
Route 
FGFR 
altered 
HNSCC 
 
20 
Investigational BGJ398 
(infigratinib) 
125mg n/a 
Daily, 21 
days on, 7 
days 
off 
(28-day 
cycle) 
PO 
4.4 
Definition of a treatment cycle 
 
A complete treatment cycle is defined as 21 days of uninterrupted continuous treatment with 
the study drug BGJ398 (infigratinib) followed by a 7 day break. The first dose of BGJ398 
(infigratinib) defines Cycle 1 Day 1. All treatment cycles have a duration of 28 days. There 
will be no delays between cycles, i.e. study day 29 represents Cycle 2 Day 1. 
4.5 
Treatment duration  
 
CT scan assessment of response / tumor measurements (RECIST) will be every 2 cycles (= 8 
weeks) for all patients. Patients will continue on therapy until disease progression, death, 
intercurrent illness that prevents further administration of treatment, unacceptable adverse 
events, patient elects to withdraw from study, or conditions which render the patient 
unacceptable for further treatment in the judgment of the investigator. Patients will be followed 
≤ every 1-3 months for survival until 5 years post treatment or until death, whichever occurs 
first.  Patients removed from this study for unacceptable adverse event(s) will be followed until 
resolution or stabilization of the adverse event. 
 
4.6 
Treatment assignment/randomization 
Patients in will receive study medication BGJ398 (infigratinib) 125 mg PO daily for 21 days, 
followed by a 7 day break. 


 
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An exception may be made per approval by the Lead Investigator and Novartis to switch to 
continual dosing 28-days, potentially at a reduced dose should evidence emerge that tumor 
progression occurs during the one-week off.    
4.7 
Rationale for the study design 
 
Based on the TCGA and our University of Chicago HNC cohort: 
- FGFR2-3 mutations are estimated to occur in 5-8% of HPV (-) HNC and 10-15% of HPV (+) 
HNC.  
- FGFR1 amplification is estimated to occur in 7-10% of HPV (-) HNC.   
- FGFR3-TACC3 translocation is estimated to occur in 3-5% of either HPV (+) or HPV (-) head 
and neck cancers (in TCGA two TACC3-FGFR3 translocations occurred in HPV (+) HNC). 
- Other translocations of FGFR genes as well as amplification of FGFR2/3 have been described 
to be oncogenic in other cancer types but based on absence in the TCGA HNC and Chicago 
HNC genomics cohort (CHGC) datasets to be rare in HNC.  
 
The primary endpoint will be: objective response rate (ORR; complete or partial response). 
 
With a Simon Two Stage Design, a preset alpha level of 0.1 and power of 80%, we determined 
the minimum sample size required to detect the hypothesized response rate of 21% for BGJ398 
(infigratinib): A sample of 20 FGFR altered patients will be large enough to detect a response 
rate of ≥21% for BGJ398 (infigratinib) compared to a null response rate of 5% (Williamson et 
al. 2010) with 80% power and one-sided type I error rate of 0.10.   
 
An interim analysis for futility will be conducted after 11 evaluable patients have been enrolled 
without interruption of enrollment.  If 0/11 responses are seen, the study will be stopped 
prematurely for futility.   
 
If at least one response is seen, an additional 9 patients will be enrolled. The results will be 
deemed negative (i.e., the 21% alternative will be rejected) if ≤2 responses are seen in 20 
patients. 
5 
Population 
Study population must meet both criteria below. 
A. Patients with recurrent/metastatic head and neck squamous cell carcinoma (HNSCC) 
not amenable to curative intent therapy (palliative treatment intent). 
B. Must harbor an FGFR genetic alterations (FGFR1-3 translocated, mutated, or 
amplified squamous cell carcinoma of the head and neck). 
Enrollment target: N=20 patients. We estimate to have at least 3-5 patients with repeat tumor 
biopsies (mandatory for responders who subsequently demonstrate disease progression). All 
patients must have tumor material available for biomarker evaluation or confirmed FGFR1-
3 translocated, mutated, or amplified squamous cell carcinoma of the head and neck. 


 
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                                                                                                                                               Protocol No. 
5.1 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Histologically documented diagnosis of squamous cell carcinoma of the head/neck 
including nasopharyngeal carcinomas (lymphephithelioma histology is ok if criteria 2 is 
met).  
 Patients must have progressed on prior platinum based therapy (or have become 
intolerant) prior to enrollment on this study. 
 Prior anti-PD-1 or other immunotherapy is acceptable 
2. FGFR genetic alterations (specifically FGFR1-3 mutation, amplification, or translocation) 
via DNA or RNA based assay. Prescreening has to be completed prior to enrollment on this 
study. Commercial or local testing is typically expected, but samples can also be sent to the 
Univ. of Chicago for testing (see 4.1.1). 
 
The following genetic aberrations will be screened for (please also see 4.1.1): 
- 
FGFR1 amplification, FGFR1 somatic mutations, FGFR1 translocations. 
- 
FGFR2 somatic mutations, FGFR2 translocations, FGFR2 amplification. 
- 
FGFR3 somatic mutations, FGFR3 translocations, FGFR3 amplificiation. 
 
Other genetic FGF/FGFR pathway aberrations may be acceptable should such genetic 
changes be observed to emerge and require approval per the Lead Investigator for 
enrollment (e.g. FGF amplification). 
Should one genetic aberration be overrepresented in one or both of the arms the Lead 
Investigator (Dr. Seiwert) may decide to restrict enrollment of such patients. A 
notification/memo will be sent out to all investigators should such a restriction on 
enrollment be implemented (see inclusion criteria). For example, if more than 5 pts 
with FGFR1 amplification are enrolled further enrollment of FGFR1 amplified 
patients will be put on hold, or if FGFR translocations are under-represented 
enrollment may be focused on this aberration.  
 
3. Consent to undergo a fresh biopsy in case of benefit from therapy and subsequent 
progression (see 7.2.5) 
4. ECOG performance status ≤1  
5. Patients must provide written informed consent prior to any screening procedures. 
6. Age 18 years or older.  
7. Willing and able to comply with scheduled visits, treatment plan and laboratory tests 
8. Patient is able to swallow and retain oral medication, unless approval per the manufacturer 
of other administration routes/methods is provided. 
9. Recovery from adverse events of previous systemic anti-cancer therapies to baseline or 
grade 1, except for: 
 Alopecia 


 
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 Stable neuropathy of ≤ grade 2 due to prior cancer therapy 
10. HPV status in Oropharyngeal Carcinomas. While HPV status (e.g. via p16) does not have 
to be known prior to consenting, the HPV status (e.g. using p16 IHC) needs to be established 
prior to start of therapy. 
11. Presence of measurable disease by RECIST 1.1 
12. Availability of tumor tissue (e.g. FFPE) for genomic profile (typically 12 unstained FFPE 
5-10 micron slides, minimum of 10). 
5.2 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. 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 has not been treated in the prior 3 months or expected to require treatment for recurrence 
during the course of the study. 
2. Patients with metastatic CNS tumors are allowed provided that they are clinically stable for 
a period of 30 days prior to study entry and there is not a requirement for steroid (other than 
close to physiologic doses) or anti-convulsant therapy. Patients with leptomeningeal 
involvement are excluded. 
3. Patients who received a prior selective FGFR inhibitor in the recurrent/metastatic disease 
setting. Prior use of a multikinase inhibitor that includes anti-FGFR activity is acceptable 
after review by the Lead Investigator (Dr. Seiwert). 
4. History and/or current evidence of tissue calcification including, but not limited to, the soft 
tissue, kidneys, intestine, myocardium and lung with the exception of calcified lymph nodes 
and asymptomatic coronary calcification  
5. Current evidence of corneal or retinal disorder/keratopathy including, but not limited to , 
bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjuctivitis, 
confirmed by ophthalmologic examination 
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral BGJ398 (infigratinib) (e.g., ulcerative diseases, uncontrolled nausea, 
vomiting, diarrhea, malabsorption syndrome, small bowel resection) 
7. History and/or current evidence of endocrine alterations of calcium/phosphate homeostasis, 
e.g., parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis, 
etc unless the lead investigator obtains approval from Novartis. 
8. Treatment with any of the following anti-cancer therapies prior to the first dose of BGJ398 
(infigratinib) within the stated timeframes 
 Cyclical chemotherapy (intravenous) within a period of 2 weeks unless there are 
ongoing side effects > Grade 2. 
 Biological therapy (including small molecules, and/or) within a period of time that is 
≤2 weeks prior to starting study drug unless there are ongoing side effects > Grade 2. 
 Any other investigational agents within a period ≤ 2 weeks prior to starting study drug 
unless there are ongoing side effects > Grade 2. 
 Wide field radiotherapy (including radioisotopes) ≤ 2 weeks prior to starting study drug 
unless there are ongoing side effects > Grade 2. 


 
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9. Patients who are currently receiving treatment with agents that are known strong inducers 
or inhibitors of CYP3A4 are prohibited. 
10. Enzyme inducing anti-epileptic drugs. 
11. Consumption of grapefruit, grapefruit juice, pomegranates, star fruits, Seville oranges or 
products within 7 days prior to first dose. 
12. Use of medications that are known to prolong the QT interval and/or are associated with a 
risk of Torsades de Pointes 7 days prior to first dose. 
13. Use of amiodarone within 90 days prior to first dose. 
14. Use of medications that increase serum levels of phosphorus and/or calcium. 
15. Current use of therapeutic doses of warfarin sodium or any other coumadin-derivative 
anticoagulants. Heparin and/or low molecular weight heparins or other anticoagulants are 
allowed. 
16. Insufficient bone marrow function 
 ANC <1,000/mm3 [1.0 x 109/L] 
 Platelets < 75,000/mm3 [75 x 109/L] 
 Hemoglobin < 10.0 g/dL 
17. Insufficient hepatic and renal function 
 Total bilirubin > 1.5x ULN (unless evidence of Gilbert’s disease) 
 AST/SGOT and ALT/SGPT > 2.5x ULN  
 Serum creatinine ≥ ULN and/or calculated or measured creatinine clearance < 75% LLN 
18. Calcium-phosphate homeostasis 
 Inorganic phosphorus outside of normal limits 
 Total and ionized serum calcium outside of normal limits 
19. 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 WHO-
ISH 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 > 450 msec (both genders) 
 History of congenital long QT syndrome 
20. 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 
21. Known positive serology for HIV, active Hepatitis B, and/or active Hepatitis C infection. 
22. Study medication cannot be administered through G-tube, unless additional information 
from the manufacturer becomes available in the future. 


 
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23. Women of child-bearing potential, defined as all women physiologically capable of 
becoming pregnant, unless they are using highly effective methods of contraception during 
dosing and for 3 months following the discontinuation of study treatment must be used by 
both sexes (=female patients and their male partners). Highly effective contraception 
methods include: 
 Total abstinence (when this is in line with the preferred and usual lifestyle of the subject. 
Periodic abstinence (e.g., calendar, ovulation, symptothermal, post-ovulation methods) 
and withdrawal are not acceptable methods of contraception 
 Female sterilization (have had surgical bilateral oophorectomy with or without 
hysterectomy) or tubal ligation at least six weeks before taking study treatment. In case 
of oophorectomy alone, only when the reproductive status of the woman has been 
confirmed by follow up hormone level assessment 
 Male sterilization (at least 6 months prior to screening). For female subjects on the 
study the vasectomized male partner should be the sole partner for that subject. 
 Combination of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
Note: Oral contraceptives (OC), injected or implanted hormonal methods are not allowed 
as the sole method of contraception because BGJ398 (infigratinib) has not been 
characterized with respect to the potential to interfere with PK and/or the effectiveness of 
OCs. 
Post-menopausal women are allowed to participate in this study.  Women are considered 
post-menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history 
of vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone, 
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment is she considered not of child bearing potential. 
24. 
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 in order to prevent 
delivery of the drug via seminal fluid. 
6 
Treatment 
The investigational drug will be BGJ398 (infigratinib) as an oral formulation. 


 
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                                                                                                                                               Protocol No. 
6.1 
Treating the patient 
The treating investigator needs to instruct the patient to take the study drug as per protocol.  All 
dosages prescribed and dispensed to the patient and any dose change or interruption must be 
recorded appropriately. 
 
6.1.1 
Administration 
BGJ398 (infigratinib) will be taken once daily on a three weeks on, one week off schedule. 
BGJ398 (infigratinib) will be dosed orally on a flat dosing scale of 125 mg/day, irrespective of 
size and weight.  
Table 6-1 
 
Treatment and treatment schedule 
Study 
treatments 
Pharmaceutical form and route of 
administration 
Dose 
Frequency 
and/or 
regimen 
BGJ398 
(infigratinib) 
Capsule for oral use 
125mg 
(administered as 
one 
100 
mg 
capsule and one 
25 mg capsule) 
Daily (3 weeks on, 
1 week off in a 28 
day cycles) 
 
6.1.2 
Instructions for Administration of BGJ398 (infigratinib) 
The following general guidelines should be followed for BGJ398 (infigratinib) administration: 
 Patients should be instructed to take the daily dose of BGJ398 (infigratinib) in the 
morning, at approximately the same time each day (24 ± 2 hr interval).  
 
 BGJ398 (infigratinib) should be administered in the fasted state, at least 1 hour before 
or 2 hours after a meal. 
 Phosphate binders should be given with meal (low phosphate diet), every day on days 
BGJ398 (infigratinib) is given. No treatment with phosphate binders is needed during 
the BGJ398 (infigratinib) off week in a cycle, unless the lab results indicate higher 
serum phosphorus levels that require continuous treatment with phosphate binders. 
 BGJ398 (infigratinib) 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, he/she should not take 
the dose more than 2 hours after the usual time and should continue treatment the next 
day.  Any doses that are missed should be skipped altogether and should not be replaced 
or made up at the next scheduled dosing. 
 If vomiting occurs following the dosing of study drug, re-dosing is not permitted that 
same day. Dosing should resume the next day.  


