Conditions: Solid Tumor Hematologic Malignancies
Keywords: Solid tumor malignancy hematologic malignancy mutation translocations amplifications, fusions signature FGFR ligand BGJ398
Allocation: NA | Intervention model: SINGLE_GROUP
Enrollment: 84
Healthy volunteers: no

Brief summary:
The purpose of this signal seeking study was to determine whether treatment with BGJ398 demonstrates sufficient efficacy in select FGFR pathway-regulated solid tumors and/or hematologic malignancies to warrant further study.

Detailed description:

Arms:
arm 1: BGJ398 was dosed on a flat scale of 125 mg (e.g., 1 x 100 mg and 1 x 25 mg capsules) once daily for the first 21 days of the 28-day cycle (3 weeks on, 1 week off in a cycle). A complete treatment cycle is defined as 28 days.

Interventions: intervention 1: BGJ398
Intervention descriptions: intervention 1: BGJ398 was dosed on a flat scale of 125 mg (e.g., 1 x 100 mg and 1 x 25 mg capsules) once daily for the first 21 days of the 28-day cycle (3 weeks on, 1 week off in a cycle). A complete treatment cycle is defined as 28 days.

Protocol document:
Prot_000.pdf: 
Clinical Development 
BGJ398 
Protocol CBGJ398XUS04 / NCT02160041
Modular phase II study to link targeted therapy to patients 
with pathway activated tumors: 
Module 6 – BGJ398 for patients with tumors with FGFR 
genetic alterations 
Author(s): 
 
Document type: 
Amended Protocol Version 
EUDRACT number 
Not applicable 
Version number 
03 (Clean) 
Development phase 
II 
Document status: 
Final 
Release date: 
30-Jan-2017
Property of Novartis 
Confidential 
May not be used, divulged, published or otherwise disclosed 
without the consent of Novartis 


 
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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 ............................................................................................................... 12 
Protocol summary .............................................................................................................. 13 
Amendment 3 (30-Jan-2017) ............................................................................................. 18 
Amendment 2 .................................................................................................................... 20 
Amendment 1 .................................................................................................................... 25 
1 
Background ........................................................................................................................ 28 
1.1 
Overview of disease pathogenesis, epidemiology and current treatment .............. 28 
1.1.1 
BGJ398 target pathway ......................................................................... 29 
1.2 
Introduction to investigational treatment(s) and other study treatment(s) ............. 29 
1.2.1 
Overview of BGJ398 ............................................................................. 29 
2 
Rationale ............................................................................................................................ 34 
2.1 
Study rationale and purpose ................................................................................... 34 
2.2 
Rationale for the study design ............................................................................... 35 
2.3 
Rationale for dose and regimen selection .............................................................. 35 
3 
Objectives and endpoints ................................................................................................... 36 
4 
Study design....................................................................................................................... 39 
4.1 
Description of study design ................................................................................... 39 
4.1.1 
Treatment phase .................................................................................... 40 
4.1.2 
Follow-up phase .................................................................................... 40 
4.2 
Definition of end of the study ................................................................................ 40 
4.3 
Early study termination .......................................................................................... 41 
5 
Population .......................................................................................................................... 41 
5.1 
Patient population .................................................................................................. 41 
5.2 
Inclusion criteria .................................................................................................... 42 
5.3 
Exclusion criteria ................................................................................................... 44 
6 
Treatment ........................................................................................................................... 48 
6.1 
Study treatment ...................................................................................................... 48 
6.1.1 
Dosing regimen ..................................................................................... 48 
6.1.2 
Guidelines for continuation of treatment .............................................. 49 
6.1.3 
Treatment duration ................................................................................ 50 
6.2 
Dose escalation guidelines ..................................................................................... 50 


 
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6.3 
Dose modifications ................................................................................................ 50 
6.3.1 
Dose modification and dose delay ........................................................ 50 
6.3.2 
Permitted study treatment adjustments for BGJ398 .............................. 50 
6.3.3 
Criteria for interruption and re-initiation of BGJ398 treatment ............ 51 
6.3.4 
Follow-up for toxicities ......................................................................... 60 
6.3.5 
Anticipated risks and safety concerns of the study drug ....................... 60 
6.4 
Concomitant medications ...................................................................................... 60 
6.4.1 
Permitted concomitant therapy .............................................................. 60 
6.4.2 
Permitted concomitant therapy requiring caution and/or action ........... 61 
6.4.3 
Prohibited concomitant therapy............................................................. 62 
6.5 
Patient numbering, treatment assignment and enrollment ..................................... 63 
6.5.1 
Patient numbering ................................................................................. 63 
6.5.2 
Treatment assignment and randomization ............................................. 63 
6.5.3 
Treatment blinding ................................................................................ 63 
6.6 
Study drug preparation and dispensation ............................................................... 63 
6.6.1 
Study drug packaging and labeling ....................................................... 63 
6.6.2 
Drug supply and storage ........................................................................ 64 
6.6.3 
Study drug compliance and accountability ........................................... 64 
6.6.4 
Disposal and destruction ....................................................................... 64 
7 
Visit schedule and assessments ......................................................................................... 65 
7.1 
Study flow and visit schedule ................................................................................ 65 
7.1.1 
Screening ............................................................................................... 74 
7.1.2 
Treatment period ................................................................................... 76 
7.1.3 
End of treatment visit, including premature withdrawal and study 
discontinuation visit .............................................................................. 76 
7.1.4 
Follow up period ................................................................................... 78 
7.1.5 
End of post-treatment follow-up (Study phase completion) ................. 78 
7.2 
Assessment types ................................................................................................... 79 
7.2.1 
Efficacy assessments ............................................................................. 79 
7.2.2 
Safety and tolerability assessments ....................................................... 86 
7.2.3 
Pharmacokinetics .................................................................................. 90 
 
 91 
7.2.5 
Other assessments ................................................................................. 93 
8 
Safety monitoring and reporting ........................................................................................ 93 
8.1 
Adverse events ....................................................................................................... 93 
8.1.1 
Definitions and reporting ...................................................................... 93 
8.1.2 
Laboratory test abnormalities ................................................................ 95 


 
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8.2 
Serious adverse events ........................................................................................... 95 
8.2.1 
Definitions ............................................................................................. 95 
8.2.2 
Reporting ............................................................................................... 96 
8.3 
Emergency unblinding of treatment assignment ................................................... 96 
8.4 
Pregnancies ............................................................................................................ 96 
8.5 
Warnings and precautions ...................................................................................... 97 
8.6 
Data Monitoring Committee .................................................................................. 97 
8.7 
Steering Committee ............................................................................................... 97 
9 
Data collection and management ....................................................................................... 97 
9.1 
Data confidentiality ............................................................................................... 97 
9.2 
Site monitoring ...................................................................................................... 98 
9.3 
Data collection ....................................................................................................... 98 
9.4 
Database management and quality control ............................................................ 99 
10 Statistical methods and data analysis ................................................................................. 99 
10.1 
Analysis sets ........................................................................................................ 100 
10.1.1 
Full Analysis Set ................................................................................. 100 
10.1.2 
Safety Set ................................................................................................ 100 
10.2 
Patient demographics/other baseline characteristics............................................ 100 
10.3 
Treatments (study treatment, concomitant therapies, compliance) ..................... 100 
10.3.1 
Study medication ................................................................................. 100 
10.3.2 
Concomitant therapies ......................................................................... 100 
10.4 
Primary objective ................................................................................................. 101 
10.4.1 
Variable ............................................................................................... 101 
10.4.2 
Statistical hypothesis, model, and method of analysis ........................ 101 
10.4.3 
Evaluation of trial success and futility ................................................ 102 
10.4.4 
Handling of missing values/censoring/discontinuations ..................... 103 
10.4.5 
Supportive analyses ............................................................................. 103 
10.5 
Secondary objectives ........................................................................................... 103 
10.5.1 
Key secondary objective(s) ................................................................. 103 
10.5.2 
Other secondary efficacy objectives ................................................... 103 
10.5.3 
Safety objectives ................................................................................. 104 
 
 106 
10.7 
Interim analysis .................................................................................................... 106 
10.8 
Sample size calculation ........................................................................................ 106 
11 Ethical considerations and administrative procedures ..................................................... 107 
11.1 
Regulatory and ethical compliance ...................................................................... 107 


 
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11.2 
Responsibilities of the investigator and IRB/IEC/REB ....................................... 107 
11.3 
Informed consent procedures ............................................................................... 107 
11.4 
Discontinuation of the study ................................................................................ 108 
11.5 
Publication of study protocol and results ............................................................. 108 
11.6 
Study documentation, record keeping and retention of documents ..................... 108 
11.7 
Confidentiality of study documents and patient records...................................... 109 
11.8 
Audits and inspections ......................................................................................... 109 
11.9 
Financial disclosures ............................................................................................ 109 
12 Protocol adherence .......................................................................................................... 109 
12.1 
Amendments to the protocol ................................................................................ 109 
13 References (available upon request) ................................................................................ 110 
14 Appendices ...................................................................................................................... 114 
14.1 
Appendix A: Criteria for therapeutic response/outcome assessment of solid 
tumors and/or lymph nodes (based on RECIST 1.1) ........................................... 114 
14.2 
Appendix B: Criteria for therapeutic response/outcome assessment in 
lymphoma studies (based on Cheson response criteria) ...................................... 120 
14.3 
Appendix C: Ann Arbor staging classification .................................................... 130 
14.4 
Appendix D: Rai Staging System a ....................................................................................................... 131 
14.5 
Appendix E: Criteria for Response assessment in Acute Myeloid Leukemia 
(based on IWG and Cheson) ................................................................................ 132 
14.5.1 
Exploratory AML response categories according to IWG .................. 133 
14.6 
Appendix F: Criteria for Response assessment in Acute Lymphoblastic 
Leukemia (based on NCCN Guidelines Version 1.2013) .................................... 134 
14.7 
Appendix G: Criteria for Response assessment in Chronic Myelogenous 
Leukemia (based on NCCN Guidelines Version 4. 2013) ................................... 135 
14.8 
Appendix H: Criteria for Response assessment in Chronic Lymphocytic 
Leukemia (based on modified IWG guidelines) .................................................. 136 
14.9 
Appendix I: Criteria for Response assessment in Myelofibrosis (based on 
modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ............................................................................................................................................. 137 
14.10 Appendix J: Criteria for Response assessment in polycythemia vera (based on 
modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ............................................................................................................................................. 140 
14.11 Appendix K: Criteria for Response assessment in Essential thrombocythemia 
(based on modified IWG-MRT guidelines and European LeukemiaNet (ELN) 
consensus report)1 ............................................................................................................................................. 141 
14.12 Appendix L: Criteria for Response assessment in Myelodysplasia (based on 
modified IWG guidelines)1 ........................................................................................................................ 142 
14.13 Appendix M: Myeloproliferative Neoplasm (MPN) Symptom Assessment 


 
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Form Total Symptom Score (MPN-SAF-TSS) ................................................... 143 
14.14 Appendix N: Eastern Cooperative Oncology Group (ECOG) 
performance status ............................................................................................... 145 
14.15 Appendix O: International Myeloma Working Group (IMWG) uniform 
response criteria for multiple myeloma ............................................................... 146 
14.16 Appendix P: List of concomitant medications ..................................................... 148 
14.16.1 
Drugs to be used with caution while on study .................................... 148 
14.17 Appendix Q: List of prohibited medication ......................................................... 150 
14.17.1 
List of prohibited medication while on study ..................................... 150 
14.18 Appendix R: Bayesian Adaptive Design Framework for the Modular phase II 
study to link targeted therapy to patients with pathway activated tumors ........... 151 
 
 
List of figures 
Figure 4-1 
Study start-up design ............................................................................. 39 
 
 
List of tables 
Table 3-1 
Objectives and related endpoints ........................................................... 37 
Table 6-1 
Dose and treatment schedule ................................................................. 48 
Table 6-2 
BGJ398 dose modifications .................................................................. 51 
Table 6-3 
BGJ398 related toxicity management guidelines .................................. 52 
Table 6-4 
Packaging and labeling .......................................................................... 64 
Table 7-1 
Visit evaluation schedule ...................................................................... 66 
 
 92 
 
 93 
Table 14-1 
Assumed control CBR values used in the simulations ........................ 155 
Table 14-2 
Probability of group success for each cohort ...................................... 156 


 
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List of abbreviations 
ADME 
Absorption Distribution Metabolism and Excretion 
AE 
Adverse Event 
AKT 
Protein Kinase B 
ALL 
Acute lymphoblastic leukemia 
ALT 
Alanine aminotransferase/glutamic pyruvic transaminase/GPT 
AML 
Acute myelogenous leukemia 
ANC 
Absolute Neutrophil Count 
AP 
Alkaline Phosphatase 
APL 
Acute promyelcytic leukemia 
aPTT 
Activated partial thromboplastin time 
ASCO 
American Society of Clinical Oncology 
AST 
Aspartate aminotransferase/glutamic oxaloacetic transaminase/GOT 
ATC 
Anatomical Therapeutic Chemical Classification System 
AUC0-24h 
Area Under the Curve 0-24 h 
BID 
bis in diem/twice a day 
BLRM 
Bayesian Logistic Regression Model 
BP 
Blood pressure 
BSC 
Best supportive care 
BUN 
Blood Urea Nitrogen 
Ca 
Calcium 
CA-125 
Cancer Antigen-125 
CABG 
Coronary artery bypass graft 
CBC 
Complete blood count 
CBR 
Clinical Benefit Rate 
cDNA 
Circulating DNA 
CFR 
Code of Federal Regulations 
CHF 
Congestive heart failure 
CI 
Confidence Interval 
CL 
Clearance 
CLIA 
Clinical Laboratory Improvement Amendments 
CLL 
Chronic lymphocytic leukemia 
Cmax 
Maximum Concentration 
CML 
Chronic Myeloid Leukemia 
CMO&PS 
Chief Medical Office and patient Safety 
CNS 
Central Nervous System 
CR 
Complete Response 
CRC 
Colorectal Cancer 
CrCl 
Creatinine clearance 
CRO 
Contract Research Organization 
CSF 
Clinical service form 
CSR 
Clinical study report 


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CT 
Computed Tomography 
CTCAE 
Common Terminology Criteria for Adverse Events 
CVA 
Cerebrovascular accident 
CYP 
Cytochrome P 
DLs 
dose levels 
DLT 
Dose Limiting Toxicity 
DNA 
Deoxyribonucleic Acid 
DOR 
Duration of Response 
DVT 
Deep vein thrombosis 
e.g. 
for example 
ECG 
Electrocardiogram 
ECHO 
Echocardiogram 
ECOG 
Eastern Cooperative Oncology Group 
eCRF 
Electronic Case Report/Record Form 
EDC 
Electronic Data Capture 
EGF 
Epidermal growth factor 
EGFR 
Epidermal growth factor receptor 
EOT 
End of Treatment 
ERK/MAPK 
Extracellular signal-regulated kinase/Mitogen-Activated Protein Kinase 
ET 
Essential thrombocythemia 
FAS 
Full Analysis Set 
FDA 
Food and Drug Administration 
FDG-PET 
Fluorodeoxyglucose-Positron Emission Tomography 
FFPE 
Formalin fixed paraffin embedded 
FGFR 
Fibroblast growth factor receptor 
FSH 
Follicle-stimulating hormone 
GCP 
Good Clinical Practice 
G-CSF 
granulocyte colony stimulating factor 
GGT 
Gamma-glutamyltranspeptidase 
GI 
Gastrointestinal 
GLP 
Good laboratory practice 
GM-CSF 
Granulocyte macrophage colony-stimulating factor 
GVHD 
Graft-versus-host disease 
HBV 
Hepatitis B Virus 
hCG 
human chorionic gonadotropin 
HCV 
Hepatitis C Virus 
HDL 
High density lipoprotein 
hERG 
human Ether-à-go-go Related Gene 
HFSR 
Hand and Foot Skin Reaction 
Hgb 
Hemoglobin 
HIV 
Human immunodeficiency virus 
hr 
hour 
IB 
Investigators Brochure 


 
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IC50 
Half maximal Inhibitory Concentration 
ICF 
Informed Consent Form 
ICH 
International Conference on Harmonization 
IEC 
Independent Ethics Committee 
IMWG 
International Myeloma Working Group 
IN 
Investigator notification 
INR 
International Normalized Ratio 
IRB 
Institutional Review Board 
IUD 
intrauterine device 
IUS 
intrauterine system 
IWG 
International working group 
KA 
Keratoacanthoma 
KRAS 
V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog 
LDH 
Lactate dehydrogenase 
LDL 
Low density lipoprotein 
LVEF 
Left Ventricular Ejection Fraction 
mCRC 
Metastatic Colorectal Cancer 
MDS 
Myelodysplasia 
MedDRA 
Medical Dictionary for Regulatory Activities 
MEK 
Mitogen-activated ERK Kinase 
MF 
Myelofribrosis 
mg 
milligram 
MI 
Myocardial infarction 
MM 
Multiple Myeloma 
MRI 
Magnetic Resonance Imaging 
MTD 
Maximum Tolerated Dose 
mTOR 
Mammalian target of rapamycin 
MUGA 
Multiple Gated acquisition scan 
N 
Sample size 
NA 
Not applicable 
Na 
Sodium 
NCCN 
National Comprehensive Cancer Network 
NCI CTC 
National Cancer Institute Common Terminology Criteria 
nM 
Nano molar 
NSCLC 
Non-small cell lung carcinoma 
OC 
Oral contraception 
OR 
Overall response 
ORR 
Overall Response Rate 
OS 
Overall survival 
PD 
Progressive disease 
PD 
Pharmacodynamics 
PE 
Pulmonary embolism 
PET 
Positron emission tomography 


 
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PFS 
Progression-free survival 
Ph 
Philadelphia chromosome 
PHI 
Protected health information 
Pi 
Inorganic Phosphorus 
PK 
Pharmacokinetics 
PLT 
Platelets 
PMT 
Phosphaturic Mesenchymal Tumour 
PR 
Partial Response 
PRBC 
Packed Red Blood Cells 
PSA 
Prostate-specific antigen 
PT 
Prothrombin time 
PTEN 
Phosphatase and tensin homolog 
PV 
Polycythemia vera 
QD 
quaque die/once a day 
QTc 
QT corrected 
QTcF 
Q-T interval in the ECG (corrected according to the formula of Fridericia) 
RAF 
v-raf murine sarcoma viral oncogene 
RAP 
Report Analysis Plan 
RAS 
RAS oncogene (rat sarcoma viral oncogene homologue) 
RBC 
Red Blood Cells 
REB 
Research Ethics Board 
RECIST 
Response Evaluation Criteria In Solid Tumors 
RP2D 
Recommended phase two dose 
RTK 
Receptor tyrosine kinase 
RU 
Resource utilization 
SAE 
Serious Adverse Event 
SBP 
Systolic blood pressure 
SC 
Steering Committee 
SCC 
Squamous cell carcinoma 
SD 
Stable disease 
SGOT 
Serum glutamic oxaloacetic transaminase/AST 
SGPT 
Serum glutamic pyruvic transaminase/ALT 
SPEP 
Serum protein electrophoresis 
SUSAR 
Suspected unexpected serious adverse reaction 
TdP 
Torsade de Pointes 
TIA 
Transient ischemic attack 
TIO 
Tumor-induced osteomalacia 
Tmax 
The time at which the maximum observed concentration (Cmax) occurs 
TSH 
Thyroid stimulating hormone 
ULN 
Upper Limit of Normal 
UPEP 
Urine protein electrophoresis 
WBC 
White Blood Cell 


 
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WHO 
World Health Organization 
WNL 
Within normal limits 


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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. For this protocol, a complete treatment cycle 
is defined as 28 days of once daily [3 weeks on 1 week off] treatment with 
BGJ398. The first dose of BGJ398 defines Day 1 of the treatment cycle and 
the last day of a complete treatment cycle is Day 28, unless extended due to 
adverse events. 
Baseline 
Pre-dose Cycle 1 day 1 
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.BGJ398 is the investigational drug in this 
study. 
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. BGJ398 is the investigational 
treatment. 
Patient Number 
(Patient No.) 
A unique identifying number assigned to each patient who enrolls in the study 
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 
Screening 
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) 
Stage related to study 
timeline 
A major subdivision of the study timeline; begins and ends with major study 
milestones such as enrollment, completion of treatment, etc. 
Stage in cancer 
The extent of 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 
BGJ398 
Study treatment 
discontinuation 
Point/time when patient permanently stops taking BGJ398, for any reason. 
Variable 
Identifier used in the data analysis; derived directly or indirectly from data 
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Protocol summary 
Protocol number 
CBGJ398XUS04 
Title 
Modular phase II study to link targeted therapy to patients with pathway 
activated tumors: 
Module - 6 BGJ398 for patients FGFR altered tumors 
Brief title 
BGJ398 for patients with FGFR altered tumors 
Sponsor and Clinical 
Phase 
Novartis 
Phase II 
Investigation type 
Drug 
Study type 
Interventional 
Purpose and rationale 
The purpose of this signal seeking study is to determine whether treatment 
with BGJ398 demonstrates sufficient efficacy in FGFR pathway-regulated 
solid tumors and/or hematologic malignancies to warrant further study. 
Primary Objective(s) 
and Key Secondary 
Objective 
Primary objectives: 
To assess clinical benefit associated with BGJ398 treatment based on 
local investigator assessment. 
For patients with solid tumors the assessment criteria will be RECIST 1.1 
and will include responses of CR or PR or SD ≥ 16 weeks. For 
hematologic tumors, other appropriate hematological response criteria will 
apply and are included in the appendices. 
For patients with TIO diagnosis without measureable/evaluable disease, 
the following criteria will be the assessment at 16 weeks: 
• 
the tumor associated changes of metabolic parameters: plasma level 
of FGF23 < or =180 RU/mL; and inorganic phosphorous, calcium, and 
1-25-dihydroxy vitamin D greater than the LLN (- 20%); and 
• 
without requirement of supplementation therapy for at least the 
preceding cycle of the 16 week assessment. 
Key Secondary objective: 
To assess Overall Response (OR) of Partial Response (PR) or greater 
based on local investigator assessment. 
For patients with solid tumors, the assessment criteria will be RECIST 1.1 
and will include responses of CR and/or PR. For hematologic tumors, 
other appropriate hematological response criteria will apply and are 
included in the appendices. 
Secondary Objectives 
To assess: 
Progression-Free Survival (PFS) based on local investigator assessment 
per RECIST 1.1 or other appropriate hematological response criteria 
Overall Survival (OS) 
Duration of Response (DOR) based on local investigator assessment per 
RECIST 1.1 or other appropriate hematological response criteria 
Safety and tolerability 
 


 
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Study design 
This is a phase II, open label study to determine the efficacy and safety of 
treatment with BGJ398 in patients with a diagnosis of solid tumors or 
hematological malignancies that have been pre-identified (prior to study 
consent) to have any FGFR genetic alterations [such as mutation, 
amplification, fusion, translocation of FGF receptors 1 – 4] and whose 
disease has progressed on or after standard treatment. 
Genomic profiling is becoming more accessible to patients and their 
physicians. As such, more patients have been identified with potentially- 
actionable mutations or pathway-activations but do not have access to 
targeted drug treatment. This is a signal-seeking study to match patients 
with tumors containing FGFR genetic alterations to treatment with the 
FGFR inhibitor BGJ398. Pre-identification of FGFR genetic alteration 
status will be performed locally at a CLIA certified laboratory prior to 
participation on the trial. Laboratory results must be ‘unambiguous’ or 
‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply low 
probability that genetic deregulation is truly present and an important driver 
of patient’s tumor. 
Once the patient has been identified, treating physicians who are qualified 
investigators may contact Novartis to consider enrollment in this study. For 
the purpose of this study, genomic profiling is not considered part of 
screening. Informed consent must be signed before any screening 
activities take place. Once eligibility (screening criteria met) has been 
confirmed by Novartis, the patient will initiate therapy with BGJ398 single- 
agent. The patient may not receive any additional anti-cancer therapy 
during treatment with BGJ398. 
Patients will continue to receive study treatment until disease progression 
(assessed by investigator per RECIST 1.1 or appropriate hematologic 
response criteria or for patients with TIO diagnosis the recurrence or 
progression of disease or recurrence of abnormal metabolic parameters), 
unacceptable toxicity, death or discontinuation from study treatment for 
any other reason (e.g., withdrawal of consent, start of a new anti- 
neoplastic therapy or at the discretion of the investigator), otherwise known 
as End of Treatment. Patients with TIO diagnosis that progress per 
RECIST but per investigator’s assessment are receiving clinical benefit 
from treatment may remain on study upon approval from Novartis. All 
patients who discontinue from study treatment due to disease progression 
must have their progression clearly documented. 
Disease assessment (per RECIST 1.1 or appropriate hematological 
response criteria) will be performed every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle), until disease progression or 
end of treatment, whichever occurs first. Upon implementation of 
amendment 2, the frequency of disease assessment will be reduced and 
evaluations should be every 16 weeks after the first 16 weeks on 
treatment. Scans will be assessed locally by the investigator. 
After discontinuation of treatment, patients, regardless of reason for 
treatment discontinuation, will be followed for safety for 30 days after the 
last dose. 
Survival information will be collected every 3 months until 2 years after the 
last patient has enrolled in the study regardless of treatment 
discontinuation reason (except if consent is withdrawn). If the study 
primary efficacy endpoint is not met, Novartis may decide not to conduct 
survival follow up for the study. 


 
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Population 
The study population consists of approximately 70-120 adult patients with 
a diagnosis of a solid tumor or hematological malignancy that have been 
pre-identified as having FGFR genetic alteration. Patients must have 
received at least one prior treatment for their recurrent, metastatic and/or 
locally advanced disease and have no remaining standard therapy options 
anticipated to result in a durable response. Patients must have progressive 
and measurable disease (per RECIST 1.1 or appropriate hematological 
response criteria) and be in need of treatment. 
This is a signal seeking study, attempting to identify additional patient 
populations who may benefit from treatment with single agent BGJ398. 
Patients must not have central nervous system (CNS) metastasis, 
leptomeningeal carcinomatosis, symptomatic cardiac disease, or 
impairment of GI function. 
Patients must have archival tissue available for submission to allow for 
molecular testing related to genetic alterations. If tissue is not available or 
not of sufficient quantity the patient must be willing to undergo a fresh 
tumor biopsy to allow for these analyses. 
Enrollment is meant to encompass solid tumors and hematologic 
malignancies as having FGFR genetic alterations that may be inhibited by 
BGJ398 who otherwise meet all the inclusion and none of the exclusion 
criteria. Though common for phase I studies, tissue-agnostic enrollment is 
unusual for phase II studies, which typically limit enrollment to one or a few 
well-defined tumor types. We expect that the study will enroll patients 
whose tumors have already been pre-identified to harbor FGFR genetic 
alterations The total number of patients to be enrolled per tumor type will 
be based on an adaptive design. The adaptive design will be patient- 
sparing and allow the early closure of non-responding arms or arms where 
early success can be declared. 
Inclusion criteria 
Patient has a confirmed diagnosis of a solid tumor (Urothelial cell 
carcinoma, Cholangiocarcinoma, and Glioblastoma multiforme with FGFR 
1-4 genetic alterations are included,) 
Patient has been evaluated and pre-identified as having a tumor with a 
FGFR genetic alteration. The qualifying alteration must be assessed and 
reported by a CLIA-certified laboratory. NOTE: 
Patient must have received at least one prior treatment for recurrent, 
metastatic and /or locally advanced disease and for whom no standard 
therapy options are anticipated to result in a durable remission. 
Patient must have progressive and measurable disease per RECIST 1.1. 
or other appropriate hematological response criteria. 
Patient has an Eastern Cooperative Oncology Group (ECOG) performance 
status ≤ 1 
See Section 5.2 for complete Inclusion criteria 


 
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Exclusion criteria 
Patient has received prior treatment with BGJ398 
Patients with Central Nervous System (CNS) metastasis or leptomeningeal 
carcinomatosis 
Patient has received chemotherapy or other anticancer therapy ≤ 4 weeks 
(6 weeks for nitrosourea, antibodies or mitomycin-C) prior to starting study 
drug. 
Patients with acute or chronic pancreatitis 
Patients with impaired cardiac function or clinically significant cardiac 
diseases 
History and/or current evidence of extensive tissue calcification 
Current evidence of corneal or retinal disorder/keratopathy 
History and/or current evidence of renal or endocrine alterations of 
calcium/phosphate homeostasis. NOTE: Not applicable for TIO diagnosis 
Patients with another primary malignancy within 3 years prior to starting 
study treatment, with the exception of adequately treated basal cell 
carcinoma, squamous cell carcinoma or other non-melanomatous skin 
cancer, or in-situ carcinoma of the uterine cervix 
See Section 5.3 for complete Exclusion criteria 
Investigational and 
reference therapy 
BGJ398 will be dosed at 125 mg once daily, 3 weeks on 1 week off. A 
complete treatment cycle is defined as 28 days. 
Efficacy assessments 
All screening evaluations must be performed as closely as possible to the 
beginning of treatment and never more than 28 days prior to starting study 
drug dose of BGJ398 to confirm patient’s eligibility. 
During treatment phase, disease assessments must be performed every 8 
weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), 
until disease progression or end of treatment, whichever occurs first. Upon 
implementation of amendment 2, the frequency of disease assessment will 
be reduced and evaluations should be every 16 weeks after the first 16 
weeks on treatment. 
Patients will continue to receive study treatment until disease progression 
(assessed by investigator per RECIST 1.1 or appropriate hematologic 
response criteria or for patients with TIO diagnosis the recurrence or 
progression of disease or recurrence of abnormal metabolic parameters, 
unacceptable toxicity, death or discontinuation from study treatment for 
any other reason (e.g., withdrawal of consent, start of a new anti- 
neoplastic therapy or at the discretion of the investigator). Patients with 
TIO diagnosis that progress per RECIST but per investigator’s assessment 
are receiving clinical benefit from treatment may remain on study upon 
approval from Novartis. 
Survival information will be collected every 3 months until 2 years after the 
last patient has enrolled in the study regardless of treatment 
discontinuation reason (except if consent is withdrawn). If the study 
primary efficacy endpoint is not met, Novartis may decide not to conduct 
survival follow up for the study. 


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Safety assessments 
Adverse events. 
Physical examination including vital signs and weight. 
Performance status evaluation 
Cardiac monitoring (cardiac enzymes, ECGs, and assessment of LVEF) 
Laboratory evaluations (hematology, biochemistries, pregnancy tests and 
urinalysis) 
Ophthalmology examinations 
Data analysis 
The Full Analysis Set (FAS) will include all patients who have received at 
least one dose of study drug. FAS will be the primary population for the 
analysis of efficacy endpoints. 
Key words 
Solid tumor malignancy, hematologic malignancy, mutation, translocations, 
amplifications, fusions, signature, FGFR, ligand, BGJ398, breast cancer, 
stomach cancer, endometrial cancer, esophageal cancer, Squamous head 
& neck cancer, tumor induced osteomalacia, TIO 


 
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Amendment 3 (30-Jan-2017) 
Amendment rationale 
The clinical benefit rate set forth in Section 10.4 does not capture Patients who achieve a 
complete response (CR) or partial response (PR) prior to 16 weeks from start of treatment if 
they cannot get a confirmatory response assessment completed by week 16. 
By achieving at least a CR or PR, the patient is receiving a clinical benef it with BGJ398, 
regardless of confirmatory response. In order to address patients who achieved unconfirmed 
CR or PR, further exploration of all responses and analysis of all response versus the clinical 
benefit rate as defined per protocol Section 10.4 is warranted. 
This study observed 6 unconfirmed and 5 confirmed responses among the following tumor 
types: HNSCC, Ovarian, Bladder, NSCLC Squamous, Glioblastoma and Cholangiocarcinoma. 
Among the six unconfirmed responses, three unconfirmed responses would fit the criteria 
mentioned above. Therefore, in conjunction with showing clinical benefit rate, treatment with 
BGJ398 could represent a significant improvement in the medical management for the 
aforementioned six tumor types. 
The main objectives of this amendment are: 
• Re-open the enrollment for patients with six tumor types, HNSCC, Ovarian, Bladder 
(urothelial cell carcinoma), NSCLC Squamous, Glioblastoma multiforme and 
Cholangiocarcinoma 
• To align with the BGJ398 Clinical Development program 
• clarifications, operational aspects, administrative changes and corrections 
The amendment contains changes to: re-open enrollments for patients that have the six tumor 
types which are, HNSCC, Ovarian, Bladder, NSCLC Squamous, Glioblastoma and 
Cholangiocarcinoma. Enrollment of each tumor cohort will remain open until each tumor 
types successfully enrolls 10 patients per cohort evaluable for futility analysis. 
 
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. 
Protocol Summary Section updated to match the body of the protocol. 
The following changes were implemented throughout the protocol: 
Section 1.2.1.2.1 
• Updated with more current information 
Section 2.1 
• Added rationale for reopening the study with 6 tumor types, HNSCC, Ovarian, Bladder, 
NSCLC Squamous, Glioblastoma and Cholangiocarcinoma 
• Removed reference for FGF ligand alteration 


 
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Table 3-1 
• Clarification added for endpoint. 
Section 5.1, Section 5.2 
• Revised the language regarding excluding FGFR alteration patients and inclusion of 6 
tumor types for the reopening of the protocol. Removed corrected for serum albumin. 
Section 7.1.4.3 
• Revised language to allow survival follow up for six tumor types only 
Section 7.2.1.1.3, Section 7.2.1.2, Section 7.2.1.3, Section 7.2.1.4 
• Notify the exclusion of the tumor types from the protocol 
Section 7.2.4.2.1, Section 8.1.1, Section 10.5.1 
• Revised to notify the exclusion of hematologic malignancies references. 
Section 8.2.2, Section 8.4.1, 
• DS&E changed to CMO&PS 
Section 10 
• Updated the tumor types that are allowed in the protocol 
Section 10.4 
• Revised Primary objective to remove hematologic tumors 
Section 10.4.1 
• Added at week 16 
Minor inconsistencies, edits, and typographical errors that were identified after the 
finalization of the protocol have been corrected with this amendment. 
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. In addition, if 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 amended protocol. 


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Amendment 2 
Amendment rationale 
The main objectives of this amendment are: 
• To include patients with a diagnosis of tumor-induced osteomalacia (TIO) 
 
 
• To modify the assessment schedule for those patients that are on treatment longer than 16 
weeks 
• To align with BGJ398 program 
• Other (clarifications, operational aspects, administrative changes and corrections) 
The amendment contains changes to: Include patients with a diagnosis of tumor-induced 
osteomalacia with FGF23-associated hypophosphatemia without good treatment options other 
than phosphate and activated vitamin D (calcitriol) supplementation, which is largely 
unsuccessful in preventing bone loss, fractures and muscle weakness. We propose that 
treatment with BGJ398 could represent a significant improvement in the medical management 
of this disease by directly addressing its molecular mechanism , especially in patients whose 
tumor is found to have an FGFR genetic alteration. 
 
