Clinical trial NCT01975701
Conditions: Recurrent Glioblastoma or Other Glioma Subtypes
Keywords: BGJ398, recurrent glioblastoma' recurrent GBM, FGFR,
Sponsor: Novartis Pharmaceuticals
Start date: 2013-12-09; Completion date: 2018-10-03
Enrollment: 26 participants; Allocation: NA; Intervention model: SINGLE_GROUP

Brief summary:
This is an open-label non-randomized, multicenter, phase II study of BGJ398 administered to adult patients with histologically confirmed GBM and/or other glioma subtypes with FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 2 or 3.

Detailed description:
Patients were enrolled in two groups. Group 1 enrolled patients who are not candidates for surgery. Group 2 was planned to enroll patients who are surgical candidates. Patients from both groups were evaluated for tumor response and progression by MRI every 8 weeks until disease progression or discontinuation from study using RANO criteria.

Arms: arm 1: To estimate anti-tumor efficacy of BGJ398
Interventions: intervention 1: BGJ398
Intervention descriptions: intervention 1: Capsule for oral use.

Protocol documents:
Prot_001.pdf: 
Clinical Development 
BGJ398 
Protocol CBGJ398X2201 / NCT01975701
A Phase 2, multicenter, open-label study of BGJ398 in 
patients with recurrent resectable or unresectable 
Glioblastoma 
Authors 
 
Document type 
Amended Protocol Version 
EUDRACT number 
2013-002200-13 
Version number 
02 (Clean) 
Development phase 
II 
Document status 
Final 
Release date 
01-Apr-2015
Property of Novartis 
Confidential 
May not be used, divulged, published, or otherwise disclosed 
without the consent of Novartis 
Template version 15-Feb-2012 


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Table of contents 
Table of contents ................................................................................................................. 2 
List of figures ...................................................................................................................... 6 
List of tables ........................................................................................................................ 6 
List of abbreviations ............................................................................................................ 7 
Glossary of terms ............................................................................................................... 10 
Amendment 2 ........................................................................................................................... 11 
IRB/IEC/HA ...................................................................................................................... 12 
Amendment 1 .................................................................................................................... 13 
Protocol summary .............................................................................................................. 15 
1 
Background ........................................................................................................................ 19 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 19 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 20 
1.2.1 
Overview of BGJ398 ............................................................................. 20 
2 
Rationale ............................................................................................................................ 24 
2.1 
Study rationale and purpose ................................................................................... 24 
2.2 
Rationale for the study design ............................................................................... 24 
2.3 
Rationale for dose and regimen selection .............................................................. 25 
3 
Objectives and endpoints ................................................................................................... 26 
4 
Study design ...................................................................................................................... 28 
4.1 
Description of study design ................................................................................... 28 
4.2 
Timing of interim analyses and design adaptations ............................................... 31 
4.3 
Definition of end of the study ................................................................................ 31 
4.4 
Early study termination .......................................................................................... 31 
5 
Population .......................................................................................................................... 31 
5.1 
Patient population .................................................................................................. 31 
5.2 
Inclusion criteria .................................................................................................... 32 
5.3 
Exclusion criteria ................................................................................................... 33 
6 
Treatment ........................................................................................................................... 36 
6.1 
Study treatment ...................................................................................................... 36 
6.1.1 
Dosing regimen ..................................................................................... 36 
6.1.2 
Ancillary treatments .............................................................................. 38 
6.1.3 
Supportive treatment needed for GBM ................................................. 38 
6.1.4 
Treatment duration ................................................................................ 38 
6.2 
Dose modifications ................................................................................................ 38 
6.2.1 
Dose modification and dose delay ........................................................ 38 


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6.2.2 
Follow-up for toxicities ......................................................................... 47 
6.2.3 
Anticipated risks and safety concerns of the study drug ....................... 47 
6.3 
Concomitant medications ...................................................................................... 47 
6.3.1 
Permitted concomitant therapy ............................................................. 47 
6.3.2 
Permitted concomitant therapy requiring caution and/or action ........... 48 
6.3.3 
Prohibited concomitant therapy ............................................................ 50 
6.4 
Patient numbering, treatment assignment or randomization ................................. 51 
6.4.1 
Patient numbering ................................................................................. 51 
6.4.2 
Treatment assignment or randomization ............................................... 51 
6.5 
Study drug preparation and dispensation ............................................................... 51 
6.5.1 
Study drug packaging and labeling ....................................................... 51 
6.5.2 
Drug supply and storage ........................................................................ 51 
6.5.3 
Study drug compliance and accountability ........................................... 52 
6.5.4 
Disposal and destruction ....................................................................... 52 
7 
Visit schedule and assessments ......................................................................................... 52 
7.1 
Study flow and visit schedule ................................................................................ 52 
7.1.1 
Molecular pre-screening ........................................................................ 58 
7.1.2 
Clinical Screening ................................................................................. 58 
7.1.3 
Treatment period ................................................................................... 60 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal ............................................................................................. 60 
7.1.5 
Follow up period ................................................................................... 61 
7.2 
Assessment types ................................................................................................... 62 
7.2.1 
Efficacy assessments ............................................................................. 62 
7.2.2 
Safety and tolerability assessments ....................................................... 62 
 
 66 
 
 69 
8 
Safety monitoring and reporting ........................................................................................ 71 
8.1 
Adverse events ....................................................................................................... 71 
8.1.1 
Definitions and reporting ...................................................................... 71 
8.1.2 
Laboratory test abnormalities ................................................................ 72 
8.2 
Serious adverse events ........................................................................................... 73 
8.2.1 
Definitions ............................................................................................. 73 
8.2.2 
Reporting ............................................................................................... 73 
8.3 
Emergency unblinding of treatment assignment ................................................... 74 
8.4 
Pregnancies ............................................................................................................ 74 


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8.5 
Warnings and precautions ...................................................................................... 75 
8.6 
Data Monitoring Committee .................................................................................. 75 
8.7 
Steering Committee ............................................................................................... 75 
9 
Data collection and management ....................................................................................... 75 
9.1 
Data confidentiality ............................................................................................... 75 
9.2 
Site monitoring ...................................................................................................... 76 
9.3 
Data collection ....................................................................................................... 76 
9.4 
Database management and quality control ............................................................ 77 
10 Statistical methods and data analysis ................................................................................ 77 
10.1 
Analysis sets .......................................................................................................... 78 
10.1.1 
Full Analysis Set ................................................................................... 78 
10.1.2 
Safety Set .............................................................................................. 78 
10.1.3 
Per-Protocol Set .................................................................................... 78 
10.1.4 
Dose-determining analysis set............................................................... 78 
 
 79 
10.2 
Patient demographics/other baseline characteristics ............................................. 79 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ....................... 79 
10.3.1 
Study Treatment .................................................................................... 79 
10.3.2 
Concomitant therapies ........................................................................... 79 
10.3.3 
Compliance ........................................................................................... 79 
10.4 
Primary objective ................................................................................................... 79 
10.4.1 
Variable ................................................................................................. 79 
10.4.2 
Statistical hypothesis, model, and method of analysis .......................... 80 
10.4.3 
Handling of missing values/censoring/discontinuations ....................... 81 
10.4.4 
Supportive analyses ............................................................................... 81 
10.5 
Secondary objectives ............................................................................................. 82 
10.5.1 
Key secondary objective(s) ................................................................... 82 
10.5.2 
Other secondary efficacy objectives ..................................................... 82 
10.5.3 
Safety objectives ................................................................................... 83 
 
 85 
 
 85 
 
 86 
10.7 
Interim analysis ...................................................................................................... 87 
10.8 
Sample size calculation .......................................................................................... 88 
10.9 
Power for analysis of key secondary variables ...................................................... 88 
11 Ethical considerations and administrative procedures ...................................................... 88 


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11.1 
Regulatory and ethical compliance ........................................................................ 88 
11.2 
Responsibilities of the investigator and IRB/IEC/REB ......................................... 88 
11.3 
Informed consent procedures ................................................................................. 89 
11.4 
Discontinuation of the study .................................................................................. 90 
11.5 
Publication of study protocol and results............................................................... 90 
11.6 
Study documentation, record keeping and retention of documents ....................... 90 
11.7 
Confidentiality of study documents and patient records ....................................... 91 
11.8 
Audits and inspections ........................................................................................... 91 
11.9 
Financial disclosures .............................................................................................. 91 
12 Protocol adherence ............................................................................................................ 91 
12.1 
Amendments to the protocol .................................................................................. 91 
13 References (available upon request) .................................................................................. 93 
14 Appendices ........................................................................................................................ 95 
14.1 
Appendix 1: List of concomitant medications ....................................................... 95 
14.2 
Appendix 2: List of prohibited medication ............................................................ 97 
14.3 
Appendix 3: Response assessment in neuro-oncology (RANO) criteria ............... 98 
14.3.1 
Antitumor Effect – Definition ............................................................... 98 
14.3.2 
Response/Progression Categories ......................................................... 99 
14.3.3 
Methods for Evaluation of Measurable Disease ................................. 101 
14.3.4 
Evaluation of Best response ................................................................ 102 
14.3.5 
Other Effect Measures ......................................................................... 102 
 


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List of figures 
Figure 4-1 
Study design .......................................................................................... 29 
Figure 10-1 
PFS6 prior distribution .......................................................................... 81 
 
List of tables 
Table 3-1 
Objectives and related endpoints .......................................................... 27 
Table 6-1 
Dose and treatment schedule ................................................................. 36 
Table 6-2 
Dose reduction table .............................................................................. 39 
Table 6-3 
Criteria for interruption and re-initiation of BGJ398 treatment ............ 40 
Table 7-1 
Visit evaluation schedule ...................................................................... 54 
Table 7-2 
ECOG performance status ..................................................................... 63 
Table 7-3 
Clinical laboratory parameters collection plan ..................................... 64 
 
 67 
 
 
 68 
 
 70 
 
 85 
Table 10-2 
Operating characteristics of study design (primary analysis – 24 
evaluable patients in PPS) ..................................................................... 88 
Table 14-1 
Drugs to be used with caution while on the study ................................ 95 
Table 14-2 
List of prohibited medication while on the study.................................. 97 
Table 14-3 
EIAEDs that are prohibited ................................................................... 97 
Table 14-4 
Summary of the RANO Response Criteria ......................................... 101 
 


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List of abbreviations 
AE 
Adverse Event 
ALT/SGPT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
ANC 
Absolutely Neutrophil Count  
AST/SOPT 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
AUC0-24 
Area Under the Curve 0-24 h 
BCRP 
Breast Cancer Resistance Protein  
BLRM 
Bayesian logistic regression model  
BSL 
Baseline 
BUN 
Blood Urea Nitrogen  
Ca 
Calcium 
CL 
Clearance  
Cmax 
Maximum Concentration 
Cmin 
Minimum Concentration 
CNS 
Central Nervous System  
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CSR 
Central Serous Retinopathy 
CSR addendum 
An addendum to CSR that captures all the additional information that is not included in the 
CSR 
CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CTL 
Clinical Trial Lead 
CYP 
Cytochrome P 
DCE-MRI 
Dynamic contrast enhanced - magnetic resonance imaging  
DDS 
Dose-determining set  
DHEA 
Dehydroepiandrosterone 
DLT 
Dose limiting toxicity 
 
 
DS&E 
Drug Safety & Epidemiology 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
eCRF 
Electronic Case Report/Record Form  
EGFR 
Epidermal growth factor receptor  
EIAED 
Enzyme induced anti-epileptic drug 
EOT 
End of Treatment 
EU 
European Union  
F 
Bioavailability 
FAS 
Full Analysis Set 
FFPE 
Formalin-fixed paraffin-embedded 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast Growth Factor receptor 
FLT1 
Fms-related tyrosine kinase 1 
FSH 
Follicle-stimulating hormone  
GBM 
Glioblastoma 


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GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice  
HbA1c 
Glycosylated Hemoglobin 
hCG 
human chorionic gonadotrophin  
hERG 
Human Ether-à-go-go-Related Gene 
HIV 
Human immunodeficiency virus  
HNSTD 
Highest non-severely toxic dose 
IB 
Investigators Brochure 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IHC 
Immunohistochemistry 
INR 
International Normalized Ratio 
IOP 
Intraocular pressure  
IRB 
Institutional Review Board 
IUD 
intrauterine device  
IUS 
intrauterine system 
LC-MS/MS 
Liquid chromatography tandem mass spectrometry  
LLN 
Lower limit of Normal 
LLOQ  
Lower Limit of Quantification 
LPLT 
Last patient last treatment 
LVEF 
Left Ventricular Ejection Fraction  
MRI 
Magnetic Resonance Imaging 
MRP-2 
Multidrug-Resistance Related Protein 
MTD 
Maximum Tolerated Dose 
MUGA 
Multiple Gated acquisition scan 
N 
Sample size 
NA 
Not applicable 
NYHA 
New York Heart Association 
OC 
Oral contraception  
OCT 2 
Organic cation transporter-2  
ORR 
Objective Response Rate 
OS 
Overall survival  
p.o. 
per os/by mouth/orally 
 
 
PBMC 
Peripheral blood mononuclear cell 
PD 
Pharmacodynamics 
PDGFR 
Platelet-derived growth factor receptors 
PFS 
Progression-free survival  
PFS6 
Progression-free survival at 6 months 
P-gp 
P-glycoprotein  
Pi 
Inorganic phosphorous 
PI3K 
Phosphatidylinositol-3-kinase  
PI3KCA 
phosphatidyl inositol 3-kinase catalytic subunit  
PK 
Pharmacokinetics 


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PPS 
Per protocol set 
PR 
Partial Response 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
q.d. 
once a day 
QTcB 
Q-T interval in the ECG (corrected according to the formula of Bazett) 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
RANO 
Response Assessment in Neuro-Oncology  
RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides evidence of 
preplanned analyses 
RNA 
Ribonucleic Acid 
RP2D 
Recommended Phase II dose 
RT 
Radiation therapy  
SAE 
Serious Adverse Event 
SGOT 
Serum glutamic oxaloacetic transaminase 
SGPT 
Serum glutamic pyruvic transaminase 
SoC 
Standard of Care Treatment  
STD10 
Severely toxic dose in 10% 
TACC 
Transforming acidic coiled-coil 
TdP 
Torsades de Pointes  
tmax 
The time at which the maximum observed concentration (Cmax) occurs 
TMZ 
Temozolomide 
U.S. FDA 
the U.S. Food and Drug Administration  
ULN 
Upper Limit of Normal 
US 
United States 
VEGF 
Vascular endothelial growth factor  
VEGFR 
Vascular endothelial growth factor receptor 
Vss 
Volume of distribution at steady state 
VTE 
Venous thromboembolism  
WBC 
White Blood Cell  


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Glossary of terms 
Assessment 
A procedure used to generate data required by the study 
Cycles 
Number and timing or recommended repetitions of therapy are usually 
expressed as number of days (e.g.,:q28 days) 
Dose level 
The dose of drug given to the patient (total daily or weekly etc.)  
Enrollment 
Point/time of patient entry into the study; the point at which informed 
consent must be obtained (i.e. prior to starting any of the procedures 
described in the protocol) 
Investigational drug 
The study treatment whose properties are being tested in the study; this 
definition is consistent with US CFR 21 Section 312.3 and is synonymous 
with “investigational new drug”. 
Investigational treatment 
Drug whose properties are being tested in the study as well as their 
associated placebo and active treatment controls (when applicable). This 
also includes approved drugs used outside of their indication/approved 
dosage, or that are tested in a fixed combination. Investigational treatment 
generally does not include other study treatments administered as 
concomitant background therapy required or allowed by the protocol when 
used in within approved indication/dosage 
Other study treatment 
Any drug administered to the patient as part of the required study 
procedures that was not included in the investigational treatment 
Patient Number 
A unique identifying number assigned to each patient/subject/healthy 
volunteer who enrolls in the study 
Period 
A subdivision of the study timeline; divides stages into smaller functional 
segments such as screening, baseline, titration, washout, etc. 
Premature patient withdrawal 
Point/time when the patient exits from the study prior to the planned 
completion of all study treatment administration and/or assessments; at this 
time all study treatment administration is discontinued and no further 
assessments are planned, unless the patient will be followed for progression 
and/or survival 
Stage related to study timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, randomization, completion of treatment, etc. 
Stage in cancer 
The extent of a cancer in the body. Staging is usually based on the size of 
the tumor, whether lymph nodes contain cancer, and whether the cancer 
has spread from the original site to other parts of the body 
Stop study participation 
Point/time at which the patient came in for a final evaluation visit or when 
study treatment was discontinued whichever is later 
Study treatment 
Includes any drug or combination of drugs in any study group 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 timepoints 


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Amendment 2  
Amendment rationale 
• The purpose for this amendment is as follows:Recent clinical data shows that FGFR 
amplification is a poor surrogate for fusion presence and that patients identified with 
FGFR-TACC fusions in GBMs and other gliomas show radiological evidence of response 
when treated with FGFR inhibitors (Di Stefano et al, 2015).  For this reason the 
Inclusion/Exclusion criteria were modified to exclude patients with FGFR1, 2, 3, and 4 
amplifications and to include GBM and/or other glioma subtype patients with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or activating mutations in FGFR1, 2 or 3 gene. 
• Following feedback from study investigators, and in order to ensure that patients who 
could potentially benefit from the trial are not excluded, the upper limit of two 
chemotherapy regimens prior to study entry was removed. 
• The safety information was updated as per the latest information in the Investigator 
Brochure. 
• Hyperphosphatemia management guidelines were updated to provide more detail 
regarding the prophylaxis of hyperphosphatemia and how to modify BGJ398 dose 
administration in response to elevated serum phosphorus levels. 
• Serum creatinine and creatinine clearance exclusion criteria were revised to align with 
current medical practice and provide consistency across BGJ398 protocols. BGJ398 has 
not been demonstrated to be nephrotoxic. 
• The criteria for drug discontinuation due to asymptomatic increase in lipase have been 
relaxed.  Asymptomatic mild to moderate increases in lipase have been seen with BGJ398 
dosing, particularly in patients with cholangiocarcinoma, but there have been no cases of 
pancreatitis.  
• The frequency of ophthalmological assessments was reduced to align with other BGJ398 
protocols.  
• The statistical methods and data analysis section was revised based on the changes to the 
inclusion criteria. 
• The list of concomitant medications was revised based on the Oncology Clinical 
Pharmacology Drug-Drug Interaction Database (release date: 29 Oct 2012) 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The following changes to the protocol have been made: 
• Updated Protocol Summary with the revisions to inclusion criteria regarding the inclusion 
of patients with GBM and/or other glioma subtype patients with FGFR1-TACC1, FGFR3-
TACC3 fusion and/or activating mutation in FGFR1, 2 or 3.  The number of allowed prior 
chemotherapy regimens was revised from two to unlimited.  Reference to amplification or 
translocation was removed throughout the protocol. 


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• Section 1.1 (Background) was updated to include background information and rationale 
on inclusion of patients with other glioma subtypes.  In addition, the rationale was 
provided on why FGFR amplification is a poor surrogate to detect FGFR fusions. 
• Section 1.2.1.2 (Clinical experience) was updated with the most recent information as per 
latest version of the Investigator Brochure. 
• Section 2 (Rationale) was updated with the additional rationale for treating glioma patients 
with FGFR inhibitor. 
• Section 3 (Objectives and endpoints), Section 4 (Study design), Section 5 (Population) 
was updated to reflect the revisions to the study inclusion criteria. 
• Section 5.2 (Inclusion criteria) inclusion criteria # 1, 3 and 6 were revised to reflect the 
changes in study inclusion criteria. 
• Section 5.3 (Exclusion criteria) exclusion criteria # 17 and 19 were revised to reflect the 
changes in study exclusion criteria. 
• Section 6.2 (Dose modifications) was revised to update the management of 
hyperphosphatemia, renal toxicities, asymptomatic amylase and/or lipase elevation 
• Section 6.3 (Concomitant medications) was updated to provide the latest recommendation 
on the management of the hyperphosphatemia. 
• Section 7.1 (Study flow and visit schedule) was updated with the reduced frequency of 
ophthalmologic assessments. 
• Section 7.1.1 (Molecular pre-screening) was updated with the number of required slides 
for molecular pre-screening. 
• Section 10 (Statistical analysis) was revised based on the updated inclusion criteria.  
• Appendix 1 and Appendix 2 (List of concomitant medications) was revised. 
IRB/IEC/HA 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Amendment 1 
Amendment rationale 
This amendment addresses changes requested following health authority review, and includes 
the following: 
• The protocol exclusion criteria has been updated to indicate that patients with current 
evidence of corneal/keratopathy or retinal disorder are not eligible to participate. This 
update is being performed to align with the BGJ398 Investigator’s Brochure (edition 6). 
• The protocol will be updated to include ophthalmologic eye exam assessments in order to 
assess for early signs of corneal or retinal changes at baseline and monitor at periodic 
intervals. This update is being performed to completely align with the BGJ398 
Investigator’s Brochure (edition 6). 
• The protocol will be updated to exclude patients with clinically significant hypokalemia. 
Clinically significant hypokalemia is known to increase the risk of dysfunction of ion 
channels in the myocardial cell membrane and therefore may increase the risk of TdP 
tachycardia. 
• The protocol has specified a recovery period of at least 2 weeks following surgery before 
patients can receive BGJ398 treatment for patients enrolled in Group 2 (surgical group). 
Also in this amendment, other sections have been modified for consistency and/or clarification, 
such as management of hyperphosphatemia. 
Changes to the protocol 
Changes to specific sections of the protocol are shown in the track changes version of the 
protocol using strike through red font for deletions and red underlined for insertions. 
The following changes to the protocol have been made: 
• Sections 2.2 (Rationale for the study design) and 4.1 (Description of study design): 
Included a minimum of 2 weeks following surgery before patients can resume and receive 
BGJ398 treatment for patients enrolled in Group 2 (surgical group). 
• Section 5.2 (Inclusion Criteria #11): Changed grading of recovery from adverse events of 
previous systemic anti-cancer therapies from grade 1 to grade 2. 
• Section 5.2 (Inclusion Criteria #7): Clarified that patients who had recent surgery and have 
no evidence of disease, the surgery should within 6 weeks of first dose. 
• Section 5.3 (Exclusion Criteria #3): Updated stable dose of steroid criteria from at least 2 
weeks to 1 week and clarified local application or prophylactic use of steroid is allowed. 
• Section 5.3 (Exclusion Criteria #17): Patients with Gilbert’s Syndrome must not have 
bilirubin ≥ 2.5 ULN, not ≥ 1.5 ULN. This typographical error is corrected. 
• Section 5.3 (Exclusion Criteria #18): (1) Clarified that it is the outside upper limit of normal 
level of serum inorganic phosphorus or calcium as the criteria for exclusion. (2) Clarified 
either serum total or ionized calcium level is measured to assess calcium-phosphate 
homeostasis 
• Section 5.3 (Exclusion Criteria #19): Included clinically significant hypokalemia as part of 
criteria of cardiac disease. 


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• Section 5.3 (Exclusion Criteria #23): Added patients with current evidence of 
corneal/keratopathy or retinal disorder as part of exclusion criteria. 
• Table 6-3 (Criteria for interruption and re-initiation of BGJ398 treatment for 
hyperphosphatemia): Clarified the instructions of management of hyperphosphatemia. 
• Table 6-4 (Follow-up for study drug induced toxicities for hyperphosphatemia): Updated 
table to reference Table 6-3 for management of hyperphosphatemia and Section 6.3.1 for 
taking oral phosphate binders as prophylactic therapy. 
• Section 6.3.1 (Permitted concomitant therapy): Inserted text paragraph that oral phosphate 
binders such as Sevelamer are allowed and should be taken with the first day of BGJ398 
therapy. 
• Table 7-1 (Visit evaluation schedule): Added schedule for ophthalmologic eye 
examinations. 
• Section 7.2.2.7.1 (Electrocardiogram): (1) Clarified that the QTcF value must be within 
eligibility criteria prior to study drug treatment for ECG collected on Cycle 1 Day 1 pre-
dose. (2) Corrected QTcF value from ≥ 501 to ≥ 500 ms. 
• Section 7.2.2.8 (Ophthalmologic assessments): Added ophthalmologic eye examination 
assessments for safety monitoring. 
• Section 8.6 (Data Monitoring Committee): Clarified the formal interim analysis plan. 
IRB/IEC/HA 
A copy of this amended protocol will be sent to the Institutional Review Board 
(IRBs)/Independent Ethics Committee (IECs) and Health Authorities. 
The changes described in this amended protocol require IRB/IEC approval prior to 
implementation. 
The changes herein affect the Informed Consent. Sites are required to update and submit for 
approval a revised Informed Consent that takes into account the changes described in this 
protocol amendment. 


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Protocol summary 
Protocol number 
BGJ398X2201 
Title 
A Phase 2, multicenter, open-label study of BGJ398 in patients with recurrent 
resectable or unresectable Glioblastoma 
Brief title 
A phase 2 study of BGJ398 in patients with recurrent GBM 
Sponsor and 
Clinical Phase 
Novartis 
Phase 2 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
Glioblastoma (GBM) is a highly malignant brain tumor of astrocytic origin 
accounting for over 50% of all gliomas. Recently Singh et al. (Singh et al, 2012) 
reported that a small subset of GBMs (3.1%) harbors oncogenic chromosomal 
translocations that fuse in-frame the tyrosine kinase coding domains of fibroblast 
growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming 
acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. 
 
There is a high unmet medical need for GBM patients: 
● the median OS is approximately 18 months    
● there are 10,000 new cases per year in US 
● annual incidence rate of 3 to 4 cases per 100,000 persons, resulting in 
240,000 new cases worldwide each year 
● virtually all patients experience recurrence and therapeutic options have 
limited benefit. 
 
Treatment options are: 
● Surgery/RT/temozolomide is the standard of care for newly diagnosed 
patients, which leads to an increase in median OS from 12.1 to 14.6 months 
● Therapy for recurrent disease includes surgery, RT, bevacizumab, 
chemotherapy, which leads to a historical median OS of 30 weeks 
 
Lentivectors expressing FGFR-TACC fusions injected directly into short term 
astrocytic cell cultures as well as the brain parenchyma of mice have been 
shown to fully recapitulate GBM. FGFR-TACC induced GBM (and derived cell 
lines) were successfully treated with FGFR inhibitors such as BGJ398.  Recent 
clinical data shows that FGFR amplification is a poor surrogate for fusion 
presence and that patients identified with FGFR-TACC fusions in GBMs and 
other gliomas show radiological evidence of response when treated with FGFR 
inhibitors (Di Stefano et al, 2015). Therefore, FGFR-TACC fusions could 
potentially identify a subset of GBM and other gliomas patients who would 
benefit from targeted FGFR kinase inhibition. 
Primary Objective(s) and 
Key Secondary Objective 
To assess the anti-tumor activity of BGJ398 in patients with GBM and/or other 
glioma subtypes with  FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating 
mutation in FGFR1,2or 3  based on PFS6 
Secondary Objectives 
To further assess the anti-tumor activity of BGJ398 in patients with GBM and/or 
other glioma subtypes with  FGFR1-TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1,2or 3 based on ORR 
 
To further assess the anti-tumor activity of BGJ398 in patients with GBM and/or 
other glioma subtypes with FGFR1-TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1,2or 3 based on OS 
 
To characterize the safety and tolerability of BGJ398 
Primary endpoints 
PFS rate at 6 months as defined by RANO criteria as assessed by the 
investigator 


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Secondary Endpoints 
ORR (patients with measurable disease) as defined by RANO criteria (Appendix 
3) as assessed by the investigator 
 
Overall survival (OS) 
 
Safety: type, frequency, and severity of AEs and SAEs 
 
Tolerability: dose interruptions, reductions and dose intensity, and evaluations of 
laboratory values 
Study design 
This is an open-label non-randomized, multicenter, phase II study of BGJ398 
administered to patients with recurrent GBM and/or other glioma subtypes, 
whose tumors demonstrate FGFR1-TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1, 2 or 3. . Patients will be enrolled in two groups. 
Group 1 will enroll patients who are not candidates for surgery. Patients in group 
1 will receive BGJ398 on a three week on, one week off schedule. Group 2 will 
enroll patients who are surgical candidates. Patients in group 2 will receive 
BGJ398 for 5-10 days prior to surgery and will continue to receive BGJ398 on a 
three week on, one week off schedule, at a minimum of 2 weeks and no more 
than 6 weeks following surgery. 
 