 
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 BGJ398 (infigratinib) 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 both compounds, and limit bioavailability. These agents include, but are 
not limited to, proton-pump inhibitors (e.g., omeprazole), H2-antagonists (e.g., 
ranitidine) and antacids. Therefore, BGJ398 (infigratinib) should be dosed at least 2 
hours before or 10 hours after dosing with a gastric protection agent.  
 Patients must avoid consumption of grapefruit, pomelos, pomegranates, star fruits, 
Seville oranges or products containing the juice of each during the entire study and 
preferably 7 days before the first dose of study medications, due to potential CYP3A4 
interaction with the study medications. Orange juice is allowed. 
 Patients on strong or moderate CYP3A4 inducers or inhibitors or medications that rely 
on CYP3A4 for metabolism, should switch whenever possible to a product with less 
interaction with/reliance on the pathway or patient should be on a stable dose of the 
medication prior to enrollment 
 
6.1.3 
Ancillary treatments with anti-emetics, phosphate lowering agents, 
anti-diarrheals, and growth factors 
 
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 do Pointes, and therefore need to be used with caution. Aprepitant is 
both a sensitive substrate and a moderate CYP3A4 inhibitor and can be used with caution if an 
alternative is not available. 
 
 
Phosphate-lowering therapy 
 
Phosphate-lowering treatment, including low phosphate diet and phosphate binding therapy, 
such as sevelamer hydrochloride, should be implemented prophylactically at study drug 
initiation and modified as clinically indicated throughout BGJ398 (infigratinib) administration 
 
Anti-diarrheals 
No prophylactic anti-diarrhea therapy is recommended. However, patients should have 
loperamide tablets at home in case BGJ398 (infigratinib) induced diarrhea occurs and should 
call the study doctor or study staff at the first onset of loose stools. Patients should also be 
instructed to record the number of stools and report severe symptoms (e.g., fever or dizziness 
on standing). Initial management of mild to moderate diarrhea should include dietary 
modifications (e.g., eliminating all lactose-containing products and high-osmolar dietary 
supplements), extra fluids to prevent dehydration and loperamide at an initial dose of 4mg 
followed by 2 mg every 4 hours or after every unformed stool but not to exceed 16 mg/day. 


 
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                                                                                                                                               Protocol No. 
In case of persistent, (i.e. >48 hrs on loperamide), or aggravated diarrhea, the patient should be 
seen at the investigational site or in the physician’s office/outpatient center for further 
evaluation, including complete stool and blood work-up and intensified anti-diarrhea treatment 
per institutional guidelines. 
 
Hematopoietic growth factors 
Prophylactic use of recombinant hematopoietic growth factors (e.g., G-CSF and related 
analogues, erythropoietin alfa and related analogues) should not be used during cycle 1. 
However, they are allowed during future cycles for prophylaxis of neutropenia and treatment 
of anemia if deemed medically appropriate or if, in the opinion of the treating investigator, 
failure to do so could compromise the patient’s ability to remain in the study. Patients receiving 
erythropoietin alfa or related analogues at time of enrollment may continue therapy with 
initiation of cycle 1 of treatment. 
 
6.1.4 
Dosing and treatment schedule 
BGJ398 (infigratinib) will be dosed at 125 mg PO daily with three weeks on therapy, and one 
week off therapy.  Dosing information will be captured per cycle given the mandated off week. 
There is no dose escalation.  Dose is the established phase II dose. 
 
6.1.5 
Dose modification 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. The following guidelines 
need to be applied:  
These changes must be recorded appropriately. 
All dose modifications should be based on the worst preceding toxicity. 
Following resolution of toxicity to baseline or ≤ grade 1, treatment is resumed at either the same 
or lower doses of study drugs as per the criteria in Table 6-3.  If treatment is resumed at the 
same doses of study drugs, and the same toxicity recurs with the same or worse severity 
regardless of duration, doses must be reduced to the next lower dose level. If treatment is 
resumed at the lower doses of study drugs, and the same toxicity recurs with the same or worse 
severity, the patient must discontinue study treatment.  
If a patient requires a dose delay of > 14 consecutive days of BGJ398 (infigratinib) from the 
intended day of the next scheduled dose, then the patient should be discontinued from the study 
treatment, unless extenuating circumstance occur and approval from Novartis is obtained.  
Patients who discontinue the study for a study related adverse event or an abnormal laboratory 
value must be followed as described in Section 6.1.5.  
 


 
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Table 6-2 
Dose reduction table 
Dose reduction 
 
Starting dose level 0 
Dose level - 1 
Dose level - 2 
BJG398 
125 mg 
100 mg 
75 mg 
 
A third or subsequent reduction (to 50 mg) in dose may be allowed if the patient is clearly 
benefiting from study treatment (i.e., stable disease, partial response, or complete response) but 
is experiencing adverse events that prevent continued treatment at the already reduced dose. 
Table 6-3 
Recommended dose modifications for BGJ398 (infigratinib) treatment  
6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
Cardiac disorders 
Cardiac - Prolonged QTcF interval 
 
Grade 1 and 2 : QTcF ≥ 481msec and  ≤ 
500 msec  
(asymptomatic)  
Maintain dose level of BGJ398 (infigratinib)  
ECG assessments should be performed for 2 
additional cycles at the same frequency as in cycle 1, 
or as clinically indicated 
 
If ECG assessments show no QTcF ≥ 481 
msec, for subsequent cycles ECG monitoring 
will be performed as per 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 > 500msec as 
identified on the ECG by the 
investigator 
 
 
Hold BGJ398 (infigratinib).  
 
Monitor patient with hourly ECGs until the 
QTcF has returned to baseline.   
 
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 (infigratinib) until electrolytes are 
documented to be within normal limits.  
 
Once the QTcF prolongation has resolved and if the 
QTcF prolongation was confirmed by the central 
reader, patients may be re-treated at one lower dose 
level at the investigator’s discretion 
 
ECG assessments should be performed for 2 
additional cycles at the same frequency as in 
cycle 1 or as clinically indicated 


 
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                                                                                                                                               Protocol No. 
6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
o 
If ECG assessments show no QTcF ≥ 
481 msec, for subsequent cycles ECG 
monitoring will be performed as per 
visit schedule. 
o 
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. 
NB: If ventricular arrhythmia or Torsades de Pointes is 
observed in a patient, he/she will be discontinued from 
the study. 
 
Cardiac disorders - others 
Grade ≥ 3, or congestive heart failure ≥ 2 
 
Discontinue patient from study treatment. 
Investigations-Hematology 
ANC decreased (Neutropenia) 
Grade 3 (ANC < 1.0 - 0.5 x 109/L) 
 
 
 
 
 
Grade 4 (ANC < 0.5 x 109/L) 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1or baseline, then 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib)  
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib).  
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE ≤ Grade 1, ↓ 1 dose level of BGJ398 
(infigratinib). 
Febrile neutropenia  
Grade 3 (ANC < 1.0 x 109/L, single 
temperature of > 38.3°C or a sustained 
temperature of ≥ 38.0°C) 
 
 
 
 
Grade 4 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1, then 
 
If resolved by ≤ 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib). 
 
If not resolved within 7 days discontinue 
patient from study drug treatment. 
 
Discontinue patient from study treatment. 
Hemoglobin 
Grade 3 (<8.0 mg/dL – 6.5 mg/dL) 
 
Grade 4 (< 6.5 mg/dL) 
 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline, then maintain dose level 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline, then ↓ 1 dose level 


 
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                                                                                                                                               Protocol No. 
6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
Platelet 
count 
decreased 
(Thrombocytopenia) 
Grade 3 (PLT < 50 - 25 x 109/L) without 
bleeding 
 
 
 
 
Grade 3 (PLT < 50 - 25 x 109/L) with 
bleeding or 
Grade 4 (PLT < 25 x 109/L ) 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib). 
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib) 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline, then ↓ 1 dose level 
Investigations – Renal 
Serum creatinine  
 
Grade 1 and Pi >5.5 mg/dL and/or  tCa x 
Pi >55 mg2/dl2 and despite phosphorus 
lowering therapy for at least 14 days 
 
 
 
 
Grade 2 (> 1.5 - 3.0 x ULN) 
 
 
 
 
 
 
Grade 2 and Pi >5.5 mg/dL and/or  tCa x 
Pi >55 mg2/dl2 and despite phosphorus 
lowering therapy for at least 14 days  
 
 
Grade ≥ 3 (> 3.0 x ULN) 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib). 
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib). 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib).  
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 
(infigratinib).  
 
Discontinue patient from study treatment 
 
 
 
 
Discontinue patient from study treatment. 
Investigations – Hepatic 
Blood bilirubin (patients with Gilbert 
Syndrome these dose modifications 
apply to changes in direct bilirubin only)  
 
Grade 2 (>1.5 – 3.0 x ULN)  
 
 
 
 
 
 
Grade ≥ 3 (> 3.0 x ULN)  
 
 
 
 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib). 
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 
(infigratinib).  
 
Discontinue patient from study treatment.  
 


 
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6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended 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 
(infigratinib) 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 
 
 
 
 
 
Grade 4 (> 20.0 x ULN) without bilirubin 
elevation >2.0 x ULN 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 or baseline  
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib). 
 
If resolved in > 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib). 
 
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 
 
 
 
 
AST or ALT > 5.0 x ULN and total bilirubin > 
2.0 x ULN  
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 
 
If resolved in ≤ 7 days, ↓ 1 dose level of 
BGJ398 (infigratinib).  
 
If resolved in > 7 days, discontinue patient from 
study treatment. 
 
 
Discontinue patient from study treatment. 
Laboratory / Metabolic  disorders 
Asymptomatic amylase and/or lipase 
elevation 
 
 
Grade 3 (> 2.0 - 5.0 x ULN) 
 
 
Hold dose of BGJ398 (infigratinib) until 
resolved to CTCAE Grade ≤ 2.  
 
↓ 1 dose level of BGJ398 (infigratinib)  
 
Note: A CT scan or other imaging study to assess the 
pancreas, liver, and gallbladder must be performed 
within 1 week of the first occurrence of any CTCAE ≥ 
Grade 3 amylase and/or lipase. 
If asymptomatic CTCAE Grade 2 elevations of lipase 
and/or amylase occur again at the reduced dose, 
patients will be discontinued permanently from study 
treatment. 
 
Grade 4 (> 5.0 x ULN) 
Discontinue patient from study treatment 
Hyperphosphatemia 
Serum phosphorus > 5.5 – 7.0 mg/dL 
 
 
 
Maintain dose level of BGJ398 (infigratinib), but modify 
phosphate lowering therapy 
 
Hold BGJ398 (infigratinib) dose until resolved to serum 
phosphorus ≤ 5.5 mg/dL 


 
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6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
Serum phosphorus >7.0 – 10.0 mg/dL 
despite 
phosphate 
lowering 
therapy  
 
 
 
 
 
 
Serum Pi > 10.0 mg/dL 
 
if resolved by ≤ 14 days after suspending 
BGJ398 (infigratinib), ↓ 1 dose level  
 
if does not resolve within 14 days of 
suspending BGJ398 (infigratinib), discontinue 
patient from the study. 
 
Discontinue patient from the study 
Hypercalcemia 
Serum 
calcium 
grade 
2 
 
 
 
 
 
 
Serum calcium ≥ grade 3 
 
Hold BGJ398 (infigratinib) dose until resolved to grade 
1 or baseline: 
 
if resolved ≤ 7 days after suspending BGJ398 
(infigratinib), maintain dose level 
 
if resolved > 7 days after suspending BGJ398 
(infigratinib), ↓ 1 dose level 
 
Discontinue patient from the study 
Nervous system disorders 
Neurotoxicity 
Grade 
2 
 
 
Grade ≥ 3  
 
Omit dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1, then ↓ 1 dose level of BGJ398 
(infigratinib)  
 
Discontinue patient from study drug treatment 
GI disorders 
Pancreatitis 
Grade ≥ 2 
 
Discontinue patient from study drug treatment 


 
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                                                                                                                                               Protocol No. 
6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
Diarrhea  
 
Grade 1 
Maintain dose level of BGJ398 (infigratinib), but initiate 
anti-diarrheal treatment 
 
Grade 2 
 
 
Hold dose of BGJ398 (infigratinib) until 
resolved to CTCAE Grade ≤ 1 
 
Optimize anti-diarrheal treatment, maintain 
dose level of BGJ398 (infigratinib). 
 
For reoccurrence of diarrhea CTCAE Grade 2, 
hold dose of BGJ398 (infigratinib) until 
resolved to CTCAE Grade ≤ 1, ↓ BGJ398 
(infigratinib) by 1 dose level  
 
 
Grade 3 
 
 
 
 
 
 
Grade 4 
 
 
Hold dose of BGJ398 (infigratinib) until 
resolved to CTCAE Grade ≤ 1 
 
Optimize anti-diarrheal treatment 
 
↓  BGJ398 (infigratinib) by 1 dose level 
 
For reoccurrence of diarrhea CTCAE Grade 3, 
despite 
optimal 
anti-diarrheal 
treatment, 
discontinue patient from study treatment. 
  
Discontinue patient from study treatment. 
 
Note: Antidiarrheal medication is recommended at the 
first sign of abdominal cramping, loose stools or overt 
diarrhea 
Vomiting 
Grade 2 not controlled by optimal anti-
emetic therapy 
 
Grade 3 not controlled by optimal anti-
emetic therapy or Grade 4 
 
Hold BGJ398 (infigratinib) doses until ≤ grade 1, ↓ 1 
dose 
level 
 
 
Discontinue patient from study  
Eye Disorders (confirmed by ophthalmologic examination) 
Retinal disorders 
 
Grade 2 CSR and CSR-like events 
 
 
 
 
 
Grade 3 CSR and CSR-like events and any 
other grade 3 eye disorders 
 
 
 
 
Hold BGJ398 (infigratinib) until resolved to ≤ grade 1 
but refer the patient to a retinal specialist for evaluation 
 
If resolved in ≤ 14 days, ↓ BGJ398 (infigratinib) 
by 1 dose level 
 
If resolved in > 14 days, discontinue BGJ398 
(infigratinib) 
 
Hold BGJ398 (infigratinib) until resolved to grade ≤ 1. 
 