 
 
 
 
 
 
Upon implementation of this amendment, the frequency of disease assessment will be reduced 
and evaluations should be every 16 weeks after the first 16 weeks on treatment. This change 
will bring the disease assessment close to standard of care after the primary endpoint. 
To align with the BGJ398 program, hyperphosphatemia management guidelines were updated 
to provide more detail regarding the prophylaxis of hyperphosphatemia and how to modify 
BGJ398 dose administration in response to elevated serum phosphorous levels. 
Additional changes include the possible discontinuation of survival follow-up if the primary 
endpoint of the study is not met, a revised definition for “End of Study” to clarify when data 
will be reported. 
Appendix R, the Bayesian adaptive design for the Modular phase II studies to link targeted 
therapy to patients with pathway activated tumors has been revised. In a single arm trial 
without a control arm, the quality of the inferences depend strongly on historical data used to 
create a credible estimate of the baseline control rate. This required an estimate of the patient 
population that would be enrolled. A control estimate was initially formed for each group 
based on that population estimate. As enrollment progressed, a different patient population 
was enrolled in terms of previous line of therapy exposure (heavily pretreated). In order to 


 
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produce the best inferences for future development decisions, it is important to change the 
assumed baseline control rates to match the population enrolled in the modular studies, rather 
than relying on the pre-trial assumptions. Previously this section was tailored to each of the 
specific study, The revised appendix will be used for all the Modular studies. The purpose of 
this section is to show how Bayesian adaptive design will be used for the analysis of the 
primary efficacy endpoint. Each study will be analyzed acco rding to the tumor cohorts that 
will be formed during the course of the study. 
 
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. 
Protocol Summary Section updated to match the body of the protocol. 
List of abbreviations updated to add the terms for CBR, cDNA, PMT, and TIO. 
The following changes were implemented throughout the protocol: 
Section 1.2.1.2.1 and Section 1.2.1.2.2 
• Updated with more current information 
Section 2.1 
• Added rationale for including patients with Tumor-induced osteomalacia (TIO) 
Section 2.1, Section 4.1, and Section 7.1.1 
• Added language regarding the need for laboratory results to be ‘unambiguous’ or 
‘unequivocal’. 
Section 2.1, Section 7.1.1, Section 7.1.1.3, Section 7.1.2, Section 7.1.3.1, Section 7.2.4.3, 
Section 10.6, Table 7-1, and Table 7-3 
• 
 
 
Table 3-1 and Section 10.4 
• Updated primary objective and related primary endpoint to capture assessment of patients 
with TIO 
Section 4.1.1, Section 6.1.2, and Section 6.1.3 
• Updated to include disease progression assessment criteria for patients with TIO 
• Updated to clarify that for patients with TIO that progress per RECIST but per 
investigator’s assessment are receiving clinical benefit from treatment may remain on 
study upon approval from Novartis 
Section 4.1.1, Section 7.1.2, Section 7.2.1.1.4, Section 7.2.1.2.3, and Table 7-1 
• Modified the frequency of efficacy assessments after the scheduled tumor assessment for 
primary endpoint, in order to align with the standard of care. The frequency of the efficacy 
assessments will be reduced allowing changes in the interval from every 8 weeks to every 
16 weeks after 16 weeks of treatment. 


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Section 4.1.2, Section 7.1.4.3, and Section 10.5.2 
• Updated to clarify that survival follow up may be discontinued if the primary endpoint of 
the study is not met. 
Section 4.2 
• Revised to include updated end of study definition and information regarding the analysis 
of study data and the CSR. 
Section 5.1 
• Updated to include TIO patient population 
Section 5.2 
• Added inclusion for patients with tumor-induced osteomalacia 
• Clarified which inclusion criteria are not applicable for patient with tumor-induced 
osteomalacia 
• Added, Leukemia patients must have peripheral blast counts < 50,000 blasts/mm 
• Added inclusion “Proteinuria ≤Grade 2 (dipstick or 24hrs urine analysis) (Not applicable 
for Urothelial cell carcinoma patients) 
Section 5.3 
• Added exclusion of drugs known to be strong inhibitors or inducers of isoenzyme CYP3A, 
or substrates of CYP3A4 whose treatment cannot be discontinued or switched to a 
different medication prior to starting study drug 
• Clarified that patients with neuropathy ≥ CTCAE grade 2 unrelated to prior cancer therapy, 
or > grade 2 neuropathy for any other reason will be excluded 
• Added timeframe on history of cardiac events 
• Updated screening to QTcF >470 msec for both male and female 
• Added that in case of use of oral contraception women should have been stable on the 
same oral contraception for a minimum of 3 months before taking study treatment 
• Clarified which exclusion criteria are not applicable for patient with tumor-induced 
osteomalacia 
Section 6.1.1.1 
• Updated to clarify administration of BGJ398 
Section 6.3.2 and Table 6-2 
• Added assessment criteria for a third dose reduction for TIO patients without 
measureable/evaluable disease 
Table 6-2 
• Added for patients with TIO diagnosis additional dose reductions may be allowed upon 
Novartis approval 
Table 6-3 
• Updated the lipase/amylase elevation information, hyperphosphatemia management and 
creatinine clearance information 


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Section 6.3.4 
• Removed Table 6-4 as the information was duplicative and the information can be found 
in Table 6-3 
Section 6.4.1 
• Added permitted supplementation for patients with TIO. 
Section 6.4.1.3 
• Removed reference to Table 6-4 
• Added that for patients with TIO diagnosis no prophylactic phosphate lowering therapy 
should be implemented 
Section 6.4.2.5 and Section 6.4.3.5 
• Revised for medications affecting QT/QTc interval 
Section 6.4.3.6 
• Added section on anticoagulants 
Table 7-1 
• Updated frequency of cardiac imaging 
• Added frequency of laboratory assessments FGF23 plasma levels and 1-25-dihydroxy 
vitamin D for patients with TIO 
Section 7.1.2, Section 7.2.2.6, and Section 7.2.2.6.7 
• Added laboratory assessments for patients with TIO 
Section 7.1.4.3 
• Added clarification that survival information will be collected for every patient regardless 
of treatment discontinuation reason (except if consent is withdrawn). 
Section 7.2.2.6.5 
• Removed language on screening analysis results and subsequent requirements 
Section 7.2.3 
• Removed reference to BYL719 
Section 7.2.3.1 
• Added details on pharmacokinetic blood sampling and collection 
Section 7.2.4.1 
Added that an archival or fresh tumor sample may not be required if the patient has had their 
genomic profiling performed at the same laboratory that will be used for confirmatory 
analysis, and the patient consents to allow Novartis to use that data as their baseline molecular 
analysis results 
References 
• Updated to include TIO publications referenced 


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Appendix P and Appendix Q 
• Revised to align with the BGJ398 program 
Appendix R and Appendix V 
• Removed Appendix R and Appendix V as the revised appendices P and Q contain the 
information included in appendices R-V previously. 
Minor inconsistencies, edits, and typographical errors that were identified after the 
finalization of the original protocol have been corrected with this amendment. IRB/IEC 
Approval 
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. In addition, if 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 amended protocol. 


 
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Amendment 1 
Amendment rationale 
The main purpose of this protocol amendment is to include endometrial tumors with FGFR 1- 
4 genetic alterations and FGF ligand amplifications that were previously excluded. 
Additionally, Urothelial cell carcinoma, Cholangiocarcinoma, and Glioblastoma multiforme 
with FGF Ligand amplifications are also allowed. 
Also, to better understand the safety picture of BGJ398, Pharmacokinetic (PK) testing of 
BGJ398 and its metabolites has been added to the study. Collection of unscheduled blood 
(Plasma) PK samples will be collected in the event of an adverse event at the investigators 
discretion. 
 
Changes to the inclusion/exclusion criteria: 
Patients with endometrial tumors will be included. Urothelial cell carcinoma, 
Cholangiocarcinoma, and Glioblastoma multiforme with FGF ligand amplifications are 
allowed. Although Urothelial cell carcinoma, Cholangiocarcinoma, and Glioblastoma 
multiforme with FGFR 1-4 genetic alterations are excluded, these tumors may be considered 
on a case by case basis upon prior approval by Novartis. 
Patients with molecular analysis performed at the confirmatory laboratory will not require 
additional tumor submission at time of study entry if subject has consented to allow transfer 
of information from pre-existing analysis to Sponsor. 
Clarification of hematological requirements applicable for leukemia patients to be included 
due to compromised bone marrow system of this patient population. Patients with Leukemia 
will be included with peripheral blast counts < 50,000 blasts/mm 3 to align with current 
standards. 
Patients with clinical evidence of CNS leukemia will be excluded. 
Patients who have received allogeneic stem cell transplant and/or have active graft -versus- 
host disease (GVHD) will be excluded. 
Patients who have received autologous stem cell transplant within last 4 weeks will be 
excluded. 
Exclusion #5 revised to add ‘significant’ to the history and/or current evidence of tissue 
calcification. It will read ‘History and/or current evidence of significant 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.’ 
Exclusion # 31 was revised to indicate ‘Patients with previous or concurrent primary 
malignancy within 3 years prior to starting study treatment, with the exception of adequately 
treated basal cell carcinoma, squamous cell carcinoma or other non-melanomatous skin cancer, 
or in-situ carcinoma of the uterine cervix treated curatively and without evidence of 
recurrence’. 


 
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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 were implemented throughout the protocol: 
Protocol summary “Purpose and rationale”, “Study design”, “Population”, Section 2.1 “Study 
rationale and purpose”, Section 2.2 “Rationale for the study design”, Section 4.1 “Description 
of study design”, Section 5.1 “Patient population”, Section 5.2 and Inclusion criteria number 3 
removed the word “select”. 
Section 2.1 and Section 5.1 were updated to clarify that Urothelial cell carcinoma, 
Cholangiocarcinoma, and Glioblastoma multiforme with FGFR 1-4 genetic alterations will be 
excluded, however these tumors may be included on a case by case basis upon prior approval 
by Novartis. Urothelial cell carcinoma, Cholangiocarcinoma, and Glioblastoma multiforme 
with FGF Ligand amplifications are allowed. 
Section 7.2.3 ‘Pharmacokinetics’ was updated to allow for PK sample collection for BGJ398 
and its metabolites. 
 
Section 8.2.2 “Reporting” was update to provide guidance on SAE follow-up. 
Section 5.1, Section 5.2, Section 7.1.1, and Section 7.2.4 were updated to include a Note 
indicating an archival or fresh tumor sample may not be required if the patient has had their 
genomic profiling performed at a laboratory selected by Novartis and the patient has agreed to 
allow Novartis to use baseline molecular analysis results. 
Table 3-1 Primary endpoint was updated to indicate that, for hematologic tumors, other 
appropriate hematological response criteria will apply and are included in the appendices. 
Section 7.1.4.3 was revised to indicate that the survival follow up may be done at the 
discretion of Novartis. 
Section 7.2.1.1 was revised to add ‘For solid tumors, an assessment of PR or greater must be 
confirmed at least 4 weeks after initial observation using RECIST 1.1.’ 
Section 7.2.1.4 Leukemia was updated to add ‘For MF and PV, the Myeloproliferative 
Neoplasm (MPN) Symptom Assessment Form Total Symptom Score (MPN-SAF TSS) will 
be completed as is indicated in Table 7-1.’ 
 
 
Table 6-4 Follow-up for toxicity was updated with a revised language for the management of 
hyperphosphatemia. 
Table 7-1 was updated to separately list the visit schedules of Myelofibrosis and 
Polycythemia vera. 
Table 7-1 was updated to add additional cardiac imaging at once a month for the first 4 cycles, 
if clinically indicated for subsequent cycles, and at EOT. 


 
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Section 8.2.2 Reporting was revised to remove ‘The follow up information should describe 
whether the event has resolved or continues, if and how it was treated, and whether the patient 
continued or withdrew from study participation.’ 
Section 9.4 Database management and quality control was revised to replace ‘violations’ with 
‘deviations’ in the statement ‘At the conclusion of the study, the occurrence of any protocol 
deviations will be determined.’ 
Section 10 “Statistical methods and data analysis” updated section to be consistent with 
Appendix M. Added clarification on safety set. Clarified primary objective. Clarified handling 
of missing values. Clarified adverse event analysis. Clarified interim analysis and sample size 
calculation for consistency with Appendix M. 
 
IRB/IEC Approval 
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. In addition, if 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 amended protocol. 


 
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1 
Background 
1.1 
Overview of disease pathogenesis, epidemiology and current 
treatment 
Cancer epidemiological and molecular studies have reported a variety of genetic alterations 
including gene amplifications, chromosomal translocations and mutations, as well as aberrant 
protein expression of FGFs/FGFRs (Fibroblast growth factor/ fibroblast growth factor 
receptors; Turner et al 2010). Several lines of evidence indicate that these lead to constitutive 
receptor activation and, thus, upregulation of the coupled signaling pathways. Gene 
amplifications and protein overexpression are associated with ligand independent receptor 
dimerization. Gene mutations affecting the extracellular ligand-binding domain can result in 
either receptor dimerization or stabilization of the active conformation of the receptor 
irrespective of ligand binding. Alternatively, intracellular point mutations in the tyrosine 
kinase domain can result in constitutively active forms of the receptor that signal in the 
absence of ligand binding or receptor dimerization. 
FGFR1 gene amplification, correlating with protein overexpression, has been described in 
about 8.5 % breast cancer by means of chromosome in situ hybridization (CISH) analysis. 
Survival analysis suggests that FGFR1 amplification may be an independent prognostic factor 
predicting poor outcome (Elbauomy Elsheikh et al 2007). Molecular epidemiology studies 
indicate that also FGFR2 is amplified in 4% triple negative breast cancers (Turner et al 2010). 
Independent efforts have identified FGFR2 amplification also in primary gastric cancers (3 - 
10%) (Mor 1993; Yoshida 1993; Hara 1998) The 11q13 amplicon, which encompasses FGF3, 
FGF4, and FGF19 has been found amplified in several cancer types including breast 
carcinomas (Haverty et al 2008). Interestingly, FGF3 and FGF4 are two of the most 
commonly activated oncogenes upon mouse mammary tumor virus (MMTV) insertion in the 
mouse genome, leading to mammary tumors. Other tumor types in which this amplicon is 
altered include ovarian tumors, oral squamous cell carcinomas and hepatocellular carcinomas. 
In the latter, FGF3 is significantly associated with metastasis and recurrence (Hu et al 2007). 
More recently, it has been shown that as much as 22% of lung squamous cell car cinoma 
strongly associated with smoking carry an amplification of FGFR1 (Weis 2010; Dutt 2011). 
Somatic activating mutations in FGFR3 have been identified in solid tumors, being 
particularly high in bladder carcinomas (Cappellen et al 1999), where FGFR3 overexpression 
is also reported (Tomlinson et al 2007). Activating point mutations of FGFR2 are known in 
gastric carcinomas (Jang et al 2001) and more recently discovered in endometrial carcinomas 
(Dutt et al 2008). 
Translocation and fusion of FGFR1 to other genes resulting in constitutive activation of its 
kinase by oligomerization is responsible for 8p11 myeloproliferative disorder ( Cross and 
Reiter 2008). Similar translocations and fusions for FGFR3 are associated with peripheral T- 
cell lymphoma while in multiple myeloma ( Maeda et al 2004), recurrent chromosomal 
translocations of 14q32 into the immunoglobulin heavy chain switch region result in 
deregulated over-expression of FGFR3 (Chesi et al 1997). FGFR1, FGFR2, and FGFR3 gene 
fusions have been identified in diverse cancer types including cholangiocarcinoma, breast 


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cancer, prostate cancer, thyroid cancer, lung SCC, bladder cancer, oral cancer, head and neck 
SCC, and glioblastoma at low frequency (Wu et al 2013). Additionally, there is evidence that 
some of the activating mutations in FGFRs still remain ligand dependent to a certain extent so 
co-expression of ligand either in an FGFR amplified setting or even in a setting of activating 
mutation the ligand may play a role (Dienstmann et al 2013). 
On the basis of the activity of BGJ398 in a variety of cancer models bearing FGFR genetic 
alterations (Guagnano et al 2012), BGJ398 can be exploited for therapeutic gain to treat 
human cancers, both solid and hematologic malignancies. 
 
1.1.1 
BGJ398 target pathway 
The FGFRs are Class IV transmembrane tyrosine kinase receptors. There are four FGFR 
genes in mammals: 1, 2, 3, and 4, encoding several splice variants. To date, 22 different FGF 
ligands have been identified which elicit a broad spectrum of biological activities, including 
cell growth, differentiation, morphogenesis and patterning, wound healing, and angiogenesis. 
Recently, a subfamily of FGF ligands, FGF19, FGF21 and FGF23, have been found to act as 
endocrine hormones and to be involved in various metabolic processes (Itoh 2007). 
The Figure below illustrates the key components of FGFR signaling pathways. Ligand 
binding promotes receptor dimerization and tyrosine kinase activation ( Eswarakumar et al 
2005). Receptor auto-phosphorylation, in turn, induces and sustains the activation of several 
downstream signaling pathways. FRS2 (FGFR substrate 2), a membrane-anchored docking 
protein, is an essential component of FGFR signaling and links the activated FGFRs to the 
Ras-MAPK pathway (Kouhara et al 1997). 
Please refer to the [Investigator’s Brochure] for additional information on BGJ398. 
 
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 chem ical 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. 


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Consistent with inhibition of FGFR autophosphorylation, BGJ398 inhibits FGFR downstream 
signaling and proliferation of human cancer cell lines harboring genetic alterations of the 
FGFRs. These include, among others, lung and breast cancer cell lines with FGFR1 gene 
amplification, gastric cancer with FGFR2 gene amplification, endometrial cancer with FGFR2 
mutations and bladder cancer with FGFR3 mutations or FGFR3 translocations (Wesche 2011). 
In line with its cellular activity, BGJ398 shows anti-tumor activity in multiple models bearing 
FGFR genetic alterations (Guagnano 2012; Konecny 2013). 
 
1.2.1.1.1 Non-clinical pharmacodynamics 
In all species tested, BGJ398 exhibited a high plasma CL (clearance) and a large Vss (Volume 
of distribution at steady state). The compound is highly bound to plasma proteins (~ 98%) but 
does not preferentially distribute to red blood cells. BGJ398 is widely distributed to tissues in 
the rat and has a high affinity to melanin containing tissues. In vitro hepatic systems 
metabolize BGJ398 predominantly to 2 pharmacologically active metabolites: BHS697 and 
BQR917. Biotransformation of BGJ398 to both metabolites was observed in human 
hepatocyte cultures. The compound is a P-gp and BCRP substrate and also inhibits BCRP- 
mediated transport with an IC50 value of 0.21μM. In addition, in vitro data indicate that 
BGJ398 is primarily a CYP3A4 substrate. 
BGJ398 is a potent reversible inhibitor of CYP3A4 (Ki 0.26μM). The compound also 
reversibly inhibits CYP2C9 and CYP2C19 with Ki of 6.09μM and 4.1μM, respectively and 
CYP2C8 with IC50 of 12μM. BGJ398 is also a time dependent inhibitor of CYP3A4 with a 
KI = 37.3 μM and Kinact = 0.0547 min -1. In addition, CQM157, a recently identified 
metabolite in circulating plasma from patients, is also shown to be an inhibitor of CYP2C8, 
CYP2C9 and CYP3A4 (IC50 less than 10 μM) and CYP2C19 (IC50 12 μM). CQM157 is also 
an inhibitor of transporters P-gp, BCRP, OATP1B1 and OATP1B3 (IC50 less than 5 μM). 
 
1.2.1.1.2 Safety pharmacology and toxicology 
BGJ398 showed no evidence of in vitro genotoxicity in Ames and chromosome aberration 
tests and no evidence of phototoxicity in a 3T3 photo-cytotoxicity test. In vitro safety 
pharmacology assessment of BGJ398 revealed a decrease in human Ether -à-go-go-related 
gene (hERG) channel activity with an IC50 of 2.0 μM (1121ng/ml). 
In vivo safety pharmacology studies in rats and dogs did not reveal an y effects on central 
nervous or respiratory systems and on hemodynamic or electrocardiographic parameters, 
respectively. 
In repeated dose (oral gavage; up to 4-weeks) toxicity studies, BGJ398 did lead to increases in 
serum FGF23 and serum phosphorous associated with partially reversible ectopic 
mineralization (kidney, lung, vascular and digestive systems) along with largely reversible 
changes in renal function parameters and bone growth plate thickening / retention of the 
primary spongiosa in rats (≥ 10 mg/kg/day) and dogs (≥ 10 mg/kg/day). These effects were 
deemed to be on-target effects mediated by pharmacological inhibition of FGFR. 
In rats, corneal changes were found upon 4 weeks of BGJ398 treatment consisting of 
irreversible, slight bilateral opacity with dose-dependent incidence, as assessed by in vivo 
ophthalmology. The clinical/ophthalmoscopic finding was associated with reversible, diffuse 


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epithelial keratopathy at the highest dose of 10 mg/kg. In the 2 -week rat toxicity study, doses 
of 20 mg/kg/day did lead to vasculopathy associated with moribundity after 6 administrations. 
In dog toxicity study, minimal, fully reversible retention of the primary spongiosa and 
minimal increase in mineralization in lung and kidney without observed functional 
impairment were observed. 
 
1.2.1.1.3 Genotoxicity study 
BGJ398 was not mutagenic in the Ames S. typhimurium test and did not produce DNA 
damage in an in vitro leukocyte Comet test. In the Comet assay using L5178Y mouse 
lymphoma cells, BGJ398 induced DNA damage in L5178Y cells after a 3-hour incubation. 
However, the elevated tail moment was observed at highly cytotoxic concentrations and it was 
therefore concluded that this effect was a consequence of excessive cytotoxicity rather than 
direct DNA interaction. BGJ398 was not clastogenic to human lymphocytes in vitro. BGJ398 
is judged to be non-genotoxic. 
 
1.2.1.2 
Clinical experience 
 
1.2.1.2.1 Clinical safety 
As of data cut-off date September 6, 2016, 207 patients have received at least one dose of 
BGJ398 in phase I study BGJ398X2101. Forty-three patients were enrolled to dose escalation 
cohorts and 164 patients to dose expansion arms. 
Enrollment to the dose escalation cohorts was as follows: 5mg [N=3], 10mg [N=3], 20mg 
[N=4], 40mg [N=6], 60mg [N=3], 100mg [N=6], 50 mg bid [N=4], 125mg [N=8], and 150mg 
[N=6]. MTD was identified to be 125 mg qd on a continuous dosing schedule. 
Dose expansion consists of 4 arms enrolling different patient populations on two different 
dosing schedules at 125 mg (daily or 3 weeks on/1 week off in 28-day cycles). Arm 1 [N=28] 
is enrolling FGFR1-amplified advanced or metastatic squamous NSCLC with FGFR1 
amplification on the continuous dosing schedule. Arm 2 [N=21], which is now closed, 
enrolled advanced solid malignancies with any FGFR mutation or amplification dosed 
continuously. Arm 3 [N=49] is enrolling advanced solid malignancies with any FGFR genetic 
alteration, mutation, or amplification on the 3 weeks on/1 week off dosing schedule. Arm 4 
[N=66] is enrolling advanced or metastatic urothelial cell carcinoma (UCC) with FGFR3 
mutation or gene fusion on the 3 weeks on/1 week off dosing schedule. 
The 3 weeks on/1 week off schedule was implemented based on observations of the timing 
and duration of drug interruptions during Cycle 1 necessitated by episodes of 
hyperphosphatemia. The data indicated that the median time to drug interruption was 22 days 
and the median duration of the interruption was 7 days. 
At the time of data cutoff, 21 patients were still receiving study medication. Of the 186 
patients who have discontinued from the study, 135 discontinued treatment due to progression 
of disease, 28 discontinued due to adverse events, 6 died while on study, 15 discontinued due 
to withdrawal of consent, 1 due to administrative problems, and 1 due to protocol deviation. 


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The treatment emergent adverse events as of the cutoff date of September 6, 2016, regardless 
of BGJ398 relationship, that occurred in 20% or more of patients are: increases in phosphorus 
levels (covered by the preferred terms of hyperphosphatemia, 57.5%, and blood phosphorus 
increased,   9.2%),   constipation   (39.6%),   decreased   appetite   (36.2%),   fatigue (34.3%), 
stomatitis (33.3%), nausea (31.4%), blood creatinine increased (28.5%), diarrhea (27.5%), 
alopecia (26.1%), dry mouth (23.7%), vomiting (20.8%), and anemia, 20.3%. Approximately 
58 percent of patients (120/207) experienced at least one grade 3 or 4 event regardles s of the 
relationship to BGJ398. Grade 3 or 4 events that occurred in at least 5% of patients were 
lipase increased (6.8%) and alanine minotransferase increased (5.3%). Overall, most adverse 
events reported have been mild to moderate in severity,reversible, and unrelated to BGJ398. 
Hyperphosphatemia has been seen in the majority of patients treated at doses of 100 mg qd 
and higher and is a pharmacodynamic (PD) marker of on-target FGFR pathway inhibition. 
Renal tubular phosphate secretion and reabsorption are controlled through the FGFR1 
pathway. Inhibition of this pathway leads to inability to secrete phosphate and secondary 
elevations in FGF23. The hyperphosphatemia has been managed in the Phase 1 study by 
dietary phosphate restrictions, phosphate lowering therapy, and 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 suggest 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 a March 15, 2014 data cut off, seventeen of 
25 patients (68%) who received BGJ398 on the 3 week on/1 week off schedule experienced 
elevated phosphorous and only 4 patients (16%) required cycle 1 interruptions or reductions. 
In contrast, 41 of 47 patients (87%) on the continuous dosing cycle experienced serum 
phosphorous elevations. Twenty patients (43%) required cycle l dose interruptions and 13 
patients (28%) required dose reductions during cycle l. 
Preliminary analysis does not show any effect of BGJ398 on QTc prolongation. Please refer 
to the BGJ398X Investigator Brochure for additional information. 
 
1.2.1.2.2 Clinical efficacy 
Preliminary antitumor efficacy has been detected in patients treated at doses of ≥ 100 mg of 
BGJ398 with the following tumor types: FGFR1-amplified squamous NSCLC, FGFR1- 
amplified squamous cell carcinoma of the head and neck, FGFR3 -mutated/gene fusion 
bladder cancer, and advanced cholangiocarcinoma with FGFR2 gene fusion. Clinical activity 
with monotherapy BGJ398 has been shown to be minimal in breast cancer patients with 
FGFR genetic alterations, including amplification, with best response achieved of stable 
disease. While all patients who responded had exposures associated with increases in blood 
phosphorus levels, not all patients who experienced increases in blood phosphorus levels 
responded to treatment with BGJ398. 
Please refer to the BGJ398X Investigator Brochure for additional information. 
Preliminary data obtained from the CBGJ398X2101 first in human trial indicate that the main 
safety findings in patients treated with BGJ398 were predicted from preclinical studies. The 
on-target effects on calcium-phosphate homeostasis result in the observed increases in 
calcium, phosphorus, and creatinine, and not associated with clinical symptoms. In general, 


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the increases have been mild to moderate in severity and manageable and reversible upon 
interruption or discontinuation of BGJ398 administration. 
Ocular adverse events are frequent, but generally mild to moderate in severity and reversible. 
Corneal or retinal adverse events are recognized on ophthalmologic evaluations. 
No effect of BGJ398 on ECG intervals, including QTc has been noted. Asymptomatic, 
reversible decreases in LVEF have been noted in patients enrolled on study as measured by 
serial TTE or MUGA scans. 
The preliminary efficacy signals observed in patients enrolled to the trial, combined with the 
emerging safety profile of BGJ398, warrant continued development of this compound for the 
treatment of solid tumors with genetic alterations of the FGFR pathway. 
 
1.2.1.2.3 Clinical pharmacokinetics 
The pharmacokinetics (PK) of BGJ398 and active metabolites have been evaluated following 
single and repeat daily doses in the ongoing phase 1 study ([CBGJ398X2101]). 
At 5 and 10 mg/day, plasma concentrations were low and frequently below the lower limit of 
quantification. Plasma concentrations were consistently quantifiable starting at 20 mg/day. 
Following a single dose, median Tmax was approximately 2-3 hours. The mean AUC0-24 on 
Day 1 increased approximately 9 fold from 20 to 150 mg. A mean terminal elimination half- 
life on Day 1(T1/2) was 3-7 hr. Despite the relatively short half-life on Day 1, accumulation 
was observed with daily dosing at doses ≥ 60 mg, likely due to auto-inhibition of CYP3A4 
mediated clearance pathways. Mean accumulation ratio (Racc) ranged from 3 to 8 on Days 15 
and 28. Since dose interruptions occurred frequently following continuous daily dosing of 
BGJ398, PK parameters on Day 28 should be viewed with caution. The inter-patient 
variability was high for BGJ398. When dosed at 125 mg with a schedule of 3 weeks on, 1 
week off, the mean Cmax and AUC0-24 were 230 ng/mL (n=12) and 3492.9 ng*hr/mL, 
(n=10), respectively at day 15. The coefficient of variation for Cmax and AUC0 -24 ranged 
from approximately 50 – 75% and higher variability was observed while estimating secondary 
pharmacokinetic parameters like clearance and volume of distribution. 
Concentration data from active metabolites BHS697 (desethyl metabolite) and BQR917 (N- 
oxide) was available across all cohorts. CQM157 (aniline metabolite) was analyzed in a few 
patients following Amendment 6 of the BGJ398X2101 clinical protocol. In most patients, 
BHS697 and BQR917 were measurable at levels of ~5-50%, and <15% of parent exposure, 
respectively. Mean exposures on Day 1 (N=8) for CQM157 relative to BGJ398 varied across 
patients (3% -300%). CQM157 (N=4) did not appear to accumulate on daily dosing, whereas 
accumulation was observed for BGJ398 and metabolites BHS697 and BQR917. 
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2 
Rationale 
2.1 
Study rationale and purpose 
Genomic profiling is becoming more accessible to patients and their physicians. As such, 
more patients have been identified with potentially actionable mutations or pathway- 
regulations but do not have access to targeted drug treatment. Additionally, there is evidence 
that some of the activating mutations in FGFRs still remain ligand dependent to a certain 
extent so co-expression of ligand either in an FGFR amplified setting or even in a setting of 
activating mutation the ligand may play a role. This is a signal seeking study to match patients 
with FGFR genetic alterations to treatment with the pan-FGFR inhibitor BGJ398. Pre- 
identification of FGFR genetic alteration or FGF ligand amplification status will be performed 
locally at a CLIA certified laboratory prior to participation on the trial . Laboratory results 
must be ‘unambiguous’ or ‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply 
low probability that genetic deregulation is truly present and an important driver of patient’s 
tumor. 
The purpose of this signal seeking study is to determine whether treatment with BGJ398 
demonstrates sufficient efficacy in pathway-activated solid tumors and/or hematologic 
malignancies to warrant further study. 
Tumor-induced osteomalacia (TIO) is a rare paraneoplastic syndrome in which patients 
present with bone pain, fractures, and muscle weakness (Chong 2011). The cause is high 
blood levels of phosphate and vitamin D-regulating hormone, fibroblast growth factor 23 
(FGF23). 
FGF23 exerts its action through the binding of the receptor FGFR4 or the IIIc isoforms of 
FGFR1 and FGFR3 and its co-receptor Klotho at the renal proximal tubule. Excess levels of 
FGF23 downregulates the sodium-phosphate co-transporters NaPi-2a and NaPi-2c and, 
thereby, enhances renal excretion of phosphate leading to h ypophosphatemia with significant 
osteomalacia and increased fracture risk. FGF23 also reduces the levels of 1,25(OH)2D3 in 
the serum by increasing its metabolism and inhibiting its synthesis. ( Shimada 2004). TIO is 
generally indolent and infrequently metastasizes. Thus, chemotherapy and radiation are 
ineffective, leaving surgical resection as the primary treatment. However, tumor location and 
surgical candidacy may preclude resection in some cases. These patients are left without good 
treatment options other than phosphate and activated vitamin D (calcitriol) supplementation, 
which is largely unsuccessful in preventing bone malformation and leaves patients 
significantly debilitated. 
In a preclinical study, effect of BGJ398 was examined using two different mouse models of 
FGF23-mediated hypophosphatemic rickets, Hyp and Dmp1-null mice, models of the human 
diseases 
X-linked 
hypophosphatemic 
rickets 
(XLH) 
and 
autosomal 
recessive 
hypophosphatemic rickets (ARHR), respectively. A single dose of BGJ398 led to significant 
increases in serum calcium, phosphorus, and 1,25(OH)2D levels in these mouse models 
(Wöhrle et al 2013). Correspondingly, it was noted that the long-term FGFR inhibition in Hyp 
mice lead to the normalization of bone mineralization and a striking reorganization of the 
disturbed growth plate structure. Elevated serum parathyroid hormone (PTH) was also 
normalized after long-term treatment with BGJ398. These results show that aberrant FGF23 


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signaling could be suppressed by pharmacological inhibition of FGFRs, which efficiently 
alleviates the hypophosphatemia and hypocalcemia. Thus, this pharmacological approach 
might prove useful for the treatment of patients with hypophosphatemic disorders such as TIO 
caused by elevated FGF23 levels (Guagnano et al 2012). More importantly, in phase I study 
of BGJ398 in patients with FGFR mutated or overexpressed solid tumors, hyperphosphatemia 
was the most common adverse event. Phosphate elevations are a biomarker of on-target FGFR 
pathway inhibition which mediates renal tubular phosphate secretion and reabsorption. As 
serum phosphate increase is a desired outcome for patients with TIO, this provides sound 
rationale for evaluating the effect of BGJ398 in this patient population. 
Recently, Lee JC et al (Lee et al 2015) identified a novel FN1–FGFR1 fusion gene in nine out 
of 11 Phosphaturic Mesenchymal Tumour (PMT) (60%) by next-generation RNA sequencing 
and Fluorescence in situ hybridization analysis. The fusion transcripts and proteins were 
subsequently confirmed with RT-PCR and western blotting. These findings may have 
therapeutic implications, as emerging FGFR1 antagonists such as BGJ398 have shown some 
anti-tumor efficacy in clinical trials, and might thus have a role in treating malignant and/or 
inoperable patients with TIO diagnosis. 
Additional tumor types may be excluded during the course of the study at the discretion of 
Novartis. 
Additionally, increased understanding of the genomic changes in tumors allows the selection 
of patients more likely to benefit from treatment. In most cases patients who respond well 
initially to treatment soon develop resistance to the new treatments; also, many patients have 
disease that does not respond. The biological complexity of cancers and lack of knowledge of 
the mechanisms responsible for resistance in patients pose challenges, therefore a successful 
development of treatments that provide sustained disease control or cure requires improving 
the understanding of the mechanisms responsible for drug resistance. 
 
 
 
Details of the study design are provided in Section 4. 
 