 Patients from both groups will be evaluated for tumor 
response and progression by Gd-enhanced MRI every 8 weeks until disease 
progression or discontinuation from study using RANO criteria. 
Population 
34 adult patients with histologically confirmed recurrent GBM and/or other glioma 
subtypes with  FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation 
in FGFR1,2 or 3. 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following 
criteria: 
1. Patients with histologically confirmed GBM and/or other glioma subtypes at 
the time of diagnosis or prior relapse. Note that all subtypes of  gliomas are 
permitted. Any question of eligibility should be discussed with Novartis. 
2. At least 15 to 20 unstained slides and/or a tumor block from at least one prior 
surgery must be available for molecular testing, unless agreed otherwise upon 
between Novartis and the Investigator. 
3. Written documentation of local or central laboratory determination of  FGFR1-
TACC1, and/or FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 
FGFR2 or FGFR3  is required. Patients identified to have an activating mutation 
in FGFR1,2or 3  may be eligible pending agreement between Novartis and 
Investigator 
4. RANO defined tumor progression by MRI in comparison to a prior scan; OR, 
progression that does not meet RANO criteria if the disease progression is 
otherwise obvious in the opinion of the investigator and is discussed with the 
Novartis; OR histologically proven recurrent/progressive disease based on 
histology if surgery was the treatment for the most recent progression. 
5. Patients must have received prior external beam radiotherapy and 
temozolomide. 
6.   Unlimited prior surgeries and chemotherapies are permitted. 
7. Group specific inclusion: 
● 
Group 1: RANO defined tumor progression as per Inclusion Criteria 4. 
Additionally, patients who recently underwent resection for RANO defined 
tumor progression and are post-operative without evidence of RANO tumor 
progression may also be eligible for Group 1 assuming all inclusion/exclusion 
criteria are met and the most recent surgery has occurred within six weeks of 
the planned first treatment dose. 
● 
Group 2: RANO defined tumor progression as per Inclusion Criteria 4 
and planned surgical resection. Additionally, if a patient assigned to Group 2 
does not undergo planned surgical resection, then the patient will be allowed 
to continue therapy as per Group 1. If a patient enrolled to Group 2 needs to 
undergo surgical resection sooner than initially planned (and having had less 


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than 5 days of BGJ398), then the patient will still be allowed to continue 
therapy post-surgically as per Group 2 regardless of the number of days the 
patient received BGJ398 pre-surgically. 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria prior to 
the first treatment. 
1. 
History of another primary malignancy except: in situ carcinoma of any-
type that has been adequately treated; 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; or any indolent malignancy that has not required treatment within the prior 
2 years (even if never previously treated). 
 
2. 
Prior or current treatment with a FGFR inhibitor (unless agreed 
otherwise between Novartis and the Investigator on a case by case basis). 
 
3. 
Neurological symptoms related to underlying disease requiring 
increasing doses of corticosteroids. Note: Steroid use for management of CNS 
tumors is allowed but must be at a stable dose for at least 1 week preceding the 
baseline MRI/CT. If the corticosteroid dose is increased between the date of 
imaging and the initiation of study treatment, a new baseline MRI/CT is required. 
Definition of stable steroids includes patients on no steroids. Local administration 
methods or prophylactic use is allowed. 
 
4. 
Patients must not be taking Enzyme Inducing Anti-Epileptic Drug 
(EIAED) (Refer to Appendix 2 for list of prohibited medications). If previously on 
an EIAED, the patient must be off of it for at least two weeks prior to study 
treatment. 
Investigational and 
reference therapy 
BGJ398, 125 mg p.o. q.d., 28 day cycle duration, 3 weeks on, 1 week off 
schedule 
Efficacy assessments 
Tumor response per RANO criteria; 6 month Progression Free Survival (PFS) 
rate, Overall Response Rate (ORR) and Overall Survival (OS) 
Safety assessments 
● Physical examinations 
● Vital signs 
● Laboratory evaluations 
● Radiological examinations 
● Cardiac assessments 
● Ophthalmologic examinations 


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Data analysis 
A Bayesian design will be used in order to estimate the PFS6 rate and to provide 
inferential statements based on the uncertainty of this quantity. Progression-free 
survival will be modeled using a Weibull distribution. 
 
An interim analysis for futility will be carried out once 17 patients in total for both 
groups have completed 6 cycles of treatment or discontinued earlier. 
 
ORR will be reported together with a two-sided 95% confidence interval. OS will 
be analyzed using the Kaplan-Meier method. 
 
All the data will be summarized with respect to demographic, baseline 
characteristics and safety observations using descriptive statistics (quantitative 
data) and contingency tables (qualitative data). 
 
The study data will be analyzed and reported based on patients from the pooled 
group 1 and group 2. Details of the statistical analysis and data reporting will be 
provided in Novartis Report and Analysis Plan. 
Key words 
BGJ398, recurrent GBM, activating mutation in FGFR 1, 2 or 3 gene, FGFR1-
TACC1, FGFR3-TACC3 


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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Glioblastoma (GBM) is a highly malignant brain tumor of astrocytic origin which accounts for 
over 50% of all gliomas. GBM has an annual incidence rate of 3 to 4 cases per 100,000 people 
resulting in 240,000 newly diagnosed cases worldwide each year (CBTRUS 2012; Ferlay et al, 
2008). 
The current standard treatment for GBM is surgical resection followed by radiotherapy with 
concurrent and adjuvant temozolomide (TMZ). For newly diagnosed GBM, the addition of 
TMZ to surgery and radiation therapy prolongs median survival (from 12.1 to 14.6 months) and 
increases the five-year survival rate (from 2% to 10%; hazard ratio 0.63; 95% CI 0.53-0.75; 
p<0.0001) (Stupp et al, 2009). 
However, at recurrence, no cytotoxic or targeted therapeutic has improved the 6-month-PFS 
rate of 10-20%, a median overall survival of 6-9 months, and an average 5 year overall survival 
of 3.3% (Stupp et al, 2006; Wong et al, 1999; Lamborn et al, 2008; Wong et al, 2011; Hofer et 
al, 2011; Wen et al, 2009; Norden et al, 2008; Yung et al, 2000) with the possible exception of 
bevacizumab. 
Bevacizumab, a monoclonal antibody against vascular endothelial growth factor (VEGF), was 
approved in the US for the treatment of recurrent GBM based on a clinically meaningful and 
durable objective tumor response rate (ORR 28%-38%, median duration of response 4.2 
months). The 6-month-PFS rate in the multiple studies ranged from approximately 29% to 50% 
and represented a significant improvement over the historical 10-20% 6-month-PFS rate. 
Despite the improvement in response provided by bevacizumab, most patients with GBM 
experience relapse within months (Friedman et al, 2009; Kreisl et al, 2009) and options for 
salvage remain extremely limited. 
Genetically, GBM is characterized by complex chromosomal abnormalities and extensive 
intratumor cytogenetic and histological heterogeneity displaying the genetic alterations that 
govern the processes of cellular proliferation, survival, invasion and angiogenesis (TCGA 2008; 
Harada et al, 2000; Walker et al, 2001). Common mutations found in GBM include: EGFR 
overexpression (70%) (Maher et al, 2006); TP53, RB, INK4a, PDGF-R, VEGF-R, C-Met and 
HGF and PTEN (Mao et al, 2012). 
Besides GBM, which features the highest grade of malignancy among glioma (grade IV), lower 
grade glioma which include grade II and grade III are a heterogeneous group of tumors in which 
specific molecular features are associated with divergent clinical outcome. 
FGFR-TACC fusion 
Recently Singh et al. (Singh et al, 2012) reported that a small subset of GBMs (3.1%) harbors 
oncogenic chromosomal translocations that fuse in-frame the tyrosine kinase coding domains 
of fibroblast growth factor receptor (FGFR) genes (FGFR1 or FGFR3) to the transforming 
acidic coiled-coil (TACC) coding domains of TACC1 or TACC3, respectively. 


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Lentivectors expressing FGFR-TACC fusions injected directly into short term astrocytic cell 
cultures as well as the brain parenchyma of mice have been shown to fully recapitulate GBM. 
Subsequently FGFR-TACC induced GBM (and derived cell lines) were successfully treated 
with FGFR inhibitors such as BGJ398, abolishing the malignant phenotype.  Subsequently 
FGFR3-TACC3 fusions have been identified in pediatric and adult gliomas (Zhang et al, 2013).   
Recent data shows that FGFR amplification is a poor surrogate for fusion presence and that 
patients identified with FGFR-TACC fusions in GBM and other gliomas shows radiological 
evidence of response when treated with FGFR inhibitors (Di Stefano et al, 2015).In conclusion, 
FGFR-TACC fusions could potentially identify a subset of patients with GBM  and/or other 
glioma subtypes who would benefit from targeted FGFR kinase inhibition. 
1.2 
Introduction to investigational treatment(s) and other study 
treatment(s) 
1.2.1 
Overview of BGJ398 
BGJ398 is an orally bio-available, selective and ATP competitive pan-fibroblast growth factor 
receptor (FGFR) kinase inhibitor which has demonstrated anti-tumor activity in preclinical, in 
vitro and in-vivo tumor models harboring FGFR genetic alterations. BGJ398 belongs to the 
pyrimidinyl aryl urea chemical class and its chemical name is 3-(2,6-Dichloro-3,5-
dimethoxyphenyl)-1-{6-[4-(4-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. 
1.2.1.1 
Non-clinical experience 
At the cellular level, BGJ398 selectively inhibits the kinase activity of FGFR1 FGFR2, FGFR3, 
and FGFR4 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 inhibits FGFR downstream 
signaling and proliferation of human cancer cell lines harboring genetic alterations of the 
FGFRs. These include, among others, lung and breast cancer cell lines with FGFR1 gene 
amplification, gastric cancer with FGFR2 gene amplification, endometrial cancer with FGFR2 
mutations and bladder cancer with FGFR3 mutations or FGFR3 translocations (Wesche et al, 
2011). In line with its cellular activity, BGJ398 shows anti-tumor activity in multiple models 
bearing FGFR genetic alterations (Guagnano et al, 2012; Konecny et al, 2013). 
1.2.1.1.1 Animal drug metabolism and pharmacokinetics 
In all species tested, BGJ398 exhibited a high plasma CL and a large Vss. The compound is 
highly bound to plasma proteins (~ 98%) but does not preferentially distribute to red blood cells. 
BGJ398 is widely distributed to tissues in the rat and has a high affinity to melanin containing 
tissues. In vitro hepatic systems metabolize BGJ398 predominantly to 2 pharmacologically 
active metabolites: BHS697 and BQR917. Biotransformation of BGJ398 to both metabolites 


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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. BGJ398 is a potent 
reversible inhibitor of CYP3A4 (Ki 0.26µM). The compound also reversibly inhibits CYP2C9 
and CYP2C19 with Ki of 6.09µM and 4.1µM, respectively and CYP2C8 with IC50 of 12µM. 
BGJ398 is also a time dependent inhibitor of CYP3A4 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 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). 
A distribution study following single dose administration of [14C]BGJ398 in rats showed 
evidence that radiolabeled components (BGJ398 and /or its metabolites) cross the blood brain 
barrier. Concentrations of BGJ398 and its active metabolite BHS697 were also detected in rat 
brain following a single oral administration of 10 mg/kg of BGJ398. 
1.2.1.1.2 Safety pharmacology and toxicology 
BGJ398 showed no evidence of in vitro genotoxicity in Ames and chromosome aberration tests 
and no evidence of phototoxicity in a 3T3 photo-cytotoxicity test. In vitro safety pharmacology 
assessment of BGJ398 revealed a decrease in human Ether-à-go-go-related gene (hERG) 
channel activity with an IC50 of 2.0 µM (1121ng/ml). 
In vivo safety pharmacology studies in rats and dogs did not reveal any effects on central 
nervous or respiratory systems and on hemodynamic or electrocardiographic parameters, 
respectively. 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, BGJ398 did lead to increases in 
serum FGF23 and serum phosphorous associated with partially reversible ectopic 
mineralization (kidney, lung, vascular and digestive systems) along with largely reversible 
changes in renal function parameters and bone growth plate thickening / retention of the primary 
spongiosa in rats (≥ 10 mg/kg/day) and dogs (≥ 10 mg/kg/day). These effects were deemed to 
be on-target effects mediated by pharmacological inhibition of FGFR. 
In rats, corneal changes were found upon 4 weeks of BGJ398 treatment consisting of 
irreversible, slight 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 10 mg/kg/day which resulted in premature death in one (1/30) animal. Doses of 20 
mg/kg/day in rats led to vasculopathy associated with moribundity after 6 administrations. In 
dogs, the highest non-severely toxic dose (HNSTD) was 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. 
1.2.1.2 
Clinical experience 
1.2.1.2.1 Clinical safety 
As of November 6, 2014, 226 patients have received BGJ398 on one of the eight clinical trials.  
In addition to this phase II trial, BGJ398 is being evaluated in three phase I trials, one other 
monotherapy phase II study, two healthy volunteer studies and an individual patient protocol 


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(protocol to patient trial) that provides BGJ398 treatment to patients with tumors with FGFR 
genetic alterations who are not covered by available trials or are unable to travel to study centers. 
The dose escalation portion of the first in human phase I study (CBGJ398X2101) has been 
completed and the MTD has been identified as 125 mg once daily (q.d.), administered 
continuously. BGJ398 was evaluated at 9 different dose levels, ranging from 5 mg per day to 
150 mg per day. The adverse events suspected to be related to BGJ398 that occurred in more 
than 20% or more patients who received BGJ398 were hyperphosphatemia (71.3%), decreased 
appetite (26.6%), fatigue (25.5%), stomatitis (24.5%), and alopecia (21.3%).  Twenty-seven 
percent of patients (26/94) experienced at least one grade 3 or 4 event.  Overall, most adverse 
events reported have been mild to moderate in severity and unrelated to BGJ398.  Please refer 
to Investigator Brochure for more information.  
Four dose limiting toxicities (DLTs) were reported during the dose escalation portion and 
occurred at the 100 mg (n=1; grade 3 AST/ALT elevation), 125 mg (n=1; hyperphosphataemia 
for > 14 days), and 150 mg (n=2; grade 1 corneal toxicity and grade 3 AST/ALT elevation) 
dose levels. 
Enrollment is continuing in the dose expansion phase of the study at the 125 mg dose level in 
three out of four arms. One arm, which enrolled patients with any solid tumor type with FGFR 
genetic pathway alterations on a continuous schedule, has been closed due to completing 
enrollment.  Of the three open arms, one arm is enrolling patients with FGFR1-amplified 
squamous non-small cell lung cancer, with dosing on a continuous 28 day cycle. A second arm 
is enrolling patients with advanced solid malignancies with any FGFR alteration and a third 
arm is enrolling patients with advanced or metastatic urothelial cell carcinoma with FGFR 
mutation or gene fusion.  Patients enrolled to these latter two arms receive BGJ398 at 125 mg 
q.d. on a 3 weeks on/1 week off drug schedule, repeated in 28 day cycles. 
The treatment emergent adverse events that occurred in 20% or more patients that were reported 
as of October 1, 2014 were increases in blood phosphorus [which include AE term of 
hyperphospatemia] (74%), constipation (40.8%), decreased appetite (40.8%), diarrhea (36.7%), 
stomatitis (36.7%), nausea (32.5%), fatigue (31.7%), alopecia (25.8%), asthenia (20.0%), blood 
creatinine increased (20.0%), and dry mouth (20.0%).  The majority of the adverse events were 
Grade 1 and 2 and were reversible upon discontinuation of study drug.  Additional information 
about the nature of these AEs and the dose levels at which they occurred can be found in the 
most recent version of the BGJ398 Investigator Brochure.Hyperphosphatemia has been seen in 
the majority of patients treated at doses of 100 mg q.d. and higher. Phosphate elevations are a 
biomarker of on-target FGFR pathway inhibition which mediates renal tubular phosphate 
secretion and reabsorption.  Inhibition of this pathway leads to inability to secrete phosphate 
and secondary elevations in FGF23. The hyperphosphatemia has been managed in Phase I study 
by dietary phosphate restrictions, phosphate lowering therapy,  drug interruptions, and dose 
reductions, which led to the introduction of the alternate 3 weeks on/1 week off drug schedule.  
Preliminary safety data with this schedule suggests improved tolerability and compliance with 
drug administration (e.g. fewer dose interruptions during cycle 1), though dose reductions in 
later cycles of therapy are not uncommon.  As of March 15, 2014 data cut off, 17 out of 25 
patients (68%) who received BGJ398 on the 3 week on/1 week of schedule experienced elevated 
phosphorus and only 4 patients (16%) required cycle 1 interruptions or reductions.  In contrast, 
41 out of 47 patients (87%) on the continuous dosing cycle experienced serum phosphorus 


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elevations.  Twenty patients (43%) required cycle 1 dose interruptions and 13 patients (28%) 
required dose reductions during cycle 1.  Please refer to the BGJ398 Investigator Brochure for 
additional information.    
1.2.1.2.2 Preliminary efficacy of BGJ398 
Preliminary anti-tumor activity, including durable partial responses (PRs), was noted in  the 
phase I first-in-human trial (BGJ398X2101) in patients treated at doses of >100mg of BGJ398 
with the following tumor types: FGFR1 amplified squamous NSCLC, FGFR amplified 
squamous cell carcinoma of the head and neck, FGFR1 amplified breast cancer, FGFR3 
mutated bladder cancer, and advanced cholangiocarcinoma with FGFR2 gene fusion.  
1.2.1.2.3 Clinical pharmacokinetics 
In Study BGJ398X2101, full PK profiles were obtained on Day 1, Day 15 and Day 28 after the 
first dose of study drug. As this study is ongoing, all data presented are current as of 02 
September 2012 (refer to the Investigator Brochure for further details). 
At 5 and 10 mg/day, plasma concentrations of BGJ398 were low (< 3.3 ng/mL) and frequently 
below the lower limit of quantification. Exposure (Cmax and AUC) was measurable in all 
treated patients starting at 20 mg/day. 
The median apparent Tmax value across all dose levels tended to be 2-3 hours post-dose. At the 
MTD (125 mg q.d.), the Cmax and AUC0-24 were ~111 ng/ml and ~817 h.ng/ml on Day 1 and 
~318 ng/mL and ~5301 h.ng/mL on Day 15. 
The inter-patient variability was moderate to high for BGJ398 and % coefficient of variation 
(% CV) ranged from 30 – 110 % for dose groups 20-150 mg on Day 15. The exposure differed 
significantly between some patients at the same dose levels. At the MTD dose of 125 mg, high 
inter-individual variability was observed on Day 1 (101% and 94% CV for Cmax and AUC0-
24, respectively). This inter-individual variability appeared to decrease on Day 15 (35% and 
41 % in CV% for Cmax and AUC0-24). 
Accumulation was observed with daily dosing. The mean AUC0-24 ratios between Cycle 1 Day 
1 and Cycle 1 Day 15 ranged from 1.5 to 6.5, which indicates some change in BGJ398 exposure 
following multiple dosing. At doses of 60 mg and above, most individual patients showed 
increased exposure on Day 15 following multiple dosing (~1.5 – 13 fold relative to Day 1 
exposure). Very limited data are available for patients who received continuous dosing for 28 
days without dose interruptions (8 patients at doses 60 mg and above, only 7 patients with PK 
data). In most of these patients who received uninterrupted dosing, a further increase in 
exposure beyond Day 15 was observed. This is based on either AUC0-24 exposure on Day 28 
or comparing predose samples after Day 15 in these patients. Refer to the BGJ398 Investigator’s 
Brochure for further details. 
In most patients, across all study days and dose levels, active metabolites were measurable. As 
a percentage of parent exposure, BHS697 was detected at ~10-15% and BQR917 at < 10%. 
Following an exploratory analysis, CQM157 was identified as a major pharmacologically active 
metabolite in plasma samples with in vitro potency that was similar to BGJ398. Preliminary 
analysis in circulating plasma following dosing with 125 mg of BGJ398 on Day 1 (n=9), showed 


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plasma exposures to CQM157 were as high as parent BGJ398 (up to ~3X). On Day 15 (n=5), 
exposure to CQM157 remained the same or decreased as compared to Day1 unlike BGJ398 
which showed accumulation following multiple dosing. 
2 
Rationale 
2.1 
Study rationale and purpose 
GBM is characterized by heterogeneous and complex genetic alterations. Common  alterations 
found in GBM include: EGFR overexpression (70%) (Maher et al, 2006); TP53, RB, INK4a, 
PDGF-R, VEGF-R, C-Met and HGF and PTEN (Mao et al, 2012). The activity of many of the 
more common oncogenes have been noted to be upregulated (either through activating 
mutations or through over-expression) and the activity of many of the more common tumor 
suppressor genes have been noted to be down-regulated (either through inactivating mutations 
or deletion). As often seen with genomically complex disease, there are limited effective clinical 
options and combination therapies have been the standard clinical trial approach (Mao et al, 
2012) 
Recently Singh et al (Singh et al, 2012) using whole-transcriptome sequencing identified novel 
FGFR-TACC fusions in short term cultures isolated from nine patients with primary GBMs. 
Based on the identification of these novel fusions models expressing FGFR-TACC within 
astrocytes both in vitro and in vivo were generated and recapitulated GBM-like malignancies. 
Finally they demonstrated that FGFR inhibition reverses the malignant phenotype. Specifically, 
BGJ398 was used in several in vitro experiments as part of this work showing growth inhibition 
of FGFR-TACC based GBM models. The reversal of the established GBM phenotype by FGFR 
inhibitors BJG398 and AZD4547 clearly establishes a role for FGFR inhibition in the treatment 
of GBMs characterized by FGFR-TACC fusions. Furthermore, this work clearly suggests that 
patients with GBM characterized by FGFR-TACC fusions may be successfully treated solely 
(i.e., as a single agent) with a therapeutically active FGFR inhibitor.  More recently JNJ-
42756493, a potent, oral pan-FGFR tyrosine kinase inhibitor with IC50 values in the low 
nanomolar range for all members of the FGFR family has shown evidence of radiological 
response in GBM patients harboring FGFR-TACC fusions [Di Stefano et al 2015]. 
Additionally the presence of the fusion is mutually exclusive of EGFR, PDGFR, or MET 
amplification (Parker et al 2013) in GBMs further suggesting the oncogenic dependency of the 
FGFR-TACC fusion on those GBMs. 
These preclinical findings support the initiation of a clinical trial to assess the efficacy of 
BGJ398 in the treatment of GBM in patients with evidence of FGFR  translocation or mutation. 
2.2 
Rationale for the study design 
This is a phase 2, multicenter, open-label study of BGJ398 in patients with recurrent resectable 
or unresectable GBM and/or other glioma subtypes with evidence of FGFR  translocation or 
activating mutation. Patients will be enrolled in two groups. Combined data from both these 
groups will provide enough information for the primary analysis of this study in a reasonable 
time-frame. 
 
 


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Group 1 will enroll recurrent, unresectable patients with GBM and/or other glioma subtypes 
with evidence of FGFR  translocation or activating mutations who will receive BGJ398 125mg 
p.o. daily three weeks on / one week off (days 1-21 of every 28). 
Group 2 (surgical) will enroll recurrent, resectable patients with GBM and/or other glioma 
subtypes with evidence of FGFR  translocation or activating mutation who will receive BGJ398 
125 mg p.o. daily presurgically for 5-10 days (a 5-day range will be allowed to accommodate 
surgical delays due to logistical issues). 
 Patients will resume treatment and receive 
BGJ398 125mg p.o. daily three weeks on / one week off (as in group 1), at a minimum of 2 
weeks and no more than 6 weeks following surgery, unless agreed otherwise between Novartis 
and the investigator. 
2.3 
Rationale for dose and regimen selection 
The rationale for treatment dose and schedule is based on the clinical data available to date from 
the first in human dose escalation study. 
The dose escalation portion of the study has been completed and the MTD has been identified 
as 125 mg once daily (q.d.), administered continuously. Results showed drug concentrations 
within the predicted efficacious dose range and signs of clinical activity (tumor size reduction 
by CT scan). However, most of the patients treated at these efficacious doses experienced 
reversible toxicities (mainly hyperphosphatemia) leading to study drug interruption. Based on 
the drug administration record, the median time until first dose interruption was approximately 
23 days for patients treated at 100mg and 22 days for patients treated at 125mg. Drug was 
discontinued for a median time of 7 days. A “three week on, one week off” schedule of 125mg 
p.o. is currently being explored as part of the ongoing CBJ398X2101. As of 01 May 2013, 7 
patients have been enrolled on this schedule and two have completed one cycle without dose 
interruption. 
The current study will employ the “3 week on, one week off” schedule with BGJ398 dosed at 
125mg p.o. q.d. Phosphate binders will be used prophylactically. 


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3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 
The primary objective of the study is to assess the anti-tumor activity for patients with GBM 
and/or other glioma subtypes that harbor FGFR1-TACC1, FGFR3-TACC3 fusion and/or 
activating mutation  in FGFR1, 2or 3 based on PFS. 
The primary endpoint will be the progression-free survival rate at 6 month (PFS6 rate) based 
on patients pooled from Group 1 and Group 2. Numerous clinical trials in recurrent GBM have 
confirmed the equivalency of the 6 month PFS rate in the resected and unresectable settings 
(Prados et al, 2011; Clarke et al, 2011; Lamborn et al, 2008). 
The secondary objectives of the study are to assess the anti-tumor activity for patients with 
recurrent GBM and/or other glioma subtypes that harbor FGFR1-TACC1, FGFR3-TACC3 
fusion and/or activating mutation in FGFR1, 2or 3 based on ORR and OS and to characterize 
the safety and tolerability of BGJ398. 
The secondary efficacy endpoints will be the objective response rate of patients from Group 1 
and Group 2 with radiologically assessable enhancing disease using RANO criteria and OS. 
The secondary safety and tolerability endpoints are listed in Table 3-1 below. 


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Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary 
 
Refer to Section 10.4 
To assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1,2 or 3, 
based on PFS6 
PFS rate at 6 months as defined by 
RANO criteria (Appendix 3) as assessed 
by the investigator 
 
Secondary 
 
Refer to Section 10.5 
To further assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation  in FGFR1,2or 3, 
based on ORR 
ORR (patients with measurable disease) 
as defined by RANO criteria (Appendix 3) 
as assessed by the investigator 
 
To further assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation with   in FGFR1,2or 3, 
based on OS 
Overall survival (OS) 
 
To characterize the safety and tolerability 
of BGJ398 
Safety: type, frequency, and severity of 
AEs and SAEs; 
Tolerability: dose interruptions, reductions 
and dose intensity, and evaluations of 
laboratory values 
 


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4 
Study design 
4.1 
Description of study design 
This is a multi-center, open label, phase II study, with 2 groups of patients. BGJ398 will be 
administered once daily as an oral single agent in 28-day cycles, on a “3 weeks on, one week 
off schedule.” The study will enroll patients with recurrent GBM and/or other glioma subtypes, 
whose tumors harbor FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation  in 
FGFR1, FGFR2or FGFR3 gene. 
Group 1 will target patients with RANO tumor progression not eligible for surgical resection. 
As the primary endpoint is the 6 month progression-free survival rate. Additionally, patients 
who recently underwent resection and are post-operative without RANO tumor progression 
may also be eligible for group 1 assuming all inclusion/exclusion criteria are met and most 
recent surgery has occurred within six weeks of planned first treatment dose. 
Group 2 will target patients who will have cytoreductive surgery for recurrent disease as part 
of their routine care. Patients enrolled to group 2 will receive BGJ398 for 5 to 10 days prior to 
resection. 
 Following recovery from surgery (a minimum of 2 weeks 
and no more than six weeks post operatively unless agreed otherwise between Novartis and the 
Investigator, on a case by case basis), these patients will receive BGJ398 in 28-day cycles, as 
for patients in group 1. If a patient assigned to group 2 does not undergo planned surgical 
resection, then the patient will be allowed to continue therapy as per group 1. If a patient 
enrolled to group 2 needs to undergo surgical resection sooner than initially planned (and having 
had less than 5 days of BGJ398), then the patient will still be allowed to continue therapy post-
surgically as per group 2 regardless of the number of days the patient received BGJ398 pre-
surgically. 
A total of 34 patients will be enrolled, and it is expected that the ratio of patients in group 1 and 
group 2 will be approximately 2:1, based on previous GBM trials (Stupp et al 2006, Wong et al 
1999; Lamborn et al 2008; Wong et al 2011; Hofer et al 2011; Wen et al 2009; Norden et al 
2008; Yung et al 2000). Please see Section 10: Statistical Methods and Data for details. 
In order to assess the antitumor activity of BGJ398, patients will be evaluated for tumor 
response and progression by Gd-enhanced MRI every 8 weeks until disease progression or 
discontinuation from study using RANO criteria. 