If resolved in ≤ 14 days, ↓ BGJ398 (infigratinib) 
by 1 dose level 
 
If resolved in > 14 days, discontinue BGJ398 
(infigratinib) 
 


 
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                                                                                                                                               Protocol No. 
6.2 Worst Toxicity CTCAE v4.03 Grade 
(unless otherwise specified) 
6.3 Recommended Dose Modifications any time 
during a cycle of therapy 
≥ grade 1 retinal vein occlusion, grade 4 
CSR and CSR-like events, and grade 4 
other eye disorders  
 
Discontinue BGJ398 (infigratinib) 
Other ocular/visual toxicity 
 
≥ grade 3 
 
 
 
 
 
 
Hold BGJ398 (infigratinib) until resolution to ≤ grade 1 
If resolution in ≤14 days, ↓ 1 dose level, otherwise 
discontinue BGJ398 (infigratinib) 
General disorders  
Fatigue 
Grade 3 
 
 
 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1 
 
If resolved in ≤ 7 days, maintain dose level of 
BGJ398 (infigratinib). 
 
If resolved in  7 days, discontinue patient from 
study treatment. 
Other clinically significant AEs 
Grade 
3 
 
 
Grade 4 
Hold dose of BGJ398 (infigratinib) until resolved to 
CTCAE Grade ≤ 1, then ↓ 1 dose level of BGJ398 
(infigratinib). 
 
Discontinue patient from study treatment. 
All dose modifications should be based on the worst preceding toxicity. Once a dose has been 
reduced it will not be increased at a later time even if there is no toxicity. Patients who require more 
than two dose reductions of BGJ398 (infigratinib) will be discontinued from study drug treatment. 
If a patient requires a dose delay of > 14 days from the intended day of the next scheduled dose of 
BGJ398 (infigratinib) then study treatment must be stopped.  
Table 6-4 Toxicity – Follow-up evaluation 
 
TOXICITY 
FOLLOW-UP EVALUATION 
Metabolic (hyperphosphatemia) 
Serum phosphorus lowering therapy consisting of 
dietary phosphate intake restriction and oral phosphate 
binders should be applied as follows: 
Calcium-containing phosphate binders are not 
recommended. 
 
Starting Cycle 1 Day 1 (beginning with the midday or 
evening meal onC1D1): 
- Restriction of dietary phosphate intake to 600 - 800 
mg/day, if BMI ≥ 21kg/m2. 
 
-Sevelamer 1 tablet (800mg) per meal; i.e. 3 x 800 
mg/day. 
 


 
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                                                                                                                                               Protocol No. 
TOXICITY 
FOLLOW-UP EVALUATION 
Serum Pi > 5.5 – 7.0mg/dL: 
- Increase the dose of sevelamer up to 1200mg tid with 
meals 
 
Serum Pi > 7.0mg – 9.0mg/dL 
- Increase the dose of sevelamer up to 1600mg (2 
tablets per meal) tid with meals 
 
If serum phosphorus increases > 7.0mg/dL despite 
phosphorus lowering therapy given for at least 14 days, 
the BGJ398 (infigratinib) dose should be held and then 
dose subsequently reduced. All patients will continue to 
be followed until resolution to serum phosphorus ≤ 5.5 
mg/dL or baseline or stabilization. 
Renal 
If serum creatinine CTCAE Grade ≥ 1 has been 
demonstrated in conjunction with hyperphosphatemia, 
this parameter must be repeated at least weekly until 
resolution. 24-hour urine collection should also be 
obtained for total phosphate, calcium, protein and 
creatinine clearance within weekly intervals. Ultrasound 
examination of the kidneys should be performed as 
indicated to evaluate de-novo calcifications until 
resolution or stabilization of creatinine. 
 
 
6.4 
Follow up for dose modifications/treatment interruptions 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
abnormal laboratory value must be followed at least once a week for 4 weeks, and subsequently 
at 4-week intervals, until resolution or stabilization of the event, whichever comes first. If a 
patient requires a dose delay of > 14 days from the intended day of the next scheduled dose, 
then the patient must be discontinued from the study.  However, the patient will continue to be 
followed for toxicity as previously described.  All patients will be followed for adverse events 
and serious adverse events for 30 days following the last dose of BGJ398 (infigratinib). 
6.5 
Concomitant therapy 
The patient must notify the investigational site 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. 


 
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                                                                                                                                               Protocol No. 
6.5.1 Permitted concomitant therapy requiring caution and/or action 
Drugs that alter the pH of the GI tract 
BGJ398 (infigratinib) 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 both 
compounds, and limit bioavailability. These agents include, but are not limited to, proton-pump 
inhibitors (e.g., omeprazole), H2-antagonists (e.g., ranitidine) and antacids. Therefore, study 
drug(s) should be dosed at least 2 hours before or 10 hours after dosing with a gastric protection 
agent.  Note that some proton-pump inhibitors may inhibit BCRP. 
Corticosteroids 
Chronic dosing of corticosteroids such as dexamethasone and prednisone is known to induce 
CYP3A enzymes, thereby increasing the risk of reducing drug exposure to sub-therapeutic 
levels. In addition BGJ398 (infigratinib) is an in vitro inhibitor of CYP3A4 and has the potential 
to increase the systemic exposure of corticosteroids that are metabolized by CYP3A4.  
 Systemic corticosteroid treatment can be used with caution. 
Substrates and inhibitors 
CYP substrates and inhibitors 
BGJ398 (infigratinib) was shown to inhibit the cytochrome p450 isoenzyme CYP3A4 in in-
vitro assays, thus, suggesting an increased risk of drug interactions with concomitant 
medications that are metabolized by CYP3A4.  However, such interactions have not been 
confirmed in patients.  Therefore, investigators may administer medications that are known to 
be metabolized by CYP3A4.  Patients must be monitored for potentiation of toxicity and may 
require dose titration or reduction of the CYP3A4 substrate.  In particular caution is advised 
when substrates with a narrow therapeutic index, such as alfentanil, fentanyl, astemizole, 
cisapride, diergotamine, ergotamine, pimozide, quinidine, sirolimus, tacrolimus, and 
terfenadine need to be administered with caution.  Please refer to the following website 
http://medicine.iupui.edu/clinpharm/DDIs/table.asp for a more complete list of the substrates 
of CYP3A4.   
Caution is advised when BGJ398 (infigratinib) is co-administered with opioid analgesics. 
Inhibition of opioid metabolism by CYP3A4 can lead to opioid toxicity, including fatal 
respiratory depression, or an enhanced risk for QTc prolongation. Patients receiving BGJ398 
(infigratinib) and opioid analgesics should be carefully monitored. Synthetic opioids with 
clinically relevant interactions with CYP3A4 inhibitors include, but are not limited to, 
propoxyphene, fentanyl, alfentanyl and sufentanil. Use of alfentanyl, a sensitive CYP3A4 
substrate with narrow therapeutic window, should be full avoided whenever possible. The use 
of methadone and levomethadyl is prohibited.  Please note that the list might not be 
comprehensive. 
Hormonal contraceptives may be affected by cytochrome P450 interactions and are therefore 
not considered effective for this study.  Highly effective contraception should be maintained 
throughout the study.   


 
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                                                                                                                                               Protocol No. 
BGJ398 (infigratinib) is a reversible inhibitor of CYP2C8, CYP2C9 and CYP2C19. Permitted 
medications to be used with caution in this study include those that are sensitive substrates of 
CYP2C8, CYP2C9, CYP2C19, or those substrates that have a narrow therapeutic index.  
BGJ398 (infigratinib) is a substrate of CYP3A4.  Therefore moderate inhibitors and inducers 
should be used with caution if no other alternative is available. 
Transporter substrates  
In vitro data show that BGJ398 (infigratinib) is an inhibitor of BCRP.  CQM157, a metabolite 
of BGJ398 (infigratinib), is an inhibitor of transporters P-gp, BCRP, OATP1B1, and OATP1B3 
(IC50 2-4 µM).   In the absence of data confirming whether such interactions occurs in patients 
receiving such medications 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 do Pointes, and therefore 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.  
QT/QTc interval prolongation or torsade de pointes medications 
Medications that have the potential to prolong the QT/QTc interval or induce torsade de pointes 
are allowed with caution.  Treating investigators at their discretion may co-administer such 
medications, as listed below, but patients should be carefully monitored.  
 
a. Class IA antiarrhythmics (e.g., quinidine, procainamide, disopyramide) 
b. Class III antiarrhythmics (e.g., amiodarone, sotalol, ibutilide) 
c. Class 1C antiarrhythmics (e.g., flecainide, propafenone) 
d. Antipsychotics (e.g., chlorpromazine, pimozide, haloperidol, droperidol) 
e. Antidepressants (e.g., fluoxetine, venlafaxine, tricyclic/tetracyclic antidepressants e.g. 
amitriptyline, imipramine, maprotiline) 
f. Opioids (e.g., methadone) 
g. Macrolide antibiotics & analogues 
h. Quinolone antibiotics (e.g., moxifloxacin, gatifloxacin) 
i. Pentamidine 
j. Antimalarials (e.g., quinine) 
k. Azole antifungals (e.g., voriconazole) 
l. Domperidone 
m. 5-HT3 antagonists (e.g., dolasetron) 
n. Beta-2 adrenoceptor agonists (e.g., salmeterol, formoterol) 
 


 
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                                                                                                                                               Protocol No. 
6.5.2 
Prohibited concomitant therapy 
Other investigational and antineoplastic therapies 
Other investigational therapies must not be used while the patient is on the study. Anticancer 
therapy (chemotherapy, biologic or radiation therapy (that includes > 30% of the bone marrow 
reserve), 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 for a patient then the patient must 
be discontinued from the study. 
CYP inhibitors 
Strong inhibitors of CYP3A4, as listed below, are prohibited because BGJ398 (infigratinib) is 
a likely substrate of this isoenzyme.  Caution should be used during administration of moderate 
inhibitors.  Please note that the list may not be comprehensive.  In addition, the following food 
products are prohibited: Seville oranges or juice, grapefruit, grapefruit juice, grapefruit hybrids, 
pomegranates, and pomelos. 
 
a. Anti-fungal agents: Ketoconazole, itraconazole, fluconazole 
b. Anti-retroviral agents: Ritonavir, nelfinavir, indinavir, saquinavir, amprenavir, 
c. atazanavir, fosamprenavir 
d. Anti-biotic agents: Clarithromycin, telithromycin, erythromycin 
e. Others: Aprepitant, diltiazem, verapamil, nefazodone, grapefruit juice 
Patient on strong or moderate CYP3A4 inducers or inhibitors or medications that rely on 
CYP3A4 for metabolism, should switch whenever possible to a product with less interaction 
with/reliance on the pathway or patient should be on a stable dose of the medication prior to 
enrollment. 
CYP inducers 
Strong inducers of CYP3A4 are prohibited because their usage would likely decrease the 
exposure of BGJ398 (infigratinib).  Caution should be used during administration of moderate 
inhibitors.  
Phosphorus and calcium  
Medications that increase the serum levels of phosphorus and/or calcium are prohibited.  
Medications include, but are not limited to, calcium, phosphate, vitamin D, parathyroid 
hormone (PTH). 
Herbal medications 
Herbal preparations/medications are not allowed throughout the study. These herbal 
medications include, but are not limited to: St. John’s wort, Kava, ephedra (ma huang), gingko 
biloba, dehydroepiandrosterone (DHEA), yohimbe, saw palmetto, and ginseng. Patients should 
stop using these herbal medications 7 days prior to first dose of study drug. 
 


 
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                                                                                                                                               Protocol No. 
6.6 
Criteria for removal from study 
Patients will be removed from study when any of the criteria listed below applies.  The reason 
for study removal and the date the patient was removed must be documented in the Case Report 
Form. 
 
In the absence of treatment delays due to adverse event(s), treatment may continue until one of 
the following criteria applies: 
 
 Disease progression, 
 
 Intercurrent illness that prevents further administration of treatment, 
 
 Unacceptable adverse event(s), 
 
 Patient decides to withdraw from the study, or 
 
 General or specific changes in the patient's condition render the patient unacceptable 
for further treatment in the judgment of the treating and/or lead investigator. 
 
 Patient refusal 
 
 Patient withdrawal 
 
 Administrative reasons after discussion/approval by the Lead Investigator 
 
 Lost to follow-up/Non-compliance  
 
 Study termination  
 
6.7 
Study drug(s) 
6.7.1 
Packaging and labeling 
 
BGJ398 (infigratinib) will be supplied by Novartis as 25mg and 100mg-mg hard gelatin 
capsules for oral use, packaged in bottles, and will be administered on a flat scale.  
Medication will be labeled for Clinical Trial use and will include storage conditions for the drug 
and the medication number but no information about the patient. 
Table  
 
Packaging and labeling 
Study drugs 
Packaging 
Labeling 
BGJ398 (infigratinib) 
 
hard gelatin capsules in bottles 
(25mg, 100mg) 
 
Labeled 
as 
“BGJ398 
(infigratinib)” 
 


 
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                                                                                                                                               Protocol No. 
6.7.2 
Supply, receipt and storage 
Study drug must be received by a designated person at the study site, handled and stored safely 
and properly, and kept in a secured location to which only the site investigator and designated 
study staff have access. Upon receipt, BGJ398 (infigratinib) should be stored according to the 
instructions specified on the drug labels. Study medication will be dispensed by an authorized 
person at the investigator’s site.  
Patients will be provided with adequate supply of BGJ398 (infigratinib) for self-administration 
at home until at least their next scheduled study visit. 
6.7.3 
Drug compliance and accountability 
Patients will be required to keep a pill diary (see Section 11.3 Appendix C for sample 
medication diary).  Pill count will be performed at the end of each cycle to confirm drug 
compliance.   
Clinical drug supply must be accounted for and patients will be asked to return all unused study 
drug and packaging on a regular basis, at the end of the study or at the time of study drug 
discontinuation. 
At the conclusion of the study, and, as appropriate during the course of the study, the Site 
Investigator will return all used and unused study drug, packaging, drug labels, and a copy of 
the completed drug accountability ledger to Novartis.  
6.7.4 
Disposal and destruction  
The drug supply will either be destroyed at a Novartis facility or the investigational study site.  
Novartis will provide guidelines for destruction, if investigational site is approved to destroy 
drug per prior agreement with Novartis.   
6.7.5 
Study drug discontinuation 
Patients who discontinue study treatment should be scheduled for an End of Study Visit within 
14 days after discontinuing study treatment, at which time all of the assessments listed for the 
End of study visit will be performed. Patients lost to follow up should be recorded as such. 
All patients who discontinue study treatment (or a knowledgeable informant), including those 
who refuse to return for the final 14-day Follow up Visit, should be contacted for safety 
evaluations, anti-neoplastic therapies received after discontinuation of study drug, and overall 
survival ≤ 30 days following the last dose of study treatment. 
Patients whose treatment is interrupted or permanently discontinued due to a study-related 
adverse event or abnormal laboratory value must be followed 30 days post study discontinuation 
until all toxicities have resolved to CTCAE ≤ 1 or until stabilization.  
Patients whose treatment is interrupted or permanently discontinued due to any dose-limiting 
ocular/visual toxicity will have appropriate follow-up ophthalmologic examinations weekly 
until the toxicity has completely resolved or until the toxicity is considered to have stabilized 
after at least 6 months of follow-up.  Refer to section on Clinical Safety. 