2.2 
Rationale for the study design 
This is a phase II, open label study to determine the efficacy and safety of treatment with 
BGJ398 in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have FGFR genetic alterations and whose 
disease has progressed on or after standard treatment. 
 
2.3 
Rationale for dose and regimen selection 
Patients enrolled in this study will receive 125 mg qd of BGJ398 on a 3 week on (21 day) /1 
week off (7 day) schedule. This dose level and regimen is based on experiences from the 
[CBGJ398X2101] trial. 
The MTD/RP2D from the CBGJ398X2101 study was identified as 125 mg administered once 
daily (qd) in continuous 28-day cycles. While dose levels of 100 mg qd and higher were 
tolerated by patients, the majority of the patients experienced reversible hyperphosphatemia, 


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which lead to study drug interruptions. An evaluation of the drug administration records for 
patients prior to receiving prophylactic phosphate-lowering therapy, indicated that the median 
time until first dose interruption was approximately 23 days and the median duration of 
interruption was 7 days. This observation led to the introduction of an expansion arm in the 
ongoing CBGJ398X2101 study to evaluate the administration of 125 mg qd on a 3 weeks on 
(21 days) / 1 week off (7 days) schedule in 28 -day cycles. To date, the majority of patients 
enrolled in this arm have completed their first cycle of therapy without hyperphosphatemia - 
induced dose interruptions, while maintaining anti-tumor activity. 
The selection of the starting dose follows the ICH S9 guidelines for choosing a starting dose 
for a first-in-human trial conducted in patients with cancer, and is shown in Table 6-2. It will 
be dosed on a flat scale and not adjusted by weight or body surface area. 
 
3 
Objectives and endpoints 
Objectives and related endpoints are described in Table 3-1 below. 


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. 
 
 
 
Table 3-1 
Objectives and related endpoints 
Objective 
Endpoint 
Analysis 
Primary: 
• 
To assess clinical benefit associated with BGJ398 
treatment based on local investigator assessment. 
• 
For patients with solid tumors the assessment criteria will 
be RECIST 1.1 and will include responses of CR or PR 
or SD. For hematologic tumors other appropriate 
hematological response criteria will apply and are 
included in the appendices 
• 
For patients with TIO diagnosis without 
measureable/evaluable disease, the assessment criteria 
will be the tumor associated changes of metabolic 
parameters (plasma level of FGF23 < or =180 RU/mL; 
and inorganic phosphorous, calcium, and 1-25-dihydroxy 
vitamin D greater than the LLN (- 20%); and without 
requirement of supplementation therapy for at least the 
preceding cycle of the 16 week assessment.) 
Key secondary: 
• 
Clinical benefit rate (e.g. defined as CR or PR or SD ≥ 16 
weeks for solid tumors) at week 16. For hematologic 
tumors, other appropriate hematological response criteria 
will apply and are included in the appendices. 
• 
For patients with TIO diagnosis without 
measureable/evaluable disease, the following criteria will 
be the assessment at 16 weeks: 
• 
the tumor associated changes of metabolic 
parameters: plasma level of FGF23 < or =180 RU/mL; 
and inorganic phosphorous, calcium, and 1-25- 
dihydroxy vitamin D greater than the LLN (- 20%); 
and 
• 
without requirement of supplementation therapy for at 
least the preceding cycle of the 16 week assessment. 
Refer to Section 10.4. 
• 
To assess Overall Response (OR) of Partial Response 
(PR) or greater based on local investigator assessment. 
• 
For patients with solid tumors the assessment criteria will 
be RECIST 1.1 and will include responses of CR and/or 
PR. For hematologic tumors other appropriate 
hematological response criteria will apply and are 
included in the appendices. 
• 
Overall response rate (PR or greater) 
Refer to Section 10.5.1. 


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Objective 
Endpoint 
Analysis 
Other secondary: 
• 
To assess Progression-Free Survival (PFS) based on 
local investigator assessment per RECIST 1.1 or other 
appropriate hematological response criteria 
• 
To assess Overall Survival (OS) 
• 
To assess Duration of Response (DOR) based on local 
investigator assessment per RECIST 1.1 or other 
appropriate hematological response criteria 
• 
To assess safety and tolerability 
 
 
 
 
• 
Time from the date of first dose to the date of first 
documented disease progression or relapse or death due 
to any cause 
• 
Time from the date of first dose to the date of death due 
to any cause 
• 
Time from the first documented response to the date first 
documented disease progression or relapse or death due 
to any cause 
• 
Incidence of adverse events (AEs), serious adverse 
events (SAEs), changes from baseline in vital signs, 
laboratory test results(hematology, biochemistry), ECG, 
and cardiac imaging will be assessed by the Common 
Terminology Criteria for Adverse Events (CTCAE), v4.03 
Refer to Section 10.5.2. 
 
 
Refer to Section 10.5.2. 
Refer to Section 10.5.2. 
 
Refer to Section 10.5.3. 
 
 
 
 


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Physician 
Tissue 
Sample 
CLIA 
Certified Lab 
Patient being 
treated for solid 
tumor or hem 
malignancy 
Genomic 
Profiling 
Report 
generated 
Actionable 
mutation 
identified by 
profiling 
Central IRB Approved 
Protocol Package and 
standardized budget and 
contract sent to site 
Research physician 
contacts Novartis to 
include patients in the 
study 
Site begins study 
start-up process 
Expedited SIV 
Open Study 
 
 
4 
Study design 
4.1 
Description of study design 
This is a phase II, open label study to determine the efficacy and safety of treatment with 
BGJ398 in patients with a diagnosis of solid tumors or hematological malignancies that have 
been pre-identified (prior to study consent) to have FGFR genetic alterations nd  whose 
disease has progressed on or after standard treatment. 
This study is intended for patients who have already had genomic profiling of their tumors in 
a CLIA certified laboratory and have already been pre-identified to have a tumor with a FGFR 
genetic alteration. Eligibility is based on FGFR genetic alteration status as assessed in the 
local, CLIA certified laboratory. The results of this testing must be known prior to signing the 
ICF and before formal screening begins. Laboratory results must be ‘unambiguous’ or 
‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply low probability that 
genetic deregulation is truly present and an important driver of patient’s tumor. Once the 
patient has been identified, treating physicians who are qualified investigators may contact 
Novartis to consider enrollment in this study. For the purpose of this study, genomic profiling 
is not considered part of screening. Informed consent must be signed before any screening 
activities take place. Once eligibility criteria are met, the patient will initiate therapy with 
BGJ398 single-agent. The patient may not receive any additional anti-cancer therapy during 
treatment with BGJ398. 
A schematic representation of the study start-up design is shown in Figure 4-1. 
 
Figure 4-1 
Study start-up design 
 


 
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4.1.1 
Treatment phase 
Patients will continue to receive study treatment until disease progression (assessed by 
investigator per RECIST 1.1 or appropriate hematologic response criteria or for patients with 
TIO diagnosis the recurrence or progression of disease or recurrence of abnormal metabolic 
parameters), unacceptable toxicity, death or discontinuation from study treatment for any 
other reason (e.g., withdrawal of consent, start of a new anti-neoplastic therapy or at the 
discretion of the investigator), otherwise known as End of Treatment. Patients with TIO 
diagnosis that progress per RECIST but per investigator’s assessment are receiving clinical 
benefit from treatment may remain on study upon approval from Novartis. Patients with TIO 
diagnosis that do not receive metabolic benefit by week 16 should discontinue unless approval 
from Novartis. All patients who discontinue from study treatment due to disease progression 
must have their progression clearly documented. 
Disease assessments (per RECIST 1.1 or appropriate hematological response criteria) will be 
performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle), 
until disease progression or end of treatment, whichever occurs first. Upon implementation of 
this amendment, the frequency of disease assessment will be reduced and evaluations should 
be every 16 weeks after the first 16 weeks on treatment. Scans will be assessed locally by the 
investigator. 
 
4.1.2 
Follow-up phase 
After discontinuation of treatment, patients, regardless of reason for treatment discontinuation, 
will be followed for safety for 30 days after the last dose. 
All patients will be followed for survival status every 3 months for 2 years after the last 
patient has enrolled in the study, regardless of treatment discontinuation reason (except if 
consent is withdrawn or patient is lost to follow-up). If the primary efficacy endpoint is not 
met, Novartis may discontinue survival follow-up for this study. 
 
 
 
 
 
 
For details on required assessments, please refer to Table 7-1. 
 
4.2 
Definition of end of the study 
End of study is defined as the time when the last patient completes survival follow-up as 
described in Section 7.1.4.3, or when the last patient on study has died, been lost to follow up 
or withdraws consent, or when the study is terminated early, whichever occurs first. 
The analysis of study data will be based on all patients’ data up to the time when all patients 
have had the opportunity to complete at least 4 cycles (or 16 weeks) of treatment or 
discontinued the study. This will be the cut-off point for the primary clinical study report 
(CSR). Additional data for patients continuing to receive study treatment past the data cutoff 


 
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date for the primary CSR will be reported once all patients have discontinued treatment or 
been lost to follow-up. It will be reported in an addendum to the CSR, as appropriate. 
At the time of CSR data cut-off, if patients are ongoing after 16 weeks on treatment and 
benefitting, they will continue to receive treatment, every effort will be made to continue 
provision of study treatment outside this study through an alternative setting to patients who 
in the opinion of the investigator are still deriving clinical benefit and the Novartis therapy is 
not commercially available and reimbursable. 
 
4.3 
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 for an end of treatment (EOT) visit and the 
assessments for EOT should be performed as described in Section 7 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 the Institutional Review Board 
(IRB) and/or Ethics Committee (EC) of the early termination of the trial. 
 
5 
Population 
5.1 
Patient population 
The study population will consist of 70- 120 adult patients with a diagnosis of a solid tumor or 
hematological malignancy that has been pre-identified as having FGFR genetic alterations. 
Patients with history/current evidence of tumor-induced osteomalacia (TIO) and FGF23- 
mediated hypophosphatemia with or without identification of an FGFR genetic alteration in 
the tumor will be allowed. Patients must have received at least one prior treatment for their 
recurrent, metastatic and/or locally advanced disease and have no remaining standard therapy 
options anticipated to result in a durable response. Patients must have progressive and 
measurable disease (per RECIST 1.1 or other appropriate hematological response assessment 
criteria) and be in need of treatment. For patients with TIO diagnosis, the presence of 
measurable or evaluable disease is not required provided there is evidence of FGF23-mediated 
hypophosphatemia (TIO patients will not be included in protocol amendment 3). This is a 
signal seeking study, attempting to identify additional patient populations who may benefit 
from treatment with single agent BGJ398. 
Additional tumor types may be excluded during the course of the study at the discretion of 
Novartis. With Amendment 3, the study is re-opening for enrollment for the following six 
tumor types only: Head and Neck Squamous Cell Carcinoma, Bladder Cancer, Ovarian 
Cancer, Non-small cell lung carcinoma – Squamous, Glioblastoma with multiforme with 
FGFR 1-4 genetic alterations and Cholangiocarcinoma. 
Patients must not have central nervous system (CNS) metastasis, leptomeningeal 
carcinomatosis, symptomatic cardiac disease, or impairment of gastrointestinal (GI) function. 
Patients must have archival tissue available for submission to allow for molecular testing 
related to pathway regulation. If tissue is not available or not of sufficient quantity the patient 
must be willing to undergo a fresh tumor biopsy to allow for this analysis. 
 


 
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Note: An archival or fresh tumor sample may not be required if the patient has had their 
genomic profiling performed at a laboratory selected by Novartis and the patient has agreed to 
allow Novartis to use baseline molecular analysis results. 
Enrollment is meant to encompass solid tumors and hematologic malignancies as having 
FGFR genetic alterations that may be inhibited by BGJ398 who otherwise meet all of the 
inclusion and none of the exclusion criteria. Amendment 3: no longer allows for patients with 
FGF ligand amplification or TIO diagnosis to be included. Though common for phase I 
studies, tissue-agnostic enrollment is unusual for phase II studies, which typically limit 
enrollment to one or a few well-defined tumors types. We expect that the study will enroll 
patients whose tumors have already been pre-identified to harbor FGFR genetic alterations 
such as Breast, Gastric, Esophageal, Colorectal, and Squamous Head and Neck cancers (the 
amendment 3 limits the tumor types from Head and Neck Squamous Cell Carcinoma, Bladder 
Cancer, Ovarian Cancer, Non-small cell lung carcinoma – Squamous, Glioblastoma with 
multiforme with FGFR 1-4 genetic alterations and Cholangiocarcinoma. ). The total number 
of patients to be enrolled per tumor type will be based on an adaptive design. The adaptive 
design will be patient-sparing and allow the early closure of non-responding arms or arms 
where early success can be declared. 
 
5.2 
Inclusion criteria 
Patients eligible for inclusion in this study have to meet all of the following criteria: 
1. Patient has provided a signed study Informed Consent Form prior to any screening 
procedure 
2. Patient is ≥ 18 years of age on the day of consenting to the study. 
3. Patient must have: 
a. Confirmed diagnosis of (Head and Neck Squamous Cell Carcinoma, Bladder Cancer 
(Urothelial cell Carcinoma), Ovarian Cancer, Non-small cell lung carcinoma – 
Squamous, Glioblastoma multiforme and Cholangiocarcinoma are the only tumor 
types allowed) and is in need of treatment because of radiologic progression or 
relapse. Additional tumor types may be excluded during the course of the study at the 
discretion of Novartis. Note: Urothelial cell carcinoma, Cholangiocarcinoma, and 
Glioblastoma multiforme with FGFR 1-4 genetic alterations are allowed without any 
prior approval. 
b. [Note: as of Amendment 3, TIO patients will not be enrolled in the study] 
Clinical evidence of tumor-induced osteomalacia (TIO) associated with FGF23- 
mediated hypophosphatemia with or without identification of an FGFR genetic 
alteration, with: 
• Advanced or inoperable malignancy 
• or tumors with contraindication to surgical resection (an elevated FGF23 level at 
baseline must be demonstrated) 
• or tumors not amenable to cure by surgical excision (documented by investigator) 


 
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• or tumor-induced osteomalacia diagnosis without the presence of measurable or 
evaluable disease 
NOTE: Patients with a diagnosis of TIO without a pre-identified tumor genetic alteration 
may be included on a case by case basis upon prior approval by Novartis 
4. Patient is in need of treatment because of progression or relapse defined as: 
• radiological progression for solid tumor and lymphoma 
• for hematologic malignancies, measureable progression or relapse by appropriate 
criteria (see appendices) 
5. Patient must have been pre-identified as having a tumor with any FGFR genetic alteration 
[such as mutation, amplification, fusion, translocation of FGF receptors 1 – 4]. The 
qualifying genetic alteration must be assessed and reported by a CLIA-certified laboratory. 
(The FGF alteration must be in combination with a mutation or fusion in FGFR.) 
6. Patient must have archival tissue available for submission to allow for molecular testing 
related to pathway regulation. If the tissue is not available or is insufficient, the patient 
must be willing to undergo a fresh tumor biopsy to allow for this analysis. The sample 
must be submitted prior to first study dose unless agreed upon between Novartis and the 
investigator. See Section 7.2.4.2.1. 
Note: An archival or fresh tumor sample may not be required if the patient has had their 
genomic profiling performed at a laboratory selected by Novartis and the patient has 
agreed to allow Novartis to use baseline molecular analysis results. () 
7. Patient must have received at least one prior treatment for recurrent, metastatic and /or 
locally advanced disease and for whom no standard therapy options are anticipated to 
result in a durable remission. 
8. Recovery from adverse events of previous systemic anti-cancer therapies to baseline or 
grade 1, except for: 
a. Alopecia 
b. Stable neuropathy of ≤ grade 2 due to prior cancer therapy 
9. [Note: as of Amendment 3 Diffuse large B cell lymphoma patients will not be enrolled in 
the study] Diffuse large B cell lymphoma only: Patient has received or is ineligible for 
autologous or allogeneic stem cell transplant. This does not apply to patients with Mantle 
cell lymphoma or follicular lymphoma 
10. Patients must have measurable disease as per appropriate guidelines:[ as of Amendment 3 
Lymphoma, Symptomatic Multiple Myeloma, Leukemia and TIO patients will not be 
enrolled in the study] 
a. Solid Tumors: by RECIST 1.1 (Appendix A) 
b. Lymphoma: Patient has at least one measurable nodal lesion (≥2 cm) according to 
Cheson criteria (Cheson 2007). In case where the patient has no measurable nodal 
lesions ≥ 2 cm in the long axis at screening, then the patient must have at least one 
measurable extra-nodal lesion (Appendix B) 
c. Symptomatic Multiple Myeloma: by International Myeloma Working Group 
(IMWG) 
• Serum M-component of ≥1 gm/dL 
• Urine M-component of ≥200 mg/24 h 


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• Patients with plasmacytoma must have a definite increase in the size; a definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by 
the sum of the products of the cross-diameters of the measurable lesion 
d. Leukemia only: Relapsed/refractory leukemia for which no standard therapy options 
are anticipated to result in a durable remission: 
• Acute myelogenous leukemia (AML) by World Health Organization (WHO) 
classification or acute lymphoblastic leukemia (ALL) relapsed or refractory to 
standard chemotherapy; unsuitable for standard chemotherapy or unwilling to 
undergo standard chemotherapy. Philadelphia chromosome (Ph) positive ALL 
eligible if failed prior tyrosine-kinase inhibitor therapy. 
• Age > 60 years with AML not candidates for or have refused standard 
chemotherapy, excluding patients with acute promyelocytic leukemia (APL) or 
with favorable cytogenetic abnormalities [inv16, t(8;21)]. 
• For patients with Chronic Myeloid Leukemia (CML) only accelerated and blast 
phase CML will be allowed. 
e. TIO diagnosis: refer to inclusion 3b 
11. Patient has an Eastern Cooperative Oncology Group (ECOG) performance status ≤ 1 
(Appendix N). 
12. Patient has a life expectancy of at least 16 weeks 
13. All patients must have adequate bone marrow as described below: 
a. Absolute Neutrophil Count (ANC) ≥ 1.0 x 109/L (not applicable for leukemia 
patients) 
b. Platelets (PLT) ≥ 75 x 109/L (no platelet transfusion within past 14 days) (not 
applicable for leukemia patients) 
c. Hemoglobin (Hgb) ≥ 9 g/dl (not applicable for leukemia patients) 
d. For Leukemia patients, peripheral blast counts < 50,000 blasts/mm3 
e. International Normalized Ratio (INR) ≤ 1.5 
f. For Leukemia patients, peripheral blast counts < 50,000 blasts/mm3 
14. All patients must have adequate organ function defined as described below: 
a. Potassium, calcium inorganic phosphorous and magnesium within normal limits 
(WNL). Supplementation is allowed to meet eligibility requirements 
b. Serum creatinine ≤ 1.5 x ULN 
c. Alanine aminotransferase (AST) and/or aspartate aminotransferase (ALT) ≤ 2.5 x 
upper limit of normal range (ULN) or ≤ 5 x ULN if liver metastases are present 
d. Total serum bilirubin within normal range (or ≤ 1.5 x ULN) 
e. Serum amylase and lipase ≤ upper limit of normal (ULN) 
f. Proteinuria ≤ Grade 2 (dipstick or 24hrs urine analysis) (Not applicable for Urothelial 
cell carcinoma patients) 
 
5.3 
Exclusion criteria 
Patients eligible for this study must not meet any of the following criteria: 
1. Patients who have received prior treatment with BGJ398 


 
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2. Patients with a known hypersensitivity to BGJ398 or to its excipients 
3. Patients with metastatic CNS tumors are excluded, unless the patient meets criteria a-e: 
a. 4 weeks from prior therapy completion (including radiation and/or surgery) 
b. Clinically stable with respect to the CNS tumor at the time of study entry 
c. Not receiving steroid therapy 
d. Not receiving anti-convulsive medications (that were started for brain metastases) 
e. Patient with no leptomeningeal involvement 
4. Current evidence of corneal or retinal disorder/ keratopathy including, but not limited to, 
bullous/band keratopathy, corneal abrasion, inflammation/ulceration, keratoconjunctivits, 
confirmed by ophthalmologic examination 
5. History and/or current evidence of significant 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. History and/or current evidence of endocrine alterations of calcium/phosphate homeostasis, 
e.g. parathyroid disorders, history of parathyroidectomy, tumor lysis, tumoral calcinosis 
etc. 
7. Use of medications that increase serum levels of phosphorus and/or calcium. NOTE: Not 
applicable for TIO diagnosis 
8. Consumption of grapefruit, grapefruit juice, pomegranates, star fruits, Seville oranges or 
products within 7 days prior to first dose 
9. Use of medications that are known to prolong the QT interval and/or are associated with a 
risk of Torsades de Pointes (TdP) 7 days prior to first dose 
10. Use of amiodarone within 90 days prior to first dose 
11. Current use of therapeutic doses of warfarin sodium or any other coumadin-derivative 
anticoagulants. Heparin and/or low molecular weight heparins are allowed. 
12. Patients who are currently treated with drugs known to be strong inhibitors or inducers of 
isoenzyme CYP3A, or substrates of CYP3A4 whose treatment cannot be discontinued or 
switched to a different medication prior to starting study drug. 
13. Patients with diarrhea ≥ CTCAE grade 2 
14. Patients with neuropathy ≥ CTCAE grade 2 unrelated to prior cancer therapy, or > grade 2 
neuropathy for any other reason 
15. Patients with acute or chronic pancreatitis. 
16. Patients with external biliary drains. 
17. Patients with impaired cardiac function or clinically significant cardiac diseases, including 
any of the following: 
a. History (<6 months) or presence of serious uncontrolled ventricular arrhythmias or 
atrial fibrillation 
b. Clinically significant resting bradycardia 
c. LVEF < 50% as determined by MUGA scan or ECHO 
d. Any of the following within 6 months prior to starting study drug: myocardial 
infarction (MI), severe/unstable angina, coronary artery bypass graft (CABG), 


 
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congestive heart failure (CHF) requiring treatment, cerebrovascular accident (CVA), 
transient ischemic Attack (TIA), deep vein thrombosis, or pulmonary embolism 
e. Uncontrolled hypertension defined by a SBP ≥ 160 mm Hg and/or DBP ≥ 100 mm Hg, 
with or without anti-hypertensive medication(s). Initiation or adjustment of 
antihypertensive medication(s) is allowed prior to study entry. 
f. QTcF >470 msec (for male and female) on screening ECGs 
18. Patients with uncontrolled diabetes mellitus. 
19. Patients with clinical evidence of active CNS leukemia 
20. Patients who have received allogeneic stem cell transplant and/or have active graft-versus- 
host disease (GVHD) 
21. Patients who have received autologous stem cell transplant within last 4 weeks 
22. Impairment of GI function or GI disease that may significantly alter the absorption of 
BGJ398 (e.g. severe ulcerative diseases, uncontrolled nausea, vomiting, diarrhea, 
malabsorption syndrome, or small bowel resection) 
23. Any other condition that would, in the Investigator’s judgment, contraindicate patient’s 
participation in the clinical study due to safety concerns or compliance with clinical study 
procedures, e.g. infection/inflammation, intestinal obstruction, unable to swallow oral 
medication, social/psychological complications 
24. Patients who have been treated with any hematopoietic colony-stimulating growth factors 
(e.g., G-CSF, GM-CSF) ≤ 2 weeks prior to starting study drug. Erythropoietin or 
darbepoetin therapy, if initiated at least 2 weeks prior to enrollment, may be continued. 
Restriction is not applicable for patients with Leukemia 
25. Patient has received chemotherapy or anticancer therapy ≤ 4 weeks (6 weeks for 
nitrosourea, monoclonal antibodies or mitomycin-C) prior to starting study drug or who 
have not recovered to a grade 1 from side effects of such therapy (except for alopecia and 
neuropathy). Patients with leukemia may receive therapy with hydroxyurea and/or steroids 
for the purpose of cytoreduction but must discontinue use prior to first dose of study drug. 
26. Patients who have received the last administration of an anticancer targeted small 
molecule therapy (e.g. sunitinib, pazopanib, everolimus) ≤ 2 weeks prior to starting study 
drug, or who have not recovered from the side effects of such therapy. 
27. Patients not able to discontinue their current anti-cancer therapy prior to first dose of study 
drug. 
28. Patients who have received radiotherapy ≤ 4 weeks prior to starting the study drug or who 
have not recovered from radiotherapy-related toxicities (note: palliative radiotherapy for 
bone lesions ≤ 2 weeks prior to starting study drug is allowed) 
29. Patients who have undergone major surgery (e.g., intra-thoracic, intra-abdominal, intra- 
pelvic) ≤ 2 weeks prior to starting study treatment or who have not recovered from side 
effects of such surgery. 
30. Patients with previous or concurrent primary malignancy within 3 years prior to starting 
study treatment, with the exception of adequately treated basal cell carcinoma, squamous 
cell carcinoma or other non-melanomatous skin cancer, or in-situ carcinoma of the uterine 
cervix treated curatively and without evidence of recurrence. 


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31. Cirrhosis of the liver or known hepatitis B or C infection that is either acute or is 
considered chronic because the virus did not become undetectable: 
a. Hepatitis C Virus (HCV) infection: acute or chronic infection as depicted by a 
positive HCV RNA testing (note: in a patient with known anti-HCV but with a 
negative test for HCV RNA, re-testing for HCV RNA 4-6 months later is requested to 
confirm the resolution of HCV infection). 
b. Hepatitis B Virus (HBV) infection: acute infection (HBsAg+ with or without 
HBeAg+ or detectable serum HBV DNA), HBV carriers as evidence by ongoing 
presence of HBsAg and detectable serum HBV DNA levels. 
32. Patients who have received investigational agents within ≤ 5t1/2 of the agent (or ≤ 4 weeks 
when half-life is unknown) prior to starting study drug. 
33. Known diagnosis of human immunodeficiency virus (HIV) infection (HIV testing is not 
mandatory). 
34. Patient has a history of non-compliance to medical regimen 
35. 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 
36. 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 patients on the 
study the vasectomized male partner should be the sole partner for that patient. 
• Combination of the following (a+b or a+c, or b+c): 
a. Use of oral, injected or implanted hormonal methods of contraception or other 
forms of hormonal contraception that have comparable efficacy (failure rate 
<1%), for example hormone vaginal ring or transdermal hormone contraception 
b. Placement of an intrauterine device (IUD) or intrauterine system (IUS) 
c. Barrier methods of contraception: Condom or Occlusive cap (diaphragm or 
cervical/vault caps) with spermicidal foam/gel/film/cream/vaginal suppository 
In case of use of oral contraception women should have been stable on the same oral 
contraception for a minimum of 3 months before taking study treatment. 
Oral contraceptives (OC), injected or implanted hormonal methods are not allowed as the sole 
method of contraception because BGJ398 has not been characterized with respect to the 
potential to interfere with PK and/or the effectiveness of OCs. 


 
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Post-menopausal women are allowed to participate in this study. Women are considered post- 
menopausal and not of child bearing potential if they have had 12 months of natural 
(spontaneous) amenorrhea with an appropriate clinical profile (e.g. age appropriate, history of 
vasomotor symptoms) or have had surgical bilateral oophorectomy (with or without 
hysterectomy) or tubal ligation at least six weeks ago. In the case of oophorectomy alone,  
only when the reproductive status of the woman has been confirmed by follow up hormone 
level assessment, then she will be considered not of child bearing potential. 
37. Sexually active males unless they use a condom during intercourse while taking drug and 
for 3 months after the last dose of the study drug and should not father a child in this 
period. A condom is required to be used also by vasectomized men in order to prevent 
delivery of the drug via seminal fluid. 
 
6 
Treatment 
6.1 
Study treatment 
The investigational or study drug to be used in the course of this trial is BGJ398 oral 
formulation. 
Novartis Drug Supply Management or its designee will provide BGJ398 as 100-mg and 25- 
mg hard gelatin capsules as individual patient supply, packaged in bottles or blisters. BGJ398 
will be dosed on a flat scale and not be adjusted to body weight or body surface area. 
 
6.1.1 
Dosing regimen 
BGJ398 will be dosed on a flat scale of 125 mg (e.g., 1 x 100 mg and 1 x 25 mg capsules) 
once daily for the first 21 days of the 28-day cycle (3 weeks on, 1 week off in a cycle). A 
complete treatment cycle is defined as 28 days (refer to Table 6-1). 
The patient must continue to meet all eligibility criteria on C1D1, as they did during the 
screening period. Refer to Section 7.1 for more details. 
 
Table 6-1 
Dose and treatment schedule 
Pharmaceutical form 
Study 
treatment 
and route of 
administration 
Dose 
Frequency and/or 
Regimen 
BGJ398 
Capsule(s) for oral use 
125 mg (administered as one 
100 mg capsule and one 25 mg 
capsule) 
Daily (3 weeks on, 1 week 
off schedule in 28-day 
cycles) 
 
 
6.1.1.1 
BGJ398 administration 
The following general guidelines should be followed for administration. 
• Patients should be instructed to take their daily dose of BGJ398 in the morning, at 
approximately the same time each day (24 ± 2 hour interval). 
• BGJ398 should be administered in the fasted state, at least 1 hour before or 2 hours after a 
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• Phosphate binders should be given with meal (low phosphate diet), every day on days 
BGJ398 is given. No treatment with phosphate binders is needed during the BGJ398 off 
week in a cycle, unless the lab results indicate higher serum phosphorus levels that require 
continuous treatment with phosphate binders. 
• BGJ398 should be taken with a large glass of water (~250 mL) and consumed over as 
short time as possible. Patients should be instructed to swallow the capsules whole and not 
to chew or crush them. 
• If the patient forgets to take the scheduled dose in the morning, he/she should not take the 
dose more than 2 hours after the usual time and should continue treatment the next day. 
Any doses that are missed should be skipped altogether and should not be replaced or 
made up at the next scheduled dosing. 
• Patients must avoid consumption of grapefruit, grapefruit juice, grapefruit hybrids, 
pomelos, pomegranates, star fruits, Seville oranges or juice within 7 days prior to the first 
dose of study medications, through the end of study participation. This is due to potential 
CYP3A4 interaction with the study medications. Orange juice is allowed. 
• 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. 
• If vomiting occurs during the course of treatment, no re-dosing of the patient is allowed 
before the next scheduled dose. The occurrence and frequency of any vomiting and/or 
diarrhea (or increased stool frequency) must be noted in the AEs section of the eCRF. 
• At each visit, responsible site personnel will ensure that the appropriate dose of each study 
drug is administered and will provide the patient with the correct amount of study drug(s) 
for subsequent dosing. Patients will be instructed to return unused study drugs to the site 
at the end of each cycle. 
• The investigator (or his/her designee) must instruct the patient to take BGJ398 exactly as 
prescribed. The patient should be instructed to contact the investigator (or his/her designee) 
if he/she is unable for any reason to take BGJ398 as prescribed. All dosages prescribed 
and dispensed to the patient, and all dose changes during the study, must be recorded on 
the Dosage Administration Record eCRF. Patients must be advised to bring their unused 
BGJ398 capsules/tablets to the investigative site at each visit. 
 
6.1.2 
Guidelines for continuation of treatment 
Patients will be treated until disease progression (as assessed by investigator per RECIST 1.1 
or appropriate hematologic response criteria or for patients with TIO diagnosis the recurrence 
or progression of disease or recurrence of abnormal metabolic parameters) or unacceptable 
toxicity death or discontinuation from study treatment for any other reason (e.g., withdrawal 
of consent, start of a new anti-neoplastic therapy or at the discretion of the investigator). 
Patients with TIO diagnosis that progress per RECIST but per investigator’s assessment are 
receiving clinical benefit from treatment may remain on study upon approval from Novartis. 


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Guidance for continuation of study treatment in case of toxicity (e.g. dose delay and/or 
modification) is provided in Section 6.3. 
 
6.1.3 
Treatment duration 
Patients may continue treatment with the study drug until the patient experiences unacceptable 
toxicity that precludes further treatment, disease progression as assessed by the investigator 
(per RECIST 1.1 or appropriate hematological response assessment criteria or for patients 
with TIO diagnosis the recurrence or progression of disease or recurrence of abnormal 
metabolic parameters), death and/or treatment is discontinued due to any other reason. 
Patients with TIO diagnosis that progress per RECIST but per investigator’s assessment are 
receiving clinical benefit from treatment may remain on study upon approval from Novartis. 
The reason for end of treatment (EOT) will be recorded in the corresponding eCRF. 
 
6.2 
Dose escalation guidelines 
Not applicable. 
 
6.3 
Dose modifications 
6.3.1 
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. Any changes in 
BGJ398 administration must be recorded on the Dosage Administration Record eCRF. 
BGJ398 dose modification guidelines are described in Section 6.3.2. Any planned variance 
from these guidelines in the view of the patient safety must be previously discussed with the 
sponsor unless there is an urgent need for action. 
All dose modifications, interruptions or discontinuations must be based on the worst 
preceding toxicity as graded by the NCI Clinical Toxicity Criteria for adverse events (NCI- 
CTCAE version 4.03). Once a dose has been reduced during a treatment cycle, re-escalation 
will not be permitted during any subsequent cycle. 
If the administration of BGJ398 is interrupted for reasons other than toxicity, then treatment 
with the study drug may be resumed at the same dose. The same applies if the patient 
experienced an unacceptable toxicity not specifically described in Table 6-3 or Section 6.3.4, 
provided this toxicity resolved to ≤ CTCAE grade 1, unless otherwise specified. 
 
6.3.2 
Permitted study treatment adjustments for BGJ398 
For patients who are unable to tolerate the protocol-specified dosing schedule, dose reductions 
or interruptions are permitted to manage drug-related toxicities. For patients with TIO 
diagnosis additional dose reductions may be allowed upon Novartis approval. 
• When dose reduction is necessary, the dose of BGJ398 may be reduced to 100 mg, QD. 
• If an additional dose reduction is required, BGJ398 may be reduced to 75 mg, QD. 
• Once the BGJ398 dose is reduced it cannot be re-escalated. 
• All dose reductions should be based on the worst preceding toxicity. 


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• Patients are allowed only 2 dose reductions (to 100 mg and 75 mg) as specified in (Table 
6-2). 
 
Table 6-2 
BGJ398 dose modifications 
BGJ398 Dose Level 
BGJ398 Dose 
 
Starting dose level (0) 125 mg po QD (3 weeks on, 1 week off in a 28 day cycle) 
Dose level – 1 
100 mg po QD (3 weeks on, 1 week off in a 28 day cycle) 
Dose level – 2 
75 mg po QD (3 weeks on, 1 week off in a 28 day cycle) 
• A third or subsequent reduction (to 50 mg, QD) 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. For patients with TIO diagnosis without measureable/evaluable 
disease, the assessment criteria for additional dose reduction will be the tumor associated 
improvement of metabolic parameters. A third reduction or subsequent dose reduction 
requires approval from Novartis. 
Patients whose treatment is interrupted or permanently discontinued due to an adverse event 
including abnormal laboratory values must be followed at least once a week for 4 weeks, and 
subsequently at 4-week intervals, until resolution or stabilization of the event, whichever 
comes first. The maximum time allowed for treatment interruption due to toxicity is 14 days 
(2 weeks) from the intended dosing day. If interruption is > 14 days, the patient must be 
discontinued from the study treatment. However, the patient will continue to be followed for 
toxicity. Dose interruptions should be reported on the appropriate Dosage Administration 
eCRF. 
 