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Figure 4-1 
Study design 
 
Molecular pre-screening 
Evidence of FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 
FGFR2, or FGFR3 is required in order to begin study screening.
 
• If pre-screening data is not available at the time of study entry, the patient must sign the 
molecular pre-screening consent to allow for the collection and/or submission of samples to 
the Novartis designated laboratory for analysis. 
If the local data or the results of the central analysis meet inclusion criteria (Section 5.2), the 
patient can proceed with the screening procedures. 
Patients identified to have an activating mutation in FGFR1, 2 or 3 may be eligible pending 
agreement between Novartis and Investigator. 


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Screening 
The screening period begins once the patient has signed the study informed consent. All 
screening evaluations are required to be performed before study treatment administration 
begins. Evaluations that were conducted prior to the signing of the informed consent document 
as a part of standard of care analysis may be used to demonstrate eligibility as long as the 
evaluations were conducted within allowed screening windows. 
Treatment period 
For patients in group 1 (non surgical group, unresectable disease), the treatment period will 
begin on cycle 1, day 1 and will continue until disease progression, unacceptable toxicity, 
withdrawal of informed consent, or death. 
For patients in group 2 (surgical group, resectable disease), the treatment will begin 5-10 days 
prior to surgery with the last pre-surgical dose given within 24 hours of surgery. The duration 
of the treatment before surgery (5 to 10 days) will be left at the investigator discretion. Patients 
will be expected to resume the treatment upon surgical recovery (a minimum of 2 weeks and 
no more than 6 weeks post operatively, unless agreed otherwise between Novartis and the 
Investigator, on a case by case basis). The post surgical treatment will begin as cycle 1, day 1 
and will continue until disease progression, unacceptable toxicity, withdrawal of informed 
consent, or death. 
End of treatment 
The EOT visit occurs within 14 days after last administration of study treatment (Section 7.1.4). 
All participating patients must complete this visit even if they have had to discontinue 
prematurely unless they are unable or unwilling to return. 
Follow up 
All patients will be followed up as described in Section 7.1.5. 
30-day safety follow-up period 
All patients must be followed up for safety assessments during 30 days after the last dose of the 
study treatment. 
Disease progression follow-up period 
All patients enrolled in the study who discontinue study treatment for any reason other than 
disease progression will be followed up monthly via a phone call and will have MRI scan every 
8 weeks, until disease progression or the initiation of subsequent anticancer therapies, or death, 
whichever occurs first. 
Survival follow-up period 
All patients enrolled in the study will be followed e.g., phone call for survival every 4 months 
for at least one year per e.g., phone call per, after last patient last treatment (LPLT). 


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4.2 
Timing of interim analyses and design adaptations 
An interim analysis will be carried out once 10 patients in total for both groups have completed 
6 cycles of treatment or discontinued earlier. Based on the interim analysis results, the decision 
to continue or not with the recruitment will be made (Section 10.7). Accrual will continue 
during the interim analysis. 
4.3 
Definition of end of the study 
End of study will be upon completion of the follow up period for the last patient treated as 
described in Section 7.1.5. This will be either upon study completion of the last patient treated 
or once the last patient has expired or all patients have completed the study and have been 
followed for at least one year after their first dose of study treatment, have been lost to follow-
up, or withdrew consent, whichever occurs first. 
The analysis of study data will be based on all patients’ data up to the time when all patients 
have potentially completed at least 6 cycles of treatment or discontinued the study. This will be 
the cut-off point for the primary clinical study report (CSR). The additional data for any patients 
continuing to receive BGJ398 beyond the cut-off point for the primary clinical study report 
(CSR), as allowed by the protocol, will be summarized in a final CSR that will be prepared once 
all patients have discontinued the study or at the end of the study (end of survival follow up 
period) which is one year after the last patient’s last dose of study treatment, whichever occurs 
first. 
4.4 
Early study termination 
The study can be terminated at any time for any reason by Novartis. Should this be necessary, 
the patient should be seen as soon as possible and the same assessments should be performed 
as described in Section 7.1.4 for a prematurely withdrawn patient. The investigator may be 
informed of additional procedures to be followed in order to ensure that adequate consideration 
is given to the protection of the patient’s interests. The investigator will be responsible for 
informing IRBs and/or ECs of the early termination of the trial, and of the early termination of 
the trial for a prematurely withdrawn patient. 
5 
Population 
5.1 
Patient population 
Adult patients with histologically confirmed GBM and/or other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, 2 or 3.   who have 
evidence of radiographic progression following either first line standard therapy or therapy for 
recurrent disease will be enrolled in this study. 
 
 
 
 


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Patients enrolled in this study are not permitted to participate in additional parallel 
investigational drug or device studies. They can participate in observational studies. Patients 
who have completed the study may not be re-enrolled for a second course of treatment. Patients 
who do not meet all of the inclusion or exclusion criteria may be re-screened for consideration 
in the trial. If a patient is re-screened, the same subject ID number should be used. 
The investigator or designee must ensure that only patients who meet all the following inclusion 
and none of the exclusion criteria are offered treatment in the study. 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patients with histologically confirmed GBM and/or other glioma subtypes at the time of 
diagnosis or prior relapse. Note that all subtypes of  gliomas are permitted. Any question 
of eligibility should be discussed with Novartis. 
2. At least 15-20 unstained slides and/or a tumor block from at least one prior surgery must 
be available for molecular testing, unless agreed otherwise between Novartis and the 
Investigator. 
3. Written documentation of local or central laboratory determination of  FGFR1-TACC1, 
FGFR3-TACC-3 fusion and/or activating mutation in FGFR1, FGFR2or FGFR3 is 
required. Patients identified to have an activating mutation in FGFR1, 2 or 3 may be 
eligible pending agreement between Novartis and Investigator 
4. RANO defined tumor progression by MRI (or CT for patients who cannot tolerate MRI) 
in comparison to a prior scan; OR, progression that does not meet RANO criteria if the 
disease progression is otherwise obvious in the opinion of the investigator and is discussed 
with Novartis OR histologically proven recurrent/progressive disease based on histology if 
surgery was the treatment for the most recent progression. 
5. Patients must have received prior external beam radiotherapy and temozolomide. 
6. Unlimited prior surgeries and chemotherapies are permitted. 
7. Group specific inclusion: 
a. Group 1: RANO defined tumor progression as per Inclusion Criteria 4. Additionally, 
patients who recently underwent resection for RANO defined contrast enhancing 
tumor progression and are post-operative without evidence of RANO tumor 
progression may also be eligible for group 1 assuming all inclusion/exclusion criteria 
are met and the most recent surgery has occurred within six weeks of the planned first 
treatment dose. 
b. Group 2: RANO defined tumor progression as per Inclusion Criteria 4 and planned 
surgical resection. If a patient assigned to group 2 does not undergo planned surgical 
resection, then the patient will be allowed to continue therapy as per group 1. If a 
patient enrolled to group 2 needs to undergo surgical resection sooner than initially 
planned (and having had less than 5 days of BGJ398), then the patient will still be 
allowed to continue therapy post-surgically as per group 2 regardless of the number of 
days the patient received BGJ398 pre-surgically. 
8. Patients ≥18 years of age. 


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9. ECOG performance status ≤ 2. Assessment via Karnofsky Performance Status (KPS) and 
subsequent conversion to ECOG is acceptable (Ma et al, 2010). 
10. Able to read and/or understand the details of the study and provide written evidence of 
informed consents as approved by IRB/EC. 
11. Recovery from adverse events of previous systemic anti-cancer therapies to baseline or no 
more than grade 2, except for the following: 
a. Alopecia 
12. Able to swallow oral medication. 
13. Willing and able to comply with scheduled visits, treatment plan and laboratory tests. 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria prior to the first 
treatment. 
1. History of another primary malignancy except: in situ carcinoma of any-type that has been 
adequately treated; 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; or any indolent malignancy that 
has not required treatment within the prior 2 years (even if never previously treated). 
2. Prior or current treatment with a FGFR inhibitor (unless agreed otherwise between 
Novartis and the Investigator on a case by case basis). 
3. Neurological symptoms related to underlying disease requiring increasing doses of 
corticosteroids. Note: Steroid use for management of CNS tumors is allowed but must be 
at a stable dose for at least 1 week preceding the baseline MRI/CT. If the corticosteroid 
dose is increased between the date of imaging and the initiation of study treatment, a new 
baseline MRI/CT is required. Definition of stable steroids includes patients on no steroids. 
Local administration methods or prophylactic use is allowed. 
4. Any other medical condition that would, in the investigator’s judgment, prevent the 
patient’s participation in the clinical study due to safety concerns or compliance with 
clinical study procedures. 
5. 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. 
6. Impairment of gastrointestinal (GI) function or GI disease that may significantly alter the 
absorption of oral BGJ398 (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. 
8. Treatment with any of the following anti-cancer therapies prior to the first dose of BGJ398 
within the stated timeframes: 
• Cyclical cytotoxic chemotherapy within a period of time that is shorter than the cycle 
length used for that treatment (e.g., 6 weeks for nitrosourea, mitomycin-C) 


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• Biological therapy (e.g., antibodies – including bevacizumab) within a period of time 
that is ≤ 5 t1/2 or ≤ 4 weeks, whichever is shorter, prior to starting study drug 
• Continuous or intermittent small molecule therapeutics (excluding traditional 
cytotoxic chemotherapy) within a period of time that is ≤ 5 t1/2 or ≤ 4 weeks 
(whichever is shorter) prior to starting study drug 
• Any other investigational agents within a period of time that is ≤ 5 t1/2 or less than the 
cycle length used for that treatment or ≤ 4 weeks (whichever is shortest) prior to 
starting study drug 
• Wide field radiotherapy (including therapeutic radioisotopes such as strontium 89) ≤ 4 
weeks or limited field radiation for palliation ≤ 2 weeks prior to starting study drug 
9. Patients who are currently receiving treatment with agents that are known strong inducers 
or inhibitors CYP3A4 are prohibited. (Refer to Appendix 2 for prohibited medications). 
10. Patients taking Enzyme Inducing Anti-Epileptic Drug (EIAED). If previously on an 
EIAED, the patient must be off of it for at least two weeks prior to study treatment. (Refer 
to Appendix 2 for list of prohibited medications). 
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 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 < 9.0 g/dL 
17. Insufficient hepatic and renal function: 
• Total bilirubin > 1.5x ULN unless bilirubin elevation is related to Gilbert’s Syndrome 
for which bilirubin ≥ 2.5 ULN is an exclusion 
• AST/SGOT or ALT/SGPT > 2.5x ULN (AST or ALT > 5x ULN in the presence of 
liver metastases) 
• Serum creatinine > 1.5xULN and calculated or measured creatinine clearance <  
45mL/min 
18. Calcium-phosphate homeostasis: 
• Inorganic phosphorus outside of institutional/laboratory normal upper limits 
• Total  serum calcium (can be corrected) outside of institutional/laboratory normal 
upper limits 
19. Clinically significant cardiac disease including any of the following. Note that this applies 
only to patients who have a documented or suspected history of cardiac disease and 
cardiac testing is not otherwise required. 


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• 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  > 470 msec  
• History of congenital long QT syndrome 
• Clinically significant hypokalemia, which cannot be corrected 
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. HIV positive patients on combination antiretroviral therapy are ineligible because of the 
potential for pharmacokinetic interactions with study drug. In addition, these patients are 
at increased risk of lethal infections when treated with marrow-suppressive therapy. This 
applies only to patients who have a documented history of HIV and HIV testing is not 
otherwise required. 
22. 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. 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): 
a. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
b. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
23. Current evidence of corneal/keratopathy or retinal disorder including, but not limited to, 
bullous/ band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits, 
confirmed by ophthalmologic examination 
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 


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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. 
6 
Treatment 
The investigational drug will be BGJ398 as an oral formulation. 
6.1 
Study treatment 
The pharmacist will dispense the correct number of capsules that will ensure that each patient 
receives sufficient drug until the next scheduled study visit. 
Study drug labels will comply with the legal requirements of each country and be printed in the 
local language. 
6.1.1 
Dosing regimen 
Table 6-1 
Dose and treatment schedule 
Study treatments 
Pharmaceutical form 
and route of 
administration 
Strength 
Frequency and/or 
Regimen 
BGJ398 
Capsule for oral use 
100 mg 
Daily, 3 weeks on 1 week 
off schedule  
BGJ398 
Capsule for oral use 
25 mg 
Daily, 3 weeks on 1 week 
off schedule 
Patients should be instructed to take the daily dose of BGJ398 in the morning, at approximately 
the same time each day (24 ± 2 hrs. interval), 
 
 
 
 The investigator should 
instruct the patient to take the study drug exactly as prescribed to promote compliance. All 
dosages prescribed and dispensed to the patient and all dose changes during the study must be 
recorded on the Dosage Administration Record CRF. 


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6.1.1.1 
Instructions for administration of BGJ398 
• Patients should consume a light breakfast each day (e.g., non-grapefruit-based juice, toast 
and jam), 
. This should be 
followed by a 2 hour fast, after which the doses of study drug should be taken. Patients 
should continue to fast for 1 hour after the administration of study drug. 
• BGJ398 should be taken with a large glass of water (~250 mL) and consumed over as short 
a time as possible. Patients should be instructed to swallow the capsules whole and not chew 
them. 
• If for any reason a breakfast was not consumed prior to taking the dose the patient should 
take the dose with a full glass of water, and continue to fast for an hour after taking the dose. 
• 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. 
 
 
• BGJ398 is characterized by pH-dependent solubility, and therefore, medicinal products that 
alter the pH of the upper gastro-intestinal tract may alter the solubility of 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 should be dosed at least 2 hours before or 10 hours after dosing with a gastric 
protection agent. 
• Patients must avoid consuming Seville oranges or juice, grapefruit, grapefruit juice, 
grapefruit hybrids, star fruits, pomegranates, or pummelos from 7 days prior to the first dose 
of study medication through the end of study participation. This is due to a potential 
CYP3A4 interaction with study medication. Normal oranges and orange juice are allowed. 
• The investigator or responsible site personnel should instruct the patient to take the study 
drug exactly as prescribed to promote compliance. All dosages prescribed and dispensed to 
the patient and all dose changes or missed doses during the study must be recorded on the 
Dosage Administration Record eCRF. 
• Drug accountability must be performed on a regular basis. Patients will be instructed to 
return unused study drug to the site at the end of each cycle. 


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6.1.2 
Ancillary treatments 
Phosphate-lowering therapy may be initiated as clinically indicated. 
Phosphate lowering treatment, including but not restricted to low phosphate diet and phosphate 
binding therapy such as sevelamer hydrochloride, should be implemented and modified as 
clinically indicated, including prophylactically, at study drug initiation and throughout BGJ398 
administration. Recommendations for treatment are provided in Section 6.2.2 (Follow up on 
drug induced toxicities), but should be modified as per country or institutional guidelines. 
6.1.3 
Supportive treatment needed for GBM 
During the course of this trial, the use of systemic anti-coagulation (such as with heparinoids or 
direct thrombin inhibitors) in the setting of venous thromboembolism (VTE) will be performed 
according to the judgment of the investigator. Prophylactic anti-coagulation with heparin or low 
molecular weight heparin (LMWH) is allowed. 
6.1.4 
Treatment duration 
Patients in the surgical group will be treated with BGJ398 once daily for 5 to 10 days before 
surgery. 
Patients from both groups being treated with BGJ398 on a three week on, one week off schedule 
may continue treatment with BGJ398 until patient experiences unacceptable toxicity, disease 
progression and/or treatment is discontinued at the discretion of the investigator or withdrawal 
of consent or if the study is terminated prematurely by Novartis. 
6.2 
Dose modifications 
6.2.1 
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. These changes must be 
recorded on the Dosage Administration Record CRF. 
All dose modifications should be based on the worst preceding toxicity. The following 
guidelines need to be applied: 
Each patient will be allowed up to 2 dose reductions. Patients must discontinue BGJ398 if 
toxicities persist following 2 dose reductions (Table 6-2) unless a continuation is allowed in 
discussion with Novartis. 
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 (Table 6-2). 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 unless a continuation is allowed in 
discussion with Novartis. 


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If a patient requires a dose delay of > 14 consecutive days of BGJ398 from the intended day of 
the next scheduled dose, then the patient should be discontinued from the study treatment unless 
a continuation is allowed in discussion with Novartis. 
Patients who discontinue the study for a study related adverse event or an abnormal laboratory 
value must be followed as described in Table 6-3 and Section 6.2.2. 
In exceptional situations, study treatment may continue even if the patient experienced one of 
the treatment stopping rules. The decision to allow for continuation of treatment will be made 
on a case-by-case basis following discussion between Novartis and the Investigator. 
Situations that may allow for continuation of treatment include but are not limited to the 
following. 
• A dose delay of > 14 days has occurred, but the patient is clearly benefiting from study 
treatment (i.e., stable disease, partial response, or complete response) and it is the 
investigator’s opinion that no safety concerns are present, after discussion with Novartis 
Medical Monitor, the patient may remain on the study treatment 
• 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 6-2 
Dose reduction table 
Dose level 
BGJ398 
 
Dose level 0 
125 mg 
Starting dose 
Dose level -1 
100 mg 
 
Dose level -2 
75 mg 
 
Dose level -3 
50 mg 
Allowed only if patients is clearly benefiting from 
study treatment, but is experiencing AE that prevent 
continued treatment at dose level -2 


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Table 6-3 
Criteria for interruption and re-initiation of BGJ398 treatment 
Worst Toxicity CTCAE using the current active CTCAE version 
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 
● 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. 
● 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 until electrolytes are documented to be within normal limits. 
 
Once the QTcF prolongation has resolved, patients may be re-treated at one lower dose 
level at the investigator’s discretion 
● 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 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. 
 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
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 until resolved to CTCAE Grade ≤ 1or baseline, then 
● If resolved in ≤ 7 days, maintain dose level of BGJ398 
● If resolved in > 7 days, ↓ 1 dose level of BGJ398. 
 
Hold dose of BGJ398 until resolved to CTCAE ≤ Grade 1, ↓ 1 dose level of BGJ398. 
Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L, single temperature of > 38.3°C or a 
sustained temperature of ≥ 38.0°C for more than one hour ) 
 
 
Grade 4 
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then 
● If resolved by ≤ 7 days, ↓ 1 dose level of BGJ398. 
● 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 until resolved to CTCAE Grade ≤ 1 or baseline, then maintain dose 
level 
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline, then ↓ 1 dose level 
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 until resolved to CTCAE Grade ≤ 1 or baseline 
● If resolved in ≤ 7 days, maintain dose level of BGJ398. 
● If resolved in > 7 days, ↓ 1 dose level of BGJ398 
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline, then ↓ 1 dose level 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations – Renal 
Serum creatinine  
 
 
 
 
Grade 2 (> 1.5 - 3.0 x ULN) 
 
 
 
 
Grade ≥ 3 (> 3.0 x ULN) 
If serum creatinine CTCAE Grade ≥ 2 has been demonstrated in conjunction with 
hyperphosphatemia, serum creatinine levels must be repeated at least weekly until 
resolution.  24-hour urine collection should be obtained as clinically indicated for total 
phosphate, calcium, protein, and creatinine clearance.  Ultrasound examination of the 
kidneys should be performed as indicated to evaluate de-novo calcifications until resolution 
or stabilization of creatinine.  
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline 
● If resolved in ≤ 7 days, maintain dose level of BGJ398. 
● If resolved in > 7 days, ↓ 1 dose level of BGJ398. 
 
 
 
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 until resolved to CTCAE Grade ≤ 1 
● If resolved in ≤ 7 days, maintain dose level of BGJ398. 
● If resolved in > 7 days, ↓ 1 dose level of BGJ398.  
 
Discontinue patient from study treatment. 
 
Note: If CTCAE Grade 3 or 4 hyperbilirubinemia is due to hemolysis, then ↓ 1 dose level of 
BGJ398 and continue treatment at the discretion of the Investigator. 
AST or ALT 
Grade 3 (> 5.0 - 20.0 x ULN) without bilirubin elevation > 2.0 x ULN 
 
 
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline 
● If resolved in ≤ 7 days, maintain dose level of BGJ398. 
● If resolved in > 7 days, ↓ 1 dose level of BGJ398. 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
 
Grade 4 (> 20.0 x ULN) without bilirubin elevation >2.0 x ULN 
 
Discontinue patient from study treatment. 
AST or ALT and Bilirubin 
AST or ALT > 3.0 – 5.0 x ULN and total bilirubin > 2.0 x ULN without liver 
metastasis or evidence of disease progression in the liver 
 
 
AST or ALT > 5.0 x ULN and total bilirubin > 2.0 x ULN  
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
● If resolved in ≤ 7 days, ↓ 1 dose level of BGJ398. 
● 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) 
 
 
 
 
 
Grade 4 (>5.0 x ULN) 
 
● Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 2. 
● ↓ 1 dose level of BGJ398 
 
For recurrent Grade 3 asymptomatic lipase or amylase elevation despite dose reduction, 
BGJ398 should be held and continuation of therapy should be discussed with the Novartis  
medical monitor following resolution to ≤ Grade 2 
 
For any Grade 4 asymptomatic lipase or amylase elevation, BGJ398 should be held and 
continuation of therapy should be discussed with the Novartis medical monitor following 
resolution to ≤ Grade 2. 
Note: A CT scan or other imaging study to assess the pancreas, liver, and gallbladder  
should be performed as clinically indicated within 1 week of the first occurrence of any 
CTCAE ≥ Grade 3 amylase and/or lipase. 
 
Grade 4 (> 5.0 x ULN) 
Discontinue patient from study treatment 
 
Hyperphosphatemia 
 
Serum phosphorus >5.5 – 7.0 mg/dL 
 
 
Serum phosphorus > 7.0 mg/dL for more than 7 days despite maximal 
phosphate lowering therapy (Sevelamer) or single serum phosphorus > 
 
Maintain dose level of BGJ398 and optimize phosphate lowering therapy as clinically 
indicated. 
 
Hold BGJ398 dose until resolved to serum phosphorus ≤ 5.5 mg/dL. 
 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
9.0 mg/dL regardless of duration or dose of phosphate lowering therapy 
(Sevelamer). 
 
 
(Optimize/maximize dose and schedule of phosphate lowering therapy in 
accordance with package insert, country or institutional guidelines). 
 
 
 
 
 
 
Restart BGJ398 at the same dose level with maximal phosphate binder dosing if the patient 
did not receive maximal phosphate binder dosing for serum phosphorus > 7.0 mg/dL for > 
7 days.      
 
Reduce one dose level of BGJ398 if the patient had received maximal phosphate lowering 
therapy for serum phosphorus >7.0 mg/dL for > 7 days or if patient had a one-time serum 
phosphorus of > 9.0 mg/dL.  Restart BGJ398 with maximal phosphate binder dosing. 
 
It is recommended that phosphate binder dosing continues during BGJ398 dose 
interruptions for hyperphosphatemia and that serum phosphorus values be monitored 
frequently, e.g. every 2-3 days. 
 
Phosphate binder dosing should be held during the week off BGJ398 therapy each cycle 
(Days 22-28) and during BGJ398 dose interruptions for non-hyperphosphatemia adverse 
events.               
 
 
 
 
Hypercalcemia 
Serum calcium grade 2 
 
 
 
Serum calcium ≥ grade 3 
 
Hold BGJ398 dose until resolved to grade 1 or baseline: 
● if resolved ≤ 7 days after suspending BGJ398, maintain dose level 
● if resolved > 7 days after suspending BGJ398, ↓ 1 dose level 
 
Discontinue patient from the study 
 
Nervous system disorders 
Neurotoxicity 
Grade 2 
 
Grade ≥ 3  
 
Omit dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then ↓ 1 dose level of BGJ398  
 
Discontinue patient from study drug treatment 
 
GI disorders 
Pancreatitis 
Grade ≥ 2 
 
Discontinue patient from study drug treatment 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
Diarrhea 
 
Grade 1 
Maintain dose level of BGJ398, but initiate anti-diarrheal treatment 
 
Grade 2 
 
● Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
● Optimize anti-diarrheal treatment, maintain dose level of BGJ398. 
● For reoccurrence of diarrhea CTCAE Grade 2, hold dose of BGJ398 until resolved to 
CTCAE Grade ≤ 1, ↓ BGJ398 by 1 dose level 
 
Grade 3 
 
 
 
 
 
Grade 4 
 
● Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
● Optimize anti-diarrheal treatment 
● ↓ BGJ398 by 1 dose level 
● For reoccurrence of diarrhea CTCAE Grade 3, despite optimal 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 doses until ≤ grade 1, ↓ 1 dose level 
 
Discontinue patient from study 
 


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Worst Toxicity CTCAE using the current active CTCAE version 
Recommended Dose Modifications any time during a cycle of therapy 
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 
 
 
 
≥ grade 1 retinal vein occlusion, grade 4 CSR and CSR-like events, and 
grade 4 other eye disorders 
 
Hold BGJ398 until resolved to ≤ grade 1 and continue ophthalmologic evaluation 
● If resolved in ≤ 14 days, ↓ BGJ398 by 1 dose level 
● If resolved in > 14 days, discontinue BGJ398 
 
Hold BGJ398 until resolved to grade ≤ 1. 
● If resolved in ≤ 14 days, ↓ BGJ398 by 1 dose level 
● If resolved in > 14 days, discontinue BGJ398 
 
Discontinue BGJ398 
Other ocular/visual toxicity 
 
≥ grade 3 
Hold BGJ398 until resolution to ≤ grade 1 
If resolution in ≤14 days, ↓ 1 dose level, otherwise discontinue BGJ398 
General disorders 
Fatigue 
Grade 3 
 
 
 
 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 
● If resolved in ≤ 7 days, maintain dose level of BGJ398. 
● If resolved in > 7 days, discontinue patient from study treatment. 
 
Other clinically significant AEs 
Grade 3 
 
Grade 4 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then ↓ 1 dose level of BGJ398. 
 
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 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 then study treatment must be stopped. 