 
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                                                                                                                                               Protocol No. 
If a patient requires a delay of ≥ 14 days since the last dose, the patient must be discontinued 
from study treatment. However, the patient will continue to be followed for toxicity as 
previously described. 
 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
The table below lists all of the assessments and indicates with an “X” the visits when they are 
performed. 
End of treatment/end of study visit to occur within 14 days after discontinuing study treatment. 
End of post-treatment follow-up to occur up to 30 days post study discontinuation until all 
toxicities have resolved to CTCAE ≤ 1 or until stabilization. 
Table 7-1 
Visit evaluation schedule 
 
Screening 
Treatment 
 
Subsequent cycles 
 
End 
of 
treatment 
/ End of 
study 
visit 
End 
of 
Post-
treatment 
follow-up  
Survival 
 
 
Cycle 1 
Cycle 2 
Cycle 3+ 
Visits on day 1 of 
each 
cycle 
unless 
more frequent visits 
are clinically indicated 
 
 
 
Visit no. 
11 
2 
3 
4 
5 
6 
7 
8 
9 
10+ 
 
 
 
Day of cycle 
Screening 
/ Baseline
1 
8 
15 
21 
1 
8 
 
 
15 
21 
 
 
1 
EOT* 
End 
of 
Post-
treatment 
follow-up 
Survival** 
Informed 
consent 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/ 
exclusion 
criteria1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Relevant 
medical history X 
 
 
 
 
 
 
 
 
 
 
 
 
Physical exam* X 
X 
 
X 
 
X 
 
  X 
 
X 
X 
X 
 
Vitals* 
X 
X 
X 
X 
X 
X 
 
  X 
 
X 
X 
X 
 
Ophthalmic 
assessment** 
X 
 
 
 
 
 
 
 
 
 
X (only cycle 3) 
 
 
 
ECG2 
X 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Performance 
Status ECOG* X 
X 
X 
X 
X 
X 
 
  X 
 
X 
X 
X 
 
Archival tissue 
(≥10 unstained 
slides) 3 
X 
 
 
 
 
 
 
 
 
 
 
 
 
Blood 
for 
banking 
of 
normal DNA 
X 
 
 
 
 
 
 
 
 
 
 
 
 


 
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                                                                                                                                               Protocol No. 
 
Screening 
Treatment 
 
Subsequent cycles 
 
End 
of 
treatment 
/ End of 
study 
visit 
End 
of 
Post-
treatment 
follow-up  
Survival 
 
 
Cycle 1 
Cycle 2 
Cycle 3+ 
Visits on day 1 of 
each 
cycle 
unless 
more frequent visits 
are clinically indicated 
 
 
 
Visit no. 
11 
2 
3 
4 
5 
6 
7 
8 
9 
10+ 
 
 
 
Day of cycle 
Screening 
/ Baseline
1 
8 
15 
21 
1 
8 
 
 
15 
21 
 
 
1 
EOT* 
End 
of 
Post-
treatment 
follow-up 
Survival** 
Radiological 
tumor 
assessment/ 
response 
assessment 
(CT Scans) 4 
X 
 
 
 
 
 
 
 
 
 
Every 
uneven 
treatment cycle and 
+/- 8 days of D1 of 
respective cycle 
X 
 
 
Hematology5 
X 
X 
X 
X 
X 
X 
 
  X 
 
X 
X 
 
 
Serum 
Chemistry6 
X 
X 
X 
X 
X 
X 
 
  X 
 
X 
X 
 
 
Pregnancy 
Test7 
X 
(bl
oo
d) 
X 
 
 
 
X 
 
   
 
X 
X 
 
 
LVEF 
assessment10 
X 
 
To be repeated every 4-6 months in asymptomatic patients. 
In symptomatic patients, LVEF assessment should be done every 2-4 months 
and more frequently as needed if symptoms occur/clinically indicated 
 
 
 
BGJ398 
(infigratinib) 
dosing8 
 
Continuous (21 days with 7 days of rest) 
 
 
Tumor biopsy9 
 
In responders with progressive disease 
 
 
Prophylactic 
phosphate-
lowering 
therapy 
 
Daily 
 
 
Concomitant  
medications 
 
Continuous monitoring 
 
 
Adverse 
events 
 
Continuous Monitoring (up to 30 days post study discontinuation) 
 
 
Overall 
Survival 
 
Overall survival [days] = date of death – date of randomization + 1 
 
X 


 
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                                                                                                                                               Protocol No. 
1 Baseline clinical/laboratory evaluations must be done within 2 weeks prior to start of protocol therapy. Imaging must be done 
within 28 days of start of therapy. 
2 ECG should be performed as a standard12 lead resting ECG (with QTc Interval report) - done at screening or baseline, then 
prior to the first administration of BGJ398 (infigratinib), on Day 1 of Cycle 1 and subsequently at day 1 of every cycle, pre-
dose and at the end of treatment. Test should be performed within ±8 days of the scheduled day of assessment. In patients 
with clinical evidence of heart failure (NYHA≥2) an assessment of cardiac function (e.g. MUGA) should be considered. 
3  Can be substituted with tissue from the fresh biopsy (if sufficient material available). 
4  Radiological tumor assessment should be performed at baseline within 28 days before start of treatment and subsequently 
every 8 weeks from initiation of study drug, until progression of disease or end of treatment. All assessments should be 
performed within ±8 days of the scheduled day of assessment. The assessment at the EOT visit is only to be performed if the 
prior assessment occurred ≥ 21 days before.  Comparable alternative imaging modalities may be used (MRI/PET) if indicated. 
5 Hematology – WBC plus differential (neutrophil including bands, lymphocyte, monocyte, eosinophil, basophil and other 
counts, hemoglobin and platelets. Should be performed on D1, D8, and D15 of cycle 1 and 2.  For subsequent cycles, day 1 
and day 15 hematology assessments are acceptable.  Test should be performed within ±8 days of the scheduled day of 
assessment. 
6 Serum chemistry: K+, Na+, chloride, bicarbonate, BUN, creatinine, Ca++, phosphorus, Mg++, ALT, AST, total bilirubin, 
alkaline phosphatase.  Test should be performed within ±8 days of the scheduled day of assessment. 
7  All women of child bearing potential (pre-menopausal or less than 1 year after the onset of menopause, and intact uterus) must 
have a serum pregnancy test (β-hCG) ≤ 72 hours before the first dose of study treatment. Additionally, a urine pregnancy test 
should be performed at Day 1 of each cycle and at the End of Treatment visit (serum test is acceptable as an alternative). A 
positive pregnancy test requires immediate interruption of study drug treatment until serum β-hCG is performed and found to be 
negative. If positive, the patient must be discontinued 
Pregnancy testing is only required in woman with child bearing potential (pre-menopausal women with intact uterus) 
8 BGJ398 (infigratinib) is taken daily (21 days on with 7 days of rest) and self-administered by the patient. Medication cannot 
be administered through G tube. Treatment courses continue until disease progression or unacceptable drug intolerance.  
Patient is supplied a new bottle of study drug on days 1 of each cycle (each bottle contains 30 tablets).   
9 Patients who demonstrate initial clinical and/or radiographic response (e.g. tumor shrinkage) to therapy, followed by 
subsequent progressive disease by RECIST, should proceed with mandatory tissue biopsy for biomarker correlative studies 
in event of accessible tumor tissue. 
10 LVEF assessment can be done by MUGA scan or Echocardiogram. A prior normal LVEF assessment in the past 6 months 
in the absence of cardiac symptoms is acceptable as a baseline assessment. 
* A scan performed for clinical reasons mid-cycle (e.g., for clinical symptoms of possible disease progression) which confirms 
progressive disease and which results in the patient being taken off study, will count as the end of treatment radiologic 
evaluation. 
** Patients will be followed for survival status, and time of death, though this is not a primary endpoint of the study. See section 
4.5 and 10.6. 
*  Tests should be performed within ±8 days of the scheduled day of assessment during treatment period with BGJ398 
(infigratinib).. 
**Ophthalmic exam should include: visual acuity testing, slit lamp examination of the anterior eye segment, IOP, and fundoscopy.  
Additional examination methods such as specular microscopy (that enables a magnified, direct view of the corneal epithelium), 
corneal pachymetry, and dilated fundoscopy. Ophthalmic exams should be done at baseline and after two cycles (=beginning 
of cycle 3). In addition ophthalmic exams should be done as clinically indicated. 
7.2 
Screening Examination 
Baseline evaluations are to be conducted within 14 days prior to start of protocol therapy.  Scans 
and x-rays must be done < 28 days prior to the start of therapy.  In the event that the patient’s 
condition is deteriorating, laboratory evaluations should be repeated within 48 hours prior to 
initiation of the next cycle of therapy. The screening examination must start with the Informed 
Consent procedure. The treating investigator is obliged to give the patient thorough information 
about the study and the study related assessments, and the patient should be given ample time 
to consider his or her participation. The treating investigator must not start any study related 
procedure before ICF is signed and dated by both patient (and impartial witness, if applicable) 
and investigator.  


 
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7.3 
Assessment types 
7.3.1 
Efficacy 
Efficacy will be assessed through RECIST 1.1 defined objective response rate (e.g. ORR, 
complete or partial response). 
Per RECIST 1.1, investigators are to obtain confirmatory scans greater than 4 weeks after 
objective response (Eisenhauer EA et al, Eur J Ca, 2009).   
 
For the purposes of this study, patients should be reevaluated for response every 8 weeks.  
Response and progression will be evaluated in this study using the new international criteria 
proposed by the revised Response Evaluation Criteria in Solid Tumors (RECIST) guideline 
(version 1.1) (Eisenhauer EA et al, Eur J Ca, 2009).  Changes in the largest diameter 
(unidimensional measurement) of the tumor lesions and the shortest diameter in the case of 
malignant lymph nodes are used in the RECIST criteria. 
 
Definitions 
 
Evaluable for toxicity.  All patients will be evaluable for toxicity from the time of their 
first treatment with BGJ398 (infigratinib). 
 
Evaluable for objective response.  Only those patients who have measurable disease 
present at baseline, have received any therapy with BGJ398 (infigratinib), and have had 
their disease re-evaluated (= at least one post-baseline scan is available) will be 
considered evaluable for response.  These patients will have their response classified 
according to the definitions stated below.  (Note:  Patients who exhibit objective disease 
progression prior to the end of cycle 2 (i.e. clinically indicated scan ahead of schedule 
shows progressive disease) will also be considered evaluable.) 
 
Evaluable Non-Target Disease Response.  Patients who have lesions present at baseline 
that are evaluable but do not meet the definitions of measurable disease, have received 
any therapy with BGJ398 (infigratinib), and have had their disease re-evaluated will be 
considered evaluable for non-target disease.  The response assessment is based on the 
presence, absence, or unequivocal progression of the lesions.  
Disease Parameters 
 
Measurable disease is defined per RECIST 1.1 (Eisenhauer et al Eur J Cancer 2009) 
 
Note:  Tumor lesions that are situated in a previously irradiated area might or might not 
be considered measurable.  If the investigator thinks it appropriate to include them, the 
conditions under which such lesions should be considered must be defined in the 
protocol. 
 
Malignant lymph nodes are defined per RECIST 1.1 (Eisenhauer et al Eur J Cancer 2009) 


 
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                                                                                                                                               Protocol No. 
 
Non-measurable disease is defined per RECIST 1.1 (Eisenhauer et al Eur J Cancer 2009) 
 
 
Target lesions nodes are defined per RECIST 1.1 (Eisenhauer et al Eur J Cancer 2009) 
 
 
Non-target lesions nodes are defined per RECIST 1.1 (Eisenhauer et al Eur J Cancer 
2009) 
  
 
Methods for Evaluation of Measurable Disease 
 
Analogous to outlined methods in RECIST 1.1 nodes are defined per RECIST 1.1 
(Eisenhauer et al Eur J Cancer 2009). Briefly: 
 
All measurements should be taken and recorded in metric notation 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. 
 
The same method of assessment and the same technique should be used to characterize 
each identified and reported lesion at baseline and during follow-up. Imaging-based 
evaluation is preferred to evaluation by clinical examination unless the lesion(s) being 
followed cannot be imaged but are assessable by clinical exam. 
 
Clinical lesions.  Clinical lesions will only be considered measurable when they are 
superficial (e.g., skin nodules and palpable lymph nodes) and ≥10 mm diameter as 
assessed using calipers (e.g., skin nodules).  In the case of skin lesions, documentation 
by color photography, including a ruler to estimate the size of the lesion, is 
recommended.  
 
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.  
 
Conventional CT and MRI.  This guideline has defined measurability of lesions on CT 
scan based on the assumption that CT slice thickness is 5 mm or less.  If CT scans have 
slice thickness greater than 5 mm, the minimum size for a measurable lesion should be 
twice the slice thickness.  MRI is also acceptable in certain situations (e.g. for body 
scans).   
 


 
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                                                                                                                                               Protocol No. 
Use of MRI remains a complex issue.  MRI has excellent contrast, spatial, and temporal 
resolution; however, there are many image acquisition variables involved in MRI, which 
greatly impact image quality, lesion conspicuity, and measurement.  Furthermore, the 
availability of MRI is variable globally.  As with CT, if an MRI is performed, the 
technical specifications of the scanning sequences used should be optimized for the 
evaluation of the type and site of disease.  Furthermore, as with CT, the modality used 
at follow-up should be the same as was used at baseline and the lesions should be 
measured/assessed on the same pulse sequence.  It is beyond the scope of the RECIST 
guidelines to prescribe specific MRI pulse sequence parameters for all scanners, body 
parts, and diseases.  Ideally, the same type of scanner should be used and the image 
acquisition protocol should be followed as closely as possible to prior scans.  Body scans 
should be performed with breath-hold scanning techniques, if possible. 
 