6.3.3 
Criteria for interruption and re-initiation of BGJ398 treatment 
If the administration of BGJ398 must be interrupted because of an unacceptable toxicity, 
BGJ398 dosing will be interrupted or modified according to rules described in Table 6-3. 
A patient who requires a dose interruption (regardless of the reason for the interruption) 
lasting >14 days (counting from the first day when a dose was missed) should discontinue the 
study treatment unless clearly demonstrating clinical benefit. 


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Table 6-3 
BGJ398 related toxicity management guidelines 
 
Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
Cardiac disorders 
Cardiac - Prolonged QTcF interval 
Grade 1 and 2 : QTcF ≥ 481msec and ≤ 500 msec 
(asymptomatic) 
Maintain dose level of BGJ398 
ECG (Electrocardiogram) 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 and if the QTcF prolongation was 
confirmed by the central reader, patients may be re-treated at one lower dose 
level at the investigator’s discretion 
• 
ECG assessments should be performed for 2 additional cycles at the same 
frequency as in cycle 1 or as clinically indicated 
• 
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), 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
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. 
Whenever QTcF > 500msec is observed, a plasma sample for determination of 
BGJ398 concentration should be obtained with the time of sample collection noted. 
Cardiac disorders - others 
Grade ≥ 3, or congestive heart failure ≥ 2 
Discontinue patient from study treatment. 
Investigations-Hematology 
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 (repeat 
parameter at least twice a week and as indicated), then 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398 
• 
If resolved within > 7 days, ↓ 1 dose level of BGJ398. 
Hold dose until resolved to CTCAE Grade ≤ 1 or baseline (repeat parameter at 
least twice a week and as indicated), then: 
• 
If resolved by ≤ 7 days after suspending BGJ398, maintain dose level. 
• 
If resolved by > 7 days after suspending BGJ398, ↓ 1 dose level. 
Febrile neutropenia 
Grade 3 (ANC < 1.0 x 109/L, single temperature of > 38.3°C or a 
sustained temperature of ≥ 38.0°C) 
Grade 4 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1, then 
• 
If resolved within ≤ 7 days, ↓ 1 dose level of BGJ398. 
• 
If not resolved within 7 days discontinue patient from study drug treatment. 
Discontinue patient from study treatment. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
Hemoglobin 
Grade 3 (<8.0 mg/dL – 6.5 mg/dL) 
Grade 4 (< 6.5 mg/dL) 
Hold dose of BGJ398 until resolved or corrected to CTCAE Grade ≤ 1 or baseline, 
then maintain dose level 
Hold dose of BGJ398 until resolved or corrected 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 orGrade 4 (PLT < 
25 x 109/L ) 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline (repeat 
parameter at least twice a week and as indicated), then: 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved within > 7 days, ↓ 1 dose level of BGJ398 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline (repeat 
parameter at least twice a week and as indicated), then ↓ 1 dose level 
Investigations – Renal 
Serum creatinine 
Grade 1 
Grade 2 
Grade ≥ 3 or 4 
Maintain dose level 
Omit dose until resolved to CTCAE Grade ≤ 1 or baseline, then: 
• 
If resolved by ≤ 7 days after suspending BGJ398, maintain dose level. 
• 
If resolved by > 7 days after suspending BGJ398, ↓ 1 dose level. 
Omit dose and discontinue patient from study. 
If serum creatinine Grade ≥ 2 has been demonstrated in conjunction with 
hyperphosphatemia, serum creatinine levels must be repeated at least weekly 
until resolution, and 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 clinically indicated to evaluate 
de-novo calcifications until resolution or stabilization of creatinine. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
Investigations – Hepatic 
Blood bilirubin (patients with Gilbert Syndrome these dose 
modifications apply to changes in direct bilirubin only) 
Grade 2 for > 7 consecutive days 
Grade ≥ 3 
Grade 4 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline (repeat 
parameter at least twice a week and as indicated), then: 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved within > 7 days, ↓ 1 dose level of BGJ398. 
Omit dose until resolved to CTCAE Grade ≤ 1or baseline (repeat parameter at least 
twice a week and as indicated), then ↓ 1 dose level. 
Discontinue patient from study treatment. 
Patients with total bilirubin ≥ Grade 1 (any duration) should have fractionation of 
bilirubin into total/direct or indirect/direct components and any additional work-up as 
clinically indicated by these results. Follow-up of hyperbilirubinemia should proceed 
as per the guidelines mentioned above, irrespective of the results of fractionation. 
AST or ALT 
Grade 3 
Grade 4 
Hold dose of BGJ398 until resolved to CTCAE Grade ≤ 1 or baseline (repeat 
parameter at least twice a week and as indicated), then: 
• 
If resolved within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved within > 7 days, ↓ 1 dose level of BGJ398. 
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 within ≤ 7 days, ↓ 1 dose level of BGJ398. 
• 
If resolved within > 7 days, discontinue patient from study treatment. 
Discontinue patient from study treatment. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
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, drug should be held and continuation of therapy should be discussed 
with the medical monitor following resolution to ≤ grade 2. 
For any grade 4 asymptomatic lipase or amylase elevation, drug should be held 
and continuation of therapy should be discussed with the medical monitor following 
resolution to ≤ grade 2. 
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 > 7.0 mg/dL for more than 7 days despite 
maximal phosphate lowering therapy (Sevelamer), Or, Single 
serum phosphorus > 9.0 mg/dL regardless of duration or dose of 
phosphate lowering therapy (Sevelamer). 
(Start phosphate lowering therapy from Cycle 1 Day 1. 
Optimize/maximize dose and schedule of phosphate lowering 
therapy in accordance with package insert, country or institutional 
guidelines.) 
Hold BGJ398 dose until resolved to serum phosphorus ≤ 5.5 mg/dL: 
Restart BGJ398 at the same dose level with maximal phosphate binder dosing if 
the patient did not receive maximal phosphate binder dosing for serum 
phosphorus > 7.0 mg/dL for > 7 days. 
Reduce one dose level of BGJ398 if the patient had received maximal phosphate 
lowering therapy for serum phosphorus > 7.0 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) for “3 weeks on / 1 week off” dosing regimen and during 
BGJ398 dose interruptions for non-hyperphosphatemia adverse events. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
Hypercalcemia 
Serum calcium grade 2 
Serum calcium ≥ grade 3 
Hold BGJ398 dose until resolved to grade 1 or baseline: 
• 
if resolved within ≤ 7 days after suspending BGJ398, maintain dose level 
• 
if resolved within > 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 
Diarrhea 
Grade 1 
Grade 2 
Grade 3 
Maintain dose level of BGJ398,initiate anti-diarrheal treatment 
• 
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 
• 
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. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
Grade 4 
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 
Eye Disorders (confirmed by ophthalmologic examination) 
Retinal and Corneal disorders 
Grade 2 CSR and CSR-like events, Grade 2 Corneal disorder 
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 within ≤ 14 days, ↓ BGJ398 by 1 dose level 
• 
If resolved within > 14 days, discontinue BGJ398 
Hold BGJ398 until resolved to grade ≤ 1. 
• 
If resolved within ≤ 14 days, ↓ BGJ398 by 1 dose level 
• 
If resolved within > 14 days, discontinue BGJ398 
Discontinue BGJ398 
Other ocular/visual toxicity 
≥ grade 3 
Hold BGJ398 until resolution to ≤ grade 1 
If resolution within ≤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 within ≤ 7 days, maintain dose level of BGJ398. 
• 
If resolved within > 7 days, discontinue patient from study treatment. 


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Worst Toxicity CTCAE v4.03 Grade (unless otherwise 
specified) 
Recommended Dose Modifications any time during a cycle of therapy 
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 reduction has occurred, no dose increases can be subsequently 
implemented. Patients who require more than two dose reductions of BGJ398 will be generally discontinued from study drug treatment. 


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6.3.4 
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 approximately 4-week intervals, until resolution or stabilization of the event, 
whichever comes first. 
Clinical experts or specialists, such as ophthalmologist, endocrinologist, 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 doses of BGJ398. 
 
6.3.5 
Anticipated risks and safety concerns of the study drug 
Appropriate eligibility criteria as well as specific dose modification are included in this 
protocol. Recommended guidelines for prophylactic or supportive treatment for expected 
toxicities, 
including 
management 
of 
study-drug 
induced 
adverse 
events, 
i.e., 
hyperphosphatemia, renal toxicities are provided in Section 6.3.3. Refer to preclinical toxicity 
and or clinical data found in the [Investigator’s Brochure]. 
 
6.4 
Concomitant medications 
In general, the use of any concomitant medication/therapies deemed necessary for the care of 
the patient is permitted (see Section 6.4.1 and Section 6.4.2), except as specifically prohibited 
(see Section 6.4.3). 
The patient must be told to notify the investigational site about any new medications he/she 
takes after the start of study treatment. All medications and non-drug therapies (including 
physical therapy, oxygen, and blood transfusions) administered to the patient within 30 days 
prior to the first dose of study drug, during the course of the study, and until 30 days after the 
last dose of study drug, must be reported on the appropriate eCRFs. 
Patients must be instructed to not take additional medications (including over-the-counter 
products and herbal/alternative medications) during the study without prior consultation with 
the investigator. 
Patients taking chronic medications should be maintained on the same dose and schedule 
throughout the study period, if medically feasible. 
 
6.4.1 
Permitted concomitant therapy 
In addition to receiving the study treatment, all patients should receive best supportive care 
(BSC), as per standard local practice for the treatment of pre-existing medical conditions or 
adverse events that may arise during the study. BSC is defined as drug or non-drug therapies, 
nutritional support, physical therapy, or any other treatment alternative that the investigator 
believes to be in the patient’s best interest, but excluding other antineoplastic treatments. 
Pain medication to allow the patient to be as comfortable as possible, nutritional support or 
appetite stimulants (e.g., megestrol), and oxygen therapy and blood products or transfusions 
will be allowed unless otherwise prohibited in Section 6.4.3. 


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For ongoing patients only: 
For patients with TIO diagnosis phosphate supplementation is allowed, and may be titrated 
until discontinuation as clinically indicated throughout BGJ398 administration. Other 
permitted supplementation for patients with TIO diagnosis includes calcitriol and cinacalcet 
supplementation. 
 
6.4.1.1 
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 as per the label of these agents or as dictated by 
local practice or guidelines established by the American Society of Clinical Oncology 
(ASCO). 
 
6.4.1.2 
Hormone replacement therapies 
Hormone replacement therapies such as thyroid and growth hormones are allowed, as well as 
estrogen replacement hormone treatment. 
 
6.4.1.3 
Phosphate-lowering therapy 
Phosphate-lowering treatment, including low phosphate diet and phosphate binding therapy, 
such as sevelamer hydrochloride, should be implemented prophylactically at study drug 
initiation and modified as clinically indicated throughout BGJ398 administration. 
For patients with TIO diagnosis no prophylactic phosphate lowering therapy should be 
implemented. 
 
6.4.2 
Permitted concomitant therapy requiring caution and/or action 
 
6.4.2.1 
Drugs that alter the pH of the GI tract 
BGJ398 is characterized by pH-dependent solubility, and therefore, medicinal products that 
alter the pH of the upper gastro-intestinal tract may alter the solubility of BGJ398, and limit 
bioavailability. 
 
6.4.2.2 
CYP substrates and inhibitors 
BGJ398 was shown to inhibit the CYP3A4 in in-vitro assays, thus, suggesting an increased 
risk of drug interactions with concomitant medications that are metabolized by CYP3A4. 
BGJ398 is a substrate of CYP3A4. Therefore moderate inhibitors and inducers should be used 
with caution if no other alternative is available. See Appendix P. 
 
6.4.2.3 
Transporter substrates 
In vitro data show that BGJ398 is an inhibitor of BCRP. Medications which are BCRP 
substrates must be monitored for potential toxicity and may require dose titration or reduction 
of the medication. 


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6.4.2.4 
Anti-emetics 
Anti-emetics are allowed for the treatment of nausea or vomiting. It is recommended to avoid 
using drugs that are known to cause QT prolongation. Note that some anti-emetics have a 
known risk for Torsade de Pointes, and therefore need to be used with caution (Appendix C). 
Aprepitant is both a sensitive substrate and a moderate CYP3A4 inhibitor and should be used 
with caution if an alternative is not available. 
 
6.4.2.5 
Medications with a possible or conditional risk of QT/QTc interval 
prolongation or Torsade de Pointes 
Preliminary data have shown that BGJ398 has no effect on cardiac conduction or ECG 
intervals (see current version of the BGJ398 Investigator Brochure). However, medications 
that have the potential to prolong the QT/QTc interval or induce Torsade de Pointes are 
allowed with caution. Investigators at their discretion may co-administer such medications, 
but patients should be carefully monitored. See Appendix P for list of drugs that need to be 
used with caution. Please note that the list might not be comprehensive. 
 
6.4.3 
Prohibited concomitant therapy 
 
6.4.3.1 
Other investigational and anti-neoplastic therapies 
Concurrent use of other investigational drugs is not permitted. 
Anticancer therapy (chemotherapy, biologic or radiation therapy (that includes > 30% of the 
bone marrow reserve and surgery) 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. 
 
6.4.3.2 
CYP inhibitors 
Strong inhibitors of CYP3A4 are prohibited because BGJ398 is a likely substrate of this 
isoenzyme. See Appendix Q. 
 
6.4.3.3 
CYP inducers 
Strong inducers of CYP3A4 are prohibited because their usage may decrease the exposure of 
BGJ398. Please note that the list may not be exhaustive. See Appendix Q. 
 
6.4.3.4 
Phosphorus and calcium 
Medications that increase the serum levels of phosphorus and/or calcium are prohibited. 
 
6.4.3.5 
Known risk of QT/QTc interval prolongation or Torsade de Pointes 
medications 
Preliminary data have shown that BGJ398 has no effect on cardiac conduction or ECG 
intervals (See current version of the BGJ398 [Investigator’s Brochure]). However, 
medications that are known to prolong the QT/QTc interval or induce Torsade de Pointes 
(Risk of TdP/QT prolongation) are prohibited. 


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Please refer to Appendix Q for the list of prohibited medications. Please note that the list 
might not be comprehensive. 
 
6.4.3.6 
Anticoagulants 
Warfarin or any other coumadin-derivative anticoagulants are not permitted. Heparin and/or 
low molecular weight heparins are allowed 
 
6.5 
Patient numbering, treatment assignment and enrollment 
6.5.1 
Patient numbering 
Each patient is identified in the study by a Patient Number (Patient No.), that is assigned when 
the patient is first screened and is retained as the primary identifier for the patient throughout 
his/her entire participation in the trial. The Patient 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 informed consent form, the patient is assigned to the next sequential Patient No. 
available at the site. 
 
6.5.2 
Treatment assignment and randomization 
Not applicable. 
 
6.5.3 
Treatment blinding 
This is an open-label study. 
 
6.6 
Study drug preparation and dispensation 
The investigator or responsible site personnel must instruct the patient or caregiver to take the 
study drugs as per protocol. Study drug(s) will be dispensed to the patient by authorized site 
personnel only. All dosages prescribed to the patient and all dose changes during the study 
must be recorded on the Dosage Administration Record eCRF. 
Patients will be provided with an adequate supply of study drug for self-administration at 
home, including instructions for administration, until at least their next scheduled study visit. 
Patients will receive BGJ398 on an outpatient basis. The investigator shall provide the patient 
with instructions for BGJ398 administration according to the protocol. 
 
6.6.1 
Study drug packaging and labeling 
BGJ398 will be supplied as 100 mg and 25 mg capsules (refer to Table 6-4). BGJ398 capsules 
are packaged in HDPE bottles with child resistant closures. 
Medication labels will comply with US legal requirements and are printed in the local 
language. The label contains BGJ398 identifying information (e.g., formulation, batch number, 
and expiration date), the patient number (to be entered by the investigator or designee) and 
storage conditions. 


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Table 6-4 
Packaging and labeling 
Study 
treatments 
Packaging 
Labeling (and dosing frequency) 
BGJ398 
(BGJ398) 
Capsules (25 mg and 100 
mg) in bottles 
Labeled as BGJ398 
Dosing frequency: once-a-day, 21 days on, 7 days 
off in a cycle of 28 days 
 
 
6.6.2 
Drug supply and storage 
Each site will be supplied by Novartis with oral BGJ398. Study drug must be received by a 
designated person at the study site, handled and stored safely and properly, and kept in a 
secured location to which only the 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]. These instructions should also be made clear to the 
patient for storage and self-administration of BGJ398 at home. 
Site staff will be responsible for managing adequate re-supplies for BGJ398. 
 
6.6.3 
Study drug compliance and accountability 
 
6.6.3.1 
Study drug compliance 
Compliance will be assessed by the investigator and/or study personnel at each patient visit 
and information provided by the patient and/or caregiver must be captured in the source 
document at each patient visit. 
 
6.6.3.2 
Study drug accountability 
The investigator or designee must maintain an accurate record of the shipment and dispensing 
of study treatment in a drug accountability log. Drug accountability will be noted by the field 
monitor during site visits and at the completion of the study. Patients will be asked to return 
all unused study treatment and packaging on a regular basis, at the end of the study or at the 
time of study treatment discontinuation. 
At study close-out, and, as appropriate during the course of the study, the investigator will 
return all used and unused study treatment, packaging, drug labels, and a copy of the 
completed drug accountability log to Novartis or designee. 
 
6.6.4 
Disposal and destruction 
The study drug supply can be destroyed at the local Novartis facility, Drug Supply group or 
third party, as appropriate. Study drug destruction at the investigational site will only be 
permitted if authorized by Novartis in a prior agreement and if permitted by local regulations. 


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7 
Visit schedule and assessments 
7.1 
Study flow and visit schedule 
Table 7-1 lists all of the assessments and indicates with an “X”, the visits when they are 
performed. All data obtained from these assessments must be supported in the patient’s source 
documentation. The table indicates which assessments produce data to be entered into the 
database (D) or remain in source documents only (S) (“Category” column). Every effort must 
be made to follow the schedule of assessments within the ±4 days. 


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Table 7-1 
Visit evaluation schedule 
 
Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
ALL PATIENTS 
INFORMED CONSENT 
Tumor sample (archival or fresh) for 
pathway activation 
D 
7.1.1 & 
7.2.4.2. 
X 
X13 
Informed consent 
D 
7.1.1. 
X 
PATIENT HISTORY 
Demography 
D 
7.1.1.3. 
X 
Inclusion/exclusion criteria 
S 
5.2 & 5.3. 
X 
Eligibility checklist 
S 
7.1.1.1. 
X 
End of phase disposition 
D 
7.1.3.1. 
X 
Relevant medical history/ 
current medical conditions 
D 
7.1.1.3. 
X 
Diagnosis and Extent of cancer 
D 
7.1.1.3. 
X 
Prior anti-neoplastic therapy 
D 
7.1.1.3. 
X 
PHYSICAL EXAMINATION 
Physical examination 
S 
7.2.2.1. 
X 
X4 
X 
X 
X 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
Vital signs 
D 
7.2.2.2. 
X 
X4 
X 
X 
X 
Height 
D 
7.2.2.3. 
X 
Weight 
D 
7.2.2.3. 
X 
X4 
X 
X 
X 
Ophthalmic examination 
D 
7.2.2.4. 
X 
X 
X 
1st day of every 
subsequent cycle 
X 
ECOG performance status 
D 
7.2.2.5. 
X 
X4 
X 
X 
X 
IMAGING AND OTHER ASSESSMENTS 
Cardiac imaging (MUGA/ECHO) 
D 
7.2.2.8.2. 
X 
Monthly for the first 4 cycles. For subsequent 
cycles, 
If clinically indicated 
X 
ECG 
D 
7.2.2.8.1. 
X 
X4 
X 
X 
X 
X 
X 
LABORATORY ASSESSMENTS 
Hematology 
D 
7.2.2.6.1. 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
Biochemistry 
(including liver function tests) 
D 
7.2.2.6.2. 
X 
X4 
X 
X 
X 
X 
X 
X 
X 
FGF23 plasma level16 
D 
7.2.2.6.7. 
X 
X4 
X 
X 
X 
X 
1-25-dihydroxy vitamin D16 
D 
7.2.2.6.7. 
X 
X4 
X 
X 
X 
X 
Thyroid Function 
D 
7.2.2.6.3. 
X 
X4 
every 3 cycles 
starting from C3D1 
or If clinically 
indicated 
X 
Cardiac enzymes 
D 
7.2.2.8.3. 
X 
If clinically indicated 
Coagulation 
D 
7.2.2.6.4. 
X 
X4 
If clinically indicated 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
Urinalysis 
D 
7.2.2.6.5. 
X 
X4 
X 
X 
X 
Pregnancy test6 
D 
7.2.2.6.6. 
X 
X4 
X 
X 
X 
SAFETY 
Prior and concomitant medications 
D 
6.4. 
X 
Continuous 
X 
Surgical and medical procedures 
D 
6.4. 
X 
Continuous 
X 
Adverse events 
D 
8.1. 
X 
Continuous 
X 
DRUG ADMINISTRATION AND OTHERS 
BGJ398 administration 
D 
6.1.1. 
Daily [3 weeks on, 1 week off every cycle] 
Prophylactic phosphate-lowering 
therapy10,15 
D 
6.4.1.3. 
Daily with meal (low-phosphate diet) on days 
BGJ398 is given10 
Survival 
D 
7.1.4.3. 
X 
ADDITIONAL EFFICACY ASSESSMENTS 
SOLID TUMOR 
Physical examination for 
measurement of superficial disease 
(only if present)9 
D 
7.2.1.1.1. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans3,5,7,8) 
D 
7.2.1.1.4. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
Cancer Antigen-125 
(for ovarian cancer only) 
D 
7.2.1.1.2. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Prostate-specific antigen (PSA) (for 
prostate cancer only) 
D 
7.2.1.1.3. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
LYMPHOMA 
Examination for enlarged spleen or 
liver 
D 
7.2.1.2.1. 
X 
To confirm response of CR 
X 
Physical examination for 
measurement of superficial disease 
and B symptoms9 
D 
7.2.1.2.2. 
X 
Day 1 of every cycle (±4 days) after first dose of 
study drug 
X 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans3,5,7,8) 
D 
7.2.1.2.3. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.2.4. 
To confirm response of CR11 
Serum protein electrophoresis 
(SPEP) 
D 
7.2.1.2.5. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter only if abnormal M-protein detected at 
baseline 
X 
PET Scan 
D 
7.2.1.2.6. 
To confirm response of CR (can be part of CT/PET) 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
SYMPTOMATIC MULTIPLE MYELOMA 
Skeletal Survey 
D 
7.2.1.3.1. 
X 
If clinically indicated 
Urine protein electrophoresis 
(UPEP)7 
D 
7.2.1.3.2. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Free light chain7 
D 
7.2.1.3.3. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Serum protein electrophoresis 
(SPEP)7 
D 
7.2.1.3.4. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
MRI/CT Scans (For plasmacytoma 
Only) 
D 
7.2.1.3.5. 
X 
Every 8 weeks (±4 days) after first dose of study drug 
(Day 1 of every odd cycle) for the first 16 weeks of 
treatment and every 16 weeks (±4 days) thereafter 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.3.6. 
X 
To confirm response of CR 
CHRONIC LYMPHOCYTIC LEUKEMIA (CLL) 
Examination for enlarged spleen or 
liver 
D 
7.2.1.2.1. 
X 
To confirm response of CR 
Physical examination for 
measurement of superficial disease 
and B symptoms9 
D 
7.2.1.2.2. 
X 
Day 1 of every cycle (±4 days) after first dose of 
study drug 
X 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
Radiological tumor assessment/ 
response assessment (MRI/CT 
Scans3,5,7,8) 
D 
7.2.1.2.3. 
X 
Every 8 weeks (±4 days) after first dose of study 
drug (Day 1 of every odd cycle) for the first 16 
weeks of treatment and every 16 weeks (±4 days) 
thereafter 
X 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.2.4. 
To confirm response of CR 
Peripheral Blood for CBC differential 
and blast count 
D 
7.2.1.4.1. 
X 
X 
X 
X 
X 
X 
X 
Physical examination for assessment 
of Extramedullary disease or 
Organomegaly (if present) 
D 
7.2.1.4.3. 
X 
X 
X 
X 
X 
X 
X 
LEUKEMIA, MDS, and ET 
Peripheral Blood for CBC 
differential and blast count 
D 
7.2.1.4.1. 
X 
X 
X 
X 
X 
X 
X 
Physical examination for assessment 
of Extramedullary disease or 
Organomegaly (if present) 
D 
7.2.1.4.3. 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.4.2. 
X 
To confirm response of CR or if clinically indicated 
Assessments of chromosomal 
abnormalities/Karyotype 
S 
7.2.1.4.4. 
X12 
Evaluation of transfusion dependency 
D 
7.2.1.4.5. 
X 
X 
X 
X 
X 
X 
X 
MF and PV 
Peripheral Blood for CBC 
differential and blast count 
D 
7.2.1.4.1. 
X 
X 
X 
X 
X 
X 
X 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
Physical examination for assessment 
of Extramedullary disease or 
Organomegaly (if present) 
D 
7.2.1.4.3. 
X 
X 
X 
X 
X 
X 
X 
Bone Marrow Biopsy or aspirate 
D 
7.2.1.4.2. 
X 
To confirm response of CR or if clinically indicated 
Assessments of chromosomal 
abnormalities/Karyotype 
S 
7.2.1.4.4. 
X12 
Evaluation of transfusion dependency 
D 
7.2.1.4.5. 
X 
X 
X 
X 
X 
X 
X 
Myeloproliferative Neoplasm (MPN) 
Symptom Assessment Form Total 
Symptom Score (MPN-SAF TSS) 
D 
7.2.1.4. 
X 
X 
X 
X 
X 
X 
X 
1 A complete cycle is defined as 28 days 
2 Additional survival assessments may be performed outside the 3 months follow-up schedules if a survival update is required for an interim assessment to meet safety or 
regulatory needs. 
3 Tumor assessments at EOT are required for patients who discontinue study treatment before the first scheduled post-screening tumor assessment and for patients 
whose previous tumor assessment did not demonstrate PD and was done at least 8 weeks (± 4 days) prior to end of treatment visit. 
4 These assessments should be performed only if the screening assessment occurred > 4 days from Cycle 1 Day 1. The patient must continue to meet all eligibility 
criteria on C1D1, as they did during the screening period prior to first dose. 
5 Tumor assessments include CT/MRI of the chest abdomen and pelvis at all timepoints. Tumor assessments are described in Section 7.2.1. 
6 Women of childbearing potential must undergo a serum pregnancy test at screening and EOT. Women of child-bearing potential will undergo monthly urine pregnancy 
tests during the study. 
7 For patients who have a response of PR or greater, a confirmation assessment must be performed at least 4 weeks after the initial observation. 
8 Upon implementation of amendment 2, the frequency of disease assessment will be reduced and evaluations should be every 16 weeks after the first 16 weeks on 
treatment. 
9 Skin lesions should be documented using a digital camera (color photography) in clear focus showing the ruler or calipers and the corresponding measurement in such 
a way that the size of the lesion(s) can be determined from the photograph 


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Category 
Reference to 
assessment 
Screening 
phase 
Treatment Phase 
Post 
treatment 
follow-up 
phase 
Survival 
phase 
Screening 
C1 
C2 
Subsequent 
cycles 
EOT 
Safety follow 
up 
Survival FU 
Visit Number 
1 
2 
3 
4 
5 
6 
7 
8 
777 
501 
701 
Cycle days1 
-28 to -1 
1 
8 
15 
21 
1 
15 
1 
EOT + 30 (±4) 
days 
EOT + every 
3 months2 
10 Phosphate binders should be given with meal (low phosphate diet), every day on days BGJ398 is given. No treatment with phosphate binders is needed during the 
BGJ398 off week in a cycle, unless the lab results indicate higher serum phosphorus levels that require continuous treatment with phosphate binders. Calcium-containing 
phosphate binders are not recommended. 
11 Only to confirm complete responses in patients with bone marrow tumor involvement prior to study treatment 
12 Information on the patient’s chromosomal abnormalities/karyotyping based on documented history prior to study entry must be present in his/her source documents. 12 
Additional testing to confirm these response categories will not be required and should be done at the discretion of the attending physician. 
13 For patients with a best response of Stable disease or better who discontinue study treatment due to disease progression, an optional tumor sample should be 
obtained for genomic analysis. For details, refer to Section 7.2.4. 
 
15 For patients with TIO diagnosis no prophylactic phosphate lowering therapy should be implemented 
16 Only applicable for patient with TIO diagnosis. FGF23 plasma levels and 1-25-dihydroxy vitamin D should be measured: at screening, C1D1 (if screening assessment 
occurred > 4 days from Cycle 1 Day 1), C1D15, and on Day1 of each subsequent cycles up to and including Day 1 of Cycle 5. Thereafter, should be measured every 16 
weeks and EOT. A +/-4 days window is allowed for each assessment 


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7.1.1 
Screening 
For the purpose of this study, genomic profiling is not considered part of screening. This  
study is intended for patients who have already had genomic profiling of their tumors in a 
CLIA certified laboratory and have already been pre-identified to have tumors with relevant 
pathway activation. Eligibility is based on the pathway-activation study as assessed in the 
local, CLIA certified laboratory. The results of this testing must be known prior to signing the 
ICF and before formal screening begins. Laboratory results must be ‘unambiguous’ or 
‘unequivocal’. Results that state ‘ambiguous’ or ‘equivocal’ imply low probability that 
genetic deregulation is truly present and an important driver of patient’s tumor. Written 
informed consent must be obtained before any study specific assessments are performed, 
including screening. All screening evaluations must be performed as closely as possible to the 
beginning of treatment and never more than 28 days prior to starting study drug dose of 
BGJ398 to confirm patient’s eligibility. 
Upon signing the Informed Consent Form (ICF), a patient will be assigned a 7-digit patient 
number. 
Patient must have archival tissue available for submission to allow for molecular testing 
related to pathway activation and other analyses. If the tissue is not available or not of 
sufficient quantity, the patient must be willing to undergo a fresh tumor biopsy to allow for 
this analysis. The tissue submitted will not be used to determine study eligibility. Eligibility is 
based on the local assessment. The tissue will be collected and may be analyzed at some 
future date for markers of pathway activation. 
Note: An archival or fresh tumor sample may not be required if the patient has had their 
genomic profiling performed at a laboratory selected by Novartis and the patient has agreed to 
allow Novartis to use baseline molecular analysis results. 
For the purposes of enrollment, the patient’s pathway activation status is based on the 
presence of known FGFR genetic alterations or FGF ligand amplification as assessed in a 
CLIA-certified laboratory and primary documentation in the form of a test result from that 
laboratory. 
Patients who fail to start on treatment may be re-screened. 
Disease assessments (per RECIST 1.1 or appropriate hematologic response criteria) must be 
performed within 28 days prior to enrollment and will be assessed locally by the investigator. 
When information from procedures (for example imaging assessments) that may have been 
previously performed as part of the patient’s routine disease care (prior to enrolling in the trial) 
is allowed to be used to satisfy inclusion criteria, if it was performed within 28 days before the 
start of study treatment. 
For laboratory evaluations used to determine eligibility, a repeated evaluation within the 
screening window is permitted for screening results out of the defined range. If the repeated 
laboratory result meets the criteria, that result may be used to determine eligibility. If the 
repeated laboratory result does not meet the criteria, the patient will be considered a screening 
failure. 


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For details of assessments, refer to Table 7-1 and Section 7.2. 
 
7.1.1.1 
Eligibility screening 
Once all screening procedures are completed, patient’s mutational status will be confirmed by 
Novartis or designee prior to the subject receiving the first dose of study drug. 
 
7.1.1.2 
Information to be collected on screening failures 
Patients who sign the ICF, but are not enrolled for any reason will be considered a screen 
failure. 
For screen failure patients, the reason for not proceeding with enrollment will be entered on 
the Screening Log eCRF. No waivers will be granted. 
The following eCRFs must be completed for screening failure patients: 
• Screening Log eCRF page (including reason for not being started on treatment) 
• Informed Consent 
• Demography 
• Serious Adverse Event after signing the ICF - see Section 8 for SAE reporting details. 
7.1.1.3 
Patient demographics and other baseline characteristics 
Patient information to be collected at screening will include: 
• Pathway regulation inhibited by BGJ398 status 
• Demographic data (age, gender, race) 
• Diagnosis and Extent of Cancer 
• Relevant Medical History (e.g., important medical, surgical, and allergic conditions from 
the patient’s medical history, which could have an impact on the patient’s evaluation) / 
Current Medical Conditions (e.g., all relevant current medical conditions which are 
present before the first dose of study drug is administered). 
• Cancer-related conditions and symptoms which are recorded on the Medical History 
eCRF should include the grade 
• Prior Anti-neoplastic Medications 
• Prior Anti-neoplastic Radiotherapy 
• Prior Anti-neoplastic Surgery 
• All other medications and non-drug therapies (including physical therapy, oxygen and 
blood transfusions) administered to the patient within 28 days prior to the first dose of 
study drug) must be reported on the appropriate eCRFs 
• Furthermore the following assessments will be performed to assess the eligibility of the 
patient: 
• Physical Examination (See Section 7.2.2.1) 
• Vital signs (See Section 7.2.2.2) 
• Height, weight (See Section 7.2.2.3) 
• ECOG performance status (See Section 7.2.2.5) 


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• Ophthalmic examination (See Section 7.2.2.4) 
• Laboratory evaluations (e.g., hematology, coagulation, biochemistry, urinalysis, liver 
function monitoring) (See Section 7.2.2.6) 
• 
 
• Serum pregnancy (See Section 7.2.2.6.6) 
• Cardiac assessment (See Section 7.2.2.8) 
• Disease evaluations (See Section 7.2.1) 
• Radiological assessments (e.g., CT scan) if clinically indicated (See Section 7.2.1) 
7.1.2 
Treatment period 
Patients will be treated with BGJ398 (125 mg, orally, once-a-day,) until disease progression, 
unacceptable toxicity, death or discontinuation from the study treatment due to any other 
reason. 
For details of safety and efficacy assessments, refer to Table 7-1 and Section 7.2. 
• Visits and associated assessments that occur ± 4 days from the scheduled date (except for 
cycle 1 Day1 where no visit window is allowed) will not constitute protocol deviations. 
• The cycle length is 28 days. Day 1 of subsequent cycles will be calculated from cycle 1, 
day 1. 
• Disease Assessments (per RECIST or appropriate hematological response criteria) must 
be performed every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd 
cycle), until disease progression or end of treatment, whichever occurs first. Upon 
implementation of this amendment, the frequency of disease assessment will be reduced 
and evaluations should be every 16 weeks after the first 16 weeks on treatment. 
• Laboratory assessments performed as part of the screening evaluations and within 4 days 
of the first dose of study treatment, are not required to be repeated on the first dosing day. 
• 
 
 
 
• For ongoing patients with TIO diagnosis FGF23 plasma assessment and 1-25-dihydroxy 
vitamin D will be collected, refer to Table 7-1 and Section 7.2.2.6.7. 
 