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6.2.2 
Follow-up for toxicities 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event or 
clinically significant laboratory value, must be followed up at least once a week (or more 
frequently if required by institutional practices, or if clinically indicated) for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever comes 
first. Clinical experts or specialists, such as ophthalmologist, endocrinologist, dermatologist, 
should be consulted as deemed necessary. All patients must be followed up for adverse events 
and serious adverse events for 30 days following the last dose of BGJ398. 
6.2.3 
Anticipated risks and safety concerns of the study drug 
Eligibility criteria as well as specific dose modification and stopping rules are included in this 
protocol. Guidelines for prophylactic or supportive treatment for expected toxicities, including 
management of study-drug induced adverse events, i.e., hyperphosphatemia, and renal toxicities 
are provided in Table 6-3. Refer to preclinical toxicity and or clinical data found in the [BGJ398 
Investigator’s Brochure]. 
6.3 
Concomitant medications 
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.  If a drug is listed 
under “Permitted concomitant therapy requiring caution and/or action” and also under 
“Prohibited concomitant therapy”, the drug should be prohibited. 
6.3.1 
Permitted concomitant therapy 
Any palliative and supportive care for disease related symptoms, including any medication for 
a concurrent medical condition are permitted, except as specifically prohibited below. 
Oral phosphate binders 
 
Phosphate lowering treatment, including a 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 administration.  
Recommendations for treatment are provided in Table 6-3, and should be modified as necessary 
as per country, package insert or institutional practice.   
Hematopoietic growth factors 
Hematopoietic growth factors (e.g., erythropoietin, G-colony stimulating factor (CSF) and GM-
CSF) are not to be administered prophylactically or to be used to meet eligibility criteria. 
However, these drugs may be administered per the labeling of these agents or as dictated by 
local practice or guidelines established by the American Society of Clinical Oncology (ASCO). 


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Hormone replacement therapies 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as well as 
estrogen replacement hormone treatment. 
6.3.2 
Permitted concomitant therapy requiring caution and/or action 
Drugs that alter the pH of the GI tract 
BGJ398 is characterized by pH-dependent solubility, and therefore, medicinal products that 
alter the pH of the upper gastro-intestinal tract may alter the solubility of 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 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 and minimized to the extent 
possible. 
Substrates and inhibitors 
CYP substrates and inhibitors 
BGJ398 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 confimed 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. Please refer to Appendix 1 for the list of medication to be used with caution. 
Caution is advised when BGJ398 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 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 avoided 
whenever possible. The use of methadone and levomethadyl should also be avoided whenever 
possible. Refer to the Appendix 1 for the list of medications to be used with caution. Note that 
the list may not be comprehensive. 


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Hormonal contraceptives may be affected by cytochrome P450 interactions and are therefore 
not considered effective for this study. For allowed contraception methods please refer to 
Section 5.3. Highly effective contraception should be maintained throughout the study. 
BGJ398 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 is a substrate of CYP3A4. Therefore moderate inhibitors and inducers should be used 
with caution if no other alternative is available. Strong inhibitors and inducers are prohibited. 
Please refer to the Appendix 1 for the list of medications to be used with caution. Please note 
that the list might not be comprehensive. 
Transporter substrates 
In vitro data show that BGJ398 is an inhibitor of BCRP. CQM157, a metabolite of BGJ398, is 
an inhibitor of transporters P-gp, BCRP, OATP1B1, and OATP1B3 (IC50 2-4 µM). In the 
absence of data confirming whether transporter interactions occurs in vivo, patients receiving 
medications that are substrate of these transporters must be monitored for potential toxicity and 
may require dose titration or reduction of the medication. 
Non-enzyme Inducing Anti-epileptic drugs (non-EIAED) 
Non-enzyme inducing anti-epileptic medication (non-EIAED) such as valproic acid, 
levetiracetam and lamotrigine are allowed with caution. Patients who were previously on a non-
EIAED and need to change anti-convulsants, should be started on another non-EIAED if at all 
possible. EIAEDs are not permitted (see Section 6.3.3 and Appendix 2). 
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. See Appendix 1 for list 
of drugs that need to be used with caution. Aprepitant is both a sensitive substrate and a 
moderate CYP3A4 inhibitor and can be used with caution if an alternative is not available. 
Possible and conditional risk of QT/QTc interval prolongation or torsade de 
pointes medications 
There is no current evidence that BGJ398 has an effect on cardiac conduction or ECG intervals 
(see current version of the BGJ398 Investigator Brochure).  However, medications that have 
the potential to prolong the QT/QTc interval or induce torsade to pointe (possible and 
conditional risk of TdP/QT prolongation) are allowed with caution. Investigators at their 
discretion may co-administer such medications, but patients should be carefully monitored. See 
Appendix 1 for list of drugs that need to be used with caution.  Please note that the list might 
not be comprehensive. 


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6.3.3 
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 and/or radiation therapy other than the study treatments) 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 such as the ones listed in Appendix 2 are prohibited because 
BGJ398 is a likely substrate of this isoenzyme. Caution should be used during administration 
of moderate inhibitors. The following food products are prohibited: Seville oranges or juice, 
grapefruit, grapefruit juice, grapefruit hybrids, and pummelos. 
CYP inducers 
Strong inducers of CYP3A4 are prohibited because their usage would likely decrease the 
exposure of BGJ398. Therefore, agents such as those listed in Appendix 2 are prohibited.   
Please note that the list may not be exhaustive.  
Phosphorus and calcium 
Medications that increase the serum levels of phosphorus and/or calcium are prohibited. These 
include, but are not limited to, calcium, phosphate, vitamin D, parathyroid hormone (PTH). 
Known Risk of QT/QTc interval prolongation or torsade de pointes medications 
There is no current evidence that BGJ398 has an effect on cardiac conduction 
or ECG intervals (See current version of the BGJ398 Investigator Brochure). 
However, medications that are known to prolong the QT/QTc interval or induce 
Torsade de Pointes (Risk of TdP/QT prolongation) are prohibited.  List of these 
medications is given in Appendix 2. Please note that the list might not be 
comprehensive.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. 
Enzyme Inducing Anti-epileptic drugs (EIAEDs) 
Enzyme inducing anti-epileptic medication is not allowed (please refer to Appendix 2). Patients 
who were previously on a non-EIAED and need to permanently change anticonvulsants, but 
who cannot change to another non-EIAED must be discussed with Novartis. These patients will 
be taken off-study unless it is felt that they have benefited from the therapy following discussion 
with Novartis. 


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6.4 
Patient numbering, treatment assignment or randomization 
6.4.1 
Patient numbering 
Each patient is identified in the study by a Subject Number (Subject No.), that is assigned when 
the patient is first enrolled for screening and is retained as the primary identifier for the patient 
throughout his/her entire participation in the trial. The Subject No. consists of the Center 
Number (Center No.) (as assigned by Novartis to the investigative site) with a sequential patient 
number suffixed to it, so that each patient is numbered uniquely across the entire database. Upon 
signing the Molecular pre-screening Informed Consent Form or Informed Consent Form for the 
Study, the patient is assigned to the next sequential Subject No. available to the investigator 
through the Oracle Clinical RDC interface. 
Once assigned, the Subject No. must not be reused for any other patient and the Subject No. for 
that individual must not be changed, even if the patient is re-screened. 
6.4.2 
Treatment assignment or randomization 
The assignment of a patient to the treatment groups will be coordinated by Novartis. No 
randomization will be performed for this study. 
6.5 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drug as per protocol. Study drug will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study must 
be recorded on the Dosage Administration Record eCRF. 
BGJ398 will be provided by Novartis Pharma in hard gelatin capsules covering dosage strengths 
of 25 and 100 mg (expressed in mg of BGJ398 free base, open label bulk). 
6.5.1 
Study drug packaging and labeling 
The study medication packaging has a 2-part label. Site personnel will add the patient number 
on the label. Immediately before dispensing the package to the patient, site personnel will detach 
the outer part of the label from the packaging and affix it to the source document (Drug Label 
Form) for that patient’s unique patient number. 
Medication labels will be in the local language and comply with the legal requirements of each 
country. They will include storage conditions for the drug but no information about the patient. 
Study drugs will be packed as open label supply which allows the patient to take medication at 
home. 
6.5.2 
Drug supply and storage 
Study treatments must be received by designated personnel at the study site, handled and stored 
safely and properly, and kept in a secured location to which only the investigator and designated 
site personnel have access. Upon receipt, BGJ398 should be stored according to the instructions 
specified on the drug labels and in the [Investigator’s Brochure]. 


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6.5.3 
Study drug compliance and accountability 
6.5.3.1 
Study drug compliance 
Dosing data for BGJ398 will be recorded on the Dosage Administration eCRF. 
Compliance will be assessed by the investigator and/or study personnel at each patient visit and 
information provided by the patient and/or caregiver will be captured in the Drug 
Accountability Form. This information must be captured in the source document at each patient 
visit. 
6.5.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return all 
unused study treatment and packaging at the end of each cycle, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will return 
all used and unused study treatment, packaging, drug labels, and a copy of the completed drug 
accountability log to the Novartis monitor or to the Novartis address provided in the investigator 
folder at each site. 
6.5.3.3 
Handling of other study treatment 
Not applicable. 
6.5.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate 
7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
For all visits, there is a ± 3-day window on assessments to take into account scheduling over 
public or religious holidays, if not explicitly specified otherwise. 
 
 For imaging assessments, a ±7 day 
window is allowed, except for the first post baseline assessment and for confirmatory scans (+7 
day window only permitted). All screening assessments, including baseline imaging 
assessments, must be completed within 28 days before the first dose, with the exception of the 
serum pregnancy test (β-hCG) that needs to be performed ≤ 72hrs before the first dose of study 
treatment. Every effort must be made to follow the schedule outlined in Table 7-1. 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. The table indicates which assessments produce data to be entered into the database 
(D) or remain in source documents only (S) (“Category” column). 


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Molecular pre-screening assessments can be performed any time prior to the initiation of 
screening. 
 
 
Assessments which are indicated to be performed at screening and on Cycle 1 Day 1, need only 
to be repeated at Cycle 1 Day 1 if screening assessment was more than 3 days earlier. 
All assessments should be performed as outlined in Table 7-1 and as clinically indicated. 


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Table 7-1 
Visit evaluation schedule 
Category 
Reference to 
section 
Molecular pre -
screening
Screening  
Pre-Surgical 
Treatment 
Day of Surgery 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30 day Follow up 
Disease 
Progression 
f ll
Survival follow up 
 
 
 
Screening 
Phase 
Surgical 
phase 
(Group 2) 
Treatment Phase 
Follow-up 
Day of cycle 
 
 
 
-28 to 
-1 
1 
5-
10 
6-
11 
1 
2 
8 
15 
22 
1 
8 
15 
22 
1 
22 
1 
22 
 
 
 
 
Informed consent for 
molecular pre-
screening if 
applicable 
D 
7.1.1 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study Informed 
Consent (ICF) 
D 
7.1.2 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Demography 
D 
7.1.2.3 
X 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Inclusion/exclusion 
criteria 
D 
7.1.2 
and 5  
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 


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Category 
Reference to 
section 
Molecular pre -
screening
Screening  
Pre-Surgical 
Treatment 
Day of Surgery 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30 day Follow up 
Disease 
Progression 
f ll
Survival follow up 
 
 
 
Screening 
Phase 
Surgical 
phase 
(Group 2) 
Treatment Phase 
Follow-up 
Day of cycle 
 
 
 
-28 to 
-1 
1 
5-
10 
6-
11 
1 
2 
8 
15 
22 
1 
8 
15 
22 
1 
22 
1 
22 
 
 
 
 
Relevant medical 
history/current 
medical conditions 
D 
7.1.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Diagnosis and extent 
of cancer 
D 
7.1.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior antineoplastic 
therapy 
D 
7.1.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Prior/ concomitant 
medications 
D 
6.3 
 
X 
X 
X 
X 
Continuous 
X 
X 
 
 
Antineoplastic 
therapies since 
discontinuation of 
study treatment 
D 
7.1.4 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 
X 
X 
X 
Physical examination 
S 
7.2.2.1 
 
X 
 
 
 
X 
 
X 
 
X 
X 
X 
 
X 
X 
X 
X 
X 
X 
 
 
 
Height 
D 
7.2.2.3 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Weight 
D 
7.2.2.3 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
 
 
X 
 
 
 
Vital signs 
D 
7.2.2.2 
 
X 
 
 
 
X 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Performance status 
D 
7.2.2.4 
 
X 
 
 
 
X 
 
 
 
X 
X 
 
 
X 
X 
 
X 
 
X 
 
 
 
Hematology 
D 
7.2.2.5.1 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 


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Category 
Reference to 
section 
Molecular pre -
screening
Screening  
Pre-Surgical 
Treatment 
Day of Surgery 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30 day Follow up 
Disease 
Progression 
f ll
Survival follow up 
 
 
 
Screening 
Phase 
Surgical 
phase 
(Group 2) 
Treatment Phase 
Follow-up 
Day of cycle 
 
 
 
-28 to 
-1 
1 
5-
10 
6-
11 
1 
2 
8 
15 
22 
1 
8 
15 
22 
1 
22 
1 
22 
 
 
 
 
Chemistry  
D 
7.2.2.5.2 
 
X 
 
 
 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
X 
 
 
 
Coagulation 
D 
7.2.2.5 
 
X 
 
 
 
If clinically indicated 
 
 
 
 
Urinalysis 
(microscopic or 
macroscopic) 
D 
7.2.2.5.3 
 
X 
 
 
 
If clinically indicated 
 
 
 
 
Pregnancy test  
D 
7.2.2.5 
 
X 
 
 
 
X 
 
 
 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Ophthalmologic 
assessment 
D 
7.2.2.8 
 
X 
 
 
 
X 
 
 
X 
 
X 
 
 
 
X 
 
X 
 
X 
 
 
 
Tumor response per 
RANO v1.0 (* : within 
72 hours of surgery) 
D 
7.2.1 
 
X 
 
 
X* 
First post baseline scan occurs cycle 3 day 1; subsequent 
scans occur every 8 weeks until unacceptable toxicity or 
disease progression, whichever occurs first 
X 
 
X 
 
Surgery  
D 
4.1 
 
 
 
 
X 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
Study drug 
administration 
 
6.1 
 
 
Continuous 
from day 1 till 
day of surgery 
Continuous on a 3 weeks on 1 week off schedule 
 
 
 
 
12-Lead ECG (*pre-
dose) 
D 
7.2.2.7 
 
X 
X* 
 
X 
X* 
 
 
 
 
X* 
 
 
 
X* 
 
X* 
 
X 
 
 
 


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Category 
Reference to 
section 
Molecular pre -
screening
Screening  
Pre-Surgical 
Treatment 
Day of Surgery 
Cycle 1 
Cycle 2 
Cycle 3 
Subsequent 
cycles 
End of study 
treatment 
30 day Follow up 
Disease 
Progression 
f ll
Survival follow up 
 
 
 
Screening 
Phase 
Surgical 
phase 
(Group 2) 
Treatment Phase 
Follow-up 
Day of cycle 
 
 
 
-28 to 
-1 
1 
5-
10 
6-
11 
1 
2 
8 
15 
22 
1 
8 
15 
22 
1 
22 
1 
22 
 
 
 
 
Adverse events 
(* SAE only) 
D 
7.2.2 
X* 
X 
X 
X 
X 
Continuous 
X 
X 
 
 
Survival follow up 
D 
7.1.5 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
X 


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7.1.1 
Molecular pre-screening 
Local pre-screen 
If local testing will be conducted to determine the molecular status of the tumor, potential 
patients will be asked to sign a “Pre-screening Informed Consent” to allow for the collection 
and analysis of the sample. 
A consent form is not needed if the molecular status of the tumor was previously determined. 
Evidence of local data must be present in the source documentation. 
7.1.2 
Clinical Screening 
The IRB/IEC study approved informed consent form (ICF) must be signed and dated before 
any screening procedure is performed. Procedures which are part of the clinical routine during 
the initial diagnostic work-up of the patient may be obtained before obtaining the ICF. A copy 
of the ICF must be given to the patient or to the person signing the form. The investigator or 
designee must record the date when the study informed consent was signed in the medical 
records of the patient. 


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Patients will be evaluated against study inclusion and exclusion criteria and safety assessments. 
For details of assessments, refer to Table 7-1. Screening assessments must be completed within 
28 days prior to the first dose of treatment with the exception of the serum pregnancy test (β-
hCG) that needs to be performed ≤ 72hrs before the first dose of study treatment. Clinical and 
radiological tumor assessment (RANO criteria) should be conducted preferably within 1 week 
(7 days) prior to the first dose of the study drug; however tumor assessments up to 4 weeks (28 
days) prior to the first dose will be acceptable. Screening assessments must be repeated if >28 
days from Cycle 1 Day 1. 
7.1.2.1 
Enrollment process 
After the patient has signed an ICF to participate in the treatment phase of the study, an 
enrollment form detailing the patient’s age, gender, disease type, screening date, and required 
genetic alteration, as well as the anticipated date of first study drug treatment. The enrollment 
form will be faxed or e-mailed to the Novartis Clinical Trial Lead or his/her designee for 
approval and acknowledgement of patient inclusion. 
7.1.2.2 
Information to be collected on screening failures 
Patient who 
• signed a molecular pre-screening ICF but are considered as ineligible after molecular 
screening 
• are found not eligible to participate in the treatment phase of the study, after signing the 
informed consent form 
• are not started on study treatment based on the opinion of the investigator 
• withdraw consent prior to initiating study drug 
will be considered as screening failures, and data will be handled in the same manner. The 
molecular pre-screening failure or screening failure will be entered on the Screening Phase 
Disposition Page. The demographic information, informed consent, and Inclusion/Exclusion 
pages must also be completed for Screen Failure subjects. No other data will be entered in the 
database for patients who are screen failures, unless the patient experienced a Serious Adverse 
Event during the screening phase (see Section 8 for SAE reporting details). 
The following data must be collected in the source documents for any patient who signs an ICF: 
• Informed consent information 
• Inclusion/exclusion 
• demography 
• Screening log page (including reason for not being started on treatment) 
• Serious Adverse Event (see Section 8 for SAE collection, requirements and reporting) 


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7.1.2.3 
Patient demographics and other baseline characteristics 
Data to be collected will include general patient demographics, relevant medical history and 
current medical conditions, prior concomitant medications, diagnosis and extent of tumor, 
baseline tumor mutation status (gene amplification or translocation) and details on prior 
antineoplastic treatments. 
7.1.3 
Treatment period 
During the treatment period, the patient is obliged to follow the investigators instructions with 
regards to contraception, concomitant medications and dosing regimen. There is no fixed 
duration; patients may continue treatment with the study drug until the development of an 
unacceptable toxicity that precludes any further treatment, disease progression, and /or 
treatment is discontinued at the discretion of the Investigator or by patient refusal. 
For the patients included in group 2 (surgical group), there is a fixed treatment duration of 5 to 
10 days before surgery. The last dose should be on the day of surgery, or the day before at the 
discretion of the investigator. At a minimum of 2 weeks post-surgery, patients may resume 
study treatment with BGJ398 until experiencing unacceptable toxicity, disease progression 
and/or the treatment is discontinued at the discretion of the investigator or by patient refusal 
(withdrawal of consent). Day 1 of treatment following surgery will be considered to be Cycle 1 
Day 1. For details of assessments during the treatment period, refer to Table 7-1. 
7.1.4 
End of treatment visit including study completion and premature 
withdrawal 
At the time patients discontinue study treatment, a visit should be scheduled within 14 days, at 
which time all of the assessments listed for the End of Treatment (EOT) visit will be performed. 
An End of Treatment Phase Disposition CRF page should be completed, giving the date and 
reason for stopping the study treatment. 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted to return 30 days after the last administration of the 
study treatment. 
In addition, patients who discontinue study treatment for any reasons other than disease 
progression, death, or withdrawal of study consent, should also return for disease follow-up and 
will be followed for survival (please refer to Section 7.1.5) and should not be considered 
withdrawn from the study. If patients refuse to return for these visits or are unable to do so, 
every effort should be made to contact them or a knowledgeable informant by telephone to 
obtain the follow-up information. 
If a patient discontinues study treatment, but continues study assessments in the follow-up 
period, the patient remains on study until such time as he/she completes protocol criteria for 
ending study assessments. At that time, the reason for study completion should be recorded on 
the Study Phase Completion Disposition CRF page. 


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7.1.4.1 
Criteria for premature patient withdrawal 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of the 
investigator at any time. Patients may be withdrawn from the study if any of the following 
occur: 
• Unacceptable AE(s) 
• Delay in dosing > 14 consecutive days (unless agreed otherwise between Novartis and the 
Investigator. 
• Pregnancy of the patient 
• Patient withdrew consent 
• Lost to follow-up 
• Disease progression (clinical or radiological) 
• Initiation of new cancer therapy 
Note: refer to Section 7.1.5 for the requirement to further follow patients after discontinuation 
of study treatment. 
7.1.4.2 
Replacement policy 
No replacement will be needed. 
7.1.5 
Follow up period 
Patients lost to follow up should be recorded as such on the eCRF. For patients who are lost to 
follow-up, the Investigator should show "due diligence" by documenting in the source 
documents steps taken to contact the patient, e.g., dates of telephone calls, registered letters, 
etc. 
30-day safety follow-up period 
All patients must complete the safety follow-up assessments 30 days after the last dose of the 
study treatment. 
All AEs suspected to be related to study drug should be followed up weekly, or as clinically 
indicated, until resolution or stability (see also Section 6.2.2). 
Disease progression follow-up period 
All patients enrolled in the study who discontinue study treatment for any reason other than 
disease progression will be followed up monthly via a phone call and will have MRI scan (or 
CT if the patient cannot tolerate MRI) every 8 weeks (± 7 days) as detailed in Table 7-1, until 
disease progression or the initiation of subsequent anticancer therapies, or death, whichever 
occurs first. 
Survival follow-up period 
All patients enrolled in the study will be followed for survival every 4 months for at least one 
year per e.g., phone call, after LPLT. Possible newly started antineoplastic therapies during this 
FU period must be recorded on the Antineoplastic therapy since discontinuation eCRF. 


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7.2 
Assessment types 
7.2.1 
Efficacy assessments 
Tumor response and progression will be assessed by the Investigator, using the Response 
Assessment in Neuro-Oncology (RANO) Working Group (Wen et al. 2010) as detailed in 
Appendix 3. 
Each patient will be evaluated for all potential sites of tumor lesions at Screening and every 8 
weeks after starting study treatment until disease progression. 
On-study tumor assessments have a ± 7 day window, except for the first post-baseline tumor 
assessment and for confirmatory scans (4 weeks +7 day window only). The first post-baseline 
tumor assessment should be performed on day 1 of cycle 3 (+7 day window permitted) after 
starting treatment. There will be a tumor assessment at the End of Treatment (+ 7 days) if the 
patient discontinues for any reason other than disease progression and the last tumor assessment 
has been performed > 28 days prior to this day. 
For group 1, the baseline scan must occur within 28 days of treatment initiation. For group 2, 
patients undergoing surgery, per standard of care, a MRI should be performed within 72 hours 
after surgery (Wen et al. 2010). This scan can function as the baseline scan if BGJ398 therapy 
is initiated within four weeks of surgery. If BGJ398 is initiated after 4 weeks following surgery, 
a baseline scan must be performed within 7 days of starting BGJ398. Subsequent post baseline 
scans will be performed as described above. For group 2 patients who do not undergo surgery 
the baseline scan will be defined as per group 1. 
Note: in case a patient cannot tolerate MRI, the patient may still participate in the study 
following discussion between Novartis and the investigator. In this case, all efficacy 
assessments will be made by CT scans for that patient. Efficacy assessments should be 
performed by using the same technique throughout the study for each patient. 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing the procedures listed below as well as collecting of the 
adverse events at every visit. For details on AE collection and reporting, refer to Section 8. 
7.2.2.1 
Physical examination 
A complete physical examination must be performed as indicated in Table 7-1. 
Physical examination will be performed on the scheduled day, even if study treatment is being 
withheld. More frequent examinations may be performed at the discretion of the Investigator 
and if medically indicated. 
Physical examination will be performed according to the standards at each institution. 
Information about the physical examination must be present in source documentation at the 
study site. Significant findings that are present prior to signing of informed consent form for 
the study must be included in the Relevant Medical History/Current Medical Conditions page 
on the patient’s eCRF. Significant new findings that begin or worsen after informed consent for 
the study must be recorded on the AE eCRF. 


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7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) must be performed before dosing and 
as indicated in Table 7-1. 
Vital signs should be assessed on the scheduled day, even if study treatment is being withheld. 
More frequent examinations may be performed at the discretion of the Investigator and if 
medically indicated. 
7.2.2.3 
Height and weight 
Height and body weight will be measured. Weight will be measured as indicated in Table 7-1. 
Height will be collected at screening only. More frequent examinations may be performed at 
the discretion of the Investigator and if medically indicated. 
7.2.2.4 
Performance status 
The ECOG performance status (please refer to Table 7-2) will be assessed as indicated in Table 
7-1. Assessment via Karnofsky Performance Scale is acceptable but requires subsequent 
conversion to ECOG (Ma et al, 2010) before being reported on the e-CRF. Assessments of 
performance status will be performed on the scheduled day, even if study treatment is being 
withheld. 
Table 7-2 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out work of a 
light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. Up and 
about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or chair 
Note: Grade 5 (dead) was removed from this table. This information will be collected on a separate eCRF page. 
7.2.2.5 
Laboratory evaluations 
Clinical laboratory analyses are to be performed by the local laboratory as indicated in Table 7-
1 and Table 7-3. Laboratory tests will be collected and analyzed on the scheduled day, even if 
study treatment is being withheld. More frequent assessments may be performed at the 
discretion of the Investigator and if medically indicated, and should be recorded on the 
Unscheduled Visit eCRFs. 
At any time during the study, abnormal laboratory parameters which are clinically relevant (e.g., 
require dose modification and/or interruption of study treatment, lead to clinical symptoms or 
signs, or require therapeutic intervention), whether specifically requested in the protocol or not, 
will be recorded on the Adverse Events eCRF page. Laboratory data will be summarized using 
the CTCAE (version 4.03). 
Novartis must be provided with a copy of the laboratory’s certification, and normal ranges for 
each parameter measured. In addition, if at any time a patient has laboratory parameters 


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obtained from a different outside laboratory, Novartis must be provided with a copy of the 
certification and normal ranges for that laboratory. 
Table 7-3 
Clinical laboratory parameters collection plan 
Test Category 
Test Name 
Hematology 
Hematocrit, Hemoglobin, Platelets, White blood cells, Differential (Basophils, Eosinophils, 
Lymphocytes, Monocytes, Neutrophils) 
Biochemistry 
Albumin, Alkaline phosphatase, ALT (SGPT), AST (SGOT), Calcium (Total), Chloride, 
Creatinine, Blood Urea Nitrogen (BUN) or Urea, Potassium, Sodium, Magnesium, 
Inorganic Phosphorous . 
Direct Bilirubin, Indirect Bilirubin, Total Bilirubin, direct/indirect bilirubin, Total Protein, 
Uric Acid, Amylase, Lipase. 
Urinalysis 
Macroscopic Panel (Dipstick) (Blood, Glucose, Ketones, pH, Protein, Specific Gravity). 
Microscopic Panel (Red Blood Cells, WBC). 
Coagulation 
Prothrombin time (PT) or International normalized ratio [INR]), Partial thromboplastin 
time (PTT), 
Pregnancy Test 
Serum hCG at screening; EOT and other times points serum hCG or urine. 
7.2.2.5.1 Hematology 
Hematology tests are to be performed by the local laboratory according to the Visit Schedules 
outlined in Table 7-1 and Table 7-3. 
7.2.2.5.2 Clinical chemistry 
Clinical chemistry tests are to be performed by the local laboratory according to the Visit 
Schedule outlined in Table 7-1. For details on the Biochemistry panel refer to Table 7-3. 
Assessment of inorganic phosphorus will be performed as part of the chemistry analysis, or as 
indicated in Table 7-1. 
• On Cycle 1, Day 1, 8 hours post dose, inorganic phosphorous will be the only test conducted 
of the chemistry panel. 
• On Cycle 1, Day 2, inorganic phosphorous will be the only test conducted of the chemistry 
panel. 
7.2.2.5.3 Coagulation 
International normalized INR, pro-thrombin time (PT), partial thromboplastin time will be 
measured according to the visit schedule in Table 7-1 and Table 7-3. 
7.2.2.5.4 Urinalysis 
Dipstick Urinalysis will be conducted as directed in Table 7-3 on the days outlined in Table 7-
1 or as clinically indicated, within the windows outlined in Section 7.1. Any significant findings 
on dipstick will be followed up with a microscopic evaluation (listed in Table 7-3) where WBC 
and RBC sediments will also be measured. 