PET-CT.  At present, the low dose or attenuation correction CT portion of a combined 
PET-CT is not always of optimal diagnostic CT quality for use with RECIST 
measurements.  However, if the site can document that the CT performed as part of a 
PET-CT is of identical diagnostic quality to a diagnostic CT (with IV and oral contrast), 
then the CT portion of the PET-CT can be used for RECIST measurements and can be 
used interchangeably with conventional CT in accurately measuring cancer lesions over 
time.  Note, however, that the PET portion of the CT introduces additional data which 
may bias an investigator if it is not routinely or serially performed.   
 
Ultrasound.  Ultrasound is not useful in assessment of lesion size and should not be used 
as a method of measurement.  Ultrasound examinations cannot be reproduced in their 
entirety for independent review at a later date and, because they are operator dependent, 
it cannot be guaranteed that the same technique and measurements will be taken from 
one assessment to the next.  If new lesions are identified by ultrasound in the course of 
the study, confirmation by CT or MRI is advised.  If there is concern about radiation 
exposure at CT, MRI may be used instead of CT in selected instances. 
 
Endoscopy, Laparoscopy.  The utilization of these techniques for objective tumor 
evaluation is not advised.  However, such techniques may be useful to confirm complete 
pathological response when biopsies are obtained or to determine relapse in trials where 
recurrence following complete response (CR) or surgical resection is an endpoint. 
 
Tumor markers.  Tumor markers alone cannot be used to assess response.  If markers 
are initially above the upper normal limit, they must normalize for a patient to be 
considered in complete clinical response.  Specific guidelines for both CA-125 response 
(in recurrent ovarian cancer) and PSA response (in recurrent prostate cancer) have been 
published [JNCI 96:487-488, 2004; J Clin Oncol 17, 3461-3467, 1999; J Clin Oncol 
26:1148-1159, 2008].  In addition, the Gynecologic Cancer Intergroup has developed 
CA-125 progression criteria which are to be integrated with objective tumor assessment 
for use in first-line trials in ovarian cancer [JNCI 92:1534-1535, 2000]. 
 


 
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                                                                                                                                               Protocol No. 
Cytology, Histology.  These techniques can be used to differentiate between partial 
responses (PR) and complete responses (CR) in rare cases (e.g., residual lesions in tumor 
types, such as germ cell tumors, where known residual benign tumors can remain). 
 
The cytological confirmation of the neoplastic origin of any effusion that appears or 
worsens during treatment when the measurable tumor has met criteria for response or 
stable disease is mandatory to differentiate between response or stable disease (an 
effusion may be a side effect of the treatment) and progressive disease. 
 
FDG-PET  While FDG-PET response assessments need additional study, it is 
sometimes reasonable to incorporate the use of FDG-PET scanning to complement CT 
scanning in assessment of progression (particularly possible 'new' disease).  New lesions 
on the basis of FDG-PET imaging can be identified according to the following algorithm:  
a. 
Negative FDG-PET at baseline, with a positive FDG-PET at follow-up is a sign of PD based on a 
new lesion. 
b. No FDG-PET at baseline and 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  scans 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 FDG-PET 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. 
c. 
FDG-PET may be used to upgrade a response to a CR in a manner similar to a biopsy in cases where 
a residual radiographic abnormality is thought to represent fibrosis or scarring.  The use of FDG-PET 
in this circumstance should be prospectively described in the protocol and supported by disease-
specific medical literature for the indication.  However, it must be acknowledged that both 
approaches may lead to false positive CR due to limitations of FDG-PET and biopsy 
resolution/sensitivity. 
 
Note:  A ‘positive’ FDG-PET scan lesion means one which is FDG avid with an uptake greater than twice 
that of the surrounding tissue on the attenuation corrected image. 
 
Response Criteria 
 
Evaluation of Target Lesions 
 
Complete Response (CR):  Disappearance of all target lesions.  Any pathological 
lymph nodes (whether target or non-target) must have reduction in short axis to <10 
mm. 
 
Partial Response (PR):  At least a 30% decrease in the sum of the diameters of target 
lesions, taking as reference the baseline sum diameters and not qualifying for 
progressive disease criteria. 
 


 
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Progressive Disease (PD):  At least a 20% increase in the sum of the diameters of 
target lesions, taking as reference the smallest sum on study (this includes the 
baseline sum if that is the smallest on study).  In addition to the relative increase of 
20%, the sum must also demonstrate an absolute increase of at least 5 mm.  (Note:  
the appearance of one or more new lesions is also considered progressions). 
 
Stable Disease (SD):  Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as reference the smallest sum diameters while on 
study. 
 
Evaluation of Non-Target Lesions 
 
Complete Response (CR):  Disappearance of all non-target lesions and 
normalization of tumor marker level.  All lymph nodes must be non-pathological in 
size (<10 mm short axis). 
 
Note:  If tumor markers are initially above the upper normal limit, they must 
normalize for a patient to be considered in complete clinical response. 
 
Non-CR/Non-PD:  Persistence of one or more non-target lesion(s) and/or 
maintenance of tumor marker level above the normal limits. 
 
Progressive Disease (PD):  Appearance of one or more new lesions and/or 
unequivocal progression of existing non-target lesions.  Unequivocal progression 
should not normally trump target lesion status.  It must be representative of overall 
disease status change, not a single lesion increase.     
 
Although a clear progression of “non-target” lesions only is exceptional, the opinion 
of the treating physician should prevail in such circumstances, and the progression 
status should be confirmed at a later time by the review panel (or Principal 
Investigator). 
 
Evaluation of Best Overall Response 
 
The best overall response is the best response recorded from the start of the treatment 
until disease progression/recurrence/death (whichever happens first) (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started).  The patient's best response assignment will depend on the 
achievement of both measurement and confirmation criteria. 
 
For Patients with Measurable Disease (i.e., Target Disease) 
 


 
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                                                                                                                                               Protocol No. 
Target 
Lesions 
Non-Target 
Lesions 
New 
Lesions 
Overall 
Response 
Best Overall Response when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation* 
CR 
Non-CR/Non-
PD 
No 
PR 
>4 wks. Confirmation* 
CR 
NE 
No 
PR 
PR 
Non-PD/NE 
No 
PR 
SD 
Non-PD/NE 
No 
SD 
Documented at least once >4 
wks. from treatment start* 
Not 
all 
evaluated 
Non-PD 
No 
NE 
-- 
PD 
Any 
Yes or No 
PD 
-- 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript (Eisenhauer et al Eur J Cancer 2009) for further details on 
what is evidence of a new lesion. 
 Only for non-randomized trials with response as primary endpoint. 
**      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
NE = non evaluable 
Note:  Patients with a global deterioration of health status requiring discontinuation of 
treatment without objective evidence of disease progression at that time should be 
reported as “symptomatic deterioration.”  Every effort should be made to document the 
objective progression even after discontinuation of treatment. 
 
For Patients with Non-Measurable Disease (i.e., Non-Target Disease) 
 
Non-Target Lesions 
New Lesions 
Overall Response 
CR 
No 
CR 
Non-CR/non-PD 
No 
Non-CR/non-PD* 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PD 
Any 
Yes 
PD 
 
‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is 
increasingly used as an endpoint for assessment of efficacy in some trials so to assign 
this category when no lesions can be measured is not advised 
NE = non evaluable 
 


 
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Confirmatory Measurement/Duration of Response 
 
Confirmation  
To be assigned a status of PR or CR, changes in tumor measurements must be confirmed 
by repeat assessments that should be performed ≥4 weeks after the criteria for response 
are first met. In the case of SD, follow-up measurements must have met the SD criteria 
at least once after study entry at an interval of ≥4 weeks). 
 
Duration of overall response:  The duration of overall response is measured from the 
time measurement criteria are met for CR or PR (whichever is first recorded) until the 
first date that recurrent or progressive disease is objectively documented (taking as 
reference for progressive disease the smallest measurements recorded since the 
treatment started). 
 
The duration of overall CR is measured from the time measurement criteria are first met 
for CR until the first date that progressive disease or death due to study indication 
(whichever happens first) objectively documented.  
 
Duration of stable disease:  Stable disease is measured from the start of the treatment 
until the criteria for progression or death due to study indication (whichever happens 
first) are met, taking as reference the smallest measurements recorded since the 
treatment started, including the baseline measurements.  
 
 
7.3.2 
Safety  
Safety assessments will consist of monitoring and recording all adverse events, including 
serious adverse events, the monitoring of hematology, blood chemistry, ECG and the regular 
monitoring of vital signs, and physical exam including weight and performance status.  
These assessments should be performed within ±8 days of the scheduled day of assessment 
except for adverse events that will be evaluated continuously through the study. Safety and 
tolerability will be assessed according to the NCI CTCAE v4. 
BGJ398 (infigratinib) has been well tolerated in its phase I, expansion, and phase II studies 
to date. 
Post-biopsy patients will be followed closely for any evidence of complications.  Dose delay 
rules will be closely followed as outlined (Section 6.1.5). In addition the Treating 
Investigator may elect to further delay treatment if any serious concerns about wound healing 
or unexpected events should occur.  
7.3.3 
Pharmacokinetics 
BGJ398 (infigratinib) will be dosed at the established phase II dose, 125 mg PO daily.  No 
specific pharmacokinetics will be obtained. 


 
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7.3.4 
Correlative Analysis 
 
For Details on FGFR aberration testing please see Section 4.1.1 
 
FGFR profiling will be performed in the following two scenarios:  
 
 
1. Genomic profiling to identify FGFR altered tumors and correlation of specific genetic 
changes with efficacy. 
 
 
2. Tumors that respond and subsequently developed resistance (acquired resistance) will 
be biopsied to explore mechanisms of resistance to FGFR inhibition. Analysis of such tumors 
may be broader and include exome sequencing, RNA-seq analysis or similar tests. 
 
While requirements for tissue and correlational studies are clearly stated and are to be 
implemented stringently, medical necessity, e.g. in the case of potential harm to the patient, or 
other extenuating circumstances may trigger a review and possible waiver per the PI on rare 
occasions. 
 
  Archival Tissue and Blood: 
In addition to FGFR testing all patients are required to provide ≥10 unstained FFPE slides. 
This requirement can be waived only if a fresh tumor biopsy provides adequate tissue or per 
discussion with the Lead Investigator (Dr. Seiwert).  
All patients are required to collect blood for banking of normal DNA  
 See Appendix B for tissue collection form 
7.3.5 
Tumor Biopsies 
1) If no archival tissue for FGFR genetic aberration testing is available a fresh tumor biopsy 
is encouraged, and should typically be processed as a fresh frozen biopsy with OCT 
embedding. 
Please 
contact 
the 
Lead 
Investigator 
(Dr. 
Seiwert 
at 
tseiwert@medicine.bsd.uchicago.edu or 773-702-2452 for more details). 
2) Tumors that showed benefit from therapy (= RECIST response, or prolonged disease 
stabilization ≥ 6 months) and subsequently progress are required to undergo a fresh biopsy. 
   
Biopsy should be performed preferentially by a surgeon (excisional biopsy or core needle 
biopsy (3-4 cores) or via interventional radiology (core biopsy (3-4 cores)).  A large (several 
pass) bronchoscopic biopsy is potentially also acceptable, but a discussion about the amount 
of required tissue between the Treating Investigator and the pulmonary attending performing 
the procedure is required prior to biopsy. An FNA is not acceptable. 
Biopsy in the above two scenarios is mandatory. 


 
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Typically a biopsy should be done in a lesion that is not the only lesion for RECIST 
measurement. A waiver of this requirement can be obtained after discussion with the Lead 
Investigator (Dr. Seiwert; tseiwert@medicine.bsd.uchicago.edu or 773-702-2452). 
7.3.6 
Biopsy safety considerations 
Biopsies (core biopsies and small excisional biopsies) are generally considered safe during 
administration of treatment. Nevertheless in difficult to assess/high risk locations the 
treatment may be held for 2 days prior to biopsy and 3-5 days afterwards. For larger scale 
surgeries or should bleeding or wound healing complications arise the treating investigator 
should contact the Lead Investigator in order to get approval to continue holding therapy and 
will assess how long to hold treatment on a cases by case basis. 
8 
Data Reporting  
 
Data reporting will be performed utilizing the eVelos electronic data capture system.  The 
University of Chicago CRA will provide applicable user registration information.  
 
All required data must be recorded in the eVelos database at the completion of each cycle.  
AEs are to be entered in real time. SAEs are to be entered on the Serious Event Form within 
24 hours of the site’s knowledge of the event and sent via email (preferred) or fax to the 
University 
of 
Chicago 
(PhaseIICRA@medicine.bsd.uchicago.edu 
or 
qaccto@bsd.uchicago.edu; Fax: 773-702-4889). All case report forms must be completed by 
designated study personnel. Each screened (consented) patient is to be entered into eVelos 
within 48 hours of patient registration. In addition to direct data entry, you may be required 
to provide supporting source documentation. Source records are original documents, data, 
and records (e.g., medical records, raw data collection forms, pharmacy dispensing records, 
recorded data from automated instruments, laboratory data) that are relevant to the clinical 
trial. Each site will prepare and maintain adequate and accurate source documents. These 
documents are designed to record all observations and other pertinent data for each subject 
enrolled in this clinical trial. Source records must be adequate to reconstruct all data 
transcribed onto the case report form. 
 
9 
Registration Procedures  
 
9.1 
General Guidelines 
Prior to registration and any study-specific evaluations being performed, all patients must 
have given written informed consent for the study and must have completed the pre-
treatment evaluations.  Patients must meet all of the eligibility requirements listed in Section 
5. Eligible patients will be entered on study centrally by the University of Chicago study 
coordinator. All sites should call the study coordinator at (773) 834-3095 or 
PhaseIICRA@medicine.bsd.uchicago.edu to verify availability of a slot.  
 