7.1.3 
End of treatment visit, including premature withdrawal and study 
discontinuation visit 
 
7.1.3.1 
End of treatment (EOT) visit 
Patients who completely discontinue study treatment should be scheduled for an End of 
Treatment (EOT) visit within 14 days following the date study treatment is permanently 
discontinued, at which time all of the assessments listed for the EOT visit will be performed. 
For details of assessments, refer to Table 7-1. If the decision to withdraw the patient occurs at 
a regularly scheduled visit, that visit may become the EOT visit rather than having the patient 
return for an additional visit. 


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An End of Treatment Phase Disposition eCRF page should be completed, giving the date and 
reason for stopping the study treatment. If a study withdrawal occurs, or if the patient fails to 
return for visits, the investigator must determine the primary reason for a patient’s premature 
withdrawal from the study and record this information on the End of Treatment Phase 
Disposition eCRF page. 
End of treatment/Premature withdrawal visit is not considered as the end of the study. 
 
 
 
 
 
At a minimum, all patients who discontinue study treatment, including those who refuse to 
return for a final visit, will be contacted for safety evaluations during the 30 days following 
the last dose of study treatment. 
 
7.1.3.2 
Criteria for premature patient withdrawal (EOT phase completion) 
Patients may voluntarily withdraw from the study or be dropped from it at the discretion of 
the investigator or by the sponsor at any time. 
Premature patient withdrawal refers to the point/time when the patient exits from the study 
treatment prior to the planned completion of all study treatment administration and/or 
assessments; at this time, all study drug treatment is discontinued and no further assessments 
are planned, unless the patient will be followed for progression and/or survival. 
Patients may be withdrawn from the study treatment if any of the following occur: 
• Adverse Event 
• Lost to follow-up 
• Non-compliance with study treatment 
• Physician decision 
• Pregnancy 
• Progressive Disease 
• Protocol deviation 
• Study terminated by sponsor 
• Subject/guardian decision 
• Death 
• In addition to the general withdrawal criteria, the following study specific criteria will 
also require study treatment discontinuation: 
• Adjustments to study treatment that result in discontinuation. Please refer to Section 
6.3. 
• Use of prohibited medication. Please refer to Section 6.4.3. 


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• Interruption of study treatment for > 14 days, regardless of reason, from the intended 
day of the next scheduled dose 
 
7.1.4 
Follow up period 
 
7.1.4.1 
Safety follow up 
All patients who discontinue study treatment, including those who refuse to return for a final 
visit, will be contacted for safety evaluations (i.e., assessment of AEs and/or SAEs, 
concomitant medications) for 30 days after the last dose of study treatment. Patients whose 
treatment is interrupted or permanently discontinued due to an adverse event, including 
abnormal laboratory value, must be followed at least once a week for 4 weeks and 
subsequently at 4-weeks intervals until resolution or stabilization of the event, whichever 
comes first. 
If patients refuse to return for safety evaluation visits or are unable to do so, every effort 
should be made to contact them by telephone to determine their status. Attempts to contact the 
patient should be documented in the source documents (e.g., dates of telephone calls, 
registered letters, etc.). 
 
7.1.4.2 
Efficacy follow-up 
Not applicable. 
 
7.1.4.3 
Survival follow-up 
Survival information will be collected, only for six tumor types that are listed in the inclusion 
criteria,every 3 months until 2 years after the last patient has enrolled in the study regardless 
of treatment discontinuation reason (except if consent is withdrawn). If the study primary 
efficacy endpoint is not met, Novartis may decide not to conduct survival follow-up for the 
study. Additional survival assessments may be performed outside the 3 months follow-up 
schedules if a survival update is required for an interim assessment to meet safety or 
regulatory needs. 
Survival information can be obtained via phone, and information will be documented in the 
source documents and relevant eCRFs. 
 
7.1.4.4 
Lost to follow-up 
Patients lost to follow up should be recorded as such in the eCRFs. 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. 
 
7.1.5 
End of post-treatment follow-up (Study phase completion) 
Not applicable. 


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7.2 
Assessment types 
7.2.1 
Efficacy assessments 
The primary efficacy endpoint is clinical benefit rate as defined in Section 10.4. The key 
secondary efficacy endpoint is overall response rate of PR or greater as defined in Section 
10.5. Other secondary endpoints are time from the date of first dose to the date of first 
documented disease progression or relapse or death due to any cause, time from the date of 
first dose to the date of death due to any cause, time from the first documented response to the 
date first documented disease progression or relapse or death due to any cause, AE rate, and 
other safety measurements as defined in Section 10. The local investigator’s assessment will 
be used for the analysis and for treatment decision making. 
Clinical suspicion of disease progression at any time will require assessment and confirmation 
to be performed promptly, rather than waiting for the next scheduled tumor assessment. In 
case of an unscheduled or delayed tumor assessment for any reason, subsequent disease 
assessments must be performed according to the originally planned schedule from baseline. 
 
7.2.1.1 
Solid tumors 
Response will be evaluated, using modified Response Evaluation Criteria in Solid Tumors, 
based on RECIST 1.1. For complete details, refer to Appendix A. 
Clinical evaluation and tumor assessments will be performed as is indicated in Table 7-1, 
based on physical examination and radiological evaluation. For solid tumors, an assessment of 
PR or greater must be confirmed at least 4 weeks after initial observation using RECIST 1.1. 
Any lesion that has been previously treated with radiotherapy should be considered as a non- 
target lesion. However, if a lesion previously treated with radiotherapy has clearly progressed 
since the radiotherapy, it can be considered as a target lesion. 
If the measurable disease is restricted to a solitary lesion, its neoplastic nature should be 
confirmed by cytology/histology. 
Definitions for measurable and non-measurable lesions, and criteria for response, should be 
based on RECIST 1.1 (Appendix A). 
 
7.2.1.1.1 Physical examination for superficial disease 
Clinical assessment of any existing superficial lesions (skin nodules and palpable lymph 
nodes) at screening and at each subsequent tumor assessment must be performed on the same 
schedule as radiological tumor assessments (see Section 7.2.1.1.4). 
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening. 


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7.2.1.1.2 Cancer Antigen-125 (CA-125) 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian cancer at screening. 
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Section 7.2.1.1.4). 
 
7.2.1.1.3 Prostate Specific Antigen (PSA) 
Prostate Specific Antigen (PSA) will be used in the assessment of prostate cancer at screening. 
Subsequent tumor assessments must be performed on the same schedule as radiological tumor 
assessments (see Section 7.2.1.1.4). 
 
7.2.1.1.4 Radiological tumor assessment 
At screening and at each subsequent tumor assessment (not applicable for patients with TIO 
diagnosis without measurable/evaluable disease), all patients must have a CT scan with 
contrast of the Chest/Abdomen and Pelvis. If a patient is known to have a contraindication to 
CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
The same type of CT scan used at screening must be used for all subsequent assessments. 
MRI with contrast will be allowed only in those cases when CT scan cannot be performed and 
will be used at baseline and all subsequent assessments in these patients. No modality change 
will be allowed during the study when assessing overall tumor status. For subsequent scans in 
the same patient, the radiologist must account for all lesions that were present at screening and 
must use the same technique as used at screening. If possible, a single radiologist should 
perform all tumor response evaluations for an individual patient. Only in exceptional cases 
when during the study a patient develops intolerance to the CT scan contrast medium, a CT 
scan without contrast will be acceptable to avoid modality change. At screening, tumor 
assessments should preferably be performed ≤ 4 days prior to the first dose of BGJ398, 
however tumor assessments ≤ 28 days prior to first dose of study drug will be acceptable. 
Tumor assessments will be performed at screening and every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle). Upon implementation of this amendment, the 
frequency of disease assessment will be reduced and evaluations should be every 16 weeks 
after the first 16 weeks on treatment. 
 
7.2.1.2 
Lymphoma 
[Please note that these assessments are for ongoing patients only. There will not be additional 
Lymphoma patients enrolled for amendment 3] 
Response will be evaluated, using modified criteria for malignant lymphoma Cheson 
(Appendix B) and Ann Arbor Staging Classification (Appendix C). 
Clinical evaluation and tumor assessments will be performed periodically, as is indicated in 
Table 7-1, based on evaluation of spleen and liver, physical examination for superficial 
disease and B symptoms, radiological evaluation, Serum Protein electrophoresis (SPEP), core 
bone marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 


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involvement prior to study treatment), and positron emission tomography (PET) (only to 
confirm complete responses in patients where PET was used for study entrance). 
 
7.2.1.2.1 Enlarged spleen and liver 
The presence of enlarged spleen or liver before start of treatment on the basis of CT scan (or 
MRI scan) should be recorded on the corresponding eCRF at baseline, and reassessed if the 
patient has a radiological CR. 
A maximum four of the largest dominant measurable nodules representing all involved 
anatomic locations should be selected as splenic and hepatic index lesions to be measured. 
All other splenic or hepatic nodules (both measurable and non-measurable) are considered as 
non-index lesions. 
 
7.2.1.2.2 Physical examination for superficial disease and B symptoms 
Tumor assessment by physical examination and evaluation of disease related B symptoms 
(unexplained fever of ≥ 38°C; unexplained, recurrent drenching night sweats; or unexplained 
loss of >10% body weight within the previous 6 months) will be performed at screening and 
day 1 of every cycle (±4 days) after first dose of study drug. Refer to Appendix B for 
specifications and measurement. 
Skin lesions should be documented using a digital camera (color photography) in clear focus 
showing the ruler or calipers and the corresponding measurement in such a way that the size 
of the lesion(s) can be determined from the photograph. Skin photographs should be 
continued at subsequent tumor assessments for any lesions that were photographed at 
screening. 
 
7.2.1.2.3 Radiological tumor assessment 
Tumor assessments will be performed at screening, and every 8 weeks (±4 days) after first 
dose of study drug (Day 1 of every odd cycle), until disease progression or end of treatment, 
whichever occurs first. Upon implementation of this amendment, the frequency of disease 
assessment will be reduced and evaluations should be every 16 weeks after the first 16 weeks 
on treatment. 
At screening and at each subsequent tumor assessment, all patients must have a CT scan with 
contrast of the Chest/Abdomen and Pelvis. If a patient is known to have a contraindication to 
CT contrast media or develops a contraindication during the trial, a non-contrast CT of the 
chest (MRI is not recommended due to respiratory artifacts) plus a contrast-enhanced MRI (if 
possible) of abdomen and pelvis should be performed. 
MRI with contrast will be allowed only in those cases when CT scan cannot be performed and 
will be used at baseline and all subsequent assessments in these patients. No modality change 
would be allowed during the study. When assessing overall tumor status. For subsequent 
scans in the same patient, the radiologist must account for all lesions that were present at 
screening and must use the same technique as used at screening. If possible, a single 
radiologist should perform all tumor response evaluations for an individual patient. Only in 
exceptional cases when during the study a patient develops intolerance to the CT scan contrast 


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medium, a CT scan without contrast will be acceptable to avoid modality change. At 
screening, tumor assessments should preferably be performed ≤ 4 days prior to the first dose 
of BGJ398, however tumor assessments ≤ 28 days prior to first dose of study drug will be 
acceptable. 
All patients should have at least one site of measurable nodal disease > 2.0 cm in the longest 
transverse diameter and clearly measurable in at least two perpendicular dimensions, as 
determined by CT scan (MRI is allowed only if CT scan cannot be performed). Complete 
guidance for selecting index lesions is provided in Appendix B. Index lesions will be 
measured and recorded at baseline and during the course of the study. They should be selected 
on the basis of their size and suitability for accurate repeat measurements. Skin lesions, if the 
area is ≥ 2 cm in at least one diameter, must be histologically confirmed for lymphoma 
involvement (the site must document the histological confirmation (yes or no) to the 
corresponding eCRF) and photographed (color photography using digital camera). 
A sum of the product of diameters (SPD) for lesions measured prior to study treatment will be 
calculated and reported at cycle 1 day 1. 
Conventional CT and MRI should be performed with contiguous cuts of 7.5 mm or less in 
slice thickness. Spiral CT should be performed using a 5 mm or less  contiguous 
reconstruction algorithm (this specification applies to tumors of the chest, abdomen and 
pelvis). 
If a very small lesion cannot be reliably measured because of its size, it is recommended to 
enter the minimum lesion size (i.e., 5 mm for spiral CT). In other cases where the lesion 
cannot be reliably measured for reasons other than its size (i.e., borders of the lesion are 
confounded by neighboring anatomical structures), no measurement should be entered and the 
lesion cannot be evaluated. 
Any measurable extranodal lesions (organs other than lymph nodes) that resolves from 
baseline (disappear completely) must be assigned a size of 0 mm when documenting on the 
corresponding eCRFs. An extranodal lesion must be ≥ 1 cm x 1 cm to be considered 
measurable. Refer to Appendix B for complete reporting guidelines. 
 
7.2.1.2.4 Bone marrow assessment 
Information on the patient’s bone marrow involvement based on documented history prior to 
study entry must be present in his/her source documents. Prior tumor bone marrow 
involvement should be entered on the corresponding eCRF. 
Core bone marrow biopsy or aspirate will not be performed at screening but is required to 
confirm complete responses (at the first occurrence of radiological and clinical evidence of 
CR) in patients with bone marrow tumor involvement prior to study treatment who achieve 
Complete Response based on clinical and radiological evidence. The biopsy sample on which 
this determination is made must be adequate (with a goal of > 20 mm unilateral core). Bone 
marrow biopsy or aspirate should be obtained no later than at the next visit immediately 
following clinical and radiological evidence of CR (i.e. < 28 days ± 7 days from the date of 
the radiological assessment, on which the CR is based on). 


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7.2.1.2.5 Serum protein electrophoresis (SPEP) 
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as radiological tumor assessments (see Section 7.2.1.2.3) only if 
abnormal M-protein is detected at screening. 
 
7.2.1.2.6 Positron emission tomography (PET) 
The use of Positron emission tomography (PET) is not standard in Novartis Oncology 
Lymphoma studies. PET evaluations that have been done as standard of care prior to 
enrollment will be recorded in the eCRF. Repeat PET will be required only for patients who 
have responses of CR for the purpose of this study and should be done within +/- 7 days of the 
CT or MRI to confirm CR. Refer to Appendix B for lesion measurements. 
 
7.2.1.3 
Symptomatic multiple myeloma 
[Please note that these assessments are for ongoing patients and no new patients with 
symptomatic myeloma will be enrolled] 
Response will be evaluated using the International Myeloma Working Group (IMWG) 
Uniform Response Criteria for Multiple Myeloma. For complete details, refer to Appendix O. 
Clinical evaluation and disease assessments will be performed periodically, as is indicated in 
Table 7-1, based on a skeletal survey Urine protein electrophoresis (UPEP), Free light chain, 
Serum Protein electrophoresis (SPEP), bone marrow biopsy, and MRI/CT Scans (For 
plasmacytoma only). 
 
7.2.1.3.1 Skeletal survey 
Skeletal survey will be performed at screening and if clinically indicated as outlined in Table 
7-1. 
 
7.2.1.3.2 Urine protein electrophoresis (UPEP) 
Urine protein electrophoresis (UPEP) will be performed by the local laboratory at screening, 
every 8 weeks (±4 days) after first dose of study drug (Day 1 of every odd cycle) and EOT. 
 
7.2.1.3.3 Free Light Chain 
Free Light Chain will be performed by the local laboratory at screening and on the same 
schedule as UPEP assessments (see Section 7.2.1.3.2). 
 
7.2.1.3.4 Serum protein electrophoresis (SPEP) 
Serum protein electrophoresis (SPEP) will be performed by the local laboratory at screening 
and on the same schedule as UPEP assessments (see Section 7.2.1.3.2). 
 
7.2.1.3.5 MRI/CT scans (for plasmacytoma only) 
For patients with plasmacytoma, a MRI/CT scan will be performed by the local laboratory at 
screening and on the same schedule as UPEP assessments (see Section 7.2.1.3.2). 


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7.2.1.3.6 Bone marrow assessment 
Information on the patient bone marrow involvement prior to study entry must be present in 
his/her source documents. Prior tumor bone marrow involvement should be entered on the 
corresponding eCRF. 
Core bone marrow biopsy is required to confirm Complete Responses (at the first occurrence 
of radiological and clinical evidence of CR) in patients with bone marrow tumor involvement 
prior to study treatment who achieve Complete Response based on clinical and radiological 
evidence. The biopsy sample on which this determination is made must be adequate (with a 
goal of > 20 mm unilateral core). Bone marrow biopsy should be obtained no later than at the 
next visit immediately following clinical and radiological evidence of CR (i.e. < 28 days ± 7 
days from the date of the radiological assessment, on which the CR is based on). 
 
7.2.1.4 
Leukemia 
[Please note that these assessments are for ongoing patients and no new patient with 
Leukemia will be enrolled] 
Response for AML will be evaluated using the revised recommendations of the International 
Working Group (IWG) as noted in Cheson (2003) (Appendix E). Response for ALL will be 
evaluated using guidelines adapted from NCCN Guidelines Version 1.2013 (Appendix F). 
CML will be evaluated using guidelines adapted from NCCN Guidelines Version 4. 2013 
(Appendix G). The response for CLL will be evaluated using the revised recommendation of 
the IWG as noted in Hallek (2008) (Appendix H). The response for myelodysplasia (MDS) 
will be evaluated using the revised recommendation of the IWG as noted in Cheson (2006) 
(Appendix L). The response for polycythemia vera (PV) and essential thrombocythemia (ET) 
will be evaluated using the recommendation of IWG-MRT as noted in Barosi (2013) 
(Appendix J and Appendix K respectively). The response for myelofibrosis (MF) will be 
evaluated using IWG-MRT as noted in Tefferi (2013) (Appendix I). 
Clinical evaluation and disease assessments for AML, ALL, CML, MDS, PV, ET, and MF 
will be performed periodically, as is indicated in Table 7-1, based on peripheral blood and 
bone marrow assessment as well as the presence or absence of extramedullary disease, and 
organomegaly, and evaluation of transfusion dependency. For MF and PV, the 
Myeloproliferative Neoplasm (MPN) Symptom Assessment Form Total Symptom Score 
(MPN-SAF TSS) will be completed as is indicated in Table 7-1. 
Clinical evaluations and disease assessments for CLL will be performed periodically as is 
indicated in Table 7-1, based on the lymphoma assessments schedule for evaluation of 
physical examination for superficial disease and B symptoms, radiological evaluation, core 
bone marrow biopsy (only to confirm complete responses in patients with bone marrow tumor 
involvement prior to study treatment) and Rai staging criteria (Appendix D). Peripheral blood, 
and the presence or absence of extramedullary disease and organomegaly will also be 
performed on the same schedule as other leukemia evaluations as indicated below. 
To assess response, the time interval between bone marrow and blood assessments may not 
exceed 5 days. If the time interval is more than 5 days, response status cannot be assessed at 
that time point. Regular bone marrow assessments are not required after achieving a CR 
unless indicated by blood counts or clinical assessments or specified in the protocol 


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The response assessment date is defined as the last of all dates of measurements which are 
required to qualify for a response category within the period listed above. This rule applies 
also in case of multiple measurements of the same variable. In case of relapse, the first of all 
measurement dates associated with a disease assessment will be used as assessment date. The 
assessment date will be used for the derivation of the time-to-event endpoints. 
 
7.2.1.4.1 Peripheral blood evaluation for CBC 
Peripheral blood evaluations will be performed by the local laboratory at screening, Day 1 and 
Day 15 of Cycles 1 and 2, at Day 1 of each subsequent cycle, and at EOT. 
Peripheral blood evaluation for CBC will be taken from the same sample and include 
evaluation of blast, neutrophil, and platelet cell count. 
 
7.2.1.4.2 Bone marrow assessment 
Bone marrow will be assessed for blast cell count at screening, to confirm response of CR or 
if clinically indicated. 
Percent blast cell count will be determined by cytological examination. This assessment can 
be performed in terms of bone marrow aspirate and/or biopsy. Results from these tests are 
considered to be interchangeable to assess blasts counts. In case both aspirate and biopsy were 
done, both tests will be considered for response assessment: 
In case of only one assessment with non-missing values: Data of the non-missing test result 
will be used. 
In case of both assessments with differing, non-missing data: For blast counts, the highest 
value will be considered. For Auer rods, the positive finding will be considered, if applicable 
 
7.2.1.4.3 Physical examination for extramedullary disease and/or organomegaly 
Extramedullary involvement (CNS and/or soft tissue) is to be assessed at each visit for 
response assessment. Presence with specification of location or absence of extramedullary 
disease is to be captured in the eCRF. Extramedullary disease is to be assessed via clinical 
examination or relevant imaging techniques as clinically appropriate. 
In case of extramedullary disease at baseline or (re-)appearance during the study, the lesions 
need to be confirmed cytologically if technically and/or clinically feasible. A clinical 
assessment will be made in case a cytological confirmation is not possible 
The presence of organomegaly (hepatomegaly and/or splenomegaly) is to be assessed at 
baseline at visits as part of the response assessment. The modality used: scan or palpation is to 
be noted. 
 
7.2.1.4.4 Assessments of chromosomal abnormalities 
Information on the patient’s chromosomal abnormalities/karyotyping based on documented 
history prior to study entry must be present in his/her source documents. Additional testing to 
confirm these response categories will not be required and should be done at the discretion of 
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7.2.1.4.5 Evaluation of transfusion dependency 
Transfusion dependency will be assessed at screening as well as during the course of the trial 
for all patients. Transfusion of blood products will be recorded in a separate module of the 
eCRF. The type and reason for transfusion, start and end date as well as the number of units 
will be captured at each visit with hematologic assessment. 
A period of one week without any transfusion has been taken as a convention to define the 
status of transfusion independence to assess response. Any sample of peripheral blood which 
was taken within seven days after a transfusion will be considered as transfusion dependent. 
For the definition of transfusion dependency, it does not matter which type of blood product 
was transfused. Moreover, the rules and time windows defined below apply not only to blood 
transfusions but also to erythropoietin, thrombopoietic agents and/or myeloid growth factors. 
 
7.2.2 
Safety and tolerability assessments 
Safety will be monitored by assessing physical examination, vital signs, weight, performance 
status evaluation, ECG, cardiac imaging, ophthalmology examinations, laboratory evaluations 
as well as collecting all serious and non-serious Adverse Events (AE). For details on AE 
collection and reporting, please refer to Section 8.1. 
Clinically significant findings that were present prior to the signing of informed consent 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 and meet the 
definition of an AE must be recorded on the Adverse Event page of the patient’s eCRF. 
 
7.2.2.1 
Physical examination 
A complete physical examination will be performed at screening at Day 1 of each cycle and at 
the EOT visit. Visit windows of ± 4 days are allowed (except at cycle 1 Day 1). As specified 
in Table 7-1, a screening physical examination performed prior to 4 days of first dosing does 
not need to be repeated at Cycle 1 Day 1. 
The physical examination comprises a total body examination that should include: general 
appearance, skin, neck (including thyroid), eyes, ears, nose, throat, lungs, heart, abdomen, 
back, lymph nodes, extremities, vascular and neurological review. If indicated, rectal, external 
genitalia, breast and pelvis exams will be performed. Information about the physical 
examination must be present in the source documentation at the study site. 
 
7.2.2.2 
Vital signs 
Vital signs (body temperature, pulse rate, blood pressure) will be monitored at screening, EOT, 
and before administration of BGJ398 at Day 1 of each cycle. Screening vital sign assessments 
performed within 4 days of first dosing do not need to be repeated at Cycle 1 Day 1. Vital 
signs will be measured according to normal medical practice. 
 
7.2.2.3 
Height and weight 
Height and body weight will be measured. Weight will be measured at the screening visit, at 
Day 1 of each cycle, and at EOT. Screening weight assessment performed within 4 days of 


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first dosing does not need to be repeated at Cycle 1 Day 1. Height will be collected at 
screening only. 
 
7.2.2.4 
Ophthalmic examination 
Ophthalmologic examination will be performed as indicated in Table 7-1 which includes: 
visual acuity testing, slit lamp examination of the anterior eye segment, IOP, and fundoscopy. 
Additional examination methods such as specular microscopy (that enables a magnified, 
direct view of the corneal epithelium), corneal pachymetry, and dilated fundoscopy will be 
performed as clinically indicated. 
 
7.2.2.5 
Eastern Cooperative Oncology Group (ECOG) Performance status 
Eastern Cooperative Oncology Group (ECOG) Performance status 
The performance status will be assessed according to the ECOG performance status scale 
(Oken 1982). ECOG performance status will be assessed at screening, at Day 1 of each cycle 
and at the EOT visit (Appendix N). ECOG performance assessment performed within 4 days 
of first dosing does not need to be repeated at Cycle 1 Day 1. 
 
7.2.2.6 
Laboratory evaluations 
Clinical laboratory analyses (hematology, biochemistry, coagulation, lipase, urinalysis, 
pregnancy test) are to be performed by the local laboratory according to the Visit Schedule 
outlined in Table 7-1. Visit windows of ± 4 days are allowed (except at cycle 1 Day 1). As 
specified in Table 7-1, screening laboratory assessments performed prior to 4 days of first 
dosing do not need to be repeated at Cycle 1 Day 1. For patients with TIO diagnosis blood 
should be collected for FGF23 plasma assessment and 1-25-dihydroxy vitamin D. Novartis 
must be provided with a copy of the local laboratory’s certification (if applicable), and a 
tabulation of the normal ranges and units of each parameter collected in the eCRF. Any 
changes regarding normal ranges and units for laboratory values assessed during the study 
must be reported via an updated tabulation indicating the date of revalidation. Additionally, if 
at any time a patient has laboratory parameters obtained from a different (outside) laboratory, 
Novartis must be provided with a copy of the certification and a tabulation of the normal 
ranges and units for this laboratory as well. The investigator is responsible for reviewing all 
laboratory reports for patients in the study and evaluating any abnormalities for clinical 
significance. 
More frequent laboratory examinations may be performed at the investigator’s discretion if 
clinically indicated. 
At any time during the study, abnormal laboratory parameters which are clinically relevant 
and require an action to be taken with study treatment (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 Common 
Terminology Criteria for Adverse events (CTCAE) version 4.0.3. Additional analyses are left 
to the discretion of the investigator. 


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7.2.2.6.1 Hematology 
Hematology tests are to be performed by the local laboratory at screening, Days 1, 8, 15, 21 of 
Cycle 1 and Days 1and 15 of Cycles 2, at Day 1 of each subsequent cycle and at EOT 
according to the Visit Schedule outlined in Table 7-1. The hematology panel includes 
hemoglobin, hematocrit, platelet count, total red blood cells (RBC), total white blood cells 
(WBC) count, and a WBC differential including neutrophils, lymphocytes, monocytes, 
eosinophils and basophils. 
 
7.2.2.6.2 Biochemistry 
Biochemistry tests are to be performed by the local laboratory at screening, Days 1, 8, 15, 21 
of Cycle 1 and Days 1and 15 of Cycles 2, at Day 1 of each subsequent cycle and at EOT 
according to the Visit Schedule outlined in Table 7-1. The full biochemistry panel includes 
blood urea nitrogen (BUN), creatinine, uric acid, sodium, magnesium, potassium, glucose, 
calcium, inorganic phosphate [Pi], LDH, total protein, albumin, bicarbonate, amylase, lipase, 
total cholesterol, high density lipoprotein (HDL), low density lipoprotein (LDL), and 
triglycerides. Additionally liver function test including AST/SGOT, ALT/SGPT, GGT, 
alkaline phosphatase, total, direct and indirect bilirubin will be measured. 
 
7.2.2.6.3 Thyroid function 
Thyroid function tests parameters include: thyroid stimulating hormone (TSH), free T3, and 
free T4. 
Thyroid function should be assessed at screening, Day 1 of Cycle 1, Day 1 of Cycle 3, every 3 
cycles from C3D1 during the treatment phase (or if clinically indicated), and at EOT. 
 
7.2.2.6.4 Coagulation 
International normalized ratio (INR) and pro-thrombin time (PT), activated partial 
thromboplastin time and fibrinogen will be measured at screening, Day 1 of Cycle 1, and 
during the treatment phase if clinically indicated. 
 
7.2.2.6.5 Urinalysis 
Urinalysis includes dipstick analysis of pH, bilirubin, ketones, leukocytes, protein, glucose, 
blood, and specific gravity, and will be performed at screening, Day 1 of each cycle and at 
EOT. 
If clinically indicated based on macroscopic urinalysis results, a microscopic evaluation 
examination will be performed and will include Red Blood Cells, White Blood Cells, Casts, 
Crystals, Bacteria, and Epithelial cells. 
 
7.2.2.6.6 Pregnancy and assessments of fertility 
Women of childbearing potential must undergo a serum pregnancy test at screening to 
confirm eligibility in the trial (≤ 4 days before first dose of study drug), and at EOT. Women 
of child-bearing potential must additionally undergo a monthly urine pregnancy test during 
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In case of pregnancy, the patient must permanently stop study treatment immediately, 
withdraw from the trial, and the pregnancy must be reported on the Clinical Trial Pregnancy 
Form. 
 
7.2.2.6.7 FGF23 plasma and 1-25-dihydroxy vitamin D 
For ongoing patients with TIO diagnosis FGF23 plasma levels and 1-25-dihydroxy vitamin D 
should be measured: at screening, C1D1 (if screening assessment occurred > 4 days from 
Cycle 1 Day 1), C1D15, and on Day1 of each subsequent cycles up to and including Day 1 of 
Cycle 4. Thereafter, should be measured every 16 weeks and EOT. A +/-4 days window is 
allowed for each assessment. Blood collection should be performed according to institutional 
guidelines. 
 
7.2.2.7 
Radiological examinations (for safety) 
Not applicable. 
 
7.2.2.8 
Cardiac assessments 
 
7.2.2.8.1 Electrocardiogram (ECG) 
A standard 12-lead ECG will be performed at screening, Day 1 and Day 15 of Cycles 1 and 2, 
at Day 1 of each subsequent cycle and at EOT according to the Visit Schedule outlined in 
Table 7-1. 
The interpretation of the tracing must be made by a qualified physician and documented in the 
ECG section of the eCRF. Each ECG tracing should be labeled with the study number, patient 
initials (if permitted by local regulations), Patient Number, date, and kept in the source 
documents at the study site. Only clinically significant abnormalities should be reported in the 
Adverse Events eCRF. Clinically significant abnormalities present when the patient signed 
informed consent should be reported on the Medical History eCRF page. 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 Adverse Events eCRF page. 
 
7.2.2.8.2 Cardiac imaging - MUGA (multiple gated acquisition) scan or 
echocardiogram 
MUGA (multiple gated acquisitions) scan or echocardiogram (ECHO) will be used to assess 
LVEF as indicated in Table 7-1 to assess signs or symptoms of cardiotoxicity. In case of 
clinically significant abnormalities, they should be reported on the Adverse Events eCRF. 
In case a patient develops left ventricular systolic dysfunction while on study treatment dose 
adjustment guidelines described in Section 6.3 must be followed. 
 
7.2.2.8.3 Cardiac enzymes 
Cardiac enzymes (Cardiac troponin-I or troponin-T) will be measured at screening and during 
the treatment phase if clinically indicated, especially in case of LVEF decrease. 


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7.2.3 
Pharmacokinetics 
Unscheduled blood samples for BGJ398 plasma concentration measurements will be collected 
in the event of an adverse event at the investigators discretion. Residual plasma samples may 
also be used for exploratory analysis to further characterize the PK of BGJ398 and its 
metabolite(s). This analysis may include using leftover samples for protein binding analysis or 
metabolite profiling (e.g., other metabolites and markers for metabolic enzyme activity) if 
there is sufficient sample remaining. Study samples may be re-analyzed at other Novartis 
approved facilities for the determination of long term stability or cross-check between 
Novartis approved laboratories. These additional investigations are not considered part of this 
study and, as such, the results of any such analyses will not be included in the final report. 
Exact dates and actual PK blood draw time will be recorded on the appropriate eCRF and the 
time of dose administration prior to the sample collection will also be recorded. Any sampling 
problems must be noted in the comments section of the eCRF and on appropriate source 
documentation. Unscheduled PK samples will be assigned PK sample numbers beginning 
with 1001 (1002, 1003 etc in the event of additional samples taken). 
Examples of rationale for the collection of unscheduled PK samples are provided below: 
• If a patient treated with investigational drug experiences an AE that results in an 
unscheduled visit or fits the criteria of a SAE or DLT, as determined by the investigator. 
• Whenever an ECG with a QTcF change from baseline > 60 ms or a new absolute QTcF ≥ 
501ms result is known, two separate unscheduled blood samples should be collected 
concomitantly to assess concentrations of BGJ398. The exact time of sample collection 
should be noted in the eCRF 
 
7.2.3.1 
Pharmacokinetic blood sample collection and handling 
All blood samples will be taken by either direct venipuncture or an indwelling cannula 
inserted in a forearm vein. Blood should be collected in accordance with institutional 
guidelines. At the specified time points, 3 mL blood sample will be collected in tubes with a 
specific anticoagulant K3-EDTA. Immediately after each tube of blood is drawn, it should be 
inverted gently several times to ensure the mixing of tube contents (e.g. anticoagulant). Avoid 
prolonged sample contact with the rubber stopper. Blood samples should be kept in an ice 
water bath at approximately until centrifugation. The tubes should be centrifuged as soon as 
possible but within no more than 30 minutes after collection at approximately 800 x g at 4ºC 
for 15 minutes to separate plasma. The plasma (approximately 1.5 mL) will be separated into 
2 aliquots (at least 0,5 mL each) to be transferred to a polypropylene screw-cap tube, the tube 
capped, and then immediately placed in a freezer set at ≤ -60ºC until shipment to Novartis for 
analysis. 
Refer to the [Laboratory Manual] for detailed instructions for the collection, handling and 
shipping of samples. 
 
7.2.3.2 
Analytical method 
Plasma concentrations of BGJ398 and its active metabolites (BHS697 and CQM157) will be 
measured using a validated liquid chromatography-tandem mass spectrometry (LC-MS/MS) 
assay with a lower limit of quantification (LLOQ) of approximately 1.0 ng/mL. 


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Concentrations below the LLOQ will be reported as 0 ng/mL and missing samples will be 
labeled accordingly. 
 
 


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7.2.5 
Other assessments 
No additional tests will be performed on patients entered into this study. 
 