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7.2.2.5.5 Pregnancy and assessments of fertility 
All women of childbearing potential (pre-menopausal or less than 1 year after the onset of 
menopause) must have a serum pregnancy test (β-hCG) ≤ 72 hrs before the first dose of study 
treatment. Additionally, a serum or urine pregnancy test should be performed at Day 1 of each 
cycle and at the End of Treatment visit. 
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 from 
the study. See Section 8.4 for pregnancy reporting. 
7.2.2.6 
Radiological examinations 
7.2.2.6.1 MRI scan (or CT if patient is unable to undergo MRI). 
Please refer to details in Section 7.2.1 and Appendix 3. The same modality (MRI/CT) must be 
used throughout the study 
First post baseline scan occurs cycle 3 day 1; subsequent scans occur every 8 weeks until 
unacceptable toxicity or disease progression, whichever occurs first. 
7.2.2.7 
Cardiac assessments 
7.2.2.7.1 Electrocardiogram (ECG) 
A standard 12 lead ECG will be performed 
• at screening 
• pre-dose, on D1 of every cycle. For Cycle 1 Day 1 pre-dose ECG, the QTcF value must be 
within eligibility criteria prior to study drug treatment. 
• Surgical group (group 2) : pre-dose on D1, and on the day of surgery 
• at the EOT visit 
A standard of 12-Lead ECG that monitors QTcF interval, heart rate, PR interval, uncorrected 
QT interval, and QRS duration will be performed as indicated in in Table 7-1. 
Interpretation of the tracing must be made by a qualified physician at the site and documented 
on the ECG eCRF. Each ECG tracing should be labeled with the study number, patient initials 
(where regulations permit), patient number, date, and kept in the source documents at the study 
site. Clinically significant abnormalities present when the patient signed informed consent 
should be reported on the Relevant Medical History/Current Medical Conditions eCRF. 
Clinically significant findings must be discussed with the Novartis Medical Monitor prior to 
enrolling the patient in the study. New or worsened clinically significant findings occurring 
after informed consent must be recorded on the AE eCRF. 
 
 


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7.2.2.8 
Ophthalmologic assessments 
Ophthalmologic examinations will be performed as indicated in Table 7-1 and includes: visual 
acuity testing, slit lamp examination of the anterior eye segment, intraocular pressure (IOP), 
and fundoscopy. Additional examination methods such as specular microscopy (that enables a 
magnified, direct view of the corneal endothelium), corneal pachymetry, and dilated 
fundoscopy will be performed as clinically indicated. 


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8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event is defined as the appearance of (or worsening of any pre-existing) undesirable 
sign(s), symptom(s), or medical condition(s) that occur after patient’s signed informed consent 
has been obtained. 
 
AEs which occur after signature of this consent will only be captured if they meet the definition 
of serious as outlined in Section 8.2 and are reported to be causally related with study 
procedures (e.g., an invasive procedure such as biopsy). Once the main study ICF is signed, all 
AEs per the descriptions below will be captured in the Adverse Event CRF. 
 
Abnormal laboratory values or test results occurring after informed consent constitute adverse 
events only if they induce clinical signs or symptoms, are considered clinically significant, 
require therapy (e.g., hematologic abnormality that requires transfusion or hematological stem 
cell support), or require changes in study medication(s). 
Adverse events that begin or worsen after informed consent should be recorded in the Adverse 
Events CRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History page of the patient’s CRF. Adverse event monitoring should 
be continued for at least 30 days following the last dose of study treatment. Adverse events 
(including lab abnormalities that constitute AEs) should be described using a diagnosis 
whenever possible, rather than individual underlying signs and symptoms. When a clear 
diagnosis cannot be identified, each sign or symptom should be reported as a separate Adverse 
Event. 
Adverse events will be assessed according to the Common Terminology Criteria for Adverse 
Events 4.03 version unless otherwise specified. 
If CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, corresponding to Grades 1 - 4, will be used. CTCAE Grade 5 (death) will 
not be used in this study; rather, information about deaths will be collected though a Death 
form. 
The occurrence of adverse events should be sought by non-directive questioning of the patient 
(subject) during the screening process after signing informed consent and at each visit during 
the study. Adverse events also may be detected when they are volunteered by the patient 
(subject) during the screening process or between visits, or through physical examination, 
laboratory test, or other assessments. As far as possible, each adverse event should be evaluated 
to determine: 


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1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) or Ongoing at End of Study 
3. Its relationship to the study treatment (Reasonable possibility that AE is related: No, Yes) 
4. Action taken with respect to study or investigational treatment (none, dose adjusted, 
temporarily interrupted, permanently discontinued, unknown, not applicable) 
5. Whether medication or therapy was given (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered / not resolved, recovered / resolved, recovering / resolving, 
recovered / resolved with sequelae, fatal, unknown) 
7. Whether it is serious, where a SAE is defined as in Section 8.2.1. 
All adverse events should be treated appropriately. If a concomitant medication or non-drug 
therapy is given, this action should be recorded on the Adverse Event eCRF. 
Once an adverse event is detected, it should be followed until its resolution or until it is judged 
to be permanent, and assessment should be made at each visit (or more frequently, if necessary) 
of any changes in severity, the suspected relationship to the study treatment, the interventions 
required to treat it, and the outcome. 
Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (for example, as per RANO criteria for GBM), should not be reported as a serious 
adverse event. 
Adverse events separate from the progression of malignancy (example, deep vein thrombosis 
at the time of progression or hemoptysis concurrent with finding of disease progression) will 
be reported as per usual guidelines used for such events with proper attribution regarding 
relatedness to the drug. 
Whenever possible, a diagnosis should be reported instead of underlying signs and symptoms. 
8.1.2 
Laboratory test abnormalities 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities that constitute an Adverse event in their own right (are considered 
clinically significant, induce clinical signs or symptoms, require concomitant therapy or require 
changes in study treatment), should be recorded on the Adverse Events CRF. Here as well, 
whenever possible, a diagnosis, rather than a symptom should be provided (e.g., anemia instead 
of low hemoglobin). Laboratory abnormalities that meet the criteria for Adverse Events should 
be followed until they have returned to normal or an adequate explanation of the abnormality 
is found. When an abnormal laboratory or test result corresponds to a sign/symptom of an 
already reported adverse event, it is not necessary to separately record the lab/test result as an 
additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAE does not automatically 
indicate a SAE unless it meets the definition of serious as defined below and/or as per 
investigator’s discretion. A dose hold or medication for the lab abnormality may be required by 


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the protocol in which case the lab abnormality would still, by definition, be an adverse event 
and must be reported as such. 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, i.e., defined as an event that jeopardizes the patient or may 
require medical or surgical intervention to prevent one of the outcomes listed above 
• Requires inpatient hospitalization or prolongation of existing hospitalization, 
• Note that hospitalizations for the following reasons should not be reported as serious 
adverse events: 
• Routine treatment or monitoring of the studied indication, not associated with any 
deterioration in condition 
• Elective or pre-planned treatment for a pre-existing condition that is unrelated to the 
indication under study and has not worsened since signing the informed consent 
• Social reasons and respite care in the absence of any deterioration in the patient’s 
general condition 
• Note that treatment on an emergency outpatient basis that does not result in hospital 
admission and involves an event not fulfilling any of the definitions of a SAE given above 
is not a serious adverse event 
8.2.2 
Reporting 
 
 SAEs will only be reported 
if the event is suspected to be causally related to a study procedure as assessed by the 
investigator (e.g., an invasive procedure such as biopsy). SAEs will be followed until resolution 
or until clinically relevant improvement or stabilization. If the main ICF is not signed 
(molecular screen failure), SAE collection ends 30 days after the last study related procedure. 
 SAE collection starts at 
time of main study informed consent whether the patient is a screen failure or not. 
To ensure patient safety, every SAE, regardless of suspected causality, occurring after the 
patient has provided informed consent and until at least 30 days after the patient has stopped 
study treatment must be reported to Novartis within 24 hours of learning of its occurrence. 
Any SAEs experienced after this 30 days period should only be reported to Novartis if the 
investigator suspects a causal relationship to the study treatment. Recurrent episodes, 
complications, or progression of the initial SAE must be reported as follow-up to the original 
episode within 24 hours of the investigator receiving the follow-up information. An SAE 


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occurring at a different time interval or otherwise considered completely unrelated to a 
previously reported one should be reported separately as a new event. 
Information about all SAEs is collected and recorded on the Serious Adverse Event Report 
Form; all applicable sections of the form must be completed in order to provide a clinically 
thorough report. The investigator must assess and record the relationship of each SAE to each 
specific study treatment (if there is more than one study treatment), complete the SAE Report 
Form in English, and send the completed, signed form by fax within 24 hours to the oncology 
Novartis Drug Safety and Epidemiology (DS&E) department. 
Serious adverse events considered by the Investigator to be possibly related to a biopsy 
procedure will be indicated as such in the AE eCRF.  This information will be followed for 30 
days after the biopsy procedure. 
The telephone and telefax number of the contact persons in the local department of Drug Safety 
and Epidemiology (DS&E), specific to the site, are listed in the investigator folder provided to 
each site. The original copy of the SAE Report Form and the fax confirmation sheet must be 
kept with the case report form documentation at the study site. 
Follow-up information is sent to the same contact(s) to whom the original SAE Report Form 
was sent, using a new SAE Report Form stating that this is a follow-up to the previously 
reported SAE and giving the date of the original report. Each re-occurrence, complication, or 
progression of the original event should be reported as a follow-up to that event regardless of 
when it occurs. The follow-up information should describe whether the event has resolved or 
continues, if and how it was treated, whether the blind was broken or not, and whether the 
patient continued or withdrew from study participation. 
If the SAE is not previously documented in the [Investigator’s Brochure] or Package Insert 
(new occurrence) and is thought to be related to the Novartis study treatment, an oncology 
Novartis Drug Safety and Epidemiology (DS&E) department associate may urgently require 
further information from the investigator for Health Authority reporting. Novartis may need to 
issue an Investigator Notification (IN), to inform all investigators involved in any study with 
the same drug that this SAE has been reported. Suspected Unexpected Serious Adverse 
Reactions (SUSARs) will be collected and reported to the competent authorities and relevant 
ethics committees in accordance with Directive 2001/20/EC or as per national regulatory 
requirements in participating countries. 
8.3 
Emergency unblinding of treatment assignment 
Not applicable. 
8.4 
Pregnancies 
To ensure patient safety, each pregnancy occurring while the patient is on study treatment must 
be reported to Novartis within 24 hours of learning of its occurrence. The pregnancy should be 
followed up to determine outcome, including spontaneous or voluntary termination, details of 
the birth, and the presence or absence of any birth defects, congenital abnormalities, or maternal 
and/or newborn complications. 


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Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Drug Safety and Epidemiology Department (DS&E). 
Pregnancy follow-up should be recorded on the same form and should include an assessment 
of the possible relationship to the investigational/study treatment any pregnancy outcome. Any 
SAE experienced during pregnancy must be reported on the SAE Report Form. 
8.5 
Warnings and precautions 
No evidence available at the time of the approval of this study protocol indicated that special 
warnings or precautions were appropriate, other than those noted in the provided [Investigator 
Brochure]. Additional safety information collected between IB updates will be communicated 
in the form of Investigator Notifications. This information will be included in the patient 
informed consent and should be discussed with the patient during the study as needed. 
8.6 
Data Monitoring Committee 
A Data Monitoring Committee (DMC) will not be in place for this trial. However, measures are 
put in place for monitoring the safety of the patients participating in this part of the study, and 
Novartis will convene a joint teleconference with the participating Investigators to ensure a 
prompt review of safety data and constant monitoring for emerging safety signals by 
participating study sites and Novartis Personnel. As for any other study conducted by Novartis, 
any SUSAR and/or new safety signals will be promptly communicated to all participating 
investigators and Health Authorities. 
Individual patient data will be reviewed on an ongoing basis and aggregate safety data and the 
primary endpoint will be monitored by the study team after every 8th patient completes the first 
cycle of treatment or discontinues the study, whichever occurs first. The data review and 
analysis will be based on the available investigator reported data in the clinical database at the 
respective time.  
8.7 
Steering Committee 
A Steering Committee constituted of members of the Oncology Translational Medicine 
Leadership Team will be formed for this study. If the monitoring of the study data require a 
decision to be taken on the continuation of the study, then the relevant data will be 
communicated to the Steering Committee for decision making purposes. 
9 
Data collection and management 
9.1 
Data confidentiality 
Information about study subjects will be kept confidential and managed under the applicable 
laws and regulations. Those regulations require a signed subject authorization informing the 
subject of the following: 
• What protected health information (PHI) will be collected from subjects in this study 
• Who will have access to that information and why 
• Who will use or disclose that information 


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• The rights of a research subject to revoke their authorization for use of their PHI. 
In the event that a subject revokes authorization to collect or use PHI, the investigator, by 
regulation, retains the ability to use all information collected prior to the revocation of subject 
authorization. For subjects that have revoked authorization to collect or use PHI, attempts 
should be made to obtain permission to collect follow-up safety information (e.g., has the 
subject experienced any new or worsened AEs) at the end of their scheduled study period. 
The data collection system for this study uses built-in security features to encrypt all data for 
transmission in both directions, preventing unauthorized access to confidential participant 
information. Access to the system will be controlled by a sequence of individually assigned 
user identification codes and passwords, made available only to authorized personnel who have 
completed prerequisite training. 
Prior to entering key sensitive personally identifiable information (Subject Initials and exact 
Date of Birth), the system will prompt site to verify that this data is allowed to be collected. If 
te site indicates that country rules or ethics committee standards do not permit collection of 
these items, the system will not solicit Subjects initials. Year of birth will be solicited (in the 
place of exact date of birth) to establish that the subject satisfies protocol age requirements and 
to enable appropriate age-related normal ranges to be used in assessing laboratory test results. 
9.2 
Site monitoring 
Before study initiation, at a site initiation visit or at an investigator’s meeting, Novartis 
personnel (or designated CRO) will review the protocol and CRFs with the investigators and 
their staff. During the study, the field monitor will visit the site regularly to check the 
completeness of patient records, the accuracy of entries on the CRFs, the adherence to the 
protocol to Good Clinical Practice, the progress of enrollment, and to ensure that study 
treatment is being stored, dispensed, and accounted for according to specifications. Key study 
personnel must be available to assist the field monitor during these visits. 
The investigator must maintain source documents for each patient in the study, consisting of 
case and visit notes (hospital or clinic medical records) containing demographic and medical 
information, laboratory data, electrocardiograms, and the results of any other tests or 
assessments. All information recorded on CRFs must be traceable to source documents in the 
patient's file. The investigator must also keep the original signed informed consent form (a 
signed copy is given to the patient). 
The investigator must give the monitor access to all relevant source documents to confirm their 
consistency with the CRF entries. Novartis monitoring standards require full verification for the 
presence of informed consent, adherence to the inclusion/exclusion criteria and documentation 
of SAEs. Additional checks of the consistency of the source data with the CRFs are performed 
according to the study-specific monitoring plan. 
9.3 
Data collection 
For studies using Electronic Data Capture (EDC), the designated investigator staff will enter 
the data required by the protocol into the Electronic Case Report Forms (eCRF). The eCRFs 
have been built using fully validated secure web-enabled software that conforms to 21 CFR Part 
11 requirements, Investigator site staff will not be given access to the EDC system until they 


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have been trained. Automatic validation programs check for data discrepancies in the eCRFs 
and, allow modification or verification of the entered data by the investigator staff. 
The Principal Investigator is responsible for assuring that the data entered into the CRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
 
 
 
Designated investigational site staff will enter the information required by the protocol into the 
appropriate eCRF (and/or designated laboratory requisition forms that are printed on 2 or 3-
part, non-carbon-required paper). Field monitors will review the eCRFs and laboratory paper 
requisition forms for accuracy and completeness and instruct site personnel to make any 
required corrections or additions. One copy of the requisition form will be forwarded to each 
analytical laboratory with the respective sample(s) by the field monitor or by the designated 
investigational site staff; and one copy will be retained at the investigational site. 
9.4 
Database management and quality control 
Novartis personnel (or designated CRO) will review the data entered by investigational staff 
for completeness and accuracy. Electronic data queries stating the nature of the problem and 
requesting clarification will be created for discrepancies and missing values and sent to the 
investigational site via the EDC system. Designated investigator site staff are required to 
respond promptly to queries and to make any necessary changes to the data. 
Concomitant treatments and prior medications entered into the database will be coded using the 
WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical classification 
system. Relevant Medical history/Current medical conditions and adverse events will be coded 
using the Medical dictionary for regulatory activities (MedDRA) terminology. 
 
 
After database lock, the investigator will receive a CD-ROM or paper copies of the patient data 
for archiving at the investigational site. 
10 
Statistical methods and data analysis 
Data will be analyzed by Novartis and/or designated CRO. Any data analysis carried out 
independently by the investigator must be submitted to Novartis before publication or 
presentation. 
It is planned that the data from participating centers in this protocol will be combined, so that 
an adequate number of patients will be available for analysis. Data will be summarized with 
respect to demographic and baseline characteristics, efficacy and safety observations and 
measurements 
 using descriptive statistics 
(quantitative data) and contingency tables (qualitative data). For all analyses, data from both 
treatment groups (surgical group and non-surgical group) will be pooled together, unless 
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The analysis of study data will be based on all patients’ data up to the time when all patients 
have potentially completed at least 6 cycles of treatment or discontinued the study. . This will 
be the cut-off point for the primary clinical study report (CSR). The additional data for any 
patients continuing to receive BGJ398 beyond the cut-off point for the primary clinical study 
report, as allowed by the protocol, will be summarized in a final CSR that will be prepared once 
all patients have discontinued the study or at the end of the study (end of survival follow up 
period) which is one year after the last patient’s first dose of study treatment, whichever occurs 
first. 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose of BGJ398. 
Patients will be classified according to the planned treatment. The FAS will be used for all 
listings of raw data. Unless otherwise specified the FAS will be the default analysis set used for 
all analyses. 
10.1.2 
Safety Set 
The Safety Set includes all patients who received at least one dose of BGJ398 and have at least 
one valid post-baseline safety assessment.  Patients with FGFR1, 2, 3 and 4 amplifications 
enrolled prior to protocol amendment 2 will be included in the safety set.  These patients will 
be included in the FAS and their data will be listed and summarized as described below, 
however they will not be part of the per-protocol set which will be used for the primary analysis. 
The statement that a patient had no AE (on the AE eCRF) constitutes a valid safety assessment. 
Patients will be classified according to treatment received, where treatment received is defined 
as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
10.1.3 
Per-Protocol Set 
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS (with FGFR1-TACC1, 
FGFR3-TACC3 and/or activating mutations in FGFR1, 2 or 3) who are compliant with 
requirements of the Clinical Study Protocol (CSP). The PPS will include patients who have an 
adequate tumor assessment at baseline, a follow-up tumor assessment >8 weeks after starting 
treatment unless disease progression is observed before that time, and no major protocol 
deviations. 
All major protocol deviations leading to exclusion from the PPS will be detailed in the 
Reporting and Analysis Plan (RAP). 
10.1.4 
Dose-determining analysis set 
Not applicable 


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10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data including disease characteristics will be summarized 
descriptively. 
10.3 
Treatments (study treatment, concomitant therapies, 
compliance) 
10.3.1 
Study Treatment 
The actual dose and duration in days of BGJ398 treatment as well as the dose intensity 
(computed as the ratio of actual dose received and actual duration) and the relative dose 
intensity (computed as the ratio of dose intensity and planned dose received/planned duration), 
will be listed and summarized by means of descriptive statistics. The summary data will be 
presented for all study days as a single category. The total daily doses of BGJ398 for each 
patient will be summarized using descriptive statistics. The FAS will be used. 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies prior to and after the start of the 
study drug treatment will be listed by patient and summarized by ATC (Anatomical therapeutic 
chemical classification system) term and dose group by means of contingency tables. 
10.3.3 
Compliance 
Compliance to the protocol will be assessed by the number and proportion of patients with 
protocol deviations. These will be identified prior to database lock and will be listed and 
summarized by treatment group. Compliance to the study drug will be assessed by the number 
of dose reductions and dose interruptions, see Section 10.5. 
10.4 
Primary objective 
10.4.1 
Variable 
Preliminary tumor activity will be assessed using RANO criteria (Appendix 3) . 
Six month progression free-survival (PFS6) rate will be the primary efficacy variable. 


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For patients in group 1 (non-surgical), PFS is defined as the number of days from the first day 
of treatment to the date of the first documented disease progression or date of death, whichever 
occurs first. 
For patients in group 2 ,who undergo surgery, PFS is defined as the number of days from the 
first day of treatment after surgery to the date of the first documented disease progression or 
date of death, whichever occurs first. 
For patients in group 2, who do not undergo surgery, PFS is defined as the number of days from 
first day of treatment to the first documented disease progression or date of death, whichever 
occurs first. 
Patients in group 2, who undergo surgery but do not receive at least one post-surgical dose of 
BGJ398 (i.e., C1D1) will be excluded from the primary efficacy analysis; their data will be 
listed. 
The Primary Analysis will be performed on the PPS (24 patients) and the FAS summary will 
be provided as a supportive analysis (34 patients).  The labs, safety, 
 etc, data for the patient 
with amplifications using the FAS will be summarized, but the efficacy focus will be on the 
PPS. 
Patients who discontinue the study and are lost to follow-up without a known date of 
progression or death due to any cause on or before the cut-off date will be censored in the 
primary analysis at the date of their last available tumor assessment. 
10.4.2 
Statistical hypothesis, model, and method of analysis 
A Bayesian design will be used in order to estimate the PFS6 rate and to provide inferential 
statements based on the uncertainty of this quantity. Progression-free survival will be modeled 
using a Weibull distribution. The Weibull distribution is a flexible distribution which allows for 
time varying hazard rate. The probability density function is given by f(x) = υλx^(υ-1)exp(-
λx^ υ) where υ is a shape parameter and λ a scale parameter. Prior distributions will be 
placed on both parameters to carry out the analysis. For the scale parameter, a normal (mean = 
0, standard deviation = 2.236 ) distribution will be used on the log of the parameter. For the 
shape parameter, an exponential with rate 1 will be used. These priors correspond to a prior 
probability of unacceptable efficacy (PFS6 <16%) of 65 %, and clinically relevant efficacy 
(PFS6 > 40%) of 25% (see Figure 10-1 below). 


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Figure 10-1 
PFS6 prior distribution 
 
The prior distributions will be updated with all the data available at the time of the analyses 
from the patients in the  PPS who are evaluable for the primary analysis as described above. 
Once updated, the posterior probability that the true PFS6 rate at the dose of BGJ398 used in 
the study lies in the following categories will be summarized: 
[0, 16%) unacceptable efficacy 
[16%, 25%) limited efficacy 
[25%, 40%) moderate efficacy 
[40%, 100%] clinically relevant efficacy 
Data from both the treatment groups will be pooled together for this analysis, since we expect 
to observe similar 6-month PFS rates for these two groups (Clarke et al, 2011). The study will 
be considered a success at the final analysis if 
• there is at least 50% confidence that BGJ398 has clinically relevant efficacy (that is, Post 
Prob(PFS6>=40%) > 50%), and 
• there is at least 80% confidence that BGJ398 has either moderate efficacy or clinically 
relevant efficacy (Post Prob(PFS6>=25%) > 80%). 
An interim analysis for futility will be conducted for patients in the PPS. Please see Section 
10.7 for details. 
10.4.3 
Handling of missing values/censoring/discontinuations 
Patients who discontinue the study and are lost to follow-up without a known date of 
progression or death due to any cause on or before the cut-off date will be censored in the 
primary analysis at the date of their last available tumor assessment. 
Other missing data will simply be noted as missing on appropriate tables/listings. 
10.4.4 
Supportive analyses 
The supportive analysis will be done using the FAS following the statistical methodology as 
presented in Section 10.4.2. As a supportive analysis, Kaplan-Meier estimates of the PFS rate 
at 4, 6 and 12 months will be derived together with 95% confidence intervals. PFS will also be 
presented descriptively using Kaplan Meier plots. This analysis will be done for all patients in 
both the treatment groups pooled together and for the PPS and FAS seperately. This analysis 


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will be repeated on the subgroups of patients defined by previous bevacizumab treatment use 
and by treatment group, if the number of patients in each group allows for meaningful 
interpretation. 
The primary analysis will be repeated on the subgroups of patients defined by previous 
bevacizumab treatment use and by treatment group, if the number of patients in each group 
allows for meaningful interpretation. 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
Not applicable. 
10.5.2 
Other secondary efficacy objectives 
Objective Response Rate 
A secondary objective of the study is to assess preliminary anti-tumor activity of the BGJ398 
using objective response rate (ORR) as the endpoint. 
Objective response rate (ORR) is defined as the proportion of patients with a best overall 
response of Complete Response (CR) or Partial Response (PR), as per the RANO criteria 
(Appendix 3). 
The ORR analysis will include patients from the FAS who have measurable disease (as per 
RANO) at their baseline scan (as defined in Section 7.2.1). ORR will be reported with 95% 
confidence interval and response will be listed. 
This analysis will be done for all patients in the PPS as well as the FAS in both treatment groups 
pooled together. 
Overall Survival 
For patients in group 1, overall survival (OS) is defined as the time from the date of start of 
treatment to the date of death due to any cause or the date of last contact (censored observation) 
at the date of data cutoff. 
For patients in group 2, who undergo surgery, OS is defined as the number of days from the 
first day of treatment after surgery to the date of death due to any cause or the date of last contact 
(censored observation) at the date of data cutoff. 
For patients in group 2, who do not undergo surgery, OS is defined as the number of days from 
first day of treatment to the date of death due to any cause or the date of last contact (censored 
observation) at the date of data cutoff. 
Patients in group 2, who undergo surgery but do not receive at least one post-surgical dose of 
BGJ398 (i.e., C1D1) will be excluded from the overall survival analysis; their data will be listed. 
The survival time for patients without documentation of death prior to analysis data cutoff, will 
be censored at the last date the patient was known to be alive prior to the cutoff date. Survival 


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time for patients with no post-baseline survival information will be censored on the date of start 
of treatment. 
OS will be analyzed using the Kaplan-Meier method. Survival rate at 4, 6, 8, 12, 18 and 24 
months and median OS will be estimated along with 95% confidence intervals. All patients in 
the FAS except patients in group 2, who undergo surgery but do not receive at least one post-
surgical dose of BGJ398 will be included in this analysis. 
This analysis will be done for all patients in the PPS as well as the FAS in both treatment groups 
pooled together.  
10.5.3 
Safety objectives 
10.5.3.1 Analysis set and grouping for the analyses 
For all safety analyses, the safety set will be used. 
The overall observation period will be divided into three mutually exclusive segments: 
1. pre-treatment period: from day of patient’s informed consent to the day before first dose 
of study medication 
2. on-treatment period: from day of first dose of study medication to 30 days after last dose 
of study medication 
3. post-treatment period: starting at day 31 after last dose of study medication. 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period. 
10.5.3.2 Adverse events (AEs) 
Summary tables for adverse events (AEs) will include only AEs that started or worsened during 
the on-treatment period, the treatment-emergent AEs. However, all safety data (including 
those from the pre and post-treatment periods) will be listed and those collected during the pre-
treatment and post-treatment period are to be flagged. 
The incidence of treatment-emergent adverse events (new or worsening from baseline) will be 
summarized by system organ class and or preferred term, severity (based on CTCAE grades), 
type of adverse event, relation to study treatment. 
Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event. 
10.5.3.3 Laboratory abnormalities 
For laboratory tests covered by the CTCAE version 4.03 laboratory data will be graded 
accordingly. For laboratory tests covered by CTCAE, a grade 0 will be assigned for all non-
missing values not graded as 1 or higher. Grade 5 will not be used. 
For laboratory tests where grades are not defined by CTCAE, results will be graded by the 
low/normal/high classifications based on laboratory normal ranges, or alternative clinically 
meaningful limits. 