 
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Following registration, patients (must/should) begin protocol treatment within 7-10 business 
days. Issues that would cause treatment delays should be discussed with the Lead 
Investigator.  If a patient does not receive protocol therapy following registration, the 
patient’s registration on the study will be canceled.  The study coordinator/CRA should be 
notified of cancellations as soon as possible. 
 
9.2 
Registration Process 
 
When a potential patient has been identified, notify the CRA via phone or email to ensure a 
reservation on the study ((773) 834-3095 or PhaseIICRA@medicine.bsd.uchicago.edu). 
Reservations for potential subjects will only be held for subjects who have signed consent 
for that particular study. 
 
When registering a subject, the following must occur:  
• 
Confirm that the institution has a current IRB approval letter for the correct version 
of protocol/consent and has an annual update on file, if appropriate.  
• 
Submit all required materials (Eligibility Checklist, Source documentation, & signed 
consent form) to confirm eligibility and required pre-study procedures to the CRA a 
minimum of 48 hours prior to the subject’s scheduled therapy start date.  
• 
Source documentation includes copies of all original documents that support each 
inclusion/exclusion criteria.  The eligibility checklist does not serve as source documentation 
but rather as a checklist that original source documentation exists for each criterion. 
• 
Communicate with the above CRA to ensure all necessary supporting source 
documents are received and the potential subject is eligible to start treatment on schedule. If 
there are questions about eligibility, the CRA will discuss it with the PI. PI may clarify, but 
not overturn, eligibility criteria.  
• 
Affiliate sites must confirm registration of subjects by obtaining a subject study ID 
number from the CRA via phone, fax or email.  
• 
If a subject does not start on the scheduled day 1 treatment date, promptly inform the 
CRA as the delay in start may deem the subject ineligible and/or require further or repeat 
testing to ensure eligibility.  
• 
The date the patient is randomized if randomization is involved or receives treatment 
for the first time will be considered the patient’s “OnStudy Date.” The patient’s subject ID 
will be assigned and a confirmation of registration will be issued by the CRA on this date. 
Subjects that sign consent and do not go “OnStudy” will be recorded in the database with 
the date they signed consent and the reason for not going “OnStudy” (e.g., Ineligible, Screen 
Failure or Withdrawn Consent). 


 
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10 
Safety monitoring and reporting 
10.1 
Adverse Events 
10.1.1 
Definitions and reporting  
 
Adverse event (AE) monitoring and reporting is a routine part of every clinical trial.  The 
following list of AEs expected by the investigational agent (Section 10.1.2) and the 
characteristics of an observed AE (Section 10.2) will determine whether the event requires 
expedited reporting in addition to routine reporting. 
10.1.2 
Adverse event list  
 
Adverse reactions are listed below by MedDRA body system organ class. 
The following convention has been utilized for the classification of frequency:  
Very common ≥ 1 in 10 
Common ≥ 1 in 100 and < 1 in 10 
Uncommon ≥ 1 in 1,000 and < 1 in 100 
Categories have been assigned based on absolute frequencies in the clinical trial data.  
 
ADVERSE EVENT 
CATEGORY 
VERY COMMON COMMON 
UNCOMMON 
EXPEDITED 
REPORTING IF
GRADE > 2 
Blood and lymphatic 
system disorders 
 
 
X 
 
Endocrine disorders 
 
 
X 
X 
Metabolism and nutrition 
disorders 
 
 
X 
 
Nervous system disorders 
 
 
X 
 
Cardiac disorders 
 
 
X 
X 
Vascular disorders 
 
 
X 
 
Hemorrhages 
 
 
X 
 
Gastrointestinal disorders 
 
 
X 
 
Hepatobiliary disorders 
 
 
X 
 
Skin and subcutaneous 
tissue disorders 
 
 
X 
 
Renal and urinary 
disorders 
 
 
X 
 


 
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                                                                                                                                               Protocol No. 
General disorders and 
administration site 
conditions 
 
 
X 
 
Corneal/ophthalmic 
disorders 
 
 
X 
 
 
 
10.2 
Adverse Event Characteristics  
 
 CTCAE term (AE description) and grade:  The descriptions and grading scales 
found in the revised NCI Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.0 will be utilized for AE reporting.  All appropriate treatment 
areas should have access to a copy of the CTCAE version 4.0.  A copy of the CTCAE 
version 
4.0 
can 
be 
downloaded 
from 
the 
CTEP 
web 
site 
http://ctep.cancer.gov/protocolDevelopment/electronic_applications/ctc.htm. 
 
 Special AE expedited reporting:   
AEs in the table under section 10.1.2 should undergo expedited reporting if the grade 
is above the grade provided in column labeled “Expedited Reporting if Grade > 2”. 
 
 Attribution of the AE: 
Definite (5) – The AE is clearly related to the study treatment. 
Probable (4) – The AE is likely related to the study treatment. 
Possible (3) – The AE may be related to the study treatment. 
Unlikely (2) – The AE is doubtfully related to the study treatment. 
Unrelated (1) – The AE is clearly NOT related to the study treatment.  
10.3 
Adverse Event Definitions 
10.3.1 
Adverse Event 
 
An adverse event is any untoward medical occurrence in a patient or clinical 
investigation subject administered a pharmaceutical product that does not necessarily 
have a causal relationship with the treatment. An adverse event can be any unfavorable 
and unintended sign (including a laboratory finding), symptom or disease temporally 
associated with the use of a medicinal (investigational) product, whether or not related 
to the medicinal (investigational) product. 
 


 
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At each evaluation patients should be interviewed in a non-directed manner to elicit 
potential adverse reactions from the patient. The occurrence of an adverse event will be 
based on changes in the patient’s physical examination, laboratory results, and/or signs 
and symptoms, and review of the patient’s own record of adverse events. 
 
Adverse events will be followed until resolution while the patient remains on-study. 
Once the patient is removed from study, events thought to be related to the study 
medication will be followed until resolution or stabilization of the adverse event, or until 
the patient starts a new treatment regimen, or death, whichever comes first. 
10.3.2 
Serious Adverse Event 
 
An adverse event is considered serious if it results in ANY of the following outcomes:  
 
1) Death 
2) Life-threatening (e.g. places subject at immediate risk of death, this does not 
include events that might have caused death if they occurred a greater severity) 
3) Results in inpatient hospitalization or prolongation of existing hospitalization 
for ≥ 24 hours  
4) A persistent or significant incapacity or substantial disruption of the ability to 
conduct normal life functions  
5) A congenital anomaly/birth defect.  
 
Important Medical Events (IME) that may not result in death, be life threatening, or 
require hospitalization may be considered serious when, based upon medical judgment, 
they may jeopardize the patient or subject and may require medical or surgical 
intervention to prevent one of the outcomes listed in this definition. 
10.3.3 
Unexpected Events 
 
Unexpected events are those not listed at the observed specificity or severity in the 
protocol, informed consent, or investigator brochure.  An event is considered 
unexpected if it is listed as occurring within the class of drugs or otherwise expected 
from the drug’s pharmacological properties but which has not been previously observed 
with this specific investigational agent. 
 
10.3.4 
Adverse Reactions 
 
An adverse event is considered to be an adverse reaction if there evidence to suggest a 
causal relationship to the study agent.  This may include a single occurrence of an event 
strongly associated with drug exposure (e.g. Stevens-Johnson Syndrome), one or more 
occurrence of an event otherwise uncommon is the study population, or an aggregate 
analysis of specific events occurring at greater than expected frequency. 
 


 
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10.4 
Adverse Event Reporting Requirements 
10.4.1 
Routine adverse event reporting 
 
All Adverse Events must be reported in routine study data submissions.  AEs reported using 
the Serious Event Reporting Form and/or MedWatch Form discussed below must also be 
reported in routine study data submissions.   
All adverse events (except grade 1 and 2 laboratory abnormalities that do not require an 
intervention), regardless of causal relationship, are to be recorded in the case report form and 
source documentation. The Site Investigator must determine the intensity of any adverse events 
according to the NCI Common Terminology Criteria for Adverse Events (CTCAE) Version 4.0 
and their causal relationship.  
10.4.2 
Serious adverse event reporting to the Coordinating Center 
 
Use the UC CCC protocol number and the protocol-specific patient ID assigned during 
trial registration on all reports. 
 
All serious adverse events (as defined in sections 10.3.2) and all adverse events that 
have been specified to require expedited reporting in the section 10.1.2 table occurring 
on this study require expedited reporting to the University of Chicago Comprehensive 
Cancer Center (UC CCC) Clinical Trials Office (CCTO).  The responsible Research 
Nurse or other designated individual at the treating site should report the SAE to the 
CCTO by the end of the business day when s/he becomes aware of the event.  Events 
occurring after business hours should be reported to the CCTO by 12pm (noon) the 
next business day.   
 
Reports should be made using the ‘Serious Event Report’ Form.  Please scan and send 
via email (preferred) or fax to the following: 
 
University of Chicago Phase II CRA General: 
PhaseIICRA@medicine.bsd.uchicago.edu 
Phone: 773-834-3095 
Fax: 773-702-4889 
 
UC CCC Cancer Clinical Trials Office Quality Assurance: 
qaccto@bsd.uchicago.edu 
 


 
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All unexpected adverse reactions must be reported to the IND holder so that the 
University of Chicago CCTO can inform the FDA.  The responsible Research Nurse or 
other designated individual at the treating site should provide a complete written report 
using the FDA MedWatch 3500A form.    The completed form should be sent to the 
CCTO at qaccto@bsd.uchicago.edu, within the specified timelines below regardless of 
whether all information regarding the event is available.  If applicable, a follow-up 
report should be provided to the CCTO if additional information on the event becomes 
available.   
 
Participating sites should not forward any adverse event reports directly to the FDA.  
The CCTO will report all events to the FDA as per the current FDA guidelines.   
 
Fatal or Life-threatening Events: within 4 calendar days from treating investigator 
knowledge of the event 
 
All Other Reportable Events: within 10 calendar days of treating investigator knowledge 
of the event 
 
All serious adverse events should also be reported to the local IRB of record according 
to their policies and procedures.   
 
10.4.3 
Serious and Unexpected Adverse Event reporting by the Coordinating 
Center 
 
The designated UC CCC Regulatory Manager will notify all participating sites of all 
unexpected and serious adverse reactions that occur on this clinical trial and which are 
reported to the FDA and/or UC Institutional Review Board (IRB).  When reported to 
the FDA, a copy of the completed Form 3500A (MedWatch) will be provided to the 
responsible Regulatory Manager by the CCTO IND Coordinator for distribution to all 
participating sites. 
 
10.4.4 
Reporting Requirements for the Institutional Review Board 
 
At the University of Chicago: Events meeting current IRB reporting criteria must be submitted 
by the principal investigator via the IRB’s electronic submission system within the IRB’s 
designated reporting timeframes.  Details of the IRB’s current reporting policy and timelines 
can be found on their website at: http://bsdirb.bsd.uchicago.edu/forms-guidelines/up.html 
 
At other centers: the local regulations for reporting to the IRB overseeing clinical research 
should be followed by the individual sites. 
 
 


 
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10.4.5 
Novartis instructions for rapid notification of serious adverse events 
All serious adverse events must be reported to Novartis Pharmaceuticals Drug Safety and 
Epidemiology Department (DS&E) and reporting will be done via the coordinating center 
(Univ. of Chicago). . Applicable events will be reported to the IRB and FDA as per their 
current policies. 
All events reported to the FDA by the investigator are to be filed utilizing the Form FDA 
3500A (MedWatch Form).   
All events must be reported, by FAX (877-778-9739) to Novartis Pharmaceuticals 
DS&E Department within 24 hours of learning of its occurrence. This includes serious, 
related, labeled (expected) and serious, related, unlabeled (unexpected) adverse experiences. 
All deaths during treatment or within 30 days following completion of active protocol 
therapy must be reported within 24 hours. 
Any serious adverse event occurring after the patient has provided informed consent and 
until 4 weeks after the patient has stopped study participation must be reported. This includes 
the period in which the study protocol interferes with the standard medical treatment given 
to a patient (e.g. treatment withdrawal during washout period, change in treatment to a fixed 
dose of concomitant medication). 
Serious adverse events occurring more than 4 weeks after study discontinuation need only 
be reported if a relationship to the Novartis study drug (or therapy) is suspected.  
For Comparator Drugs/Secondary Suspects (Concomitant Medications), all serious adverse 
experiences will be forwarded to the product manufacturer by the investigator. 
 
10.5 
Pregnancies 
Any pregnancy that occurs during study participation should be reported by the site. To ensure 
patient safety each pregnancy must also be reported to Novartis within 24 hours of learning of 
its occurrence. The pregnancy should be followed up to determine outcome, including 
spontaneous or voluntary termination, details of birth, and the presence or absence of any birth 
defects, congenital abnormalities or maternal and newborn complications. 
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. 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the Novartis study treatment of any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
 
 
10.6 
Duration of Follow up 
 


 
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Patients will be followed for any medical issues for a minimum of 8 weeks (6 months is 
recommended) after removal from study or until death, whichever occurs first.  Patients 
removed from study for unacceptable adverse events will be followed until resolution or 
stabilization of the adverse event.  In addition patients will be followed ≤ every 1-3 months for 
survival until 5 years post treatment or until death, whichever occurs first. Information on 
progression (as defined in this protocol) or death will be collected even if the patient has been 
removed from the study previously. 
11 
Statistical methods and data analysis 
 
This phase IIa open label, proof-of-concept trial, that will be a arm study across several centers 
through the University of Chicago Personalized Cancer Care Consortium (PCCC) in which all 
eligible patients with histologically-confirmed recurrent/metastatic HNSCC and FGFR 
alteration will receive BGJ398 (infigratinib) at 125 mg PO daily.   
20 patients will be enrolled on the study.  Accrual of 20 patients is estimated to occur over 
18-24 months.  
Primary objective will be to assess efficacy of BGJ398 (infigratinib) in FGFR altered HNSCC 
(regardless of HPV status) using objective response rate (e.g. complete and partial response 
per RECIST 1.1 measurement). 
11.1 
Sample size calculation 
 
Based on TCGA and our U Chicago cohort, FGFR2-3 mutations are estimated to occur in 5-8% 
of HPV (-) HNC and 10-15% of HPV (+) HNC.  High level FGFR1 amplification (defined as 
copy number ≥ 4) is estimated to occur in 7-10% of HPV (-) HNC.  FGFR3-TACC3 
translocation is estimated to occur in 3-5% of either HPV (+) or HPV (-) head and neck cancers 
(in TCGA two TACC3-FGFR3 translocations occurred in HPV (+) HNC). It is expected that 
FGFR aberration will be mutually exclusive.  The primary endpoint will be objective response 
rate (ORR; complete or partial response) in each of the two treatment arms (HPV(+) and 
HPV(-)).   
 