8 
Safety monitoring and reporting 
8.1 
Adverse events 
8.1.1 
Definitions and reporting 
An adverse event (AE) 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 
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For patients who sign the ICF, all AEs will be captured in the AE eCRF from time of 
signature through 30 days after permanent study treatment discontinuation. For patients who 
fail the screening, only SAEs will be captured in the AE eCRF page. 
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 eCRF. Conditions that were already present at the time of informed consent should be 
recorded in the Medical History eCRF. 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 (CTCAE) version 4.03. If CTCAE grading does not exist for an adverse event, the 
severity of mild, moderate, severe, and life-threatening, corresponding to Grades 1-4, will be 
used. CTCAE Grade 5 (death) will not be used in this study; rather, 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: 
1. The severity grade (CTCAE Grade 1-4) 
2. Its duration (Start and end dates) 
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 taken (no concomitant medication/non-drug therapy, 
concomitant medication/non-drug therapy) 
6. Outcome (not recovered/not resolved, recovered/resolved, recovering/resolving, 
recovered/resolved with sequalae, fatal, unknown) 
7. Whether it is serious, where a serious adverse event (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. 


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Progression of malignancy (including fatal outcomes), if documented by use of appropriate 
method (as per RECIST 1.1 criteria for solid tumors), should not be reported as a serious 
adverse event or 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. 
 
8.1.2 
Laboratory test abnormalities 
 
8.1.2.1 
Definitions and reporting 
Laboratory abnormalities will be assessed according to the Common Terminology Criteria for 
Adverse Events (CTCAE) version 4.03. 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 eCRF. Whenever possible, a diagnosis, rather than a 
symptom should be provided (e.g. anemia instead of low hemoglobin). Laboratory 
abnormalities that meet the criteria for Adverse Events should be followed until they have 
returned to normal or an adequate explanation of the abnormality is found. When an abnormal 
laboratory or test result corresponds to a sign/symptom of an already reported adverse event,  
it is not necessary to separately record the lab/test result as an additional event. 
Laboratory abnormalities, that do not meet the definition of an adverse event, should not be 
reported as adverse events. A Grade 3 or 4 event (severe) as per CTCAEv4.03 does not 
automatically indicate an SAE unless it meets the definition of serious as defined below 
and/or as per investigator’s discretion. A dose hold or medication for the lab abnormality may 
be required by the protocol and is still, by definition, an adverse event. 
 
8.2 
Serious adverse events 
8.2.1 
Definitions 
Serious adverse event (SAE) is defined as one of the following: 
• Is fatal or life-threatening 
• Results in persistent or significant disability/incapacity 
• Constitutes a congenital anomaly/birth defect 
• Is medically significant, 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 (specify what this includes) 
• 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 


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• Treatment on an emergency outpatient basis for an event not fulfilling any of the 
definitions of a SAE given above and not resulting in hospital admission 
• 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 
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. 
SAE collection starts at time of ICF signature whether the patients is a screen failure or not. 
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 
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 (either initial or follow up information) is collected and recorded 
on the Serious Adverse Event Report Form on a paper SAE Form. The investigator must 
assess and record the relationship of each SAE to the study treatment, and complete the SAE 
Report Form in English. 
The SAEs recorded on the paper SAE form should be faxed to 
 within 24 hours 
of awareness of the SAE to the oncology Novartis Chief Medical Office and Patient Safety 
(CMO&PS). 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. 
Note that any follow up information provided should describe whether the event has resolved 
or continues, if and how it was treated, and whether the patient continued or withdrew from 
study participation. 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. 
Refer to Section 7.1.1.2 for additional details regarding the reporting of SAEs which occur 
during the screening period. 
 
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, 


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details of the birth, and the presence or absence of any birth defects, congenital abnormalities, 
or maternal and/or newborn complications. 
Pregnancy should be recorded on a Clinical Trial Pregnancy Form and reported by the 
investigator to the oncology Novartis Chief Medical Office and Patient Safety 
(CMO&PS)department. Pregnancy follow-up should be recorded on the same form and 
should include an assessment of the possible relationship to the Novartis study treatment of 
any pregnancy outcome. Any SAE experienced during pregnancy must be reported on the 
SAE Report Form. 
Pregnancy outcomes should be collected for the female partners of any males who took study 
treatment in this study. Consent to report information regarding these pregnancy outcomes 
should be obtained from the mother. 
 
8.5 
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’s Brochure]. Additional safety information collected between IB updates will be 
communicated in the form of Investigator Notifications. This information will be included in 
the patient informed consent and should be discussed with the patient during the study as 
needed. 
 
8.6 
Data Monitoring Committee 
Not applicable. 
 
8.7 
Steering Committee 
Not applicable. 
 
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 
• 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 at least vital status (i.e. that the subject is alive) 
at the end of their scheduled study period. 


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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. 
 
9.2 
Site monitoring 
Before study initiation, Novartis personnel (or designated CRO) will review the protocol and 
eCRFs with the investigators and their staff. During the study, the Investigator or designee 
will enter all required patient data into the eCRF within 72 hours (3 days) of the patient visit. 
The field monitor will visit the site regularly to check the completeness of patient records, the 
accuracy of entries on the eCRFs, 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 eCRFs 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 eCRF 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 
eCRFs are performed according to the study-specific monitoring plan. 
 
9.3 
Data collection 
This study will use Electronic Data Capture (EDC) and the designated investigator staff will 
enter the data required by the protocol into the 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 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 eCRF is 
complete, accurate, and that entry and updates are performed in a timely manner. 
Mutational analysis data will be generated by CLIA certified local labs. We anticipate that the 
data available in the report will vary from lab to lab. The PI will enter data directly onto the 
eCRF to verify that the patient meets the requirements of “pathway activation” as outlined in 
the inclusion criteria Section 5. Anonymized lab reports will be collected to gather 
information regarding pathway activations. 
If a tumor sample is obtained at the time of disease progression (optional), data about the 
sample will be collected in the eCRF. 


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Laboratory assessments for hematology, biochemistry, coagulation, urinalysis, MUGA and 
ECGs will be collected locally and entered directly onto the eCRFs. 
 
9.4 
Database management and quality control 
This study will be using eCRFs and the designated CRO will review the data entered by 
investigational staff for completeness and accuracy. Electronic data queries stating the nature 
of the problem and requesting clarification will be created for discrepancies and missing 
values and sent to the investigational site via the EDC system. Designated investigator site 
staff are required to respond promptly to queries and to make any necessary changes to the 
data. 
Concomitant treatments and prior medications entered into the database will be coded using 
the WHO Drug Reference List, which employs the Anatomical Therapeutic Chemical 
classification system. Medical history/current medical conditions and adverse events will be 
coded using the Medical dictionary for regulatory activities (MedDRA current version) 
terminology. 
Data from the screening molecular analysis will be collected locally and entered directly onto 
the eCRF. Tissue samples for pathway activation confirmation will be analyzed centrally. 
At the conclusion of the study, the occurrence of any protocol deviations will be determined. 
After this action has been completed and the data has been verified to be complete and 
accurate, the database will be declared locked and the data made available for data analysis. 
Authorization is required prior to making any database changes to locked data, by joint 
written agreement between the US Oncology Medical Affairs Franchise Head and the US 
Oncology Medical Affairs Franchise Vice President. 
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 
All data except the primary efficacy variable clinical benefit rate will be analyzed by a 
designated CRO in collaboration with Novartis. The analysis of the clinical benefit rate will 
be performed by a separate CRO using the Bayesian adaptive design approach described in 
details in Appendix R. Any data analysis carried out independently by the investigator should 
be submitted to Novartis before publication or presentation. The data from all centers that 
participate in this study will be combined in the final safety and efficacy analysis. 
This trial will enroll patients from at 6 histologic groups: 
• NSCLC - Squamous 
• Ovarian 
• Glioblastoma Multiforme 
• Squamous Head and Neck 
• Bladder 
• Cholangiocarcinoma 


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In addition, another group currently simply referred to as “Other” may be identified and 
enrolled throughout the study (e.g. “Other” will be a focused histologic group, but may not be 
explicitly identified until the trial is ongoing due to recruitment issues). We discuss the 
logistics in more detail below, but a decision will only be made for a group other than the 6 
listed if 1) more than 3 patients are enrolled in the group, and 2) a reasonable estimate of the 
clinical benefit rate is available. 
 
10.1 
Analysis sets 
10.1.1 
Full Analysis Set 
The Full Analysis Set (FAS) will include all patients who have received at least one dose of 
the study drug. 
FAS will be used for the analysis of all efficacy endpoints. 
 
10.1.2 
Safety Set 
The Safety Set will include all patients who received at least one dose of study treatment and 
had at least one post-baseline safety assessment. 
Please note: the statement that a patient had no adverse event (on the Adverse Event eCRF) 
constitutes a safety assessment. 
The Safety Set will be used for the analysis of all safety endpoints. 
 
10.2 
Patient demographics/other baseline characteristics 
Demographic and other baseline data (including disease characteristics) will be listed and 
summarized by patients groups formed by the type of cancer at study entry using the FAS 
(please see Table 4-1 of Appendix B for predicted target cancer population).  Additional 
groups may be added based on enrollment (See Appendix R). Categorical data, such as gender, 
race, etc., will be presented by frequencies and percentages. Descriptive summary statistics 
(e.g., frequency, mean, median, range and standard deviation) will be used to present numeric 
data. 
 
10.3 
Treatments (study treatment, concomitant therapies, compliance) 
10.3.1 
Study medication 
Duration of study treatment exposure, cumulative dose and dose intensity will be summarized 
by the patient groups as above using the Safety Set. The number of patients with dose 
changes/interruptions will be presented along with reasons for the dose change/interruption. 
The Safety Set will be used for the tables and listings. 
 
10.3.2 
Concomitant therapies 
Concomitant medications and significant non-drug therapies taken concurrently with the study 
drugs will be listed and summarized for the FAS by Anatomical Therapeutic Chemical 
Classification System (ATC) term and preferred term by means of frequency counts and 
percentages. These summaries will include medications starting on or after the start of study 


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treatment (defined as cycle 1 day 1) or medications starting prior to the start of study 
treatment and continuing after the start of study treatment. 
Any prior concomitant medications or significant non-drug therapies starting and ending prior 
to the start of study treatment will be listed. The Safety Set will be used for all above 
mentioned concomitant medication tables and listings. 
 
10.4 
Primary objective 
The primary endpoint is clinical benefit rate (CBR) in each group, with clinical benefit being 
assessed at 16 weeks. 
For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR or PR or SD ≥ 16 weeks. For hematologic tumors other appropriate 
hematological response criteria will apply and are included in the appendices. 
For patients with TIO diagnosis without measureable/evaluable disease, the following criteria 
will be the assessment at 16 weeks: 
• the tumor associated changes of metabolic parameters: plasma level of FGF23 < or =180 
RU/mL; and inorganic phosphorous, calcium, and 1-25-dihydroxy vitamin D greater than 
the LLN (- 20%); and 
• without requirement of supplementation therapy for at least the preceding cycle of the 16 
week assessment. 
For solid tumors, an assessment of CR or PR must be confirmed at least 4 weeks after initial 
observation, using RECIST 1.1. If the two assessments differ, the best response will be 
determined by Table 3-3 of Appendix A. 
 
10.4.1 
Variable 
The primary efficacy variable is the clinical benefit rate (CBR) (e.g. defined as CR or PR or 
SD ≥ 16 weeks for solid tumors) at week 16. 
 
10.4.2 
Statistical hypothesis, model, and method of analysis 
The study will enroll patients from at least 6 histologic groups. In addition, another group 
simply referred to as “Other” may be identified and enrolled throughout the study. 
Let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g. We transform to the logit scale for modeling purposes. Let θg be the 
mean log odds treatment effect, i.e.: 
 
Thus, θg is the group specific logistic regression coefficient for the treatment within group g. 
The primary analysis is a set of group specific tests that θg>0, meaning that the treatment is 
better than the assumed control rate within that group. Thus, we wish to test the set of 
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H0g : θg≤0 
H1g : θg>0 
We proceed in a Bayesian fashion, assigning a prior distribution (details in Appendix R) and 
computing the posterior probability of H1g within each group g. If, at the final analysis, 
Pr(θg>0 | data) > 0.90 
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below. 
The statistical design borrows information across subgroups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ. In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR. 
The purpose of such an analysis (discussed in more detail in the appendix) is to produce 
higher power or lower type I error in situations where we see some commonality (identical 
effects are not required) among the groups. The model will borrow more in situations where 
the groups appear similar than situations where the groups appear different. 
Details of the hierarchical model are provided in Appendix R. 
 
10.4.3 
Evaluation of trial success and futility 
The clinical benefit rate will be evaluated for futility and early success by comparing posterior 
quantities for the rate to pre-specified early stopping criteria. The evaluations are planned to 
occur after the first 30 patients have been dosed for at least 16 weeks or discontinued, then 
every 13 weeks thereafter. 
 
Early futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if: 
Pr(πg > Rg) < 0.10. 
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group. 
 
Early success 
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success. Formally, enrollment will stop early for 
success if: 
Pr(πg  > Rg) > 0.95. 


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A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious. 
 
Final analysis 
The final analysis will occur when both accrual and follow-up are complete for all subjects. If, 
at the completion of the trial, there is at least 90% probability that the response rate in a group 
exceeds the historical rate, then the group will be considered a success. Formally: 
Pr(πg  > Rg) > 0.90. 
In addition, a group will be considered as “promising’ if: 
0.80=<Pr(πg  > Rg) < 0.90. 
The control rates Rg are shown in Table 14-1 of Appendix R. 
 
10.4.4 
Handling of missing values/censoring/discontinuations 
A patient who has not progressed or died at the date of the analysis cut-off would have his/her 
PFS and OS censored at the time of the last adequate assessment before the cut-off date. Any 
disease assessment indicating response status other than “unknown” or “not done” is 
considered an adequate response assessment. 
No imputation of missing values will be performed on any of the efficacy endpoints. 
 
10.4.5 
Supportive analyses 
Not applicable. 
 
10.5 
Secondary objectives 
10.5.1 
Key secondary objective(s) 
The key secondary objective of this study is to assess Overall Response (OR) of Partial 
Response (PR) or greater based on local investigator assessment. 
For patients with solid tumors the assessment criteria will be RECIST 1.1 and will include 
responses of CR and/or PR. For hematologic tumors other appropriate hematological response 
criteria will apply and are included in the appendices. 
The overall response rate (PR or greater) and its 95% exact confidence interval will be 
provided for each patient group. 
 
10.5.2 
Other secondary efficacy objectives 
The secondary efficacy objectives of the study: 
• To assess progression free survival (PFS) based on local investigator assessment per 
RECIST 1.1 or other appropriate hematological response criteria 
• To assess overall survival 
• To assess duration of response (DOR) based on local investigator assessment per RECIST 
1.1 or other appropriate hematological response criteria 


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The secondary efficacy variable progression free survival (PFS) is defined as the time from 
the date of first dose to the date of first documented disease progression or relapse or death 
due to any cause. 
PFS will be summarized and graphed using the Kaplan-Meier product-limit method for each 
patient group. Patients who drop-out without progression will be censored at the time of last 
adequate assessment. The estimates of the 25th, median, 75th percentiles of the PFS and their 
95% confidence intervals will be provided, if applicable. 
Overall survival (OS) is defined as the time from the date of first dose to the date of death due 
to any cause. If a patient is not known to have died, survival time will be censored at the date 
of the last contact. 
OS will be summarized and graphed using the product-limit method as above. 
The duration of response (PR or greater) applies only to patients whose best response was PR 
or greater. For patients with solid tumors the assessment criteria will be RECIST 1.1 and will 
include responses of CR and/or PR. For hematologic tumors other appropriate hematological 
response criteria will apply and are included in the appendices. The duration of response is 
defined as the time from the first documented response to the date first documented disease 
progression or relapse or death due to any cause. The duration of response will be summarized 
descriptively for each patient group. 
If the study primary efficacy endpoint is not met, Novartis may decide not to conduct some of 
the above secondary efficacy analyses but instead provide those endpoints in listings only. 
 
10.5.3 
Safety objectives 
For all safety analyses, the Safety Set will be used. All listings and tables will be presented by 
patient groups. 
The assessment of safety will be based mainly on the frequency of adverse events and on the 
number of laboratory values that fall outside of pre-determined ranges. Other safety data (e.g., 
electrocardiogram, vital signs) will be considered as appropriate. All safety data will be listed. 
The safety summary tables will include only assessments collected no later than 30 days after 
study treatment discontinuation. Those collected later than 30 days after study treatment 
discontinuation will be flagged in listings. 
 
10.5.3.1 Analysis set and grouping for the analyses 
 
10.5.3.1.1 
Adverse events (AEs) 
All adverse events recorded during the study will be summarized. The incidence of treatment- 
emergent adverse events (new or worsening from baseline) will be summarized by presenting 
the number and percentage of patients by system organ class and/or preferred term, maximum 
severity (based on CTCAE v4.03), type of adverse event, and relationship to the study 
treatment. In addition, adverse events of related nature may be analyzed by categories 
regrouping the relevant preferred terms, as appropriate. Adverse events that occurred on the 
same subject in the same system organ class and/or preferred term will be counted only once 
for the one with the highest severity. 


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Deaths reportable as SAEs and non-fatal serious adverse events will be listed by patient and 
tabulated by type of adverse event and patient group. 
 
10.5.3.1.2 
Laboratory abnormalities 
All laboratory values will be converted into SI units and the severity grade will be calculated 
using appropriate common terminology criteria (CTCAE v4.03). 
A severity grade of 0 will be assigned when the value is within normal limits. For lab 
parameters for which severity grades are determined both through normal limits and absolute 
cut-offs, in the unlikely case when a local laboratory normal range overlaps into the higher 
(i.e. non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits 
and assigned a CTCAE grade of zero. 
A listing of laboratory values will be provided by laboratory parameter, patient, and visit. A 
separate listing will display notable laboratory abnormalities (i.e., newly occurring CTCAE 
grade 3 or 4 laboratory toxicities). Lab values collected later than 30 days after study 
treatment discontinuation will be flagged in the listings 
The following by-group summaries will be generated separately for hematology, and 
biochemistry parameters: 
• 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. 
 
10.5.3.1.3 
Other safety data 
Summary statistics for data from other tests will be provided, notable values will be flagged, 
and any other information collected will be listed as appropriate. 
Descriptive summary statistics will be provided for : 
• Electrocardiograms: changes from baseline to last available ECG results 
• Cardiac imaging: number and percentage of patients with notable LVEF values 
• Vital signs: number and percentage of patients with at least one post-baseline vital sign 
abnormality 
• ECOG performance status: shift table comparing baseline to worst post baseline ECOG 
performance status. 
• All other safety related procedures as required 
• Listings with flagged notable values and any other information collected will be provided 
as appropriate. 


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10.7 
Interim analysis 
Scheduled interim analysis will occur for the primary endpoint of clinical benefit rate only as 
required by the Bayesian Hierarchical design. The first interim analysis will be performed 
after the first 30 patients have been dosed for at least 16 weeks or discontinued, then every 13 
weeks thereafter. Interim analyses may be performed more frequently dependent on 
enrollment rate to avoid over-enrollment in any of the disease cohorts. At each interim 
analysis, the groups will be evaluated for early futility and early success by comparing 
posterior quantities for the response rate to pre-specified early stopping criteria. 
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable and all important safety 
endpoints will be summarized. No formal report will be issued for these interim data reviews. 
 
10.8 
Sample size calculation 
The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in Section 14.4.4.1 of Appendix R. This hypothesis 
corresponds to a generally effective treatment across groups and incorporates variation in 
treatment effects to reflect the realistic expectation that treatment effects may differ by group. 
In this setting, analytical power calculations are not possible, but the design was simulated to 
obtain the power of the study as shown in the appendix. The sample sizes shown (minimum of 
10 for futility stopping, minimum of 15 for early success and maximum of 30 as a group cap) 
achieve adequate power for the alternative hypothesis. The simulations included the expected 


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variable accrual by simulating a Poisson process with expected accrual also shown in the 
Appendix R. 
 
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 
International Conference on Harmonization (ICH) Harmonized Tripartite Guidelines for Good 
Clinical Practice (GCP), 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. A signed and dated statement that the 
protocol and informed consent have been approved by the IRB/IEC/REB must be given to 
Novartis before study initiation. 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, 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 investigators in a separate document with a proposed informed consent 
form (ICF) that is considered appropriate for this study and complies with the ICH and 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 approval. 
Women of child bearing potential and fertile males 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. Women of child bearing potential must agree to 
adhere to contraception requirement until at least 4 weeks after the final dose of study 
treatment. Fertile males must agree to adhere to contraception requirement until at least 12 


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weeks after the final dose of study treatment. If there is any question that the patient will not 
reliably comply, they should not be entered in the study. 
 
11.4 
Discontinuation of the study 
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 
4.2. 
 
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 eCRF 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 eCRFs and all other required reports. Data reported on 
the eCRF, that are derived from source documents, should be consistent with the source 
documents or the discrepancies should be explained. All data requested on the eCRF must be 
recorded. Any missing data must be explained. An audit trail will be maintained by the system. 
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. 


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Essential documents (written and electronic) should be retained for a period of not less than 
fifteen (15) years from the completion of the Clinical Trial unless Sponsor provides written 
permission to dispose of them or, requires their retention for an additional period of time 
because of applicable laws, regulations and/or guidelines. 
 
11.7 
Confidentiality of study documents and patient records 
The investigator must ensure 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 is 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 clinical study report (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/REB at the 
study site should be informed within 10 working days. 


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13 
References (available upon request) 
Barosi G, et al (2013) Revised response criteria for polycythemia vera and essential 
thrombocythemia: an ELN and IWG-MRT consensus project. Blood 121: 4778-4781. 
Barosi G, Mesa RA, Thiele J, et al (2008) International Working Group for Myelofibrosis 
Research and Treatment (IWG-MRT). Proposed criteria for the diagnosis of post- 
polycythemia vera and postessential thrombocythemia myelofibrosis: a consensus statement 
from the International Working Group for Myelofibrosis Research and Treatment. 
Leukemia.;22(2):437-438. 
Basch E, Prestrud AA, Hesketh PJ, et al (2011) Antiemetics: American Society of Clinical 
Oncology clinical practice guideline update. J Clin Oncol2011 Nov 1;29(31):4189-98. 
Cappellen D, De Oliveira C, Ricol D, et al (1999) Frequent activating mutations of FGFR3 in 
human bladder and cervix carcinomas. Nature Genetics; 23:18-20. 
Chesi M, Nardini E, Brents LA, et al (1997) Frequent translocation t(4;14)(p16.3;q32.3) in 
multiple myeloma is associated with increased expression and activating mutations of 
fibroblast growth factor receptor 3. Nature Genetics; 16:260-264. 
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854. 
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743. 
Cheson BD, et al (2003) Revised Recommendations of the International Working Group for 
Diagnosis, Standardization of Response Criteria, Treatment Outcomes, and Reporting 
Standards for Therapeutic Trials in Acute Myeloid Leukemia, J Clin Oncol: pp 4642-4649. 
Cheson BD, Greenberg JM, Bennett JM, et al (2006) Clinical application and proposal for 
modification of the International Working Group (IWG) response criteria in myelodysplasia. 
Blood; 108: 419-425. 
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an International Workshop to 
standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253. 
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586. 
Cheson, et al (2005) Clinical application and proposal for modification of the 
InternationalWorking Group (IWG) response criteria in myelodysplasia. blood-2005-10-4149. 
Cheson, et al (2005) Clinical application and proposal for modification of the 
InternationalWorking Group (IWG) response criteria in myelodysplasia. Blood:-10-4149. 
Chong W, et al (2011) Tumor-induced osteomalacia Endocr Relat Cancer. June ; 18(3): R53– 
R77. 
Cross NC, Reiter A (2008) Fibroblast Growth Factor Receptor and Platelet-Derived Growth 
Factor Receptor Abnormalities in Eosinophilic Myeloproliferative Disorders. Acta 
Haematologica; 119:199-206. 


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Dienstmann R, Tabernaro J, Rodon J, et al (2014) Genomic aberrations in the FGFR pathway: 
opportunities for targeted therapies in solid tumors. Annals of Oncology; 2013 November; 
Vol. 25 March 2014. 
Dutt A, Ramos AH, Hammersman PS, et al (2011) Inhibitor-Sensitive FGFR1 Amplification 
in Human Non-Small Cell Lung cancer. PLos One 6(6):e20351. 
Dutt A, Salvesen HB, Chen T-H, et al (2008) Drug-sensitive FGFR2 mutations in endometrial 
carcinoma. P.N.A.S.; 105:8713-8717. 
Elbauomy Elsheikh S, Green AR, Lambros MB, et al (2007) FGFR1 amplification in breast 
carcinomas: a chromogenic in situ hybridisation analysis. Breast Cancer Res.; 9(2):R23. 
Emanuel RM, Dueck AC, Geyer HL, et al (2012) Myeloproliferative neoplasm (MPN) 
symptom assessment form total symptom score: prospective international assessment of an 
abbreviated symptom burden scoring system among patients with MPNs [published correction 
appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103. 
Eswarakumar VP, Lax I, Schlessinger J (2005) Cytokine & Growth Factor Reviews 16:139– 
149. 
Guagnano V, Kauffmann A, Wöhrle S, et al (2012) FGFR genetic alterations predict for 
sensitivity to NVP-BGJ398, a selective pan-FGFR inhibitor. Cancer Discovery 2(12): 1118- 
1133. 
Hara T, Ooi A, Kobayashi M, et al (1998) Amplification of c-myc, K-sam, and c-met in 
gastric cancers: detection by fluorescence in situ hybridization. Lab Invest; 9:43-53. 
Haverty PM, Fridlyand J, Li L (2008) High-resolution genomic and expression analyses of 
copy number alterations in breast tumors. Genes, chromosomes and cancer; 47:530-542. 
Hu L, Sham JS, Xie D, et al (2007) Up-regulation of fibroblast growth factor 3 is associated 
with tumor metastasis and recurrence in human hepatocellular carcinoma. Cancer Lett; 252: 
36-42. 
Itoh N (2007) The Fgf families in humans, mice, and zebrafish: their evolutional processes 
and roles in development, metabolism, and disease. Biol. Pharm. Bull.; 30(10):1819-1825. 
Jang JH, Shin KH, Park JG (2001) Mutations in fibroblast growth factor receptor 2 and 
fibroblast growth factor receptor 3 genes associated with human gastric and colorectal cancers. 
Cancer Res; 61:3541-3. 
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. 
Kouhara H, Hadari YR, Spivak-Kroizman T, et al (1997) FRS2, a lipid-anchored Grb2- 
binding protein that links FGF-receptor activation to the Ras/MAPK signaling pathway. Cell; 
89:693-702. 
Lee JC, et al (2015) Identification of a novel FN1–FGFR1 genetic fusion as a frequent event 
in phosphaturic mesenchymal tumour. J Pathol; 235: 539–545. 


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Maeda T, Yagasaki F, Ishikawa M, et al (2004) Transforming property of TEL-FGFR3 
mediated through PI3-K in a T-cell lymphoma that subsequently progressed to AML. Blood 
105(5):2115-23. 
Mor O, Ranzani GN, Ravia Y, et al (1993) DNA amplification in human gastric carcinomas. 
Cancer Genet Cytogenet; 65:111-4. 
National Cancer Institute (NCI) (2009) Common terminology Criteria for Adverse Events 
(CTCAE) v4.03. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for Acute 
Lymphoblastic Leukemia Version 1. 2013. 
National Comprehensive Cancer Network Clinical Practice Guidelines in Oncology for 
Chronic Myelogenous Leukemia Version 4. 2013. 
Oken MM, Creech RH, Tormey DC, et al (1982) Toxicity And Response Criteria Of The 
Eastern Cooperative Oncology Group. Am J Clin Oncol 5; 649-655. 
Robert C, et al (2011) RAF inhibition and induction of cutaneous squamous cell carcinoma. 
Current opinion in Oncology, 23. 
Roila F, Herrstedt J, Aapro, et al (2010) Guideline update for MASCC and ESMO in the 
prevention of chemotherapy- and radiotherapy-induced nausea and vomiting: results of the 
Perugia consensus conference.; ESMO/MASCC Guidelines Working Group. Ann Oncol. 
2010 May;21 Suppl 5:v232-43. 
Shimada T, et al (2004) Targeted ablation of Fgf23 demonstrates an essential physiological 
role of FGF23 in phosphate and vitamin D metabolism. J. Clin. Invest. 113:561–568. 
Swerdlow SH, Campo E, Harris NL, et al (2008) eds. WHO Classification of Tumours of 
Haematopoietic and Lymphoid Tissues. Lyon, France: IARC; 2008. 
Tefferi, et al (2013) Revised response criteria for myelofibrosis: International Working (IWG- 
MRT) and European LeukemiaNet (ELN) consensus report Group-Myeloproliferative 
Neoplasms Research and Treatment. Blood; 122: 1395-1398. 
Tomlinson DC, Baldo O, Harnden P, et al (2007) FGFR3 protein expression and its 
relationship to mutation status and prognostic variables in bladder cancer. J Pathol.; 213:91-98. 
Turner N, Grose R (2010) Fibroblast growth factor signalling: from development to cancer. 
Nature Reviews Cancer; 10(116-129). 
Von Moos R, Thuerlimann B, Chair M, et al (2008) Pegylated liposomal doxorubicin- 
associated hand-foot syndrome: Recommendations of an international panel of experts. Eur J 
Cancer; 1016: 1-10. 
Weiss J, Sos ML, Seidel D, et al (2010) Frequent and focal FGFR1 amplification associates 
with therapeutically tractable FGFR1 dependency in squamous cell lung cancer. Sci Transl 
Med. 2(62):62ra93. 
Wesche J, Haglund K, Haugsten E (2011) Fibroblast growth factors and their receptors in 
cancer. Biochem. J. (2011) 437, 199–213. 


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Wöhrle, et al (2013) Pharmacological Inhibition of Fibroblast Growth Factor (FGF) Receptor 
Signaling Ameliorates FGF23-Mediated Hypophosphatemic Rickets. Journal of Bone and 
Mineral Research, Vol. 28, No. 4, pp 899–911. 
Wu Y, Su F, Kalyana-Sundaram S, et al (2013) Identification of targetable FGFR gene 
fusions in diverse cancers. Cancer Discov; 3(6);636-47. 
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Semin Cancer Biol; 4:33-40. 
BGJ398 Investigator’s Brochure ed.6 


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14 
Appendices 
14.1 
Appendix A: Criteria for therapeutic response/outcome 
assessment of solid tumors and/or lymph nodes (based on 
RECIST 1.1) 
Tumor assessments will be based on Response Evaluation Criteria in Solid Tumors (RECIST 
1.1) guidelines (Eisenhauer 2009). 
 
1 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
 
1.1 
Measurable 
Tumor lesions: Must be accurately measured in at least one dimension (longest diameter in 
the plane of measurement is to be recorded) with a minimum size of: 
• 10mm by CT scan (CT scan slice thickness no greater than 5 mm). 
• 10mm caliper measurement by clinical exam (lesions which cannot be accurately 
measured with calipers should be recorded as non-measurable). 
• 20mm by chest X-ray. 
Malignant lymph nodes: To be considered pathologically enlarged and measurable, a lymph 
node must be ≥15mm in short axis when assessed by CT scan (CT scan slice thickness 
recommended to be no greater than 5 mm). 
 
1.2 
Non-measurable 
All other lesions, including small lesions (longest diameter <10mm or pathological lymph 
nodes with ≥10 to <15mm short axis) as well as truly non-measurable lesions. Lesions 
considered truly non-measurable include: Leptomeningeal disease, ascites, pleural or 
pericardial effusion, inflammatory breast disease, lymphangitic involvement of skin or lung, 
abdominal masses/abdominal organomegaly identified by physical exam that is not 
measurable by reproducible imaging techniques. 
 
1.2.1 
Bone lesions 
• B, PET and plain films are not adequate to measure bone lesions; they may be used to 
determine the presence or absence of a lesion. 
• Lytic or lytic-blastic lesions with identifiable soft tissue component that can be measured 
by CT or MRI and meets size requirement can be considered measurable. Blastic bone 
lesions are non-measurable 
 
1.2.2 
Cystic lesions 
• Cystic lesions that meet the criteria for simple cysts are not measurable 


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• Cystic lesions that are thought to be cystic metastatic disease can be considered 
measurable disease, however if non-cystic lesions are present in the same patient these are 
preferable to include as target lesions. 
 
1.2.3 
Lesions previously treated 
• Lesions within radiotherapy ports or who have been subject to other loco-regional 
treatment are usually not considered to be measurable and will be allowed on this study 
only with approval of the sponsor. 
 
2 
Specification by methods of measurement 
 
2.1 
Measurement of lesions 
All measurements should be taken and recorded in metric notation. 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. 
 
2.1.1 
Target lesions 
All lesions up to a maximum of five lesions total (and a maximum of two lesions per organ) 
representative of all involved organs should be identified as target lesions. If the largest lesion 
does not lend itself to reproducible measurement, the next largest lesion which can be 
measured reproducibly should be selected. 
Pathological lymph nodes which are measurable may be identified as target lesions if they 
have a short axis of ≥15mm by CT scan. Only the short axis of these nodes will contribute to 
the baseline sum. Nodal size is normally reported as two dimensions in the plane in which the 
image is obtained. The smaller of these measures is the short axis. All other pathological 
nodes (those with short axis ≥10mm but <15 mm) should be considered non-target lesions. 
Nodes that have a short axis <10mm are considered non-pathological and should not be 
recorded or followed. 
 
2.1.2 
Non-target lesions 
All other lesions (or sites of disease) should be identified as non-target lesions and should 
also be recorded at baseline. It is possible to record multiple non-target lesions involving the 
same organ as a single item on the case record form (e.g. “multiple enlarged pelvic lymph 
nodes” or “multiple liver metastases”). Measurements of these lesions are not required, but  
the presence or absence of each should be noted throughout follow-up. 
 
2.2 
Response criteria 
 
2.2.1 
Evaluation of target lesions 
This section provides the definitions of the criteria used to determine overall tumor response 
for target lesions as shown below in Table 2-1. 


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Table 2-1 
Evaluation of target lesions 
Response Criteria 
Evaluation of target lesions 
 
Complete Response (CR): 
Disappearance of all target lesions. Any pathological lymph nodes 
(whether target or non-target) must have reduction in short axis to <10 
mm.1 
 
Partial Response (PR): 
At least a 30% decrease in the sum of diameters of target lesions, taking 
as reference the baseline sum diameters. 
 