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The following by-treatment summaries will be generated separately for hematology, 
biochemistry and urinary laboratory tests: 
• frequency table for newly occurring on-treatment grades 3 or 4 
• shift tables using CTCAE grades to compare baseline to the worst on-treatment value 
• for laboratory tests where CTCAE grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-treatment 
value. 
• listing of all laboratory data with values flagged to show the corresponding CTCAE grades 
and the classifications relative to the laboratory normal ranges. 
In addition to the above mentioned tables and listings, other exploratory analyses, for example 
figures plotting time course of raw or change in laboratory tests over time or box plots may be 
specified in the RAP. 
10.5.3.4 Other safety data 
Data from other tests (e.g., electrocardiogram or vital signs) will be listed, notable values will 
be flagged, and any other information collected will be listed as appropriate. Any statistical tests 
performed to explore the data will be used only to highlight any interesting comparisons that 
may warrant further consideration. Additionally, the following outputs will be produced: 
ECG 
• shift table baseline to worst on-treatment result for overall assessments 
• listing of ECG evaluations for all patients with at least one abnormality. 
Vital signs 
• shift table baseline to worst on-treatment result 
• table with descriptive statistics at baseline, one or several post-baseline time points and 
change from baseline to this/these post-baseline time points. 
Ocular 
• Table with frequency of ocular events by cycle will be produced by treatment group. 
• Listing of ocular assessments for all patients with at least one abnormality. 
10.5.3.5 Tolerability 
Tolerability of study drug will be assessed by summarizing the number of dose interruptions 
and dose reductions. Reasons for dose interruption and dose reductions will be listed by patient 
and summarized. Cumulative dose, dose intensity and relative dose intensity of BGJ398 will be 
listed by patient and summarized. Categories for relative dose intensity of BGJ398 will be 
specified as < 0.5, ≥ 0.5 - < 0.75, ≥ 0.75 - < 0.9, ≥ 0.9 - < 1.1 and ≥ 1.1. The number and 
proportion of patients within each category will be presented. 


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10.7 
Interim analysis 
An interim analysis for futility will be carried out once 10patients in the PPS have completed 6 
cycles of treatment or discontinued earlier. The analysis will follow the methodology described 
for the primary efficacy analysis. If the following criterion is met, recruitment will continue, 
otherwise recruitment will be stopped: 
Prob ( PFS6 > 16% ) > 80% and Prob ( PFS6 > 25%) > 50% 
This rule corresponds to approximately 16% predictive probability of success (assuming only 
administrative censoring at the time of data cut-off for interim analysis, and therefore using a 
beta-binomial distribution for calculating the predictive probability of success). In other words, 


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given the data at interim, if the predictive probability that the study will have  a success at the 
final analysis is less than 16%, this study will be stopped at the interim for futility. 
10.8 
Sample size calculation 
The operating characteristics of the design (with the primary analysis using PPS) have been 
assessed via simulations (see Table 10-2 below). For each scenario, 1000 trials were simulated. 
A scenario was defined by assumption regarding the true PFS6 rate, an accrual rate of one 
patient per month with the final analysis taking place after the last patient completed 6 cycles 
of treatment or discontinued. A success was defined as follows: 
Prob ( PFS6 > 16% ) > 80% and Prob ( PFS6 > 25%) > 50% at the interim analysis and Prob 
( PFS6 > 25% ) > 80% and Prob ( PFS6 > 40%) > 50% at the final analysis. 
Table 10-2 
Operating characteristics of study design (primary analysis – 24 
evaluable patients in PPS) 
True PFS6 
  
0.16 
0.25 
0.35 
0.4 
0.45 
0.5 
Prob. of stopping at interim 
0.816 
0.521 
0.26 
0.143 
0.068 
0.039 
Average sample size 
12.576 
16.706 
20.304 
31.998 
23.048 
23.454 
Prob. of success (final) 
0.000 
0.026 
0.229 
0.465 
0.708 
0.861 
Average study duration (months) 
15.855 
21.12 
25.19 
27.58 
28.76 
29.39 
Assuming a true PFS6 rate of 50% and a uniform accrual of one patient per month, with 24 
evaluable patients in  the PPS (~17 PFS events), there is about 86.1% chance to achieve success 
at the end of the study. 
10.9 
Power for analysis of key secondary variables 
Not applicable. 
11 
Ethical considerations and administrative procedures 
11.1 
Regulatory and ethical compliance 
This clinical study was designed, shall be implemented and reported in accordance with the 
ICH Harmonized Tripartite Guidelines for Good Clinical Practice, with applicable local 
regulations (including European Directive 2001/20/EC and US Code of Federal Regulations 
Title 21), and with the ethical principles laid down in the Declaration of Helsinki. 
11.2 
Responsibilities of the investigator and IRB/IEC/REB 
The protocol and the proposed informed consent form must be reviewed and approved by a 
properly constituted Institutional Review Board/Independent Ethics Committee/Research 
Ethics Board (IRB/IEC/REB) before study start. Prior to study start, the investigator is required 
to sign a protocol signature page confirming his/her agreement to conduct the study in 
accordance with these documents and all of the instructions and procedures found in this 
protocol and to give access to all relevant data and records to Novartis monitors, auditors, 


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Novartis Clinical Quality Assurance representatives, designated agents of Novartis, 
IRBs/IECs/REBs and regulatory authorities as required. 
11.3 
Informed consent procedures 
Eligible patients may only be included in the study after providing written (witnessed, where 
required by law or regulation), IRB/IEC/REB-approved informed consent 
Informed consent must be obtained before conducting any study-specific procedures (i.e. all of 
the procedures described in the protocol). The process of obtaining informed consent should be 
documented in the patient source documents. The date when a subject’s Informed Consent was 
actually obtained will be captured in their eCRFs. 
Novartis will provide to investigators, in a separate document, a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH GCP 
guideline and regulatory requirements. Any changes to this ICF suggested by the investigator 
must be agreed to by Novartis before submission to the IRB/IEC/REB, and a copy of the 
approved version must be provided to the Novartis monitor after IRB/IEC/REB approval. 
Women of child bearing potential should be informed that taking the study medication may 
involve unknown risks to the fetus if pregnancy were to occur during the study and agree that 
in order to participate in the study they must adhere to the contraception requirement for the 
duration of the study. If there is any question that the patient will not reliably comply, they 
should not be entered in the study. 


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11.4 
Discontinuation of the study 
Novartis reserves the right to discontinue this study under the conditions specified in the clinical 
study agreement. Specific conditions for terminating the study are outlined in  
Section 4.4. 
11.5 
Publication of study protocol and results 
Novartis assures that the key design elements of this protocol will be posted in a publicly 
accessible database such as clinicaltrials.gov. In addition, upon study completion and 
finalization of the study report the results of this study will be either submitted for publication 
and/or posted in a publicly accessible database of clinical study results. 
11.6 
Study documentation, record keeping and retention of 
documents 
Each participating site will maintain appropriate medical and research records for this trial, in 
compliance with [Section 4.9 of the ICH E6 GCP], and regulatory and institutional requirements 
for the protection of confidentiality of subjects. As part of participating in a Novartis-sponsored 
study, each site will permit authorized representatives of the sponsor(s) and regulatory agencies 
to examine (and when required by applicable law, to copy) clinical records for the purposes of 
quality assurance reviews, audits and evaluation of the study safety and progress. 
Source data are all information, original records of clinical findings, observations, or other 
activities in a clinical trial necessary for the reconstruction and evaluation of the trial. Examples 
of these original documents and data records include, but are not limited to, hospital records, 
clinical and office charts, laboratory notes, memoranda, subjects’ diaries or evaluation 
checklists, pharmacy dispensing records, recorded data from automated instruments, copies or 
transcriptions certified after verification as being accurate and complete, microfiches, 
photographic negatives, microfilm or magnetic media, x-rays, and subject files and records kept 
at the pharmacy, at the laboratories, and medico-technical departments involved in the clinical 
trial. 
Data collection is the responsibility of the clinical trial staff at the site under the supervision of 
the site Principal Investigator. The study case report form (CRF) is the primary data collection 
instrument for the study. The investigator should ensure the accuracy, completeness, legibility, 
and timeliness of the data reported in the CRFs and all other required reports. Data reported on 
the CRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the CRF must be 
recorded. Any missing data must be explained. For electronic CRFs an audit trail will be 


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maintained by the system. The investigator should retain records of the changes and corrections 
to CRFs. 
The investigator/institution should maintain the trial documents as specified in Essential 
Documents for the Conduct of a Clinical Trial [ICH E6 Section 8] and as required by applicable 
regulations and/or guidelines. The investigator/institution should take measures to prevent 
accidental or premature destruction of these documents. 
Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Novartis provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure anonymity of the patients; patients must not be identified by names 
in any documents submitted to Novartis. Signed informed consent forms and patient enrollment 
log must be kept strictly confidential to enable patient identification at the site. 
11.8 
Audits and inspections 
Source data/documents must be available to inspections by Novartis or designee or Health 
Authorities. 
11.9 
Financial disclosures 
Financial disclosures should be provided by study personnel who are directly involved in the 
treatment or evaluation of patients at the site - prior to study start. 
12 
Protocol adherence 
Investigators ascertain they will apply due diligence to avoid protocol deviations. Under no 
circumstances should the investigator contact Novartis or its agents, if any, monitoring the study 
to request approval of a protocol deviation, as no authorized deviations are permitted. If the 
investigator feels a protocol deviation would improve the conduct of the study this must be 
considered a protocol amendment, and unless such an amendment is agreed upon by Novartis 
and approved by the IRB/IEC/REB it cannot be implemented. All significant protocol 
deviations will be recorded and reported in the CSR. 
12.1 
Amendments to the protocol 
Any change or addition to the protocol can only be made in a written protocol amendment that 
must be approved by Novartis, Health Authorities where required, and the IRB/IEC/REB. Only 
amendments that are required for patient safety may be implemented prior to IRB/IEC/REB 
approval. Notwithstanding the need for approval of formal protocol amendments, the 
investigator is expected to take any immediate action required for the safety of any patient 
included in this study, even if this action represents a deviation from the protocol. In such cases, 
Novartis should be notified of this action and the IRB/IEC at the study site should be informed 


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according to local regulations (e.g., UK requires the notification of urgent safety measures 
within 3 days) but not later than 10 working days. 


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13 
References (available upon request) 
Central Brain Tumor Registry of the United States (CBTRUS) 2012. Statistical Report: 
Primary Brain and Central Nervous System Tumors Diagnosed in the United States in 2004–
2008 (Revised March 23, 2012). Central Brain Tumor Registry of the United States, Hinsdale, 
IL. 
Clarke JL, Ennis MM, Yung WK, et al (2011) Is surgery at progression a prognostic marker 
for improved 6-month progression-free survival or overall survival for patients with recurrent 
glioblastoma Neuro Oncol; 13(10):1118-24. 
Di Stefano AL, Fucci A, Frattini V, et al (2015) Detection, characterization and inhibition of 
FGFR-TACC fusions in IDH wild type glioma.  CCR.; 14-2199. 
Ferlay J, Shin HR, Bray F, et al (2010) Estimates of worldwide burden of cancer in 2008: 
GLOBOCAN 2008. Int J Cancer.;127(12) 
Friedman HS, Prados MD, Wen PY, et al (2009) Bevacizumab alone and in combination with 
irinotecan in recurrent glioblastoma. J Clin Oncol.; 27(28):4733-40. 
Guagnano V, Kauffmann A, Wöhrle S, et al (2012) FGFR genetic alterations predict for 
sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discov.; 2(12):1118-33. 
Harada K, Kurisu K, Tahara H, et al (2000) Telomerase activity in primary and secondary 
glioblastomas multiforme as a novel molecular tumor marker. J Neurosurg.; 93(4):618-25 
Hofer S, Elandt K, Greil R,et al (2011) Clinical outcome with bevacizumab in patients with 
recurrent high-grade glioma treated outside clinical trials. Acta Oncol.; 50(5):630-5. 
Konecny GE, Kolarova T, O'Brien NA, et al (2013) Activity of the Fibroblast Growth Factor 
Receptor Inhibitors Dovitinib (TKI258) and NVP-BGJ398 in Human Endometrial Cancer 
Cells. Mol Cancer Ther.; Epub 2013 Feb 26 
Kreisl TN, Kim L, Moore K, et al (2009) Phase II trial of single-agent bevacizumab followed 
by bevacizumab plus irinotecan at tumor progression in recurrent glioblastoma. J Clin Oncol.; 
27(5):740-5. 
Lamborn KR, Yung WK, Chang SM, et al (2008) Progression-free survival: an important end 
point in evaluating therapy for recurrent high-grade gliomas. Neuro Oncol.; 10(2):162-70. 
Ma C, Bandukwala S, Burman D, Bryson J, Seccareccia D, Banerjee S, Myers J, Rodin G, 
Dudgeon D, Zimmermann C. (2010) Interconversion of three measures of performance status: 
an empirical analysis. Eur J Cancer. Dec;46(18):3175-83. 
Macdonald DR, Cascino TL, Schold SC Jr, Cairncross JG: Response criteria for phase II 
studies of supratentorial malignant glioma. J Clin Oncol 1990, 8(7):1277-80. 
Maher EA, Brennan C, Wen PY, et al (2006) Marked genomic differences characterize 
primary and secondary glioblastoma subtypes and identify two distinct molecular and clinical 
secondary glioblastoma entities. Cancer Res.; 66(23):11502-13. 
Mao H, Lebrun DG, Yang J, Zhu VF, Li M (2012) Deregulated signaling pathways in 
glioblastoma multiforme: molecular mechanisms and therapeutic targets. Cancer Invest.; 
30(1):48-56. 
Neuenschwander B, Branson M, Gsponer T. (2008) Critical aspects of the Bayesian approach 
to phase I cancer trials. Stat Med. 2008 Jun 15;27(13):2420-39. 


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Norden AD, Young GS, Setayesh K, et al (2008) Bevacizumab for recurrent malignant 
gliomas: efficacy, toxicity, and patterns of recurrence. Neurology; 70(10):779-87. 
Parker BC, Annala MJ, Cogdell DE, et al (2013) The tumorigenic FGFR3-TACC3 gene 
fusion escapes miR-99a regulation in glioblastoma. J Clin Invest. 1;123(2):855-65. 
Prados M, Cloughesy T, Samant M, et al (2011) Response as a predictor of survival in 
patients with recurrent glioblastoma treated with bevacizumab. Neuro Oncol.; 13(1):143-51. 
Singh D, Chan JM, Zoppoli P, et al (2012) Transforming fusions of FGFR and TACC genes 
in human glioblastoma. Science; 337(6099):1231-5. 
Stupp R, Hegi ME, Mason WP, et al (2009) Effects of radiotherapy with concomitant and 
adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised 
phase III study: 5-year analysis of the EORTC-NCIC trial. Lancet Oncol.; 10(5):459-66. 
Stupp R, Dietrich PY, Ostermann Kraljevic S, et al (2006) Promising survival for patients 
with newly diagnosed glioblastoma multiforme treated with concomitant radiation plus 
temozolomide followed by adjuvant temozolomide. J Clin Oncol.; 20(5):1375-82. 
TCGA (2008) - Comprehensive genomic characterization defines human glioblastoma genes 
and core pathways. Cancer Genome Atlas Research Network. Nature; 455(7216):1061-8. 
Erratum in: Nature. 2013 Feb 28;494(7438):506. 
Walker C, Joyce KA, Thompson-Hehir J, et al (2001) Characterisation of molecular 
alterations in microdissected archival gliomas. Acta Neuropathol.; 101(4):321-33. 
Wen PY (2009) New developments in targeted molecular therapies for glioblastoma. Expert 
Rev Anticancer Ther.; 9(1):7-10. 
Wen PY, Macdonald DR, Reardon DA, et al (2010) Updated response assessment criteria for 
high-grade gliomas: response assessment in neuro-oncology working group. J Clin Oncol.; 
28(11):1963-72. 
Wesche J, Haglund K, Haugsten EM (2011) Fibroblast growth factors and their receptors in 
cancer. Biochem J.; 437(2):199-213. 
Wong ET, Gautam S, Malchow C, et al (2011) Bevacizumab for recurrent glioblastoma 
multiforme: a meta-analysis. J Natl Compr Canc Netw.; 9(4):403-7. 
Wong ET, Hess KR, Gleason MJ, et al (1999) Outcomes and prognostic factors in recurrent 
glioma patients enrolled onto phase II clinical trials. J Clin Oncol.;17(8):2572-8. 
Yung WK, Albright RE, Olson J, et al (2000) A phase II study of temozolomide vs. 
procarbazine in patients with glioblastoma multiforme at first relapse. Br J Cancer; 83(5):588-
93. 
Zhang J, Wu G, Miller CP, et al (2013) Whole-genome sequencing identifies genetic 
alterations in pediatric low-grade gliomas.  Nat Genet; 45(6):602-12. 


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14 
Appendices 
14.1 
Appendix 1: List of concomitant medications  
In general, the use of any concomitant medication deemed necessary for the care of the patient 
is permitted in this study, except as specifically prohibited below. Combination administration 
of study drugs could result in drug-drug interactions (DDI) that could potentially lead to reduced 
activity or enhanced toxicity of the concomitant medication and/or BGJ398. 
The following lists are based on the Oncology Clinical Pharmacology Drug-Drug Interaction 
Database (release date: 29 Oct 2012), which was compiled from the Indiana University School 
of Medicine’s “Clinically Relevant” Table and supplemented with the FDA Draft guidance. 
Table 14-1 
Drugs to be used with caution while on the study 
Category 
Drug Names 
Sensitive CYP3A Substrates 
Alpha-dihydroergocryptine, aplaviroc, aprepitant, 
atorvastatin, brecanavir, brotizolam, budesonide, 
buspirone, capravirine, casopitant, conivaptan, 
darifenacin, darunavir, dasatinib, dronedarone, 
ebastine, eletriptan, eplerenone, everolimus, 
felodipine, fluticasone, indinavir, levomethadyl, 
lopinavir, lovastatin, lumefantrine, lurasidone, 
maraviroc, midazolam, neratinib, nisoldipine, 
perospirone, quetiapine, ridaforolimus, saquinavir, 
sildenafil, simvastatin, ticagrelor, tipranavir, tolvaptan, 
triazolam, vardenafil, vicriviroc 
Moderate inhibitors of CYP3A4 
Amprenavir, aprepitant, atazanavir, casopitant, 
cimetidine, ciprofloxacin, cyclosporine, darunavir, 
diltiazem, dronedarone, erythromycin, fluconazole, 
fosamprenavir, imatinib, Schisandra sphenanthera, 
tofisopam, verapamil 
Moderate inducers of CYP3A4 
Bosentan, efavirenz, etravirine, genistein, modafinil, 
nafcillin, ritonavir, talviraline, thioridazine, tipranavir 
Medications which alter the pH of the GI tract1 
Proton-pump inhibitors (e.g., omeprazole), H2-
antagonists (e.g., ranitidine) and antacids.  
Medications that have possible risk of TdP/QT 
prolongation 
Dronedarone, eribulin, lapatinib, sunitinib, nilotinib, 
tamoxifen, gatifloxacin, gemifloxacin, levofloxacin, 
ofloxacin, roxithromycin, telithromycin, clozapine, 
iloperidone, paliperidone, quetiapine, risperidone, 
sertindole, ziprasidone, dolasetron, granisertron, 
ondansetron, escitalopram, venlafaxine, Ranolazine, 
voriconazole, amantadine, foscarnet, isradipine, 
moexipril, nicardipine, fingolimod, tacrolimus, 
atazanavir, felbamate, famotidine, fosphenytoin, 
alfuzosin, chloral hydrate, indapamide, lithium, 
octreotide, pasireotide, oxytocin, ranolazine, 
tizanidine, vardenafil 
Medications that have conditional risk of TdP/QT 
prolongation 
Amisulpride, amiptriptyline, clomipramine, 
desipramine, doxepin, fluoxetine, imipramine, 
nortriptyline, paroxetine, protriptyline, sertraline, 
trazodone, trimipramine, ciprofloxacin, trimethoprim-
sulfa, diphenhydramine, fluconazole, itrazonazole, 
ketoconazole, ritonavir, galantamine, solifenacin 
BCRP substrates 
Rosuvatstatin, methotrexate, irinotecan, atorvastatin, 
simvastatin, topotecan, sulfasalazine 


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Category 
Drug Names 
1 BGJ398 should be dosed at least 2 hours before or 10 hours after dosing with a gastric protection agent. 
Reference: 
FDA Guidance for Industry, Drug Interaction Studies — Study Design, Data Analysis, Implications for Dosing, 
and Labeling Recommendations. Accessed 10 November 2013 
http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf. 
Indiana University School of Medicine’s “Clinically Relevant” table (2009). 
http://medicine.iupui.edu/clinpharm/ddis/clinicalTable.aspx. Accessed 14 July 2011 
University of Washington’s Drug Interaction Database (2013) http://.druginteractioninfo.org 
Drug-Drug Interactions (DDI) Database: Novartis Oncology Clinical Pharmacology Internal Memorandum, Final 
(v04), 12-Oct-2012 
 


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14.2 
 Appendix 2: List of prohibited medication 
Table 14-2 
List of prohibited medication while on the study 
Category 
Drug Names 
Strong inducers of 
CYP3A4 
Avasimibe, carbamazepine, phenobarbital, phenytoin, rifabutin, rifampin, St. John's 
wort 
Strong Inhibitors of 
CYP3A4 
 
Clarithromycin, conivaptan, indinavir, itraconazole, ketoconazole, voriconazole, 
lopinavir, mibefradil, nefazodone, nelfinavir, posaconazole, ritonavir, saquinavir, 
telithromycin, grapefruit juice, juice from Seville oranges, star fruits, pomegranates 
and pummelos. 
Medications which 
increase serum 
phosphorus and/or 
calcium 
Calcium, phosphate, vitamin D, parathyroid hormone (PTH) 
Narrow Therapeutic 
index substrates of 
CYP3A4 
Quinidine, astemizole, terfanadine, cyclosporine, sirolimus, tacrolimus, 
diergotamine, cisapride, ergotamine, pimozide, alfentanil, fentanyl thioridazine, 
diergotamine, dihydroergotamine, ergotamine 
Medications with 
established potential for 
QT prolongation or 
Torsades de pointes 
Amiodarone, Anagrelide, Arsenic trioxide, Astemizole (Off US mkt), Azithromycin, 
Bepridil (Off US mkt), Chloroquine, Chlorpromazine, Cisapride (Off US mkt), 
Citalopram, Clarithromycin, Cocaine, Disopyramide, Dofetilide, Domperidone (Not 
on US mkt), Dronedarone, Droperidol, Erythromycin, Escitalopram, Flecainide, 
Grepafloxacin  (Off market worldwide), Halofantrine, Haloperidol, Ibutilide,  
Levofloxacin, Levomethadyl (Off US mkt), Mesoridazine (Off US mkt), Methadone, 
Moxifloxacin, Ondansetron, Pentamidine, Pimozide, Probucol (Off US mkt), 
Procainamide (Oral off US mkt), Quinidine, Sevoflurane, Sotalol, Sparfloxacin (Off 
US mkt), Sulpiride (Not on US Mkt), Terfenadine (Off US mkt), Thioridazine, 
Vandetanib 
Table 14-3 
EIAEDs that are prohibited 
Strong CYP3A inducers 
Moderate CYP3A inducers 
carbamazepine 
felbamate 
phenobarbital 
topiramate (>200 mg/day) 
phenytoin 
oxcarbazepin 
fosphenytoin 
eslicarbazepin 
primidone 
rufinamide 


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14.3 
Appendix 3: Response assessment in neuro-oncology (RANO) 
criteria  
Antitumor response will be evaluated by the Response Assessment in Neuro-Oncology 
(RANO) working group (Wen et al 2010) criteria in this study. The RANO Criteria updates its 
established predecessor, the modified Macdonald Criteria (Macdonald et al 1990), by adding 
assessment of non-enhancing lesions and incorporating issues of pseudoprogression. 
Patients will undergo MRI assessments for response evaluation on an approximately every 8 
weeks interval from the start of the study until disease progression, as outlined in the Visit 
schedule Table 7-1. 
The following components will be taken into account when assessing a patient’s overall 
response at an individual evaluation. 
• Tumor evaluation eCRF for measureable enhancing lesions (T1-Gd+) 
• Tumor evaluation eCRF for non-enhancing lesions (T2/FLAIR) 
• Tumor evaluation eCRF for new lesion 
• Concomitant medication eCRF for steroid usage 
• Clinical status eCRF for ECOG and other clinical evaluation finding 
• Overall response eCRF for response category (CR/PR/PD/SD/NA) 
14.3.1 
Antitumor Effect – Definition 
14.3.1.1 Evaluable for toxicity 
All participants who receive at least one dose of study treatment will be evaluable for toxicity 
from the time of their first treatment. 
14.3.1.2 Evaluable for objective response 
Only those participants who have measurable disease present at baseline (Cycle 1, Day 1 scan) 
or post-operatively (group 2) and have received at least one dose of therapy will be considered 
evaluable for response. These participants will have their response classified according to the 
definitions stated below. (Note: Participants who exhibit objective disease progression or die 
prior to the end of Cycle 1 will also be considered evaluable.) 
14.3.1.3 Measurable disease 
Bidimensionally, contrast-enhancing, measurable lesions with clearly defined margins by CT 
or MRI scan, with a minimal diameter of 1 cm, and visible on at least 2 axial slices which are 
preferably at least 5 mm apart with 0 mm skip. If the MRI is performed with thicker slices, the 
size of the measurable lesion at baseline should be two times the slice thickness. Measurement 
of tumor around a cyst or surgical cavity should be considered non measurable unless there is 
a nodular component measuring ≥ 10 mm in diameter. The cystic or surgical cavity itself should 
not be measured in determining response. If there are too many measurable lesions to measure 
at each evaluation, the investigator must measure at least the largest two to be followed before 
a participant is entered on study, with the total measurement representing the sum of products 
of the perpendicular diameters. A maximum of five lesions should be measured. The remaining 


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lesions will be considered non-measureable for the purpose of objective response 
determination. Unless progression is observed, objective response can only be determined when 
all measurable and non-measurable lesions are assessed. 
Patients without measurable disease, such as those who undergo a gross total resection, cannot 
respond and can only achieve stable disease as their best radiographic outcome. 
14.3.1.4 Non-measurable evaluable disease 
Unidimensionally measurable lesions, masses with margins not clearly defined, lesions with 
maximal diameter < 1 cm. 
14.3.2 
Response/Progression Categories 
Complete response (CR) 
All of the following criteria must be met: 
a. Complete disappearance of all enhancing measurable and non-measurable disease sustained 
for at least 4 weeks. In the absence of a confirming scan 4 weeks later, this scan will be 
considered only stable disease. 
b. No new lesions. 
c. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
d. Participants must be on no steroids or on physiologic replacement doses only. 
e. Stable or improved non-enhancing (T2/FLAIR) lesions 
f. Stable or improved clinically, for clinical signs and symptoms present at baseline and 
recorded to be disease related 
Participants with non-measurable disease cannot have a complete response. The best 
response possible is stable disease. 
Partial response (PR) 
All of the following criteria must be met: 
a. Greater than or equal to 50% decrease compared to baseline in the sum of products of 
perpendicular diameters of all measurable enhancing lesions sustained for at least 4 weeks. 
In the absence of a confirming scan 4 weeks later, this scan will be considered only stable 
disease. 
b. No progression of non-measurable disease. 
c. No new lesions. 
d. All measurable and non-measurable lesions must be assessed using the same techniques as 
baseline. 
e. The steroid dose at the time of the scan evaluation should be no greater than the dose at time 
of baseline scan. 
f. Stable or improved non-enhancing (T2/FLAIR) lesions on same or lower dose of 
corticosteroids compared to baseline scan. 