With a Simon Two Stage Design (Minimax), a preset one-sided alpha level of 0.1 and power of 
80%, we determined the minimum sample size required to detect the hypothesized response 
rate of 21% for BGJ398 (infigratinib) in each Cohort: A sample of 20 FGFR alteration (+) 
patients will be large enough to detect a response rate of 20% for BGJ398 (infigratinib) 
compared to a null response rate of 5% (Williamson et al. 2010, de Souza et al 2012) with 80% 
power and one-sided type I error rate of 0.10.   
 
An interim analysis for futility will be conducted after 11 response evaluable patients without 
interruption of enrollment.  If 0/11 responses are seen, the study will be stopped prematurely 
for futility.  If at least one response is seen, an additional 9 patients will be enrolled. The results 
of the study will be deemed negative if ≤2 responses are seen in 20 patients.   
 


 
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Response rate of BGJ398 (infigratinib) in FGFR subgroups (as defined by certain genetic 
changes in FGFR1-3) will be reported if relevant as the grouping of genetic aberration as well 
as the size each group may not be sufficient for statistical analysis. The following grouping is 
suggested, but may be adapted as new information becomes available: 
1. FGFR3 translocations 
2. Other FGFR translocations 
3. FGFR1 amplification 
4. FGFR1 mutations 
5. FGFR2 mutations 
6. FGFR3 mutations 
7. Other rare FGFR aberrations such as FGFR2 amplification, or FGFR3 
amplification. 
 
Kaplan-Meier estimates and 90% confidence intervals, using Greenwood’s standard error 
estimate, will be tabulated at planned imaging intervals for progression-free survival (at 8 weeks, 
16 weeks, 24 weeks, and every 8 weeks thereafter). Also, median PFS and 90% CI will be 
determined. We will perform similar analysis for Overall survival (OS) for up to 5 years. 
We will report on duration of response and duration of stable disease and may consider a 
landmark analysis in responders versus non-responders.    
12 
Ethical considerations and administrative procedures 
 
12.1 
Ethics and good clinical practice 
This study must be carried out in compliance with the protocol and Good Clinical Practice, as 
described in:  
1. ICH Harmonized Tripartite Guidelines for Good Clinical Practice 1996. 
2. Directive 91/507/EEC, The Rules Governing Medicinal Products in the European 
Community. 
3. US 21 Code of Federal Regulations dealing with clinical studies (including parts 50 and 56 
concerning informed consent and IRB regulations). 
4. Declaration of Helsinki, concerning medical research in humans (Recommendations 
Guiding Physicians in Biomedical Research Involving Human Subjects, Helsinki 1964, 
amended Tokyo 1975, Venice 1983, Hong Kong 1989, Somerset West 1996). 
The investigator agrees, when signing the protocol, to adhere to the instructions and procedures 
described in it and thereby to adhere to the principles of Good Clinical Practice that it conforms 
to. 
 


 
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12.2 
Discontinuation of the study 
Novartis reserves the right to discontinue support for any study under the conditions specified 
in the clinical trial agreement. 
 
12.3 
Publication of results 
Any formal presentation or publication of data from this trial may be published after review and 
comment by Novartis and prior to any outside submission.  Novartis must receive copies of any 
intended communication in advance of publication (at least twenty-one working days for 
presentational materials and abstracts and thirty working days for manuscripts).   These 
requirements acknowledge Novartis’ responsibility to provide peer input regarding the 
scientific content and conclusions of such publications or presentations.  Principal 
Investigation/Institution shall have the final authority to determine the scope and content of its 
publications, provided such authority shall be exercised with reasonable regard for the interests 
of Novartis and, in accord with the trial contract and shall not permit disclosure of Novartis 
confidential or proprietary information. 
12.4 
Disclosure and confidentiality 
The investigator agrees to keep all information provided by Novartis in strict confidence and to 
request similar confidentiality from his/her staff and the IRB/IEC/REB. Study documents 
provided by Novartis (investigators' brochures and other material) will be stored appropriately 
to ensure their confidentiality. The information provided by Novartis to the investigator may 
not be disclosed to others without direct written authorization from Novartis, except to the 
extent necessary to obtain informed consent from patients who wish to participate in the trial. 
12.5 
Declaration of Helsinki 
The investigator must conduct the trial in accordance with the principles of the Declaration of 
Helsinki. Copies of the Declaration of Helsinki and amendments will be provided upon request 
or can be accessed via the website of the World Medical Association at 
http://www.wma.net/e/policy/17-c_e.html. 
 
13 
Study Management and Regulatory Affairs 
 
13.1 
Multicenter guidelines 
 
The specific responsibilities of the Lead Investigator and the Coordinating Center are presented 
in Appendix B.  Clinical studies coordinated by The University of Chicago must be conducted 
in accordance with the ethical principles that are consistent with Good Clinical Practices (GCP) 
and in compliance with other applicable regulatory requirements 
 


 
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The Study Lead Invesgiator/Coordinating Center is responsible for distributing all official 
protocols, amendments, and IND Action Letters or Safety Reports to all participating 
institutions for submission to their individual IRBs for action as required.  
 
13.2 
Institutional Review Board (IRB) Approval and Consent 
 
Before implementing this study, the protocol, the proposed informed consent form and other 
information to subjects, must be reviewed by a properly constituted Institutional Review 
Board/Independent Ethics Committee (IRB/IEC/REB). A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. The name and occupation of the chairman and the members of 
the IRB/IEC/REB must be supplied to Novartis. Any amendments to the protocol, other than 
administrative ones, must be approved by this committee. 
 
Unless otherwise specified, each participating institution must obtain its own IRB approval. It 
is expected that the IRB will have the proper representation and function in accordance with 
federally mandated regulations.  The IRB should approve the consent form and protocol. 
 
In obtaining and documenting informed consent, the investigator should comply with the 
applicable regulatory requirement(s), and should adhere to Good Clinical Practice (GCP) and 
to ethical principles that have their origin in the Declaration of Helsinki. 
 
 
 
Before recruitment and enrollment onto this study, the patient will be given a full explanation 
of the study and will be given the opportunity to review the consent form. Each consent form 
must include all the relevant elements currently required by the FDA Regulations and local or 
state regulations. Once this essential information has been provided to the patient and the 
investigator is assured that the patient understands the implications of participating in the study, 
the patient will be asked to give consent to participate in the study by signing an IRB-approved 
consent form. 
 
Prior to a patient’s participation in the trial, the written informed consent form should be signed 
and personally dated by the patient and by the person who conducted the informed consent 
discussion. 
 
The treating investigator (or their designee) must explain to each subject (or legally authorized 
representative) the nature of the study, its purpose, the procedures involved, the expected 
duration, the potential risks and benefits involved and any discomfort it may entail. Each subject 
must be informed that participation in the study is voluntary and that he/she may withdraw from 
the study at any time and that withdrawal of consent will not affect his/her subsequent medical 
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This informed consent should be given by means of a standard written statement, written in 
non-technical language. The subject should read and consider the statement before signing and 
dating it, and should be given a copy of the signed document. If the subject cannot read or sign 
the documents, oral presentation may be made or signature given by the subject’s legally 
appointed representative, if witnessed by a person not involved in the study, mentioning that 
the patient could not read or sign the documents. No patient can enter the study before his/her 
informed consent has been obtained. 
The informed consent form is considered to be part of the protocol, and must be submitted by 
the site investigator with it for IRB/IEC/REB approval.  
Fertile men and 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 as outlined in this protocol 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 
 
13.3 
Food and Drug Administration (FDA) Approval 
This study will be conducted under an IND held by Tanguy Seiwert at the University of Chicago.  
The University of Chicago CCTO will be responsible for facilitating all communications with 
the FDA on behalf of the IND holder.   Participating sites should not communicate directly with 
the FDA.   
 
13.4 
Required Documentation 
Prior to the selection of a study site that is not a full member of the Personalized Cancer Care 
Consortium, the audit and trial oversight processes for the site must be reviewed and approved 
by the UC CCC Clinical Research Advisory Committee.   
 
Before the study can be initiated at any site, the following documentation must be provided to 
the Cancer Clinical Trials Office (CCTO) at the University of Chicago Comprehensive Cancer 
Center. 
 
 A copy of the official IRB approval letter for the protocol and informed consent 
 IRB membership list 
 CVs and medical licensure for the principal investigator and any sub-investigators 
who will be involved in the study. 
 Form FDA 1572 appropriately filled out and signed with appropriate documentation  
 CAP and CLIA Laboratory certification numbers and institution lab normal values 
 Investigational drug accountability standard operating procedures 
 Additionally, before the study can be initiated at any site, the required executed 
research contract/subcontract must be on file with the University of Chicago. 
 


 
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13.5 
Data and Safety Monitoring  
This study will be remotely monitored by the designated University of Chicago Clinical 
Research Associate (CRA) in accordance with the University of Chicago, Section of 
Hematology/Oncology standard operating procedure titled Monitoring of Multi-Institutional 
Investigator Initiated Clinical Trials. 
 
Prior to subject recruitment, and unless otherwise specified, a participating site will undergo a 
Site Initiation Teleconference to be conducted by the designated University of Chicago research 
team. The site’s principal investigator and his or her study staff must attend the site initiation 
meeting.  
 
Monitoring will be conducted to verify the following: 
 
 Adherence to the protocol 
 Completeness and accuracy of study data and samples collected 
 Compliance with regulations  
 Submission of required source documents  
 
Participating sites will also undergo a site close-out teleconference upon completion, 
termination or cancellation of a study to ensure fulfillment of study obligations during the 
conduct of the study, and to ensure that the site Investigator is aware of his/her ongoing 
responsibilities. 
 
Unless otherwise specified, this protocol will undergo weekly review at the multi-institutional 
data and safety monitoring teleconference as per procedures specified by the UC CCC NCI-
approved Data and Safety Monitoring Plan. The conference will review: 
 
 Enrollment rate relative to expectations, characteristics of participants 
 Safety of study participants (Serious Adverse Event & Adverse Event reporting) 
 Adherence to protocol (protocol deviations) 
 Completeness, validity and integrity of study data 
 Retention of study participants 
 
Protocol deviations are to be documented using the Protocol Deviation Form in the eVelos 
clinical trial management system. Deviations that are considered major because they impact 
subject safety or alter the risk/benefit ratio, compromise the integrity of the study data, and/or 
affect subjects’ willingness to participate in the study must be reported into the eVelos system 
within 7 days. 
 


 
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13.6 
Auditing 
In addition to the clinical monitoring procedures, the University of Chicago Cancer Clinical 
Trials Office (CCTO) will perform routine Quality Assurance Audits of investigator-initiated 
clinical trials as described in the NCI-approved UC CCC DSM Plan. Audits provide assurance 
that trials are conducted and study data are collected, documented and reported in compliance 
with the protocol. Further, they ensure that study data are collected, documented and reported in 
compliance with Good Clinical Practices (GCP) Guidelines and regulatory requirements by 
performing annual quality assurance audits. The CCTO will review subjects enrolled at the 
University of Chicago and at institutions who are formal members of the Personalized Cancer 
Care Consortium (PCCC) in accordance with audit procedures specified in the Data and Safety 
Monitoring plan.  
 
Auditing procedures for participating sites that are not full members of the PCCC must be 
specified and approved by the UC CCC Clinical Research Advisory Committee.  In general, for 
sites that are not full members of the PCCC, auditing responsibility will be delegated to the 
participating center, with the annual audit report forwarded to the University of Chicago for 
review.   
 
A regulatory authority (e.g. FDA) may also wish to conduct an inspection of the study, during 
its conduct or even after its completion. If an inspection has been requested by a regulatory 
authority, the site investigator must immediately inform the University of Chicago Cancer 
Clinical Trials Office and Regulatory Manager that such a request has been made. 
 
13.7 
Amendments to the Protocol 
Any change or addition to this protocol requires a written protocol amendment that must be 
approved by Novartis and the Lead Investigator before implementation.  Following this review, 
all modifications to the protocol, consent form will be submitted to the University of Chicago 
IRB for review and approval. A list of the proposed modifications or amendments to the 
protocol and/or an explanation of the need of these modifications will be submitted, along 
with a revised protocol incorporating the modifications. Only the Study Lead Investigator can 
authorize any modifications, amendments, or termination of the protocol. Once a protocol 
amendment has been approved by the University of Chicago IRB, the Regulatory Manager 
will send the amended protocol and consent form (if applicable) to the affiliate institutions 
electronically. Upon receipt of the packet the affiliate institution is expected to do the 
following: 
 
 The affiliate must reply to the email from the Regulatory Manager indicating that the 
amendment was received by the institution and that it will be submitted to the local IRB.  
 
 The amendment should be submitted to the affiliate institution’s IRB as soon as 
possible after receipt. The amendment must be IRB approved by the institution within 
3 months from the date that it was received.  
 


 
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 The  University  of  Chicago  version  date  and/or  amendment  number  must  
appear  on  the  affiliate consent form and on the affiliate IRB approval letter.  The 
version dates can be found on the footer of every page of the protocol and consent form.  
The amendment number can be found on the University of Chicago IRB amendment 
approval letter that is sent with the protocol/amendment mailing.  
 
 The IRB approval for the amendment and the amended consent form (if amended 
consent is necessary) for the affiliate institution must be sent to the designated UC 
Regulatory Manager as soon as it is received.  
 
 
13.8 
Annual IRB Renewals, Continuing Review and Final Reports 
A continuing review of the protocol will be completed by the University of Chicago IRB and 
the participating institutions’ IRBs at least once a year for the duration of the study. The 
annual IRB renewal approvals for participating institutions should be forwarded promptly to 
the Regulatory Manager. If the institution’s IRB requires a new version of the consent 
form with the annual renewal, the consent form should be included with the renewal letter. 
 