Progressive Disease (PD): 
At least a 20% increase in the sum of diameter of all measured target 
lesions, taking as reference the smallest sum of diameter of all target 
lesions recorded at or after baseline. In addition to the relative increase 
of 20%, the sum must also demonstrate an absolute increase of at least 
5 mm (Note: the appearance of one or more new lesions is also 
considered progression) 
 
Stable Disease (SD): 
Neither sufficient shrinkage to qualify for PR nor sufficient increase to 
qualify for PD, taking as reference the smallest sum diameters while on 
study 
 
Notes on the assessment of Lymph nodes: Lymph nodes identified as target lesions should 
always have the actual short axis measurement recorded (measured in the same anatomical 
plane as the baseline examination), even if the nodes regress to below 10mm on study. This 
means that when lymph nodes are included as target lesions, the ‘sum’ of lesions may not be 
zero even if complete response criteria are met, since a normal lymph node is defined as 
having a short axis of <10mm. In order to qualify for CR, each node must achieve a short axis 
<10mm. For PR, SD and PD, the actual short axis measurement of the nodes is to be included 
in the sum of target lesions. 
 
2.2.2 
Evaluation of non-target lesions 
This section provides the definitions of the criteria used to determine the tumor response for 
the group of non-target lesions as shown below in Table 2-2. While some non-target lesions 
may actually be measurable, they need not be measured and instead should be assessed only 
qualitatively at the time points specified in the protocol. 
 
Table 2-2 
Evaluation of non-target lesions 
Response Criteria 
Evaluation of target lesions 
 
Complete Response (CR): 
Disappearance of all non-target lesions and normalization of tumor 
marker level. All lymph nodes must be non-pathological in size 
(<10mm short axis) 
 
Non-CR/Non-PD: 
Persistence of one or more non-target lesion(s) and/or maintenance of 
tumor marker level above the normal limits. 
 
Progressive Disease (PD): 
Unequivocal progression of existing non-target lesions. (Note: the 
appearance of one or more new lesions is also considered 
progression). 
 
 
2.2.3 
New lesions 
The appearance of a new lesion is always associated with Progressive Disease (PD) and has to 
be recorded appropriately in the eCRF. 


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• If a new lesion is equivocal, for example because of its small size, continued therapy and 
follow-up evaluation will clarify if it represents truly new disease. If repeat scans confirm 
there is definitely a new lesion, then progression should be declared using the date of the 
first observation of the lesion 
• If new disease is observed in a region which was not scanned at baseline or where the 
particular baseline scan is not available for some reason, then this should be considered as 
a PD. The one exception to this is when there are no baseline scans at all available for a 
patient in which case the response should be UNK, as for any of this patient's assessment. 
• A lymph node is considered as a “new lesion” and, therefore, indicative of progressive 
disease if the short axis increases in size to ≥10 mm for the first time in the study plus 5 
mm absolute increase. 
a. Negative FDG-PET at baseline, with a positive1 FDG-PET at follow-up is a sign of 
PD based on a new lesion. 
b. No FDG-PET at baseline and a positive FDG-PET at follow-up: If the positive FDG- 
PET at follow-up corresponds to a new site of disease confirmed by CT, this is PD. If 
the positive FDG-PET at follow-up is not confirmed as a new site of disease on CT, 
additional follow-up CT scans are needed to determine if there is truly progression 
occurring at that site (if so, the date of PD will be the date of the initial abnormal 
FDG-PET scan). If the positive FDG-PET at follow-up corresponds to a pre-existing 
site of disease on CT that is not progressing on the basis of the anatomic images, this 
is not PD 
 
2.2.4 
Tumor markers 
Tumors markers alone will not be used to assess overall response. If elevated at baseline, they 
must normalize for a patient to be considered as having a CR. For the purpose of this protocol, 
Cancer Antigen-125 (CA-125) will be used in the assessment of ovarian and Prostate Specific 
Antigen (PSA) will be used in the assessment of prostate. 
 
3 
Evaluation of best overall response 
The evaluation of overall lesion response at each assessment is a composite of the target 
lesion response, non-target lesion response and presence of new lesions as indicated below in 
Table 3-1 and Table 3-2. 
The best overall response is the best response recorded from the start of treatment until 
disease progression/recurrence. The best overall response for CR and PR will be determined 
at 8 weeks as indicated below in Table 3-3. 


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Table 3-1 
Time point response: patients with target (plus/minus non-target) 
disease 
Target lesions 
Non-target lesions 
New lesions 
Overall lesion response 
 
CR 
CR 
No 
CR 
CR 
Non-CR/Non-PD 
No 
PR 
CR 
Not evaluated 
No 
PR 
PR 
Non-PD or not all evaluated 
No 
PR 
SD 
Non-PD or not all evaluated 
No 
SD 
Not all evaluated 
Non-PD 
No 
NE 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
 
 
Table 3-2 
Time point response: patients with non-target disease only 
 
Non-target lesions 
New lesions 
Overall lesion response 
CR 
No 
CR 
Non-CR/Non-PD 
No 
Non-CR/non-PRa 
Not all evaluated 
No 
NE 
Unequivocal PD 
Yes or No 
PR 
Any 
Yes 
SD 
a ‘Non-CR/non-PD’ is preferred over ‘stable disease’ for non-target disease since SD is increasingly 
used as endpoint for assessment of efficacy in some trials so to assign this category when no lesions 
can be measured is not advised. 
 


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Table 3-3 
Best overall response when confirmation of CR and PR required 
Overall lesion response at first 
time point 
Overall lesion response at 
subsequent time point 
Best overall lesion 
response 
 
CR 
CR 
CR 
CR 
PR 
SD, PD or PRa 
CR 
SD 
SDb 
CR 
PD 
SDb 
CR 
NE 
SDc 
PR 
CR 
PR 
PR 
PR 
PR 
PR 
SD 
SD 
PR 
PD 
SDb 
PR 
NE 
SDc 
NE 
NE 
NE 
 
a If a CR is truly met at first time point, then any disease seen at a subsequent time point, even 
disease meeting PR criteria relative to baseline, makes the disease PD at that point (since disease 
must have reappeared after CR). Best response would depend on whether minimum duration for SD 
was met. However, sometimes ‘CR’ may be claimed when subsequent scans suggest small lesions 
were likely still present and in fact the patient had PR, not CR at the first time point. Under these 
circumstances, the original CR should be changed to PR and the best response is PR. 
b  Provided minimum criteria for SD duration met, otherwise, PD 
c  Provided minimum criteria for SD duration met, otherwise, NE 
 
 
4 
References (available upon request) 
Dent S, Zee (2001) application of a new multinomial phase II stopping rule using response 
and early progression, J Clin Oncol; 19: 785-791. 
Eisenhauer E, et al (2009) New response evaluation criteria in solid tumors: revised RECIST 
guideline (version 1.1). European Journal of Cancer, Vol.45: 228-47. 
Ellis S, et al (2008) Analysis of duration of response in oncology trials. Contemp Clin Trials 
2008; 29: 456-465. 
FDA Guidelines (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 
FDA Guidelines (2007) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, May 2007. 
Morgan TM (1988) Analysis of duration of response: a problem of oncology trials. Cont Clin 
Trials; 9: 11-18. 
Therasse P, Arbuck S, Eisenhauer E, et al (2000) New Guidelines to Evaluate the Response to 
Treatment in Solid Tumors, Journal of National Cancer Institute, Vol. 92; 205-16. 


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14.2 
Appendix B: Criteria for therapeutic response/outcome 
assessment in lymphoma studies (based on Cheson response 
criteria) 
Disease assessments will be based on the International Working Group response criteria 
(Cheson 1999), and the International Harmonization Project revised response criteria (Cheson 
et al 2007b). Further clarification on these criteria has been published by (Cheson 2007a). 
 
1 
Definitions and criteria for normalization 
a 
Definitions 
i 
Nodal vs extranodal lesion 
A lesion is categorized based on the location as: 
• Nodal lesion, 
• Extranodal lesion, if it is located in organs other than lymph node or nodal mass, but 
including spleen and liver. 
 
2 
Measurability of tumor lesions at baseline 
All tumor lesions/lymph nodes will be categorized as measurable or non-measurable as 
follows: 
 
a 
Measurable nodal and extranodal lesions 
A lesion will be called measurable if it can be measured accurately in 2 perpendicular 
dimensions and: 
• For nodal lesion, if the long axis is > 15 mm, regardless of the length of the short axis, 
• For extranodal lesion, if the long and short axes are ≥ 10 mm. 
Patients should have at least one measurable nodal lesion greater than 20 mm in the long 
axis. 
In cases where the patient has no measurable nodal lesions greater than 20 mm in the long 
axis at Screening, then the patient must have at least one measurable extranodal lesion 
 
b 
Classification of lymph nodes 
Lymph nodes are classified according to their size and/or relationship to the disease: 
• A lymph node meeting the measurability requirement above will constitute a measurable 
nodal lesion. 
• A lymph node not meeting the measurability requirement but with long axis ≥15 mm (e.g. 
short axis cannot be measured accurately) will constitute a non-measurable nodal lesion. 
• A lymph node not meeting the measurability criteria but with a size of 11 mm to 15 mm in 
the long axis and ≥ 10 mm in the short axis will be checked for relationship to disease: 


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• If it is thought to be disease related, it will constitute a non-measurable nodal lesion 
• If it is not thought to be disease related, it will constitute an abnormal lymph node 
but not a lesion. 
• All other lymph nodes will be considered normal and will not constitute nodal lesions. 
c 
Criteria for normalization of lesions 
The normalization of lesions is defined as follow: 
• A measurable nodal lesion must become ≤ 15 mm in long axis to be considered 
normalized. 
• A non-measurable nodal lesion must decrease to ≤ 10 mm in the short axis and be ≤ 15 
mm in long axis to be considered normalized. 
• An extranodal lesion must disappear completely (assigned a size of 0 mm x 0 mm) to be 
considered normalized. 
3 
Specification by methods of measurement 
a 
Measurement of lesions 
All radiological measurements should be taken in two perpendicular dimensions and recorded 
in metric notation, using a ruler or calipers. 
 
i 
PET 
Visual assessment currently is considered adequate for determining whether a PET scan is 
positive, and use of the standardized uptake value is not necessary.1 In brief, a positive scan is 
defined as focal or diffuse FDG uptake above background in a location incompatible with 
normal anatomy or physiology, without a specific standardized uptake value cutoff.1 Other 
causes of false-positive scans should be ruled out. Exceptions include mild and diffusely 
increased FDG uptake at the site of moderate- or large-sized masses with an intensity that is 
lower than or equal to the mediastinal blood pool, hepatic or splenic nodules 1.5 cm with FDG 
uptake lower than the surrounding liver/spleen 
 
ii 
CT scan (or MRI) 
For optimal evaluation of patients, the same methods of assessment and technique should be 
used to characterize each identified and reported lesion at Screening and during follow-up. 
Contrast-enhanced CT of chest, abdomen and pelvis should preferably be performed using a 
5mm slice thickness with a contiguous reconstruction algorithm. CT/MRI scan slice thickness 
should not exceed 8 mm cuts using a contiguous reconstruction algorithm. If at Screening a 
patient is known to be allergic to CT contrast or develops allergy during the trial, the 
following change in imaging modality will be accepted for follow up: a non-contrast CT of 
chest (MRI not recommended due to respiratory artifacts) plus contrast-enhanced MRI of 
abdomen and pelvis. 
A change in methodology can be defined as either a change in contrast use (e.g. keeping the 
same technique, like CT, but switching from with to without contrast use or vice-versa, 


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regardless of the justification for the change) or a change in technique (e.g. from CT to MRI, 
or vice-versa), or a change in any other imaging modality. A change in methodology will 
result by default in an “Unknown” overall radiological response assessment. However, 
another overall radiological response than the Novartis calculated “Unknown” response may 
be accepted from the investigator if a definitive overall radiological response can be justified 
to be based on the available information. 
In order to calculate the sum of the product of the diameters (SPD) of all index lesions (or 
extranodal lesions), their size must be entered throughout the study. 
Actual lesion measurements should be entered on the corresponding eCRFs. If, during the 
course of the study, either of the perpendicular diameters of a lesion cannot be reliably 
measured because of its small size, it is recommended to enter the minimum limit of detection 
as the diameter size (e.g. 5 mm for spiral CT). In other cases when, during the course of the 
study, the diameter cannot be reliably measured for reasons other than its size (i.e. borders of 
the lesion are confounded by neighboring anatomical structures), no measurement should be 
entered and the lesion cannot be evaluated. 
If lesions become confluent over time, it is recommended to measure them as one lesion, 
report the overall diameters to one of the lesions and assign 0 mm x 0 mm to each of the other 
previously measured lesions. If a lesion splits during the study, each sub-lesion should be 
measured separately for all subsequent assessments and all sub-lesions contribute to the SPD. 
 
iii 
Bone marrow assessment 
Documentation of status of bone marrow involvement by lymphoma based on prior bone 
marrow biopsy or aspirate findings is required at Screening for all patients. 
If no such documentation is available then a bone marrow biopsy or aspirate should be 
performed at Screening. 
If bone marrow involvement is assessed by biopsy, the biopsy sample should have a goal of > 
20 mm unilateral core. If the biopsy sample is indeterminate by morphology 
(immunohistochemistry), then flow cytometry may be performed on bone marrow aspirate to 
confirm the findings. 
 
iv 
Physical examination and assessment of B-symptoms 
Skin lesions, if the size is ≥ 20 mm in at least one diameter, must be histologically confirmed 
for lymphoma involvement (the investigational site must document the histological 
confirmation (yes or no) on the corresponding eCRF) and photographed including a ruler 
(color photography using digital camera). Tumor assessment will be performed and results 
will be recorded on the corresponding eCRF at Screening and at Day 1 of every cycle (±4 
days) after first dose of study drug. 
B-symptoms are of importance in determining prognosis and should resolve completely in 
patients who have achieved complete response. B-symptoms in lymphoma patients are disease 
related clinical symptoms and are not caused by anticancer therapy (or drug toxicity). 
B-symptoms are defined as follows: 


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• Significant unexplained fever (≥ 38°C), 
• Unexplained, recurrent drenching night sweats 
• Unexplained loss of > 10% body weight within the previous 6 months, as assessed and 
reported (present vs. absent) by the Investigator. 
 
4 
Evaluation of radiological response 
For the sake of simplicity, complete remission and complete response will both be referred to 
as complete response. 
Definitions of Response for Lymphoma patients are listed in Table 4-1. To evaluate disease 
response to treatment, all index and non-index lesions will be followed and assessed 
throughout the study. At each assessment, response is evaluated separately for the index 
lesions (Table 4-1) and non-index lesions (Table 4-2) identified at Screening, then a 
combined overall radiological response is determined (Table 4-3). 


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Table 4-1 
Response definition for lymphoma 
Response 
Definition 
Nodal Masses 
Spleen. Liver 
Bone Marrow 
CR 
Disappearance 
of all evidence 
of disease 
 
 
 
 
 
PR 
Regression of 
measurable 
disease and no 
new sites 
 
 
 
 
 
SD 
Failure to attain 
CR/PR or PD 
a FDG-avid or PET positive prior 
to therapy; mass of any size 
permitted if PET negative 
b Variably FDG-avid or PET 
negative; regression to normal 
size on CT 
 
 
≥ 50% decrease in SPD of up to 
6 largest dominant masses; no 
increase in size of other nodes 
a FDG-avid or PET positive prior 
to therapy; one or more PET 
positive at previously involved 
site 
b Variably FDG-avid or PET 
negative; regression on CT 
a FDG-avid or PET positive prior 
to therapy; PET positive at prior 
sites of disease and no new sites 
on CT or PET 
b Variably FDG-avid or PET 
negative; no change in size of 
previous lesions on CT 
Not palpable, 
nodules 
disappeared 
 
 
 
 
 
≥ 50% decrease 
in SPD of 
nodules (for 
single nodule in 
greatest 
transverse 
diameter); no 
increase in size 
of liver or spleen 
Infiltrate 
cleared on 
repeat biopsy; if 
indeterminate 
by morphology, 
immunohistoch 
emistry should 
be negative 
Irrelevant if 
positive prior to 
therapy; cell 
type should be 
specified 
Relapsed 
disease or 
PD 
Any new lesion 
or increase by 
≥ 50% of 
previously 
involved sites 
from nadir 
Appearance of a new lesion(s) > 
1.5 cm in any axis, ≥50% 
increase in SPD of more than 
one node, or ≥ 50% increase in 
longest diameter of a previously 
identified node > 1 cm in short 
axis 
Lesions PET positive if FDG-avid 
lymphoma or PET positive prior 
to therapy 
> 50% increase 
from nadir in the 
SPD of any 
previous lesions 
New or 
recurrent 
involvement 
 
 
a 
Evaluation of index lesions (nodal and extranodal) 
 
i 
When index nodal lesions are not in complete response 
The response for index lesions is evaluated by calculating the Sum of the Products of 
Diameters (SPD) of all index lesions (see Table 4-2), except when there is a Complete 
Response for index nodal lesions (i.e. complete normalization of all index nodal lesions) (see 
Section ii). 


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Table 4-2 
Radiological status based on SPD calculation for all index lesions 
Response Criteria1 
Evaluation of index lesions 
 
Complete Response (CR) 
See Table 4-4 below (not based on SPD calculation for all index lesions) 
Partial Response (PR) 
At least 50% decrease from Screening in the SPD of all index lesions 
Stable Disease (SD) 
Failure to attain the criteria needed for CR or PR and failure to fulfill the 
criteria for PD 
Progressive Disease (PD) 
At least a 50% increase from nadir2 in the SPD of all index lesions 
 
1 At each assessment (if the index nodal lesions are not in CR status), the response status based on 
SPD calculation will be first assessed for meeting PD status criteria, then PR status and SD status. 
2 Nadir is defined as the smallest sum of the product of the diameters of all index lesions recorded so 
far, at or after Screening. 
 
 
ii 
When index nodal lesions are in complete response 
When there is a Complete Response for index nodal lesions (i.e. complete normalization of all 
index nodal lesions as defined in Section v: all index lesion ≤ 15 mm in long axis), the SPD 
for these index nodal lesions may not be equal to zero and therefore a calculation of a SPD for 
all index lesions may be misleading. Therefore, by default, a specific response for extranodal 
index lesions needs to be evaluated, based on the SPD calculation restricted to all index 
extranodal lesions only (see Table 4-3). 
 
Table 4-3 
Radiological response criteria for index extranodal lesions in case 
of CR in index nodal lesions 
Response Criteria1 
Evaluation of index extranodal lesions 
 
Complete Response (CR) 
Complete disappearance of all index extranodal lesions 
Partial Response (PR) 
At least 50% decrease from Screening in the SPD restricted to all index 
extranodal lesions 
Stable Disease (SD) 
Failure to attain the criteria needed for CR or PR and failure to fulfill the 
criteria for PD 
Progressive Disease (PD) 
At least a 50% increase from nadir2 in the SPD restricted to all index 
extranodal lesions 
 
1 At each assessment, response will be first assessed for meeting CR status. If CR status is not met, 
response will be assessed for PD status, then PR status and SD status. 
2 Nadir is defined as the smallest sum of the product of the diameters restricted to all index extranodal 
lesions recorded so far, at or after Screening. 
 
The algorithm for evaluating the response integrating index extranodal lesions and the SPD 
calculated on all index lesions (where appropriate) provides an overall response for index 
lesions. 
 
iii 
Evaluation of response for all index lesions 
The evaluation of response for all index lesions is based on the combination of the response 
for index nodal lesions (CR or non-CR), the response for index extranodal and the status 
based on the SPD calculated on all index lesions (nodal and extranodal), as described in Table 
4-4. 


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Table 4-4 
Radiological response for index lesions 
 
Response for index 
nodal lesions1 
Response for index 
extranodal lesions1 
Status based on SPD 
calculation for all index lesions 
Response for 
index lesions 
CR 
CR 
Not calculated 
CR 
CR 
SD/ PR 
Not calculated 
PR 
CR 
PD 
PD 
PD 
CR 
PD 
PR 
PR 
CR 
PD 
SD 
SD 
Non-CR 
Not evaluated 
PD 
PD 
Non-CR 
Not evaluated 
PR 
PR 
Non-CR 
Not evaluated 
SD 
SD 
1 If no index nodal lesions are present at Screening, then index lesions response is equal to the index 
extranodal lesions response. A similar rule applied if no index extranodal lesions are present at 
Screening, then index lesions response is equal to the index nodal lesions response. 
 
In case of missing measurements of any of the index lesions, the radiological response for 
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen. 
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for index lesions at that assessment will be “Unknown 
(UNK)”. 
 
iv 
Evaluation of non-index lesions (including nodal, splenic 
and/or hepatic nodules and other extranodal lesions) 
At each reassessment, a non-index lesion (or a group of non-index lesions) will be given one 
of the following designations: 
• Normalization (non-index nodal lesion has regressed to normal size; non-index extranodal 
lesion is no longer present). Normalization of non-index nodal lesions should be 
determined based on their size at Screening. 
• Improved, stable or worsened, but without unequivocal evidence of disease progression 
(non-index lesion is present but there is not sufficient worsening to declare PD based on 
the existing non-index lesions). 
• Unequivocal evidence of disease progression (worsening of existing non-index lesions is 
sufficient to declare PD) 
• Not assessed 
Then, this status for each non-index lesion (or group of non-index lesions) will lead to a 
global response for non-index lesions (Table 4-5): 


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Table 4-5 
Response criteria for non-index lesions (nodal, splenic and/or 
hepatic nodules and other extranodal lesions) 
Response Criteria 
Evaluation of non-index lesions 
 
Complete Response (CR) 
Complete normalization of all non-index nodal and extranodal lesions: 
Radiological regression to normal size of all lymph nodes and complete 
disappearance of all extranodal (including splenic and/or hepatic nodules) 
lesions 
Stable Disease (SD) 
Failure to attain the criteria needed for CR and failure to fulfill the criteria 
for PD 
 
Progressive Disease (PD) 
Unequivocal disease progression of any existing non-index lesions (nodal 
or extranodal) 
 
In case of a missing status of any of the non-index lesions, the radiological response for non- 
index lesions at that assessment will be “Unknown (UNK)”, unless progression was seen. 
All lesions must have been measured with the same method as the one used at Screening, 
otherwise the radiological response for non-index lesions at that assessment will be 
“Unknown (UNK)”. 
 
v 
New lesions 
The appearance of 
• any new nodal lesion ≥15 mm in any axis. New nodal lesion is defined by: 
• either a previously normal lymph node becoming > 15 mm in any axis, 
• or a previously identified abnormal lymph node showing an increase of at least 50% 
in the long axis, 
• as assessed by investigator 
OR 
• any discrete extranodal (including splenic and/or hepatic nodules) lesions reliably 
appearing on CT scan or MRI after Screening 
is always considered as Progressive Disease (PD) and has to be recorded as a new lesion in 
the appropriate module of the eCRF. Determination of new lymphoma involvement in organs 
other than lymph nodes or liver or spleen should be confirmed histologically and the site must 
document that in a comment to the corresponding eCRF. 
 
vi 
Overall radiological response 
Overall radiological response is calculated as shown in Table 4-6. 


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Table 4-6 Overall radiological response at each assessment 
 
Index lesions 
Non-index lesions1 
New lesions 
Overall radiological response 
CR 
CR 
No 
CR 
CR 
SD 
No 
PR 
PR 
CR or SD 
No 
PR 
SD 
CR or SD 
No 
SD 
PD 
Any 
Yes or No 
PD 
Any 
PD 
Yes or No 
PD 
Any 
Any 
Yes 
PD 
1 If no non-index lesions are present at Screening, then this column is not used in evaluating overall 
radiological response. 
 
If the evaluation of any of the index or non-index lesions identified at Screening could not be 
made during follow-up or if the index or non-index response is “Unknown (UNK)”, the 
overall response status at that assessment must be “Unknown (UNK)” unless progression or a 
new lesion was seen. 
 
vii 
Evaluation of overall disease response 
The evaluation of overall disease response at each assessment is a composite of the individual 
radiological responses (index and non-index lesions, new lesions), laboratory test (bone 
marrow) and clinical responses (lymphoma related clinical symptoms). 
 
viii 
Bone marrow re-assessment at time of radiological CR 
In order to confirm a Complete disease response (CR), bone marrow biopsy or aspirate may 
be required when a radiological CR has been achieved. Details are provided in the Study 
Protocol. The infiltrate of lymphoma in bone marrow must have cleared on repeat bone 
marrow biopsy or aspirate. Patients who achieve a CR by other criteria but who have 
persistent morphologic positive or inconclusive bone marrow involvement will be considered 
partial responders. New or recurrent bone marrow involvement anytime during the follow up 
will be considered PD. Bone marrow biopsy or aspirate will be performed after the first 
assessment of CR or when clinically indicated. 
The biopsy sample of bone marrow must be adequate (with a goal of > 20 mm unilateral core). 
If the sample is indeterminate by morphology, it should be negative by immunohistochemistry. 
 
ix 
Overall disease response 
If a patient has an overall radiological response of CR then this response must be confirmed 
by bone marrow biopsy or aspirate (if required as per the Study Protocol), presence of normal 
liver and spleen size, and evaluation of lymphoma related B-symptoms. The patient’s overall 
response will be calculated as follows: 
A patient will be deemed to have overall disease response of CR if bone marrow biopsy or 
aspirate becomes negative for tumor involvement (if the bone marrow was involved by 
lymphoma at Screening) and the liver and spleen are normal in size and there are no 
lymphoma related B-symptoms in addition to radiological CR. 


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If assessments of any of the following: lymphomatous infiltration of bone marrow (If required 
as per the Study Protocol), or evaluation of B-symptoms is not done, unknown or 
indeterminate or B-symptoms are still present when the overall radiological response is 
assessed as CR or the liver or spleen are enlarged, then the overall disease response will be 
assessed as PR until evaluation of these factors have shown normalized results and recorded 
on the corresponding eCRF. 
For patients whose radiological response is anything other than CR, assessment of bone 
marrow, liver, spleen and B-symptoms will not be required in evaluating overall response and 
overall disease response is the same as radiological response. However any new or recurrent 
bone marrow involvement at any time during follow-up will be considered PD. 
Of note, appearance of B-symptoms or enlarged spleen or liver will not in themselves 
constitute documentation of progression. They are however expected to be associated with 
progressive disease. Every effort should be made to document that evidence radiologically 
and report the corresponding tumor assessments. Such tumor assessments are expected to be 
performed within 2 months of appearance of B-symptoms or enlarged spleen or liver. 
 
5 
References (available upon request) 
Cheson BD (2007a) The international harmonization project for response criteria in 
lymphoma clinical trials. Hematol Oncol Clin N Am 21:841-854. 
Cheson BD (2009) The case against heavy PETing. J Clin Oncol 27:1742-1743. 
Cheson BD, Horning SJ, Coiffier B, et al (1999) Report of an International Workshop to 
standardize response criteria for non-Hodgkin's lymphomas. J Clin Oncol 17:1244-1253. 
Cheson BD, Pfistner B, Juweid ME, et al (2007b) Revised response criteria for malignant 
lymphoma. J Clin Oncol 25:579-586. 
FDA Guideline (2005) Clinical Trial Endpoints for the Approval of Cancer Drugs and 
Biologics, April 2005. 


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14.3 
Appendix C: Ann Arbor staging classification 
Not applicable. Please refer to BGJ398XUS04 Protocol Version 02 
 
 
Stage 
Area of involvement 
 
I 
Single lymph node group 
II 
Multiple lymph node groups on the same side of the diaphragm 
III 
Multiple lymph node groups on both sides of the diaphragm 
IV 
Multiple extranodal sites or lymph nodes and extranodal disease 
X 
Bulk disease > 10 cm 
E 
Extranodal extension or single isolated site of extranodal disease 
Class A are patients who experience no B symptoms 
Class B are patients experience unexplained fever of ≥ 38°C; unexplained, recurrent drenching night 
sweats; or unexplained loss of >10% body weight within the previous 6 months 
 
1 Cotswolds modification of Ann Arbor staging system adapted from 2007 NCCI guidelines for non- 
Hodgkin’s lymphoma 
 


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14.4 
Appendix D: Rai Staging System a 
 
 
Stage 
Area of involvement 
Risk Status 
0 
Lymphocytosis, lymphocytes in blood >15 x 109/L and >40% lymphocytes 
in bone marrow 
Low 
I 
Stage 0 with enlarged node(s) 
Intermediate 
II 
Stage 0-1 with splenomegaly, hepatomegaly, or both 
Intermediate 
IIIb 
Stage 0-II with hemoglobin < 11.0 g/dL or hematocrit <33% 
High 
IVb 
Stage 0-III with platelets <100 x 109/L 
High 
 
a Research originally published in Blood. Rai KR,et al. Clinical staging of chronic lymphocytic 
leukemia. Blood 1975;46(2):219-234. (c) The American Society of Hematology 
b Immune-mediated cytopenias are not the basis for these stage definitions. 
 


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14.5 
Appendix E: Criteria for Response assessment in Acute Myeloid 
Leukemia (based on IWG and Cheson) 
Disease assessments will be based on standardized response criteria as defined by the 
International Working Group (IWG) for AML (Cheson et al 2003). 
 
 
Response classification in AML at a given evaluation time (Cheson 2003) 
Response category 
Definition# 
Complete remission (CR) 
Bone marrow 
< 5% blasts 
no blasts with Auer rods 
Peripheral blood 
neutrophils ≥ 1.0 x 109/L 
platelets ≥ 100 x 109/L 
≤ 1% blasts 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement). 
Transfusion independent (see Section 7.2.1.4.5). 
In case all criteria for CR apply and the patient receives platelet and/or 
neutrophil transfusions, the patient will be assessed as CRi. 
Complete remission with 
incomplete blood count 
recovery (CRi) 
Bone marrow 
< 5% blasts 
no blasts with Auer rods 
Peripheral blood 
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L 
≤ 1% blasts 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement). 
Transfusion-independent (see Section 7.2.1.4.5). Exception: Platelet 
and neutrophil transfusions are allowed. 
Partial Remission (PR) 
Bone marrow 
50% or greater decrease (absolute range 5-25% blasts) 
< 5% of blasts contain Auer rods 
Peripheral blood 
neutrophils < 1.0 x 109/L and/or platelets < 100 x 109/L 
No evidence of extramedullary disease (such as CNS or soft tissue 
involvement). 
Treatment failure 
Treatment failure includes those patients for whom treatment has 
failed to achieve PR, CRi or CR throughout the treatment. 
Relapse from CR or CRi* 
Only in patients with a CR or CRi: 
Reappearance of blasts in peripheral blood (> 1%) OR 
≥ 5% blasts in bone marrow OR 
(Re-)appearance of extramedullary disease 


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Response classification in AML at a given evaluation time (Cheson 2003) 
Response category 
Definition# 
No response 
In case a patient does not achieve CR, CRi, PR or relapse for an 
individual response assessment. 
Unknown 
In case the response assessment was not done, the baseline 
assessment was not done, the assessment was incomplete or was not 
done within the respective time frame. 
# If not defined otherwise, all of the criteria apply. 
* Cheson et al (2003) does not specify relapse after PR but this may be considered in Phase I or II 
protocols. 
 
  14.5.1 
Exploratory AML response categories according to IWG 
 
Response category 
Definition 
 
Cytogenetic complete remission (CRc) 
All criteria for CR plus 
no cytogenetic abnormalities 
 
Molecular complete remission (CRm) 
All criteria for CRc plus 
no leukemic cells by RQ-PCR assay 
 


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14.6 
Appendix F: Criteria for Response assessment in Acute 
Lymphoblastic Leukemia (based on NCCN Guidelines 
Version 1.2013) 
 
 
Response classification in ALL for Blood and Bone Marrow at a given evaluation time 
Response category 
Definition# 
Complete remission (CR) 
No circulating blasts or extramedullary disease (such as 
lymphadenopathy, splenomegaly, skin/gum infiltration, testicular mass, 
CNS or soft tissue involvement) 
Trilineage hematopoiesis (TLH) and < 5% blasts 
neutrophils ≥ 1.0 x 109/L 
platelets ≥ 100 x 109/L 
No recurrence for 4 weeks 
Complete remission with 
incomplete blood count 
recovery (CRi) 
Peripheral blood 
Recovery of platelets but < 100 x 109/L or neutrophils is < 1.0 x 109/L. 
Progressive Disease (PD) 
Increase of at least 25% in the absolute number of circulating or bone 
marrow blasts or development of extramedullary disease. 
Treatment failure 
Treatment failure includes those patients for whom treatment has 
failed to achieve a CR at the end of treatment 
Relapse from CR or CRi* 
Only in patients with a CR or CRi: 
Reappearance of blasts in peripheral blood (> 1%) OR 
≥ 5% blasts in bone marrow OR 
(Re-)appearance of extramedullary disease 
No response 
In case a patient does not achieve CR, CRi, PR or relapse for an 
individual response assessment. 
Unknown 
In case the response assessment was not done, the baseline 
assessment was not done, the assessment was incomplete or was not 
done within the respective time frame. 
# If not defined otherwise, all of the criteria apply. 


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14.7 
Appendix G: Criteria for Response assessment in Chronic 
Myelogenous Leukemia (based on NCCN Guidelines Version 4. 
2013) 
Response classification in CML for hematologic, cytogenetic, and molecular evaluation at a 
given evaluation time 
Response category 
Definition# 
Complete hematologic 
response (CR)1 
Complete normalization of peripheral blood counts with leukocyte 
count < 10 x 109/L 
platelets < 450 x 109/L 
No immature cells such as myelocytes, promyelocytes, or blasts in 
peripheral blood 
No signs and symptoms of disease with disappearance of 
splenomegaly 
Cytogenetic response2,3 
Complete 
No Ph-positive metaphases 
Partial 
1% - 35% Ph-positive metaphases 
Major 
0% - 35% Ph-positive metaphases (complete + partial) 
Minor 
> 35% Ph-positive metaphases 
Molecular response4,5 
Complete 
No detectable BCR-ABL mRNA by QPCR using an assay with a 
sensitivity of at least 4.5 logs below standardized baseline. 
Major 
≥ 3 log reduction in international scale of BCR-ABL mRNA 
Treatment failure 
Treatment failure includes those patients for whom treatment has 
failed to achieve a complete hematologic response (CR) throughout 
treatment. 
No response 
In case a patient does not achieve CR, PR or relapse for an individual 
response assessment. 
Unknown 
In case the response assessment was not done, the baseline 
assessment was not done, the assessment was incomplete or was not 
done within the respective time frame 
# If not defined otherwise, all of the criteria apply. 
1. Federl S et al: Chronic myelogenous leukemia: Biology and therapy. Ann Intem Med 1999; 131:207- 
219. 
2. A minimum of 20 metaphases should be examined. 
3. O’Brien SG, et al: Imatinib compared with interferon and low-dose cytarabine for newly diagnosed 
chronic-phase chronic myeloid leukemia. N Engl J Med 2003;348:994-1004. 
4. Hughes TP, et al: Frequency of major molecular responses to imatinib or interferon alfa plus 
cytarabine in newly diagnoses chronic myeloid leukemia. N Engl J Med 2003;349:1423-1432 
5. Hughes T, et al: Monitoring CML patients responding to treatment with tyrosine kinase inhibitors; 
review and recommendations for harmonizing current methodology for detecting BCR-ABL transcripts 
and kinase domain mutations and for expressing results. Blood 2006;108:28-37 


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14.8 
Appendix H: Criteria for Response assessment in Chronic 
Lymphocytic Leukemia (based on modified IWG guidelines) 
Disease assessments will be based on standardized response criteria as defined by the 
modified IWG guidelines for CLL. Response in CLL must meet the criteria in both Group A 
and Group B. Group A criteria defines tumor load. Group B criteria defines the function of the 
hematopoietic system (or marrow). 
 