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g. Stable or improved, for clinical signs and symptoms present at baseline and recorded to be 
disease related clinically.  
Participants with non-measurable disease cannot have a partial response. The best 
response possible is stable disease. 
Progressive disease (PD) 
The following criterion must be met: 
a. 25% increase in sum of the products of perpendicular diameters of enhancing lesions (over 
best response or baseline if no decrease) on stable or increasing doses of corticosteroids 
and/or one or more of the following: 
b. Significant increase in T2/FLAIR non-enhancing lesion on stable or increasing doses of 
corticosteroids steroids compared to baseline scan or best response following initiation of 
therapy, not due to co-morbid events (radiation therapy, demyelination, ischemic injury, 
infection, seizures, post-operative changes, or other treatment effects). 
c. Any new lesion 
d. Clear clinical deterioration not attributable to other causes apart from the tumor (e.g., 
seizures, medication side effects, complications of therapy, cerebrovascular events, 
infection, etc.). The definition of clinical deterioration is left to the discretion of the 
investigator but it is recommended that a decline in the KPS from 100 or 90 to 70 or less, a 
decline in KPS of at least 20 from 80 or less, or a decline in KPS from any baseline to 50 or 
less, for at least 7 days, be considered neurologic deterioration unless attributable to 
comorbid events or changes in corticosteroid dose. Similarly, a decline in the Easter 
cooperative Oncology Group (ECOG) performance scores from 0 or 1 to 2 or 2 to 3 would 
be considered neurologic deterioration, unless attributable to co-morbid events or changes 
in corticosteroid dose. 
e. Failure to return for evaluation due to death or deteriorating condition 
f. Patients with non measurable enhancing disease whose lesions have significantly increased 
in size and become measurable (minimal bidirectional diameter of ≥ 10 mm and visible on 
at least two axial slices that are preferably, at most, 5 mm apart with 0-mm skip) will also 
be considered to have experienced progression. The transition from a non measurable lesion 
to a measurable lesion resulting in progression can theoretically occur with relatively small 
increases in tumor size (e.g., a 9 × 9 mm lesion [non measurable] increasing to a 10 × 11 
mm lesion [measurable]). Ideally, the change should be significant (> 5 mm increase in 
maximal diameter or ≥ 25% increase in sum of the products of perpendicular diameters of 
enhancing lesions). In general, if there is doubt about whether the lesion has progressed, 
continued treatment and close follow-up evaluation will help clarify whether there is true 
progression. 
Note that if there is uncertainty regarding whether there is progression, the patient may continue 
on treatment and remain under close observation (e.g., evaluated at 4-week intervals). If 
subsequent evaluations suggest that the patient is in fact experiencing progression, then the date 
of progression should be the time point at which this issue was first raised. 


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Amended Protocol Version 02 (Clean) 
 
Protocol No. CBGJ398X2201 
 
Stable disease (SD) 
All of the following criteria must be met: 
a. Does not qualify for CR, PR, or progression. 
b. All measurable and non-measurable sites must be assessed using the same techniques as 
baseline. 
c. Stable non-enhancing (T2/FLAIR) lesions on same or lower dose of corticosteroids 
compared to baseline scan. In the event that the corticosteroid dose has been increased, the 
last scan considered to show stable disease will be the scan obtained when the corticosteroid 
dose was equivalent to the baseline dose. 
d. Stable clinically. 
Unknown response status 
Progressive disease has not been documented and one or more measurable or non-measurable 
lesions have not been assessed. 
These RANO Response Criteria are also summarized in Table 14-4: 
Table 14-4 
Summary of the RANO Response Criteria 
 
CR 
PR 
SD 
PD# 
T1-Gd + 
None 
≥50% decrease 
<50% decrease but 
≤ 25% increase 
≥25% increase* 
T2/FLAIR 
Stable or decrease 
Stable or decrease 
Stable or decrease 
Increase* 
New Lesion 
None 
None 
None 
Present* 
Corticosteroids 
None 
Stable or decrease 
Stable or decrease 
NA** 
Clinical Status 
Stable or improve 
Stable or improve 
Stable or improve 
Deterioration* 
Requirement for 
Response 
All 
All 
All 
Any* 
CR=complete response; PR=partial response; SD=stable disease; PD=progressive disease 
 
*: Progression when this criterion is met **: Increase in corticosteroids alone will not be taken into account in 
determining progression in the absence of persistent clinical deterioration 
 
14.3.3 
Methods for Evaluation of Measurable Disease 
All measurements should be taken and recorded in metric notation, using a ruler, calipers, or 
digital measurement tool. All baseline evaluations should be performed as closely as possible 
to the beginning of treatment and never more than 14 days 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. 


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14.3.4 
Evaluation of Best response 
The best overall response is the best response recorded from the start of the treatment until 
disease progression (taking as reference for progressive disease the smallest measurements 
recorded since the treatment started). If a response recorded at one scheduled MRI does not 
persist at the next regular scheduled MRI, the response will still be recorded based on the prior 
scan, but will be designated as a non-sustained response. If the response is sustained, i.e. still 
present on the subsequent MRI, it will be recorded as a sustained response, lasting until the time 
of tumor progression. Participants without measurable disease may only achieve SD or PD as 
their best “response.” 
14.3.5 
Other Effect Measures 
14.3.5.1 Performance Status 
Participants will be graded according to ECOG score. 
14.3.5.2 Overall survival time 
From date of first dose (date of first post-surgery treatment for participants in group 2) to date 
of death due to any cause. 
14.3.5.3 Progression-free survival time 
From date of first dose (date of first post-surgery treatment for participants in group 2) to date 
of progression or death. Participants who stop treatment for causes other than progression may 
be censored if other therapy is initiated or if regular assessments for assessing progression are 
no longer available. 

SAP_000.pdf: 
Clinical Development 
BGJ398 
Trial Protocol CBGJ398X2201 / NCT01975701
A Phase 2, multicenter, open-label study of BGJ398 in 
patients with recurrent resectable or unresectable 
Glioblastoma  
Statistical Analysis Plan (SAP) 
Author: 
Trial Statistician, 
 
Document type: 
SAP Documentation 
Document status: 
Final v1.0 
Release date: 
21-Dec-2017
Number of pages: 
33 
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


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Document History  
 
Date 
Version 
number 
Summary of changes 
21-Dec-2017 1.0 
 
BGJ398X2201 SAP amendment 1 after 2017 dry run 
 
 


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Table of contents 
Table of contents ................................................................................................................. 3 
List of tables ........................................................................................................................ 5 
List of figures ...................................................................................................................... 5 
List of abbreviations ............................................................................................................ 5 
1 
Introduction ......................................................................................................................... 8 
1.1 
Study design............................................................................................................. 8 
1.2 
Study objectives and endpoints ............................................................................... 9 
2 
Statistical methods ............................................................................................................. 10 
2.1 
Data analysis general information ......................................................................... 10 
2.1.1 
General definitions ................................................................................ 11 
2.2 
Analysis sets .......................................................................................................... 14 
2.3 
Patient disposition, demographics, disease history and medical history ............... 16 
2.3.1 
Patient disposition ................................................................................. 16 
2.4 
Treatments (study treatment, rescue medication, concomitant therapies, 
compliance) ............................................................................................................ 17 
2.4.1 
Study treatment / compliance ................................................................ 17 
2.4.2 
Prior, concomitant and post therapies ................................................... 19 
2.5 
Analysis of the primary objective .......................................................................... 19 
2.5.1 
Primary endpoint ................................................................................... 20 
2.5.2 
Statistical hypothesis, model, and method of analysis .......................... 20 
2.5.3 
Handling of missing values/censoring/discontinuations ....................... 21 
2.5.4 
Supportive analyses ............................................................................... 21 
2.6 
Analysis of the key secondary objective ............................................................... 21 
2.7 
Analysis of secondary efficacy objective(s) .......................................................... 21 
2.7.1 
Objective Response Rate ....................................................................... 21 
2.7.2 
Overall Survival .................................................................................... 22 
2.8 
Safety analyses ....................................................................................................... 22 
2.8.1 
Adverse events (AEs) ............................................................................ 22 
2.8.2 
Laboratory data ..................................................................................... 24 
2.8.3 
ECOG performance status ..................................................................... 25 
2.8.4 
Other safety data ................................................................................... 25 
 
 27 
 
 28 
2.11 
Interim analysis ...................................................................................................... 28 
3 
Sample size calculation ..................................................................................................... 28 


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4 
Change to protocol specified analyses .............................................................................. 28 
5 
Appendix ........................................................................................................................... 28 
5.1 
Imputation rules ..................................................................................................... 28 
5.1.1 
Study drug ............................................................................................. 28 
5.1.2 
AE, ConMeds and safety assessment date imputation .......................... 30 
5.2 
AEs coding/grading ............................................................................................... 32 
5.3 
Laboratory parameters derivations ........................................................................ 32 
6 
Reference ........................................................................................................................... 33 
 
 
 
 


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List of tables 
Document History – Changes compared to previous version of SAP. .... Error! Bookmark not 
defined. 
Table 1-1 
Objectives and related endpoints ............................................................ 9 
Table 2-1 
Time windows for assessments ............. Error! Bookmark not defined. 
Table 2-2 
Last contact date data sources ............... Error! Bookmark not defined. 
Table 2-3 
Determination of analysis set membership ........................................... 15 
Table 2-4 
Laboratory parameters to be presented in grade shift tables based 
on CTC grade ........................................ Error! Bookmark not defined. 
Table 2-5 
Laboratory parameters to be presented in shift tables based on local 
lab normal ranges .................................. Error! Bookmark not defined. 
Table 2-6 
 ECOG performance status .................... Error! Bookmark not defined. 
Table 2-7 
Clinically notable changes in vital signs ............................................... 26 
 
 27 
Table 3-1 
Operating characteristics of study design ............................................. 28 
Table 5-1 
Imputation of start dates (AE, CM) and assessments(LB, EG, VS) ..... 30 
Table 5-2 
Imputation of end dates (AE, CM) ........ Error! Bookmark not defined. 
 
List of figures 
Figure 1-1 
Study design ............................................................................................ 9 
Figure 2-1 
PFS6 prior distribution .......................................................................... 20 
 
 
List of abbreviations 
AE 
Adverse Event 
ALT/SGPT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AST/SOPT 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
CL 
Clearance  
 
 
 
 
CR 
Complete Response 
CRF 
Case Report/Record Form; the term CRF can be applied to either EDC or Paper 
CSP 
Clinical Study Protocol 
CSR 
Clinical study report 
CSR 
addendum 
An addendum to CSR that captures all the additional information that is not 
included in the CSR 
CT 
Computed Tomography 
CTCAE 
DAR 
Common Terminology Criteria for Adverse Events 
Dosage Administration Record 


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DDS 
Dose-determining set  
ECG 
Electrocardiogram 
(e)CRF 
Electronic Case Report/Record Form  
EGFR 
Epidermal growth factor receptor  
EOT 
End of Treatment 
EU 
European Union  
FAS 
Full Analysis Set 
FGF 
Fibroblast growth factor 
FGFR 
Fibroblast Growth Factor receptor 
GBM 
Glioblastoma 
GCP 
Good Clinical Practice 
GI 
Gastrointestinal 
GLP 
Good Laboratory Practice  
IB 
Investigators Brochure 
IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IRB 
Institutional Review Board 
LLN 
Lower limit of Normal 
LLOQ  
Lower Limit of Quantification 
LPLT 
Last patient last treatment 
LVEF 
Left Ventricular Ejection Fraction  
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
N 
Sample size 
NA 
Not applicable 
OC 
Oral contraception  
ORR 
Objective Response Rate 
OS 
Overall survival  
p.o. 
per os/by mouth/orally 
 
 
 
 
PFS 
Progression-free survival  
PFS6 
Progression-free survival at 6 months 
 
 
PPS 
Per protocol set 
PR 
Partial Response 
q.d. 
once a day 
QTcB 
Q-T interval in the ECG (corrected according to the formula of Bazett) 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
RANO 
Response Assessment in Neuro-Oncology  


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RAP 
The Report and Analysis Plan (RAP) is a regulatory document which provides 
evidence of preplanned analyses 
SAE 
Serious Adverse Event 
SoC 
Standard of Care Treatment  
TACC 
Transforming acidic coiled-coil 
 
 
U.S. FDA 
the U.S. Food and Drug Administration  
US 
United States 
WBC 
White Blood Cell  
 


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1 
Introduction 
This statistical analysis plan (SAP) describes all planned analyses for the Clinical Study Report 
(CSR) of study CBGJ398X2201, a multi-center, open label, phase II study of BGJ398 for the 
treatment of patients with recurrent GBM and/or other glioma subtypes, whose tumors harbor 
FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation in FGFR1, FGFR2, or 
FGFR3 gene. 
The content of this SAP is based on protocol CBGJ398X2201 Amendment version 2. All 
decisions regarding final analysis, as defined in the SAP document, have been made prior to 
database lock of the study data. Detailed tables, figures and listings can be found in TFL shells 
version 1.0. 
 
1.1 
Study design 
The study is planned to enroll patients with recurrent GBM in two groups. Non Surgery Group 
enrolls patients who are not candidates for surgery. Patients in Non Surgery Group receive 
BGJ398 on a three weeks on, one week off schedule. Surgery Group enrolls patients who are 
surgical candidates. Patients in Surgery Group receive BGJ398 for 5-10 days prior to surgery. 
After recovery of surgery (a minimum of two weeks and no more than six weeks following 
surgery), patients in Surgery Group  receive BGJ398 on a three weeks on, one week off 
schedule. Patients from both Non Surgery Group and Surgery Group are evaluated for tumor 
response and progression by Gd-enhanced MRI every 8 weeks until disease 
progression/discontinuation from study using RANO criteria. 
The study plans to enroll 34 adult patients with histologically confirmed recurrent GBM and/or 
other glioma subtypes with FGFR1-TACC1, FGFR3-TACC3 fusion and/or activating mutation 
in FGFR1, 2, or 3.  


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Figure 1-1 
Study design 
 
 
 
 
1.2 
Study objectives and endpoints 
Objectives and related endpoints are described in Table 1-1 below. 
Table 1-1 
Objectives and related endpoints 
Objective 
Endpoint 
Primary 
 
To assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1,2 or 3, 
based on PFS6 
PFS rate at 6 months as defined by RANO criteria as assessed 
by the investigator 
Secondary 
 
To further assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1,2or 3, based 
on ORR 
ORR (patients with measurable disease) as defined by RANO 
criteria as assessed by the investigator 


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Objective 
Endpoint 
To further assess the anti-tumor activity of 
BGJ398 for patients with GBM and/or 
other glioma subtypes with FGFR1-
TACC1, FGFR3-TACC3 fusion and/or 
activating mutation with   in FGFR1,2or 3, 
based on OS 
Overall survival (OS) 
To characterize the safety and tolerability 
of BGJ398 
Safety: type, frequency, and severity of AEs and SAEs; 
Tolerability: dose interruptions, reductions and dose intensity, 
and evaluations of laboratory values 
 
2 
Statistical methods 
2.1 
Data analysis general information 
The final analysis will be performed by Novartis personnel. SAS® version 9.4 will be used to 
perform all data analyses and to generate tables, figures and listings. 
Data included in the analysis 
The study data will be analyzed and reported (in a primary CSR if final DBL has not occurred) 
based on all patient’s data when all patients have completed at least 6 cycles of treatment or 
discontinued the study. The primary CSR will include all outputs planned in the TFL Shells 
documents. Additional data of any patients continuing to receive BGJ398 beyond the cut-off 
date, as allowed by the CSP, will be summarized in a final CSR that will be prepared once all 
patients have discontinued the study or at the end of the study (end of survival follow up period) 
which is one year after the last patient’s last dose of study treatment, whichever occurs first. 


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General analysis conventions 
Pooling of centers: Unless specified otherwise, data from all participating centers will be 
combined for the analysis, so that an adequate number of patients will be available for analysis. 
Due to expected small number of patients enrolled at centers, no center effect will be assessed.  
Qualitative data (e.g., gender, race, etc.) will be summarized by means of contingency tables, 
a missing category will be included as applicable. Percentages will be calculated using the 
number of patients in the relevant population or subgroup as the denominator. 
Quantitative data (e.g., age, body weight, etc.) will be summarized by appropriate 
descriptive statistics (i.e. mean, standard deviation, median, minimum, and maximum). 
 
2.1.1 
General definitions  
Investigational drug and study treatment 
Investigational drug refers to the BGJ398 only.  
Study treatment = investigational drug. 
Date of first administration of investigational drug 
The date of first administration of investigational drug is defined as the first date when a non-
zero dose of investigational drug BGJ398 is administered and recorded on the Dosage 
Administration Record (DAR) (e)CRF. The date of first administration of investigational drug 
will also be referred as the start date of investigational drug. 
Date of last administration of investigational drug 
The date of last administration of investigational drug is defined as is the last date when a 
nonzero dose of investigational drug is administered and recorded on DAR (e)CRF. The date 
of last administration of investigational drug will also be referred as the last date of 
investigational drug. 
Study day 
The study day, describes the day of the event or assessment date, relative to the reference start 
date.  
The study day is defined as: 
 •   The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date + 1 if event is on or after the reference start date; 
• The date of the event (visit date, onset date of an event, assessment date etc.) − 
reference start date if event precedes the reference start date. 
The reference date for all assessments (safety, efficacy, 
 etc) is the start date of study 
treatment.  
The study day will be displayed in the data listings. If an event starts before the reference start 
date, the study day displayed on the listing will be negative. 


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Time unit 
A year length is defined as 365.25 days. A month length is 30.4375 days (365.25/12). If duration 
is reported in months, duration in days will be divided by 30.4375.  If duration is  reported in 
years, duration in days will be divided by 365.25. A week length is 7 days. If duration is reported 
in weeks, duration in days will be divided by 7. 
Baseline 
For non-efficacy assessments, Baseline is the last available and valid assessment performed 
or value measured within 21 days before the first administration of study treatment, unless 
otherwise stated under the related assessment section. Baseline can be the day before first 
treatment administration or the same day as first treatment administration if a pre-dose 
assessment/value is available (e.g., ECG, 
). 
If time is recorded for the first treatment dose and for a specific assessment performed the day 
of first dose, this assessment will be considered as baseline only if it is actually performed 
before the first dose, as checked using both times. 
If time is not recorded, a specific assessment performed the day of first dose administration will 
be considered as baseline if, according to CSP, it should be performed before the first treatment 
administration. 
Patients with no data on a particular parameter before the first treatment administration will 
have a missing baseline for this parameter. 
The baseline ECG interval value will be obtained by averaging each of the ECGs available 
before the first dose of BGJ398 up to 21 days before the first dose of investigational drug. 
For efficacy assessments, Baseline is defined as:   
Non Surgery Group: baseline scan must occur within 28 days after the initiation of study 
treatment. 
Surgery Group: an MRI scan, performed within 72 hours after surgery, can function as the 
baseline scan if BGJ398 therapy is initiated within 4 weeks of surgery. If BGJ398 is initiated 
after 4 weeks following surgery, a baseline scan must be performed within 7 days of starting 
BGJ398. 
On-treatment assessment/event and observation periods  
For adverse event reporting the overall observation period will be divided into three mutually 
exclusive segments:  
1. pre-treatment period: from day of patient’s informed consent to the day before first 
administration of study treatment 
2. on-treatment period: from date of first administration of study treatment to 30 days after 
date of last actual administration of study. 
3. post-treatment period: starting at day 30+1 after last administration of study treatment. 
If dates are incomplete in a way that clear assignment to pre-, on-, post-treatment period cannot 
be made, then the respective data will be assigned to the on-treatment period.   


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Safety summaries (tables, figures) include only data from the on-treatment period with the 
exception of baseline data which will also be summarized where appropriate (e.g. change from 
baseline summaries). In addition, a separate summary for death including on treatment and post 
treatment deaths will be provided.  In particular, summary tables for adverse events (AEs) will 
summarize only on-treatment events, with a start date during the on-treatment period 
(treatment-emergent AEs).   
 
Windows for multiple assessments  
In order to summarize ECOG performance status, 
 vital signs, and other data collected over 
time (including unscheduled visits), the assessments will be time slotted. The following general 
rule will be applied in creating the assessment windows: If more than one assessment is done 
within the same time window, the assessment performed closest to the target date will be used. 
If 2 assessments within a time window are equidistant from the target date, then the earlier of 
the 2 assessments will be used. If multiple assessments on the same date then the worst case 
will be used. Data from all assessments (scheduled and unscheduled), including multiple 
assessments, will be listed. 
Table 2-1 Time windows for assessments  
 
 
Assessment 
Target day of assessment 
Time Interval 
Baseline 
         
 ≤ Day 1  
        Cycle 1 Day 15 
15 
Day 2 to day 21 
Cycle 2 Day 1 
29 
Day 22 to day 42 
Cycle 3 Day 1 
57 
Day 43 to day 63 
Cycle 3 Day 15 
71 
Day 64 to day 77 
Cycle 4 Day 1 
85 
Day 78 to day 98 
Cycle k Day 1 (k≥5) 
d=(k-1)*28+1 
Day d-14 to day d+13 
End of Treatment 
 
Assessment taken at the 
end of treatment visit 
Last contact date  
The last contact date will be derived for patients not known to have died at the analysis cut-off 
using the last complete date among the following: 
 
Table 2-2 
Last contact date data sources  
Source data 
Conditions 
Last contact date/last date patient was known to 
be alive from Survival Follow-up page  
 
- Patient status is reported to be alive, lost to 
follow-up or unknown. 
Start/End dates from further antineoplastic 
therapy 
Non-missing medication/procedure term. 


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Source data 
Conditions 
Start/End dates from drug administration record  
 
Non-missing dose. Doses of 0 are allowed. 
End of treatment date from end of treatment page 
 
No condition. 
RANO assessment date 
Evaluation is marked as ‘done’. 
Laboratory
 collection dates 
 
Sample collection marked as ‘done’.  
Vital signs date 
 
At least one non-missing parameter value 
Performance Status date 
 
Non-missing performance status 
Start/End dates of AE  
Non-missing verbatim term 
The last contact date is defined as the latest complete date from the above list on or before the 
data cut-off date. The cut-off date will not be used for last contact date, unless the patient was 
seen or contacted on that date. No date post cut-off date will be used. Completely imputed 
dates (e.g. the analysis cut-off date programmatically imputed to replace the missing end date 
of a dose administration record) will not be used to derive the last contact date. Partial date 
imputation is allowed for event (death)/censoring is coming from ‘Survival information’ 
(e)CRF.  
The last contact date will be used for censoring of patients in the analysis of overall survival. 
2.2 
Analysis sets 
Treatment group will be named as: Non Surg BGJ398 125 mg and Surg BGJ398 125 mg. If 
there are no patients in the surgery group, only Non Surg BGJ398 125 mg will be presented. 
Full Analysis Set 
The Full Analysis Set (FAS) includes all patients who received at least one dose of BGJ398. 
The FAS will be used for all listings of raw data. Unless otherwise specified the FAS will be 
the default analysis set used for all analyses. 
Per protocol set (PPS)  
 
The Per-Protocol Set (PPS) will consist of a subset of patients in the FAS (with FGFR1-TACC1, 
FGFR3-TACC3 and/or activating mutations in FGFR1, 2 or 3) who are compliant with 
requirements of the CSP. The PPS will include patients who have an adequate tumor assessment 
at baseline, a follow-up tumor assessment >8 weeks after starting treatment unless disease 
progression is observed before that time, and no protocol deviations. 
Safety 
The Safety Set includes all patients who received at least one dose of BGJ398 and have at least 
one valid post-baseline safety assessment.  


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The statement that a patient had no AE (on the AE (e)CRF) constitutes a valid safety 
assessment. 
The treatment received is defined as: 
• The treatment assigned if it was received at least once, or 
• The first treatment received when starting therapy with study treatment if the assigned 
treatment was never received. 
Patient Classification:  
Patients may be excluded from the analysis populations defined above based on the protocol 
deviations entered in the database and/or on specific subject classification rules defined in Table 
2-3.  
Table 2-3 
Determination of analysis set membership 
Description used 
to report Protocol 
Deviations 
    Protocol deviation IDs 
Analysis set(s) to be 
excluded 
Inclusion criteria not 
met  
INC01, INC02, INC04 
  PPS 
 
Use of prohibited 
concomitant 
medication 
WITH04, WITH05, TRT05 
 
PPS 
 
Withdrawal of Informed Consent 
Any data collected in the clinical database after a subject withdraws informed consent from all 
further participation in the trial, will not be included in the analysis.  The date on which a patient 
withdraws full consent is recorded in the (e)CRF.   


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2.3 
Patient disposition, demographics, disease history and medical 
history 
The Full Analysis Set (FAS) will be used for all baseline and demographic summaries and 
listings unless otherwise specified. No inferential statistics will be provided. 
Basic demographic and background data 
All demographic and baseline disease characteristics data will be summarized and listed. 
Categorical data, e.g. gender, age groups: <65 and ≥ 65 years, race, ECOG performance status, 
FGFR status (FGFR1/2/3 Amplified/Mutated/Translocated), will be summarized by frequency 
counts and percentages; the number and percentage of patients with missing data will be 
provided. Continuous data, e.g. age, weight, height, body mass index, will be summarized by 
descriptive statistics (N, mean, median, standard deviation, minimum and maximum). BMI 
(kg/m2) will be calculated as weight[kg] / (height[m]2) using weight at Baseline.   
Diagnosis and extent of cancer (disease history) 
Diagnosis and extent of cancer will be tabulated for primary site of cancer, details of tumor 
histology/cytology and histological grade.  
Medical history 
Medical history and ongoing conditions, including cancer-related conditions and symptoms 
entered on (e)CRF will be summarized and listed. Separate summaries will be presented for 
ongoing and historical medical conditions.  The summaries will be presented by primary system 
organ class (SOC) and preferred term (PT). Medical history and current medical conditions will 
be coded using the Medical Dictionary for Regulatory Activities (MedDRA) terminology. The 
MedDRA version 20.1used for reporting will be specified in the CSR and as a footnote in the 
applicable tables/listings. 
 
2.3.1 
Patient disposition 
The following patient disposition information will be summarized for patients in the FAS:  
• Enrolled patients who remained on treatment or discontinued treatment, based on the end 
of treatment (e)CRF (note that patients remained on treatment if the last known date the 
patient took study drug is later than the cut-off date) 
• Primary reasons for end of treatment (EOT). 
• Number (%) of patients who are discontinued and have entered the 30 day safety follow-
up (based on the ‘End of Treatment Phase Completion’ page); 
• Number (%) of patients who have entered the survival follow-up (based on the ‘End of 
Treatment Phase Completion’ page). 
• Primary reasons for end of study 
A listing of EOT details will be produced. Patients enrolled but not treated will be listed along 
with the reason for discontinuing from the study. Additionally, a listing of screen failure 


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patients, with reason for screen failure will be produced. Since screening failures are not part 
of any analysis sets, they will not be included in any of the summary tables. 
Protocol deviations 
The number (%) of patients in the FAS with any protocol deviation will be tabulated by 
deviation category (as specified in the study Data Handling Plan). Protocol deviations leading 
to exclusion from analysis sets will be tabulated separately. All protocol deviations will be 
listed. 
Analysis sets 
The number (%) of patients in each analysis set (defined in Section 2.2) will be summarized. 
2.4 
Treatments (study treatment, rescue medication, concomitant 
therapies, compliance) 
2.4.1 
Study treatment / compliance 
Duration of exposure, actual dose intensity (ADI) and relative dose intensity (RDI) will be 
summarized. The number (%) of subjects who have dose reductions or interruptions, and the 
reasons, will be summarized.  
Subject level listings of all doses administered on treatment along with dose change reasons 
will be produced.   
The safety set will be used for all summaries and listings of study treatment.  
Duration of exposure to study treatment 
The duration of exposure is calculated as detailed below. 
For patients who discontinued permanently from the study as of the data cut-off date: 
Duration of exposure (days) = (end date of study drug + X) – (start date of study drug) + 1, 
where study drug is BGJ398 and X is the number of days from last administered dose to the 
next planned dose taking into account the minimal allowed dosing interval. If the last dose of a 
cycle was taken later than the scheduled cycle length (28 days), X will be set to 0 days. For 
BGJ398, X equals to 0 if the cycle day of the last dose is less than 21 days; otherwise, X equals 
to (28 – cycle day of the last dose).  
For patients who are still on-treatment as of data cut-off date: 
Duration of exposure (days) = data cut-off date – (start date of study drug) + 1. 
Summary of duration of exposure of study treatment in weeks will include categorical 
summaries and continuous summaries (i.e. mean, standard deviation etc.). Duration of exposure 
will be categorized into time intervals (i.e. < 4 weeks, 4 - < 8 weeks, 8 - < 12 weeks, 12 - < 16 
weeks, 16 - < 24 weeks, 24 - < 32 weeks and >= 32 weeks); frequency counts and percentages 
will be presented for the number (%) of subjects in each interval. 
Exposure will be summarized on the Safety Set. 