13.9 
Record Retention 
Study documentation includes all CRFs, data correction forms or queries, source documents, 
Sponsor-Investigator correspondence, monitoring logs/letters, and regulatory documents (e.g., 
protocol and amendments, IRB correspondence and approval, signed patient consent forms). 
 
Source documents include all recordings of observations or notations of clinical activities and 
all reports and records necessary for the evaluation and reconstruction of the clinical research 
study. 
 
Government agency regulations and directives require that all study documentation pertaining 
to the conduct of a clinical trial must be retained by the study investigator.  In the case of a 
study with a drug seeking regulatory approval and marketing, these documents shall be retained 
for at least two years after the last approval of marketing application in an International 
Conference on Harmonization (ICH) region.  In all other cases, study documents should be kept 
on file until three years after the completion and final study report of this investigational study. 
 
13.10 
Obligations of Study Site Investigators 
The Study Site Principal Investigator is responsible for the conduct of the clinical trial at the 
site in accordance with Title 21 of the Code of Federal Regulations and/or the Declaration of 
Helsinki.  The Study Site Principal Investigator is responsible for personally overseeing the 
treatment of all study patients.  He/she must assure that all study site personnel, including sub-
investigators and other study staff members, adhere to the study protocol and all FDA/GCP/NCI 
regulations and guidelines regarding clinical trials both during and after study completion. 
 


 
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The Study Site Principal Investigator at each institution or site will be responsible for assuring 
that all the required data will be collected and entered into the CRFs. Periodically, monitoring 
visits or audits will be conducted and he/she must provide access to original records to permit 
verification of proper entry of data.  
 


 
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14 
Appendices 
14.1 
Appendix A: Performance Status Criteria 
 
 
ECOG Performance Status Scale 
Karnofsky Performance Scale 
Grade 
Descriptions 
Percent 
Description 
0 
Normal activity.  Fully active, able 
to 
carry 
on 
all 
pre-disease 
performance without restriction. 
100 
Normal, no complaints, no evidence 
of disease. 
90 
Able to carry on normal activity; 
minor signs or symptoms of disease. 
1 
Symptoms, 
but 
ambulatory.  
Restricted in physically strenuous 
activity, but ambulatory and able to 
carry out work of a light or 
sedentary 
nature 
(e.g., 
light 
housework, office work). 
80 
Normal activity with effort; some 
signs or symptoms of disease. 
70 
Cares for self, unable to carry on 
normal activity or to do active work. 
2 
In 
bed 
<50% 
of 
the 
time.  
Ambulatory and capable of all self-
care, but unable to carry out any 
work activities.  Up and about more 
than 50% of waking hours. 
60 
Requires occasional assistance, but is 
able to care for most of his/her needs. 
50 
Requires considerable assistance and 
frequent medical care. 
3 
In bed >50% of the time.  Capable 
of only limited self-care, confined 
to bed or chair more than 50% of 
waking hours. 
40 
Disabled, requires special care and 
assistance. 
30 
Severely disabled, hospitalization 
indicated.  Death not imminent. 
4 
100% bedridden.  Completely 
disabled.  Cannot carry on any self-
care.  Totally confined to bed or 
chair. 
20 
Very sick, hospitalization indicated. 
Death not imminent. 
10 
Moribund, 
fatal 
processes 
progressing rapidly. 
5 
Dead. 
0 
Dead. 
 


 
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14.2 
Appendix B:  Multicenter Guidelines 
 
Responsibility of the Study Lead PI  
 The Study Lead PI will be the single liaison with regulatory and data management staff, 
outside sponsor/s, FDA, and funding agencies  The Study Lead PI is responsible for the 
coordination, development, submission, and approval of the protocol as well as its 
subsequent amendments.  The protocol must not be rewritten or modified by anyone 
other than the Study Lead PI.  There will be only one version of the protocol, and each 
participating institution will use that document.  The Study Lead PI is responsible for 
assuring that all participating institutions are using the correct version of the protocol. 
 The Study Lead PI is responsible for the overall conduct of the study at all participating 
institutions and for monitoring its progress.  All reporting requirements are the 
responsibility of the Study Lead PI.  
 The Study Lead PI is responsible for the timely review of Adverse Events (AE) to assure 
safety of the patients. 
 The Study Lead PI will be responsible for the review of and timely submission of data 
for study analysis. 
 
Responsibilities of the Coordinating Center 
 The Coordinating Center is responsible for maintaining copies of IRB approvals from 
each participating site.  
 The Coordinating Center is responsible for central patient registration.  The 
Coordinating Center is responsible for assuring that IRB approval has been obtained at 
each participating site prior to the first patient registration from that site. 
 The Coordinating Center is responsible for the preparation of all submitted data for 
review by the Study Lead PI. 
 The Coordinating Center will maintain documentation of AE reports.  The Coordinating 
Center will submit AE reports to the Study Lead PI for timely review. 
 
 
 
 
 
 
 
 
 
 


 
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14.3 
Appendix C: Tissue Sample Collection Form 
 
BGJ398 (infigratinib) – HNC 
 
Clinician/Research Nurse: Please Fill Out 
Tissue Samples 
Patient Name: ___________________  
 MRN# (if applicable): _______________ 
Patient Protocol ID #: ______________  
Date Tissue Obtained: _________________ 
Institution: ______________________________         Attending Physician: __________________ 
Site of Biopsy: ___________________________Site 
of 
Primary 
Tumor: 
_______________ 
 
Did Surgical Pathology review tissue for presence of tumor (please circle)?  Yes   No 
Number of unstained slides (≥10 slides (5 m thick), 12-18 ideal):___________ 
Frozen Sample from biopsy:  [ ] Pre-treatment 
 
  
 
 
 
 
     
 
 
 
 
   [ ] Re-biopsy (acquired resistance) 
 
Blood collection (please check):  
 
2 EDTA tubes (purple top, serum), 2x10ml: ___        1 SST tube 7.5ml (gold top):_________  
 
Date of blood draw: ________________      Time of blood draw:____________ 
Contact Person’s Phone Number/pager/email address: 
 
Dept. of Pathology (University of Chicago) 
Tissue Bank Intake Coordinator 
5841 S Maryland, MC 3083 
Chicago, IL 60637 
Phone 773-834-8392 or 773-702-0119 
 
Please notify Dr. Seiwert once the sample was submitted: 
Email: tseiwert@medicine.bsd.uchicago.edu; or call tissue bank Tel: 773-599-7501 
 


 
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14.4 
Appendix D: Tumor Response Assessment RECIST 1.1 
 
Response criteria for target lesions 
1.   Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have a reduction in short axis 
to < 10mm) 
2.   Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions 
taking as reference the baseline sum diameters and does not meet 
PD criteria 
3.   Progression (PD): 
At least a 20% increase in the sum of diameters of target lesions, 
taking as references the smallest sum on study (this includes the 
baseline sum if that is the smallest on study). In addition to the 
relative increase of 20%, the sum must also demonstrate an 
absolute increase of at least 5 mm (note: the appearance of one or 
more new lesions is also considered progression). 
4.   Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient 
increase to qualify for PD, taking as references the smallest sum 
diameters while on study 
 
Response criteria for non-target lesions 
1.   Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size (< 
10mm short axis) 
2.   Non-CR/ Non-PD: 
Persistence of one or more non-target lesion(s) or/and 
maintenance of tumor marker level above the normal limits. 
3.   Progression (PD): 
Unequivocal progression of existing non-target lesions (Note: the 
appearance of one or more new lesions is also considered 
progression) 
 
Overall response 
 
Target Lesions Non-Target 
Lesions 
New Lesions 
Overall 
Response 
Best 
Overall 
Response 
when 
Confirmation is Required* 
CR 
CR 
No 
CR 
>4 wks. Confirmation* 
CR 
Non-CR/Non-PD 
No 
PR 
>4 wks. Confirmation* 
CR 
NE 
No 
PR 
PR 
Non-PD/NE 
No 
PR 


 
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SD 
Non-PD/NE 
No 
SD 
Documented at least once >4 wks. 
from treatment start* 
Not 
all 
evaluated 
Non-PD 
No 
NE 
-- 
PD 
Any 
Yes or No 
PD 
-- 
Any 
PD** 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
See RECIST 1.1 manuscript (Eisenhauer et al Eur J Cancer 2009) for further details on what is evidence 
of a new lesion. 
Only for non-randomized trials with response as primary endpoint. 
**      In exceptional circumstances, unequivocal progression in non-target lesions may be 
            accepted as disease progression. 
NE = non evaluable 
Note:  Patients with a global deterioration of health status requiring discontinuation of treatment without objective 
evidence of disease progression at that time should be reported as “symptomatic deterioration.”  Every 
effort should be made to document the objective progression even after discontinuation of treatment. 
 
 


 
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14.5 
 Appendix E: Drug Accountability - Sample Medication Diary 
 
Site Number 
Subject Number 
Subject Initials 
Cycle 
  
  
  
  
  
Subject Drug Diary 
 
Bring your diary and study drug bottles (containing unused drug  
and empty bottles) to EACH appointment with the research nurse. 
  
Please complete the diary every day. Write the date and time of each dose of study drug 
you take.  If you did not take your daily dose, or did not take your full dose, please write 
down the actual amount taken.  If you experience any health/medical complaints, please 
record this information on the back of this card. 
Day 
Date 
time of dose 
# of ________ 
1 
  
  
  
  
  
      
2 
  
  
  
  
  
      
3 
  
  
  
  
  
      
4 
  
  
  
  
  
      
5 
  
  
  
  
  
      
6 
  
  
  
  
  
      
7 
  
  
  
  
  
      
8 
  
  
  
  
  
      
9 
  
  
  
  
  
      
10 
  
  
  
  
  
      
11 
  
  
  
  
  
      
12 
  
  
  
  
  
      
13 
  
  
  
  
  
      
14 
  
  
  
  
  
      
15 
  
  
  
  
  
      
16 
  
  
  
  
  
      
17 
  
  
  
  
  
      
18 
  
  
  
  
  
      
19 
  
  
  
  
  
      
21 
  
  
  
  
  
      
22-28 
Treatment Break (restart BGJ398 (infigratinib) on Day 1 of next cycle (=Day 
29)) 
 
 


 
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Health / Medical Complaints 
Please describe what you experienced 
Date started Dated stopped 
  
  
  
  
  
  
  
  
  
  
  
  
Other Medications 
Record 
only 
medications 
(prescription 
and/or 
over-the 
counter,  
including herbal medications and vitamins) taken other than study drug. 
Name of Medication 
Why 
did 
you 
take 
the 
medication? 
Date started Dated stopped 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
  
 


 
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15 
References  
 
 
Chaturvedi AK, Engels EA, Pfeiffer RM, et al. Human papillomavirus and rising oropharyngeal cancer 
incidence in the United States. Journal of Clinical Oncology. 2011 Nov 10;29(32):4294-301. 
 
 
de Souza JA, Davis DW, Zhang Y, et al A phase II study of lapatinib in recurrent/metastatic squamous cell 
carcinoma of the head and neck. Clin Cancer Res. 2012 Apr 15;18(8):2336-43 
 
 
Freier K, Schwaenen C, Sticht C, et al. Recurrent FGFR1 amplification and high FGFR1 protein expression 
in oral squamous cell carcinoma (OSCC). Oral Oncology 2007; 43: 60–66. 
 
 
Halec G, Holzinger D, Schmitt M, et al. Biological evidence for a causal role for HPV16 in a small fraction 
of laryngeal squamous cell carcinoma. British Journal of Cancer. 2013 Jul 9;109(1):172-83. 
 
 
Hayes, D. N., Grandis, J. R. & El-Naggar, A. K. The Cancer Genome Atlas: Integrated analysis of genome 
alterations in squamous cell carcinoma of the head and neck. Journal of Clinal Oncology 2013, 31 (suppl; 
abstr 6009) (2013). 
 
 
Javle M, Lowery M, Shroff RT, et al Phase II Study of BGJ398 in Patients With FGFR-Altered Advanced 
Cholangiocarcinoma. J Clin Oncol. 2018 Jan 20;36(3):276-282.  
 
 
Keck, M. K. et al. Genomic profiling of kinase genes in head and neck squamous cell carcinomas to 
identify potentially targetable genetic aberrations in FGFR1/2, DDR2, EPHA2, and PIK3CA. Journal of 
Clinical Oncology 2013, 31 (suppl; abstr 6010) 
 
 
Marshall ME, Hinz TK, Kono SA, et al. Fibroblast Growth Factor Receptors Are Components of Autocrine 
Signaling Networks in Head and Neck Squamous Cell Carcinoma Cells. Clinical Cancer Research. 2011; 
17: 5016–5025. 
 
 
Marur S, D’Souza G, Westra WH, et al. HPV-associated head and neck cancer: a virus-related cancer 
epidemic. Lancet Oncology. 2010 Aug;11(8):781-9. 
 
 
Nogova L, Sequist LV, Perez Garcia JM, et al. Evaluation of BGJ398, a Fibroblast Growth Factor Receptor 
1-3 Kinase Inhibitor, in Patients With Advanced Solid Tumors Harboring Genetic Alterations in Fibroblast 
Growth Factor Receptors: Results of a Global Phase I, Dose-Escalation and Dose-Expansion Study. J Clin 
Oncol. 2017 Jan 10;35(2):157-165. 
 
Vermorken JB, Mesia R, Rivera F, et al. Platinum-based chemotherapy plus cetuximab in head and neck 
cancer. The New England journal of medicine. 2008;359(11):1116-27. 
 
 
Vokes EE and Seiwert TY. EGFR-directed treatments in SCCHN. Lancet Oncology. 2013 Jul 14;14(8):672-
3. 
 
 
Williamson SK, Moon J, Huang CH, et al. Phase II Evaluation of Sorafenib in Advanced and Metastatic 
Squamous Cell Carcinoma of the Head and Neck: Southwest Oncology Group Study S0420. Journal of 
Clinical Oncology. 2010 July 10;28(20):3330-3335. 
 
 
 
Wu YM, Su F, Kalyana-Sundaram S, et al. Identification of Targetable FGFR Gene Fusions in Diverse 
Cancers. Cancer discovery. 2013;3(6):636-47. 


 
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