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Cumulative dose 
Cumulative dose of a study treatment is defined as the total dose given during the study 
treatment exposure and will be summarized for each of the study treatment components.  
The planned cumulative dose for a study treatment component refers to the total planned dose 
as per the protocol up to the last date of investigational drug administration.  
The planned cumulative dose is not summarized/listed. It is used for relative dose intensity 
calculations.  
The actual cumulative dose refers to the total actual dose administered, over the duration for 
which the subject is on the study treatment as documented in the DAR (e)CRF.  
For patients who did not take any drug the cumulative dose is by definition equal to zero. 
Relative dose intensity 
Actual dose intensity (ADI) for patients with non-zero duration of exposure is defined as 
follows:  
ADI (mg / day) = Actual Cumulative dose (mg) / Duration of exposure to study treatment (day). 
For patients who did not take any drug the ADI is by definition equal to zero.  
Planned dose intensity (PDI) is defined as follows: 
PDI (mg / day) = Planned Cumulative dose (mg) / Duration of exposure (day). 
Relative dose intensity (RDI) is defined as follows: 
RDI = ADI (mg / day)  / PDI (mg / day).   
 
Dose reductions, interruptions or permanent discontinuations 
The number of subjects who have dose reductions, dose interruptions, or dose permanent 
discontinuations, and the reasons, will be summarized. ‘Dose Changed’, ‘Dose interrupted’, and 
‘Dose permanently discontinued’ fields from the DAR (e)CRF will be used to determine the 
dose reductions, dose interruptions, and permanent discontinuations, respectively. Note: 
planned 1 week off in dosing schedule will not be collected or counted as dose interruption. The 
corresponding field ‘Reason’ for dose changed, dose interrupted, and dose permanently 
discontinued will be used to summarize the reasons. 
A dose reduction is defined as a decrease in total daily dose from the protocol planned dose, 
and a decrease from the previous non-zero dose, even if this decrease has been directly preceded 
by an interruption, and the dose change flag is checked.  For example, in the sequence 125 mg 
– 0 mg – 100 mg, the 100 mg dose will be counted as a reduction. 
A dose interruption is defined as an instance that no study drug (0 mg) is taken when the 
protocol planned dose is non-zero. For example, in the sequence 125 mg – 0 mg – 100 mg, the 
0 mg dose will be counted as an interruption. 


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2.4.2 
Prior, concomitant and post therapies 
Prior anti-cancer therapy 
The number and percentage of patients who received any prior anti-neoplastic medications, 
prior anti-neoplastic radiotherapy or prior anti-neoplastic surgery will be summarized. For prior 
medications. Summaries will include prior antineoplastic regimens, total number of regimens, 
setting at last treatment based on end date, best response at last treatment based on end date. 
For prior radiotherapy, locations and setting at last radiotherapy will be summarized. For prior 
surgery, procedure at last surgery (biopsy or other) and residual disease will be summarized.  
Separate listings will be produced for prior anti-neoplastic medications, radiotherapy, and 
surgery.  
The above analyses will be performed using the FAS. 
Concomitant medications 
Concomitant therapy is defined as all interventions (therapeutic treatments and procedures) 
other than the study treatment administered to a patient coinciding with the study treatment 
period. Concomitant therapy includes medications (other than study drugs) starting on or after 
the start date of study treatment or medications starting prior to the start date of study treatment 
and continuing after the start date of study treatment.  
Concomitant medications will be coded using the World Health Organization (WHO) Drug 
Reference Listing  (DRL)  dictionary  that  employs  the  WHO  Anatomical  Therapeutic 
Chemical (ATC) classification system and summarized by lowest ATC class and preferred term 
using frequency counts and percentages. Surgical and medical procedures will be coded using 
MedDRA and summarized by SOC and preferred term. These summaries will include: 
1. Medications starting on or after the start of study treatment but no later than 30 days 
after start of last dose of study treatment and 
2. Medications starting prior to start of study treatment and continuing after the start of 
study treatment. 
All concomitant therapies will be listed. Any concomitant therapies starting and ending prior 
to the start of study treatment or starting more than 30 days after the last date of study treatment 
will be flagged in the listing. The safety set will be used for all concomitant medication tables 
and listings. 
2.5 
Analysis of the primary objective 
The primary objective of the study is to assess the anti-tumor activity of BGJ398 for patients 
with GBM and/or other glioma subtypes with FGFR1-TACC1, FGFR3-TACC3 fusion and/or 
activating mutation in FGFR1, 2 or 3. 
2.5.1 
Primary endpoint 
PFS rate at 6 months (PFS6) as defined by RANO criteria assessed by the investigator will be 
the primary endpoint.  


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Non Surgery Group: PFS is defined as the number of days from the first day of treatment to 
the date of the first documented disease progression or date of death, whichever occurs first.   
Surgery Group: PFS is defined as the number of days from the first day of treatment after 
surgery to the date of the first documented disease progression or date of death, whichever 
occurs first. 
2.5.2 
Statistical hypothesis, model, and method of analysis 
A Bayesian design will be used in order to estimate the PFS6 rate and to provide inferential 
statements based on the uncertainty of this quantity. Progression free survival will be modeled 
using a Weibull distribution. The Weibull distribution is a flexible distribution which allows for 
time varying hazard rate. The probability density function is given by f(x) = υλx^(υ-1)exp(-
λx^ υ) where υ is a shape parameter and λ a scale parameter. Prior distributions will be 
placed on both parameters to carry out the analysis. For the scale parameter, a normal (mean = 
0, standard deviation = 2.236 ) distribution will be used on the log of the parameter. For the 
shape parameter, an exponential with rate 1 will be used. These priors correspond to a prior 
probability of unacceptable efficacy (PFS6 <16%) of 65 %, and clinically relevant efficacy 
(PFS6 > 40%) of 25% (see Figure 2-1 below). 
Figure 2-1 
PFS6 prior distribution 
 
The posterior distributions will be updated with all the data available at the time of the analyses 
from the patients in the PPS who are evaluable for the primary analysis. Once updated, the 
posterior probability that the true PFS6 rate at the dose of BGJ398 used in the study lies in the 
following categories will be summarized: 
[0, 16%) unacceptable efficacy 
[16%, 25%) limited efficacy 
[25%, 40%) moderate efficacy 
[40%, 100%] clinically relevant efficacy 


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Data from both the treatment groups will be pooled together for this analysis, since we expect 
to observe similar 6-month PFS rates for these two groups. The study will be considered a 
success at the final analysis if 
• there is at least 50% confidence that BGJ398 has clinically relevant efficacy (that is, Post 
Prob(PFS6>=40%) > 50%), and 
• there is at least 80% confidence that BGJ398 has either moderate efficacy or clinically 
relevant efficacy (Post Prob(PFS6>=25%) > 80%). 
 
2.5.3 
Handling of missing values/censoring/discontinuations 
Patients who discontinue the study and are lost to follow-up without a known date of 
progression or death due to any cause on or before the cut-off date will be censored in the 
primary analysis at the date of their last available tumor assessment. 
2.5.4 
Supportive analyses 
As a supportive analysis, Kaplan-Meier estimates of the PFS rate at 4, 6,12, 16, 18 and 24 
months, 25th/75th percentile and median PFSwill be derived together with 95% confidence 
intervals. PFS will also be presented descriptively using Kaplan Meier plots. This analysis will 
be done with all patients in both the treatment groups pooled together.  
2.6 
Analysis of the key secondary objective 
Not applicable. 
2.7 
Analysis of secondary efficacy objective(s) 
The secondary objectives of the study is to assess the anti-tumor activity of BGJ398 based on 
objective response rate and overall survival using RANO criteria.  
Each patient will be evaluated for all potential sites of tumor lesions at Screening and every 8 
weeks after starting study treatment until disease progression. 
On-study tumor assessments have a ± 7 day window, except for the first post-baseline tumor 
assessment and for confirmatory scans (4 weeks +7 day window only). The first post-baseline 
tumor assessment should be performed on day 1 of cycle 3 (+7 day window permitted) after 
starting treatment.  There will be a tumor assessment at the End of Treatment (+ 7 days) if the 
patient discontinues for any reason other than disease progression and the last tumor assessment 
has been performed > 28 days prior to this day. 
2.7.1 
Objective Response Rate 
Objective response rate (ORR) is defined as the proportion of patients with a best overall 
response of Complete Response (CR) or Partial Response (PR), as per the RANO criteria. 
The ORR analysis will include patients from the FAS who have measurable disease (as per 
RANO) at their baseline scan. ORR will be reported with 95% confidence interval and response 
will be listed. 


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This analysis will be done for all patients in the PPS as well as the FAS in both treatment groups 
pooled together. 
2.7.2 
Overall Survival 
Non-Surgery Group: overall survival (OS) is defined as the time from the date of start of 
treatment to the date of death due to any cause or the date of last contact (censored observation) 
at the date of data cutoff. 
Surgery Group: OS is defined as the number of days from the first day of treatment after 
surgery to the date of death due to any cause or the date of last contact (censored observation) 
at the date of data cutoff. If the patient does not receive at least one post-surgical dose of BGJ398 
(i.e., C1D1), the patient will be excluded from the overall survival analysis.  
The survival time for patients without documentation of death prior to analysis data cutoff, will 
be censored at the last date the patient was known to be alive prior to the cutoff date. Survival 
time for patients with no post-baseline survival information will be censored on the date of start 
of treatment. 
OS will be analyzed using the Kaplan-Meier method. Survival rate at 4, 6, 8, 12, 18 and 24 
months and median OS will be estimated along with 95% confidence intervals.  
This analysis will be done for all patients in the PPS as well as the FAS in both treatment groups 
pooled together.  
 
2.8 
Safety analyses 
A secondary objective of the study is to characterize the safety and tolerability of BGJ398. 
The assessment of safety is based on the frequency and severity of AEs and SAEs, changes in 
hematology and chemistry values, specifically those associated with calcium/phosphate 
homeostasis and renal function, and on the number of laboratory values that fall outside of pre-
determined ranges (CTCAE v 4.03 grading limits or normal ranges as appropriate). Other safety 
(e.g., ECGs, vital signs and special tests, e.g. pregnancy test) analyses will be considered as 
appropriate. 
All safety analyses will be based on the safety set.  
The safety summary tables will include only on-treatment assessments. All safety assessments 
will be listed, and those collected later than 30 days after study treatment discontinuation will 
be flagged. 
2.8.1 
Adverse events (AEs) 
AE summaries 
AEs will be coded using MedDRA terminology, the latest version which will be available at 
the time of analysis.  
AE summaries will include all AEs occurring during on treatment period. All AEs collected in 
the AE (e)CRF page will be listed along with the information collected on those AEs e.g. AE 


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relationship to study drug, AE outcome etc. AEs with start date outside of on-treatment period 
will be flagged in the listings.  
AEs will be summarized by number and percentage of subjects having at least one AE, having 
at least one AE in each primary system organ class (SOC) and for each preferred term (PT) 
using MedDRA coding. A subject with multiple occurrences of an AE will be counted only 
once in the respective AE category. A subject with multiple CTCAE grades for the same 
preferred term will be summarized under the maximum CTCAE grade recorded for the event. 
AE with missing CTCAE grade will be included in the ‘All grades’ column of the summary 
tables. 
In AE summaries, the primary system organ class will be presented alphabetically and the 
preferred terms will be sorted within primary SOC in descending frequency. The sort order for 
the preferred term will be based on their frequency. 
The following adverse event summaries will be produced: 
• Overview of adverse events and deaths (number and % of subjects who died, with any AE, 
any SAE, any dose reductions/interruptions, AE leading to discontinuation);  
• AEs by SOC and PT, summarized by relationship (all AEs and AEs related to study 
treatment); 
• Seriousness (SAEs and non-SAEs);  
• Leading to treatment discontinuation; 
The following listings will be produced: 
• All adverse events (safety set)  
• Adverse events among subjects who were not treated (all screened subjects) 
Deaths  
• Summaries for on-treatment and all deaths (including post-treatment death) will be 
produced by system organ class and preferred term.  
• All deaths will be listed for the safety set, post treatment deaths will be flagged. A separate 
listing of deaths prior to starting treatment will be provided for all screened subjects.  
EudraCT and clinicaltrials.gov requirements for AEs and Deaths summaries For the legal 
requirements of clinicaltrials.gov and EudraCT, two required tables on treatment-emergent 
adverse events which are not serious adverse events with an incidence greater than 5% and on 
treatment emergent SAEs and SAEs suspected to be related to study treatment will be provided 
by SOC and PT on the safety set population. 
If for a same patient, several consecutive AEs (irrespective of study treatment causality, 
seriousness and severity) occurred with the same SOC and PT: 
• a single occurrence will be counted if there is  ≤ 1 day gap between the end date of the 
preceding AE and the start date of the consecutive AE 
• more than one occurrence will be counted if there is > 1 day gap between the end date of 
the preceding AE and the start date of the consecutive AE 


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For occurrence, the presence of at least one SAE / SAE suspected to be related to study 
treatment / non SAE has to be checked in a block e.g., among AE's in a ≤ 1 day gap block, if at 
least one SAE is occurring, then one occurrence is calculated for that SAE. 
2.8.2 
Laboratory data 
On analyzing laboratory, data from all sources (central and local laboratories) will be combined. 
The summaries will include all assessments available for the lab parameter collected no later 
than 30 days after the last study treatment administration. 
The following summaries will be produced for hematology and biochemistry laboratory data 
(by laboratory parameter and treatment): 
• Shift tables using CTC grades to compare baseline to the worst on-treatment  value  
• For laboratory tests where CTC grades are not defined, shift tables using the 
low/normal/high/(low and high) classification to compare baseline to the worst on-
treatment value. 
The following listings will be produced for the laboratory data: 
• Listing of all CTC grade 3 or 4 laboratory toxicities 
 
Table 2-4 lists those entire laboratory parameters for which CTCAE grades are defined, Table 
2-5 lists the remaining laboratory parameters for which shift tables were based upon the local 
lab normal range. 
Table 2-4 Laboratory parameters to be presented in grade shift tables based on 
CTC grade 
Hematology 
Biochemistry 
Coagulation 
White blood cell count (WBC) 
AST (SGOT) 
Fibrinogen 
Hemoglobin 
ALT (SGPT) 
PT 
Platelets counts 
Total Bilirubin 
PTINR  
Abs. Neutrophils 
Albumin 
PTT 
Abs. Lymphocytes 
Creatinine 
 
 
Alkaline Phosphatase 
 
 
Glucose 
 
 
Calcium 
 
 
Sodium 
 
 
Magnesium 
 
 
Potassium 
 
 
Hypophosphatemia 
 
ALT (SGPT) = Alanine aminotransferase/glutamic pyruvic transaminase; AST (SGOT) = Aspartate 
aminotransferase/glutamic oxaloacetic transaminase; PT = prothrombin time; PTINR = prothrombin time 
International normalized ratio 


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Table 2-5 
Laboratory parameters to be presented in shift tables based on 
local lab normal ranges 
Hematology 
Biochemistry 
Coagulation 
Absolute eosinophils 
BUN 
 
Absolute basophils 
Total protein 
 
Absolute monocytes 
Direct bilirubin 
 
Red blood cell count (RBC) 
LDH 
 
Hematocrit (HCRIT) 
 
 
 
 
 
2.8.3 
ECOG performance status 
Frequencies and percentages for the categories of the ECOG performance scale will be listed.  
Table 2-6 
ECOG performance status 
Grade 
ECOG Status 
0 
Fully active, able to carry on all pre-disease performance without restriction 
1 
Restricted in physically strenuous activity but ambulatory and able to carry out 
work of a light or sedentary nature (e.g., light house work, office work) 
2 
Ambulatory and capable of all self-care but unable to carry out any work activities. 
Up and about more than 50% of waking hours 
3 
Capable of only limited self-care, confined to bed or chair more than 50% of 
waking hours 
4 
Completely disabled. Cannot carry on any self-care. Totally confined to bed or 
chair 
Note: Grade 5 (dead) was removed from this table. This information will be collected on a separate 
(e)CRF page. 
 
2.8.4 
Other safety data 
2.8.4.1 
ECG and cardiac imaging data 
12-lead ECGs including PR, QRS, QT, and QTcF, will be obtained central/local for each subject 
during the study. ECG data will be read and interpreted centrally locally  
The number and percentage of subjects with notable ECG values will be presented.  
• QT, or QTcF 
- 
New value of > 450 and ≤ 480 ms 
- 
New value of > 480 and ≤ 500 ms 
- 
New value of > 500 ms 
- 
Increase from Baseline of > 30 ms to ≤  60ms 
- 
Increase from Baseline of > 60 ms 
• HR 
- 
Increase from baseline >25% and to a value > 100 bpm 


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- 
Decrease from baseline >25% and to a value < 50 bpm 
• PR 
- 
Increase from baseline >25% and  to a value > 200 ms 
- 
New value of > 200 ms 
• QRS 
- 
Increase from baseline >25% and  to a value > 120 ms  
- 
New values of QRS > 120 ms  
A listing of notable ECG values will be produced. In the listing, the assessments collected 
during the post-treatment period will be flagged. 
2.8.4.2 
Vital signs 
Vital sign assessments are performed in order to characterize basic body function. The 
following parameters were collected: height (cm), weight (kg), body temperature (°C), heart 
rate (beats per minute), systolic and diastolic blood pressure (mmHg).  
Data handling 
Vital signs collected on treatment will be summarized. Values measured outside of on treatment 
period will be flagged in the listings. 
Data analysis 
For analysis of vital signs the clinically notable vital sign criteria are provided in Table 2-7 
below. 
Table 2-7 
Clinically notable changes in vital signs 
Vital sign 
(unit) 
Clinically notable criteria 
 
above normal value  
below normal value 
Weight (kg) 
increase > 10% from Baseline 
decrease  > 10% from Baseline 
Systolic blood 
pressure 
(mmHg) 
>=180 with increase from baseline 
of >=20 
<=90 with decrease from baseline 
of >=20 
 
Diastolic blood 
pressure 
(mmHg) 
>=105 with increase from baseline 
of >=15 
<=50 with decrease from baseline 
of >=15 
 
Pulse rate 
(bpm) 
>=100 with increase from baseline 
of >25% 
<=50 with decrease from baseline of  
> 25% 
 
Body 
temperature 
>= 39.1  
- 
 
The number and percentage of subjects with notable vital sign values (high/low) will be 
presented.          


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A listing of notable vital values will be produced. In the listing, the assessments collected 
outside of on-treatment period will be flagged.  


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2.11 
Interim analysis 
Not applicable. 
3 
Sample size calculation 
The operating characteristics of the design have been assessed via simulations (see Table 3-
1below). For each scenario, 1000 trials were simulated. A scenario was defined by assumption 
regarding the true PFS6 rate, an accrual rate of one patient per month with the final analysis 
taking place after the last patient completed 6 cycles of treatment or discontinued. A success 
was defined as follows: 
Prob ( PFS6 > 25% ) > 80% and Prob ( PFS6 > 40%) > 50% at the final analysis. 
Table 3-1 
Operating characteristics of study design 
True PFS6 
  
0.16 
0.25 
0.35 
0.4 
0.45 
0.5 
Prob. of stopping at interim 
0.870 
0.506 
0.165 
0.082 
0.035 
0.014 
Average sample size 
21.589 
27.016 
31.799 
32.922 
33.547 
33.822 
Prob. of success (final) 
0.000 
0.003 
0.227 
0.488 
0.746 
0.917 
Average study duration 
(months) 
20.674 
27.388 
33.650 
35.269 
36.261 
36.807 
Assuming a true PFS6 rate of 50% and a uniform accrual of one patient per month, with 34 
patients in total (~27 PFS events), there is about 92% chance to achieve success at the end of 
the study.  
 
4 
Change to protocol specified analyses 
Interim analysis is planned in the CSP: an interim analysis for futility was planned to be 
carried out once 10 patients in the PPS have completed 6 cycles of treatment or discontinued 
earlier. No actual interim analysis was performed. 
5 
Appendix 
5.1 
Imputation rules 
5.1.1 
Study drug 
The following rule should be used for the imputation of the dose end date for a given study 
treatment component: 


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Scenario 1: If the dose end date is completely missing and there is no EOT page and no death 
date, the patient is considered as on-going:  
The patient should be treated as on-going and the cut-off date should be used as the dose end 
date.  
Scenario 1 should not applicable for final CSR. All patients should have EOT page complete 
before the Database lock for Final CSR  
Scenario 2: If the dose end date is completely or partially missing and the EOT page is 
available:  
Please note that date of assessment on EOT CRT might be very different from last date of 
dose.  
Case 1: The dose end date is completely missing, and the EOT completion date is complete, 
then this latter date should be used.   
Case 2: Only Year(yyyy) of the dose end date is available and yyyy < the year of EOT date:   
            Use Dec31yyyy 
Case 3: Only Year(yyyy) of the dose end date is available and yyyy  = the year of EOT date:  
            Use EOT date 
Case 4: Both Year(yyyy) and Month (mm) are available for dose end date, and yyyy  = the 
year of EOT date and mm < the month of  EOT date:  
            Use last day of the Month (mm) 
After imputation, compare the imputed date with start date of treatment, if the imputed date is 
< start date of treatment:  
Use the treatment start date 
Patients with missing start dates are to be considered missing for all study treatment component 
related calculations and no imputation will be made. If start date is missing then end-date should 
not be imputed. 
5.1.2 
AE, ConMeds and safety assessment date imputation 
Table 5-1 
Imputation of start dates (AE, CM) and assessments (LB, EG, VS) 
Missing 
Element 
Rule 
day, month, 
and year 
• No imputation will be done for completely missing dates 
day, month 
• If available year = year of study treatment start date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date = 01JanYYYY  
o Else set start date = study treatment start date.  
• If available year > year of study treatment start date then 01JanYYYY 
• If available year < year of study treatment start date then 01JulYYYY 


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Missing 
Element 
Rule 
day 
• If available month and year = month and year of study treatment start 
date then  
o If stop date contains a full date and stop date is earlier than 
study treatment start date then set start date= 01MONYYYY.  
o Else set start date = study treatment start date. 
• If available month and year > month and year of study treatment start 
date then 01MONYYYY   
• If available month and year < month year of study treatment start date 
then 15MONYYYY   


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Table 5-2 
Imputation of end dates (AE, CM)  
Missing 
Element 
Rule  
(*=last treatment date plus 30 days not > (death date, cut-off date, 
withdrawal of consent date)) 
day, month, 
and year 
• 
Completely missing end dates (incl. ongoing events) will be imputed 
by the end date of the on-treatment period*  
day, month 
• 
If partial end date contains year only, set end date = earliest of 
31DecYYYY or end date of the on-treatment period *  
day 
• 
If partial end date contains month and year, set end date = earliest of 
last day of the month or end date of the on-treatment period* 
Any AEs and ConMeds with partial/missing dates will be displayed as such in the data listings. 
Any AEs and ConMeds which are continuing as per data cut-off will be shown as ‘ongoing’ 
rather than the end date provided.  
The above imputations are only used for analyses of time to and duration of AEs and 
concomitant medications.  
5.1.2.1 
Other imputations 
Incomplete date of initial diagnosis of cancer and date of most recent 
recurrence  
Missing day is defaulted to the 15th of the month and missing month and day is defaulted to 01-
Jan.  
Incomplete assessment dates for tumor assessment 
All investigation dates (e.g. MRI scan, CT scan) must be completed with day, month and year. 
If one or more assessment dates are incomplete but other investigation dates are available, 
this/these incomplete date(s) are not considered for calculation of the assessment date and 
assessment date is calculated as the latest of all investigation dates (e.g. MRI scan, CT scan) if 
the overall response at that assessment is CR/PR/SD/UNK. Otherwise – if overall response is 
progression – the assessment date is calculated as the earliest date of all investigation dates at 
that evaluation number.  If all measurement dates have no day recorded, the 1st of the month is 
used. If the month is not completed, for any of the investigations, the respective assessment will 
be considered to be at the date which is exactly between previous and following assessment. If 
a previous and following assessment is not available, this assessment will not be used for any 
calculation. 
Applying the cut-off to tumor assessment 
For tumor related assessments, if an evaluation has some assessments done prior to  cut-off date 
and  others after the cut-off date, then the evaluation is considered post-cut-off date and will be 
excluded from analysis. 


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Prior anti-neoplastic therapy 
No imputation of therapy start or end date will be done. 
5.2 
AEs coding/grading 
Adverse events are coded using the Medical dictionary for regulatory activities (MedDRA) 
terminology. 
AEs will be assessed according to the Common Terminology Criteria for Adverse Events 
(CTCAE) version 4.03. 
The CTCAE represents a comprehensive grading system for reporting the acute and late effects 
of cancer treatments. CTCAE grading is by definition a 5-point scale generally corresponding 
to mild, moderate, severe, life threatening, and death. This grading system inherently places a 
value on the importance of an event, although there is not necessarily proportionality among 
grades (a grade 2 is not necessarily twice as bad as a grade 1).  
 
5.3 
Laboratory parameters derivations 
Grade categorization of lab values will be assigned programmatically as per NCI Common 
Terminology Criteria for Adverse Events (CTCAE) version 4.03. The calculation of CTCAE 
grades will be based on the observed laboratory values only, clinical assessments will not be 
taken into account. The criteria to assign CTCAE grades are given in Novartis internal criteria 
for CTCAE grading of laboratory parameters. The latest available version of the document 
based on the underlying CTCAE version 4.03 at the time of analysis will be used. For laboratory 
tests where grades are not defined by CTCAE v4.03, results will be graded by the 
low/normal/high (or other project-specific ranges, if more suitable) classifications based on 
laboratory normal ranges. 
A severity grade of 0 will be assigned for all non-missing lab values not graded as 1 or higher. 
Grade 5 will not be used. For laboratory tests that are graded for both low and high values, 
summaries will be done separately and labelled by direction, e.g., sodium will be summarized 
as hyponatremia and hypernatremia. 
 
Imputation Rules   
CTC grading for blood differentials is based on absolute values. However, this data may not be 
reported as absolute counts but rather as percentage of WBC.  
If laboratory values are provided as ‘<X’ (i.e. below limit of detection) or ‘>X’, prior to 
conversion of laboratory values to SI unit, these numeric values are set to X.   
The following rules will be applied to derive the WBC differential counts when only 
percentages are available for a xxx differential 
xxx count = (WBC count) * (xxx %value / 100) 


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Further derivation of laboratory parameters might be required for CTCAE grading. For 
instance, corrected calcium can be derived using the reported total calcium value and albumin 
at the same assessment using the following formula: 
Corrected Calcium (mg/dL) = Calcium (mg/dL) – 0.8 [Albumin (g/dL)-4] 
In order to apply the above formula, albumin values in g/L will be converted to g/dL by  
multiplying by 0.1), calcium values in mmol/L will be converted to mg/dL by dividing by 
0.2495. For calculation of laboratory CTC grades 0 and 1, the normal range for derived 
corrected calcium is set to the same limits (in mg/dL) as for calcium. 
CTC grades for the derived absolute WBC differential counts (neutrophils, lymphocytes) and 
corrected calcium will be assigned as described above for grading 
6 
Reference 
Clinical trial Protocol CBGJ398X2201 
 Developing and Completing the Clinical Study Report