Response Definition for Chronic Lymphocytic Leukemia1 
Group A Response for Tumor Burden 
 
Response    Nodal Masses 
Organomegaly 
Bone Marrow 
CR 
None > 1.5 cm 
No splenomegaly 
No hepatomegally 
CRi 
None > 1.5 cm 
No splenomegaly 
No hepatomegally 
Normocellular >30% Lymph. No B 
lymphoid nodules 
Hypocellular marrow 
 
PR 
Decrease ≥50% 
Spleen/Liver decrease ≥50 
50% reduction in marrow infiltrate, 
or B-lymphoid nodules 
 
Group B Response for hepatopoietic system2 
Response 
Platelet count 
Hemoglobin 
Neutrophils 
 
CR 
>100 x 109/L 
>11 g/dL 
>1.5 x 109/L 
 
CRi 
If meets criteria from Group A but does not meet criteria from Group B 
PR 
>100 x 109/or increase 
≥50% over baseline 
>11 g/dL or increase ≥50% 
over baseline 
>1.5 x 109/L or >50% 
improvement over baseline 
 
SD 
Failure to attain CR/CRi/PR or PD 
Relapsed 
disease or 
PD 
Appearance of any new lesions; at least one of the above criteria. Isolated progressive 
lymphocytosis in the setting of reduced lymph node size or organomegaly or 
improvement in hemoglobin/platelets will not be considered progressive disease 
 
1. 
Hallek M, et al. Guidelines for the diagnosis and treatment of chronic lymphocytic leukemia 
updating the National Cancer Institute-Working Group 1996 Guidelines. Blood 2008; 111:5446- 
5456 
2. 
All values are without transfusion or hepatopoietic growth factors 
 


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14.9 
Appendix I: Criteria for Response assessment in Myelofibrosis 
(based on modified IWG-MRT guidelines and European 
LeukemiaNet (ELN) consensus report)1 
 
 
Response category 
Definition 
CR 
Bone marrow*: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF† and 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥ 1 X 
109/L and <UNL; 
Platelet count ≥100 X 109/L and <UNL; <2% immature myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
PR 
Peripheral blood: Hemoglobin ≥100 g/L and <UNL; neutrophil count ≥1 X 
109/L and <UNL; platelet count ≥100 X 109/L and <UNL; <2% immature 
myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH or 
Bone marrow*: Age-adjusted normocellularity; <5% blasts; ≤grade 1 MF†, 
and peripheral blood: Hemoglobin ≥85 but <100 g/L and <UNL; neutrophil 
count ≥1 X 109/L and <UNL; platelet count ≥50, but <100 X 109/L and <UNL; 
<2% immature myeloid cells‡ and 
Clinical: Resolution of disease symptoms; spleen and liver not palpable; no 
evidence of EMH 
Clinical improvement 
(CI) 
The achievement of anemia, spleen or symptoms response without 
progressive disease or increase in severity of anemia, thrombocytopenia, or 
neutropenia§ 
Anemia response 
Transfusion-independent patients: a ≥20 g/L increase in hemoglobin level|| 
Transfusion-dependent patients: becoming transfusion-independent^ 
Spleen response# 
A baseline splenomegaly that is palpable at 5-10 cm, below the LCM, 
becomes not palpable** or 
A baseline splenomegaly that is palpable at >10 cm, below the LCM, 
decreases by ≥50%** 
A baseline splenomegaly that is palpable at <5 cm, below the LCM, is not 
eligible for spleen response 
A spleen response requires confirmation by MRI or computed tomography 
showing ≥35% spleen volume reduction 
Symptoms response 
A ≥50% reduction in the MPN-SAF TSS†† 
Progressive disease‡‡ 
Appearance of a new splenomegaly that is palpable at least 5 cm below the 
LCM or 
A ≥100% increase in palpable distance, below LCM, for baseline 
splenomegaly of 5-10 cm or 
A 50% increase in palpable distance, below LCM, for baseline splenomegaly 
of >10 cm or 
Leukemic transformation confirmed by a bone marrow blast count of ≥20% 
or 
A peripheral blood blast content of ≥20% associated with an absolute blast 
count of ≥1 X 109/L that lasts for at least 2 weeks 


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Response category 
Definition 
Stable disease 
Belonging to none of the above listed response categories 
Relapse 
No longer meeting criteria for at least CI after achieving CR, PR, or CI, or 
Loss of anemia response persisting for at least 1 month or 
Loss of spleen response persisting for at least 1 month 
Recommendations for assessing treatment-induced cytogenetic and molecular changes 
Cytogenetic remission 
At least 10 metaphases must be analyzed for cytogenetic response 
evaluation and 
requires confirmation by repeat testing within 6 months window 
CR: eradication of a preexisting abnormality 
PR: ≥50% reduction in abnormal metaphases 
(partial response applies only to patients with at least ten abnormal 
metaphases at baseline) 
Molecular remission 
Molecular response evaluation must be analyzed in peripheral blood 
granulocytes and 
requires confirmation by repeat testing within 6 months window 
CR: Eradication of a pre-existing abnormality 
PR: ≥50% decrease in allele burden 
(partial response applies only to patients with at least 20% mutant allele 
burden at baseline) 
Cytogenetic/molecular 
relapse 
Re-emergence of a pre-existing cytogenetic or molecular abnormality that is 
confirmed by repeat testing 
1 Tefferi et al. (2013) Revised response criteria for myelofibrosis: International Working (IWG-MRT) 
and European LeukemiaNet (ELN) consensus report Group-Myeloproliferative Neoplasms Research 
and Treatment. Blood; 2013 122: 1395-1398 
EMH, extramedullary hematopoiesis (no evidence of EMH implies the absence of pathology- or 
imaging study-proven nonhepatosplenic EMH); LCM, left costal margin; UNL, upper normal limit. 
†Grading of MF is according to the European classification 
Thiele et al. European consensus on grading bone marrow fibrosis and assessment of cellularity. 
Haematologica. 2005;90:1128. 
It is underscored that the consensus definition of a CR bone marrow is to be used only in those 
patients in which all other criteria are met, including resolution of leukoerythroblastosis. It should also 
be noted that it was a particularly difficult task for the working group to reach a consensus regarding 
what represents a complete histologic remission. 
‡Immature myeloid cells constitute blasts + promyelocytes + myelocytes + metamyelocytes + 
nucleated red blood cells. In splenectomized patients, <5% immature myeloid cells is allowed. 
§See above for definitions of anemia response, spleen response, and progressive disease. Increase in 
severity of anemia constitutes the occurrence of new transfusion dependency or a ≥20 g/L decrease in 
hemoglobin level from pretreatment baseline that lasts for at least 12 weeks. Increase in severity of 
thrombocytopenia or neutropenia is defined as a 2-grade decline, from pretreatment baseline, in 
platelet count or absolute neutrophil count, according to the Common Terminology Criteria for Adverse 
Events (CTCAE) version 4.0. In addition, assignment to CI requires a minimum platelet count of ≥25 
000 X 109/L and absolute neutrophil count of ≥0.5 X 109/L. 
||Applicable only to patients with baseline hemoglobin of<100 g/L. In patients not meeting the strict 
criteria for transfusion dependency at the time of study enrollment (see as follows), but have received 
transfusions within the previous month, the pre-transfusion hemoglobin level should be used as the 
baseline. 
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Response category 
Definition 
packed red blood cells (PRBC), in the 12 weeks prior to study enrollment, for a hemoglobin level of 
<85 g/L, in the absence of bleeding or treatment-induced anemia. In addition, the most recent 
transfusion episode must have occurred in the 28 days prior to study enrollment. Response in 
transfusion-dependent patients requires absence of any PRBC transfusions during any consecutive 
“rolling” 12-week interval during the treatment phase, capped by a hemoglobin level of ≥85 g/L. 
#In splenectomized patients, palpable hepatomegaly is substituted with the same measurement 
strategy. 
**Spleen or liver responses must be confirmed by imaging studies where a ≥35% reduction in spleen 
volume, as assessed by MRI or CT, is required. Furthermore, a ≥35% volume reduction in the spleen 
or liver, by MRI or CT, constitutes a response regardless of what is reported with physical examination. 
††Symptoms are evaluated by the MPN-SAF TSS.1 The MPN-SAF TSS is assessed by the patients 
themselves and this includes fatigue, concentration, early satiety, inactivity, night sweats, itching, bone 
pain, abdominal discomfort, weight loss, and fevers. Scoring is from 0 (absent/as good as it can be) to 
10 (worst imaginable/as bad as it can be) for each item. The MPN-SAF TSS is the summation of all 
the individual scores (0-100 scale). Symptoms response requires ≥50% reduction in the MPN-SAF 
TSS. 
‡‡Progressive disease assignment for splenomegaly requires confirmation my MRI or computed 
tomography showing a ≥25% increase in spleen volume from baseline. Baseline values for both 
physical examination and imaging studies refer to pretreatment baseline and not to post-treatment 
measurements. 


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14.10 
Appendix J: Criteria for Response assessment in polycythemia 
vera (based on modified IWG-MRT guidelines and European 
LeukemiaNet (ELN) consensus report)1 
 
 
Response categories 
Required criteria 
Complete remission 
A. Durable resolution of disease-related signs including palpable 
hepatosplenomegaly, large symptoms improvement† AND 
B. Durable peripheral blood count remission, defined as Ht lower than 45% 
without phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, 
AND 
C. Without progressive disease, and absence of any hemorrhagic or 
thrombotic event, AND 
D. Bone marrow histological remission defined as the presence of age- 
adjusted normocellularity and disappearance of tri-linear hyperplasia, and 
absence of >grade 1 reticulin fibrosis 
Partial remission 
A. Durable resolution of disease-related signs including palpable 
hepatosplenomegaly, large symptoms improvement† AND 
B. Durable peripheral blood count remission, defined as Ht lower than 45% 
without phlebotomies; platelet count ≤400 X 109/L, WBC count <10 X 109/L, 
AND 
C. Without progressive disease, and absence of any hemorrhagic or 
thrombotic event, AND 
D. Without bone marrow histological remission defined as persistence of tri- 
linear hyperplasia. 
No response 
Any response that does not satisfy partial remission 
Progressive disease 
Transformation into post-PV myelofibrosis, myelodysplastic syndrome or 
acute leukemia‡ 
Molecular response is not required for assignment as complete response or partial response. 
Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete response 
is defined as eradication of a preexisting abnormality. Partial response applies only to patients with at 
least 20% mutant allele burden at baseline. Partial response is defined as ≥ 50% decrease in allele 
burden. 
WBC, white blood cell. 
Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.2 
For the diagnosis of post-PV myelofibrosis, see the IWG-MRT criteria3; for the diagnosis of 
myelodysplastic syndrome and acute leukemia, see WHO criteria. 
1 Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an 
ELN and IWG-MRT consensus project. Blood 2013 121: 4778-4781 
2 Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment 
form total symptom score: prospective international assessment of an abbreviated symptom burden 
scoring system among patients with MPNs [published correction appears in J Clin Oncol. 
2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103 
3 Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and 
postessential thrombocythemia myelofibrosis: a consensus statement from the International Working 
Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437-438 


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14.11 
Appendix K: Criteria for Response assessment in Essential 
thrombocythemia (based on modified IWG-MRT guidelines and 
European LeukemiaNet (ELN) consensus report)1 
 
 
Response category 
Definition 
Complete remission 
A. Durable resolution of disease-related signs including palpable 
hepatosplenomegaly, large symptoms improvement,† AND 
B. Durable peripheral blood count remission, defined as: platelet count ≤400 X 
109/L, WBC count <10 X 109/L, absence of leukoerythroblastosis, AND 
C. Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND 
D. Bone marrow histological remission defined as disappearance of 
megakaryocyte hyperplasia and absence of >grade 1 reticulin fibrosis. 
Partial remission 
A. Durable resolution of disease-related signs including palpable 
hepatosplenomegaly, and large symptoms improvement, AND 
B. Durable peripheral blood count remission, defined as: platelet count ≤400 X 
109/L, WBC count <10 X 109/L, absence of leukoerythroblastosis, AND 
C. Without signs of progressive disease, and absence of any hemorrhagic or 
thrombotic events, AND 
D. Without bone marrow histological remission, defined as the persistence of 
megakaryocyte hyperplasia. 
No response 
Any response that does not satisfy partial remission 
Progressive disease 
Transformation into PV, post-ET myelofibrosis, myelodysplastic syndrome or 
acute leukemia‡ 
Molecular response is not required for assignment as complete response or partial response. 
Molecular response evaluation requires analysis in peripheral blood granulocytes. Complete response 
is defined as eradication of a preexisting abnormality. Partial response applies only to patients with at 
least 20% mutant allele burden at baseline. Partial response is defined as ≥50% decrease in allele 
burden. 
WBC, white blood cell. 
†Large symptom improvement (≥10-point decrease) in MPN-SAF TSS.3 
‡For the diagnosis of PV see World Health Organization criteria (WHO)4; for the diagnosis of post-ET 
myelofibrosis, see the IWG-MRT criteria2; for the diagnosis of myelodysplastic syndrome and acute 
leukemia, see WHO criteria.4 
1 Barosi G, et al; Revised response criteria for polycythemia vera and essential thrombocythemia: an 
ELN and IWG-MRT consensus project. Blood 2013 121: 4778-4781 
2 Barosi G, Mesa RA, Thiele J, et al; International Working Group for Myelofibrosis Research and 
Treatment (IWG-MRT). Proposed criteria for the diagnosis of post-polycythemia vera and 
postessential thrombocythemia myelofibrosis: a consensus statement from the International Working 
Group for Myelofibrosis Research and Treatment. Leukemia. 2008;22(2):437-438. 
3 Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm (MPN) symptom assessment 
form total symptom score: prospective international assessment of an abbreviated symptom burden 
scoring system among patients with MPNs [published correction appears in J Clin Oncol. 
2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103. 
4 Swerdlow SH, Campo E, Harris NL, et al, eds. WHO Classification of Tumours of Haematopoietic 
and Lymphoid Tissues. Lyon, France: IARC; 2008. 


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14.12 
Appendix L: Criteria for Response assessment in 
Myelodysplasia (based on modified IWG guidelines)1 
 
 
Category 
Response Criteria 
Complete remission 
Bone marrow: ≤ 5% myeloblasts with normal maturation of all cell lines* 
Persistent dysplasia will be noted* 
Peripheral blood 
• 
Hgb ≥ 11 g/dL 
• 
Platelets ≥ 100 x 109/L 
• 
Neutrophils ≥ 1.0 x 109/L 
• 
Blasts 0% 
Partial remission 
All CR criteria if abnormal before treatment except: 
Bone marrow blasts decreased by ≥ 50% over pretreatment but still > 5% 
Cellularity and morphology not relevant 
Marrow CR 
Bone marrow: ≤ 5% myeloblasts and decrease by ≥ 50% over pretreatment 
Peripheral blood: if HI responses, they will be noted in addition to marrow CR 
Stable disease 
Failure to achieve at least PR, but no evidence of progression for > 8 wks 
Failure 
Death during treatment or disease progression characterized by worsening of 
cytopenias, increase in percentage of bone marrow blasts, or progression to a 
more advanced MDS FAB subtype than pretreatment 
Relapse after CR or 
PR 
At least 1 of the following: 
• 
Return to pretreatment bone marrow blast percentage 
• 
Decrement of ≥ 50% from maximum remission/response levels in 
granulocytes or platelets 
• 
Reduction in Hgb concentration by ≥ 1.5 g/dL or transfusion dependence 
Cytogenetic 
response 
Complete - Disappearance of the chromosomal abnormality without 
appearance of new ones 
Partial - At least 50% reduction of the chromosomal abnormality 
Disease progression 
For patients with: 
• 
Less than 5% blasts: ≥ 50% increase in blasts to > 5% blasts 
• 
5%-10% blasts: ≥ 50% increase to > 10% blasts 
• 
10%-20% blasts: ≥ 50% increase to > 20% blasts 
• 
20%-30% blasts: ≥ 50% increase to > 30% blasts 
Any of the following: 
• 
At least 50% decrement from maximum remission/response in 
granulocytes or platelets 
• 
Reduction in Hgb by > 2 g/dL 
• 
Transfusion dependence 
*Dysplastic changes should consider the normal range of dysplastic changes (modification). 
1 Cheson, et al. Clinical application and proposal for modification of the International Working Group 
(IWG) response criteria in myelodysplasia. blood-2005-10-4149. 


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14.13 
Appendix M: Myeloproliferative Neoplasm (MPN) Symptom 
Assessment Form Total Symptom Score (MPN-SAF-TSS) 
Name:     
 
Fill out the form below to track the burden of your symptoms. 
Date: 
  
 
For each symptom, please circle the number that best describes how severe that symptom is, 
on a scale of 0 to 10, with 0 being absent or as good as it can be and 10 being worst 
imaginable. Make sure you circle a number for every symptom. Be sure to share your 
answers with your hematologist or other healthcare professional. 
Symptom - 1 to 10, 0 if absent and 10 being worst imaginable 
Please rate your fatigue (weariness, tiredness) by circling the one number that best describes 
your WORST level of fatigue during the past 24 hours 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Circle the one number that describes how much difficulty you have had with each of the 
following symptoms during the past week 
 
 
 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Abdominal discomfort 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Inactivity 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Problems with concentration - compared to before my diagnosis 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Night sweats 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Itching (pruritus) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Filling up quickly when you eat (early satiety) 
Fatigue 


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Bone pain (diffuse, not joint pain or arthritis) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Fever (> 37.8°C or 100°F) 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
Unintentional weight loss last 6 months 
0 
1 
2 
3 
4 
5 
6 
7 
8 
9 
10 
(ABSENT) 
(WORST IMAGINABLE) 
 
 
To help you get a clear overall picture of how you are feeling, you can add up all 
your scores to calculate your Total Symptom Score. 
 
Total 
1 Adapted from Emanuel RM, Dueck AC, Geyer HL, et al. Myeloproliferative neoplasm 
(MPN) symptom assessment form total symptom score: prospective international assessment 
of an abbreviated symptom burden scoring system among patients with MPNs [published 
correction appears in J Clin Oncol. 2012;30(36):4590]. J Clin Oncol. 2012;30(33):4098-4103 


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14.14 
Appendix N: Eastern Cooperative Oncology Group (ECOG) 
performance status 
 
 
Score 
Performance 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 housework, 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. 
5 
Dead 


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14.15 
Appendix O: International Myeloma Working Group (IMWG) 
uniform response criteria for multiple myeloma 
 
 
Response 
IMWG Criteria 
 
sCR 
CR as defined below plus normal FLC ratio and absence of clonal cells in bone marrow3 
by immunohistochemistry or immunofluorescence4 
CR 
Negative immunofixation on the serum and urine and disappearance of any soft tissue 
plasmacytomas and < 5% plasma cells in bone marrow3 
 
VGPR 
Serum and urine M-component detectable by immunofixation but not on electrophoresis 
or ≥ 90% reduction in serum M-component plus urine M-component < 100 mg per 24 hr 
 
PR 
> 50% reduction of serum M-protein and reduction in 24 hours urinary M-protein 
by >90% or to < 200 mg/24 h 
If the serum and urine M-protein are unmeasurable,5 a > 50% decrease in the difference 
between involved and uninvolved FLC levels is required in place of the M-protein criteria 
If serum and urine M-protein are not measurable, and serum free light assay is also not 
measureable, > 50% reduction in plasma cells is required in place of M-protein, provided 
baseline bone marrow plasma cell percentage was > 30% 
In addition to the above listed criteria, if present at baseline, a > 50% reduction in the 
size of soft tissue plasmacytomas is also required 
 
SD 
Not meeting criteria for CR, VGPR, PR, or progressive disease 
 
PD5 
Increase of > 25% from lowest response value in any one or more of the following: 
Serum M-component and/or (the absolute increase must be > 0.5 g/dL)6 
Urine M-component and/or (the absolute increase must be > 200 mg/24 h) 
Only in patients without measurable serum and urine M-protein levels; the difference 
between involved and uninvolved FLC levels. The absolute increase must be > 10 mg/dL 
Bone marrow plasma cell percentage; the absolute percentage must be > 10%7 
Definite development of new bone lesions or soft tissue plasmacytomas or definite 
increase in the size of existing bone lesions or soft tissue plasmacytomas 
Development of hypercalcaemia (corrected serum calcium > 11.5 mg/dL or 2.65 mmol/L) 
that can be attributed solely to the plasma cell proliferative disorder 
 
Relapse 
Clinical relapse requires one or more of: 
Direct indicators of increasing disease and/or end organ dysfunction (CRAB features).6 It 
is not used in calculation of time to progression or progression-free survival but is listed 
here as something that can be reported optionally or for use in clinical practice 
Development of new soft tissue plasmacytomas or bone lesions 
Definite increase in the size of existing plasmacytomas or bone lesions. A definite 
increase is defined as a 50% (and at least 1 cm) increase as measured serially by the 
sum of the products of the cross-diameters of the measurable lesion 
Hypercalcemia (> 11.5 mg/dL) [2.65 mmol/L] 
Decrease in haemoglobin of > 2 g/dL [1.25 mmol/L] 
Rise in serum creatinine by 2 mg/dL or more [177 mmol/L or more] 
 
1. BGM Durie et al. International uniform response criteria for multiple myeloma. Leukemia (2006) 1- 
7. 
2. Adapted from Durie BGM, et al. Leukemia 2006; 20: 1467-1473; and Kyle RA, Rajkumar SV. 
Leukemia 2008;23:3-9 
 


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Response 
IMWG Criteria 
Note: A clarification to IMWG criteria for coding CR and VGPR in patients in whom the only 
measurable disease is by serum FLC levels: CR in such patients is defined as a normal FLC ratio of 
0.26–1.65 in addition to CR criteria listed above. VGPR in such patients is defined as a >90% 
decrease in the difference between involved and uninvolved free light chain (FLC) levels. 
3. Confirmation with repeat bone marrow biopsy not needed. 
4.   Presence/absence of clonal cells is based upon the kappa/lambda ratio. An abnormal 
kappa/lambda ratio by immunohistochemistry and/or immunofluorescence requires a minimum of 100 
plasma cells for analysis. An abnormal ratio reflecting presence of an abnormal clone is kappa/lambda 
of > 4:1 or < 1:2. 
5. All relapse categories require two consecutive assessments made at any time before classification 
as relapse or disease progression and/or the institution of any new therapy. In the IMWG criteria, CR 
patients must also meet the criteria for progressive disease shown here to be classified as progressive 
disease for the purposes of calculating time to progression and progression-free survival. The 
definitions of relapse, clinical relapse and relapse from CR are not to be used in calculation of time to 
progression or progression-free survival. 
6. For progressive disease, serum M-component increases of >1 gm/dL are sufficient to define 
relapse if starting M-component is >5 g/dL. 
7. Relapse from CR has the 5% cut-off versus 10% for other categories of relapse. 
8. For purposes of calculating time to progression and progression-free survival, CR patients should 
also be evaluated using criteria listed above for progressive disease. 
 


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14.16 
Appendix P: 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. 
 
  14.16.1 Drugs to be used with caution while on 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 
Medications that have possible risk of 
TdP/QT prolongation 
Proton-pump inhibitors (e.g., omeprazole), H2- 
antagonists (e.g., ranitidine) and antacids. 
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 
 


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Category 
Drug Names 
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 
 
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 
fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm292362.pdf. 
Indiana University School of Medicine’s “Clinically Relevant” table (2009). 
medicine.iupui.edu/clinpharm/ddis/clinicalTable.aspx. Accessed 14 July 2011 
University of Washington’s Drug Interaction Database (2013) druginteractioninfo.org 
Drug-Drug Interactions (DDI) Database: Novartis Oncology Clinical Pharmacology Internal 
Memorandum, Final (v04), 12-Oct-2012 
 


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14.17 
Appendix Q: List of prohibited medication 
14.17.1 List of prohibited medication while on 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 
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 


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14.18 
Appendix R: Bayesian Adaptive Design Framework for the 
Modular phase II study to link targeted therapy to patients with 
pathway activated tumors 
14.1.1.0 Introduction 
This document outlines the adaptive design framework to be used for this study and all 
modules. 
Although the selected tumor types may vary by trial, this document outlines the design and 
analysis approach based on 8 example tumor cohorts: 
• Lung NSCL 
• Bladder 
• Breast 
• Colorectal 
• GIST 
• HNSCC 
• Ovarian 
• Sarcoma 
Other tumor types may be considered for trials if 1) 4 or more patients are enrolled in the 
cohort, and 2) a reasonable estimate of the clinical benefit rate is available. 
The primary endpoint is clinical benefit rate (CBR) in each cohort, with clinical benefit being 
assessed at 16 weeks. All patients will receive the experimental treatment for that particular 
trial. 
 
14.1.1.1 Primary analysis 
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability 
of response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying 
probability of response for group g within the trial. We transform to the logit scale for 
modeling purposes. Let θg be the mean log odds treatment effect, i.e.: 
Thus, θg is the group specific logistic regression coefficient for group g. The primary analysis 
is a set of group specific tests that θg>0, meaning that the experimental treatment is better 
than the assumed control rate for that group. Thus, we wish to test the set of hypotheses 
H0g : θg≤0 
H1g : θg>0 
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis, 


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Pr(θg>0 | data) > 0.80 
Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below. 
 
14.1.1.2 Trial logistics 
Each trial will enroll all available subjects in all cohorts for 2 years unless a cohort cap is 
reached, or a cohort is stopped early, or the trial is stopped early by Novartis. Each trial will 
enroll no more than 30 evaluable subjects in each cohort. Interim monitoring will be 
conducted starting after the first 30 patients are enrolled overall (across all cohorts), and 
continuing each 13 weeks thereafter till study enrollment closure. After that, one CBR 
analysis will be done after database lock. At each interim data review, response information 
for the various cohorts will be evaluated to determine the current Pr(θg>0 | data) within each 
cohort, with sufficiently high/low values used to stop the cohort for success/futility. A 
minimum of 10 patients will be required in a cohort before it may discontinue enrollment for 
futility, and a minimum of 15 patients are required before discontinuing a cohort for efficacy. 
If a cohort stops enrolling early, the remaining cohorts will continue until the end of 2 years or 
until the other cohorts reach their own early stopping criteria. The final analysis will occur 
after the database lock for the primary CSR. 
Each trial will enroll subjects in all listed cohorts. In addition, should other cohorts be 
identified throughout the trial, the following mechanism will be used. If another cohort is 
identified, it will not be placed into the statistical analysis unless 3 subjects enroll within the 
cohort (thus, the trial may enroll multiple additional cohorts, but a cohort will only be added 
to the list if at least 3 patients enroll from that cohort). Thus, it is possible (but not viewed as 
likely) that multiple additional cohorts may be added to the trial if the trial has sufficient 
enrollment in multiple additional cohorts. In addition to sufficient enrollment, the sponsor 
must have a reasonable estimate of the control clinical benefit rate. 
Subjects within any cohort which does not reach the minimum enrollment will be excluded 
from the interim and final analyses. As the study continues, early interim data reviews may be 
based on fewer cohorts than later interim data reviews, as the interim data reviews will 
include whatever cohorts have satisfied the criteria at the time of the data review. 
 
14.2.2.0 Statistical modeling 
We let Yi be the response indicator for the ith subject, and let Rg be the probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.: 
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ. In this way, the model is a compromise between the two alternate extremes of either a 


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completely pooled analysis or a separate analysis in each group. We additionally incorporate a 
clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR. 
The purpose of such an analysis (discussed in more detail in the appendix) is to produce 
higher power or lower type I error in situations where we see some commonality (identical 
effects are not required) among the groups. The model will borrow more in situations where 
the groups appear similar than situations where the groups appear different. 
 
14.2.2.1 Hierarchical model with clustering 
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data. 
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in the appendix. 
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the θg have an across groups distribution 
θg ~ N(μ, τ2) 
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2. 
The variance component τ controls the degree of borrowing among groups. Small values of τ 
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 


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different results with borrow far less information between them (they will have a low 
probability of being in the same cluster). 
Details of the two stages may be found in the appendix. 
 
14.3.3.0 Evaluation of trial success and futility 
Interim monitoring will occur after the first 30 patients are on the study for 16 weeks (112 
days), then every 13 weeks thereafter till study enrollment closure. At each interim data 
review, the groups will be evaluated for early futility and early success by comparing 
posterior quantities for the response rate to pre-specified early stopping criteria. 
 
14.3.3.1 Early futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility. Formally, enrollment will stop 
early for futility if: 
Pr(πg > Rg) < 0.10. 
A group is only eligible for early stopping once a minimum of 10 patients has been evaluated 
for response in that group. 
 
14.3.3.2 Early success 
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success. Formally, enrollment will stop early for 
success if: 
Pr(πg > Rg) > 0.95. 
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious. 
 
14.3.3.3 Final analysis 
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups, or after the database lock for the primary CSR. If, at the completion of the trial, 
there is at least 80% probability that the response rate in a group exceeds the historical rate, 
then the group will be considered a success. Formally: 
Pr(πg > Rg) > 0.80. 
 
14.4.4.0 Simulation 
We evaluated type I error and power for each of the 8 possible groups under a variety of 
possible “truths” indicating various possible true underlying probabilities within each group. 
 
14.4.4.1 Assumptions 
Accrual – Two scenarios for the assumed two-year expected accrual are investigated: 1) 10 
subjects per group and 2) 5 subjects per group. Note that these are averages, the actual number 


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of available patients is simulated as a Poisson distribution with the specified mean. Also note 
that the group cap of 30 applies, and thus if the number of available patients in a group 
exceeds 30, only the first 30 available patients in that group will be enrolled in the study. 
Dropouts – We assume no dropouts for the purpose of this simulation. 
Control Rates –Table 14-1 shows the assumed control clinical benefit rates for each group. 
 
Table 14-1 
Assumed control CBR values used in the simulations 
 
Tumor Type 
Assumed Control Rate (Rg) 
Lung LSCL 
0.45 
Bladder 
0.47 
Breast 
0.50 
Colorectal 
0.38 
GIST 
0.50 
HNSCC 
0.45 
Ovarian 
0.47 
Sarcoma 
0.40 
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups. 
Treatment Rates - The treatment rates for each scenario are shown in the table below. Values 
identical to the control are shown in red, while values greater than the assumed control rate 
are shown in green. 
Null 
Alternative 
Two 
Half 
Lung LSCL 
0.45 
0.71 
0.45 
0.45 
Bladder 
0.47 
0.73 
0.47 
0.47 
Breast 
0.50 
0.75 
0.50 
0.50 
Colorectal 
0.38 
0.65 
0.38 
0.38 
GIST 
0.50 
0.75 
0.50 
0.75 
HNSCC 
0.45 
0.71 
0.45 
0.71 
Ovarian 
0.47 
0.73 
0.73 
0.73 
Sarcoma 
0.40 
0.67 
0.67 
0.67 
Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin. 
 
14.4.4.2 Results 
A total of 8 scenarios were simulated (two accrual scenarios and four possible ‘truths’ for the 
clinical benefit rate). The probability of group success for each group is provided for each 
scenario in the below two tables. 
Table 14-2 provides the probability of group success for each of the cohort – assuming 
expected accrual of 10 subjects/cohort and 5 subjects/cohort separately 


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Table 14-2 
Probability of group success for each cohort 
 
Two-year expected accrual: 10 subjects/cohort 
Group 
Null 
Alternative 
Two 
Half 
Lung LSCL 
0.158 
0.915 
0.208 
0.305 
Bladder 
0.131 
0.918 
0.232 
0.322 
Breast 
0.147 
0.909 
0.233 
0.312 
Colorectal 
0.138 
0.921 
0.200 
0.276 
GIST 
0.162 
0.921 
0.233 
0.826 
HNSCC 
0.139 
0.906 
0.217 
0.834 
Ovarian 
0.145 
0.929 
0.786 
0.829 
Sarcoma 
0.135 
0.939 
0.758 
0.852 
Two-year expected accrual: 5 subjects/cohort 
Group 
Null 
Alternative 
Two 
Half 
Lung LSCL 
0.132 
0.803 
0.204 
0.258 
Bladder 
0.140 
0.830 
0.196 
0.265 
Breast 
0.160 
0.807 
0.232 
0.261 
Colorectal 
0.135 
0.794 
0.194 
0.278 
GIST 
0.155 
0.826 
0.212 
0.688 
HNSCC 
0.140 
0.820 
0.190 
0.657 
Ovarian 
0.151 
0.819 
0.587 
0.652 
Sarcoma 
0.139 
0.799 
0.579 
0.667 
Entries in red represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in red are type I errors. Entries in green appear where the treatment 
is effective, and thus indicate the power of the design. 
Generally, type I error is controlled below 0.20 under the null scenario (the borrowing 
compensates for the multiple interim data reviews) and power is an increasing function of the 
expected sample size (power is higher in the higher accrual situation across treatment rate 
scenarios). In the alternative scenario there remains decently high probability of success even 
in the lower accruing situations. When fewer groups are effective in truth, the scenarios “half” 
and “two” are harder to discern. Note in any particular trial there should be a mix of high and 
low enrolling groups, thus some groups may enroll closer to 10 subjects while others may 
only enroll five. This would produce a power value somewhere between the two tables. 
Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the groups. Generally power is a function of the sample 
size. 
 
Appendix 1 - Modeling details 
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model. 
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 


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clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 
clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing 
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering. 
The details of the prior are as follows. Let zg represent the cluster to which group g belongs. 
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and 
We construct p using a stick-breaking process: 
and 
βk ~ Beta(1, α). 
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster. 
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution 
θg ~ N(μ, τ2) 
As discussed above, this across group distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions 
μ ~ N(0, 1.82) 
and 
τ2 ~ IG(3,0.5), 
where IG(α, β) is the inverse gamma distribution defined by: 
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 


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distribution for each group parameter θg, which is then used to drive the decisions in the 
model. 

SAP_001.pdf: 
Clinical Development & Medical Affairs
BGJ398
Protocol CBGJ398XUS04 / NCT02160041
Modular phase II study to link targeted therapy to patients with 
pathway activated tumors: Module 3 – BGJ398 for patients with 
FGFR genetic alterations
Statistical Analysis Plan (SAP)
Author:
Document type:
Statistical Analysis Plan
Document status:
Final v2.0
Release date:
13Jul2017
Number of pages:
25
Property of Novartis
Confidential
May not be used, divulged, published or otherwise disclosed
without the consent of Novartis


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Document History – Changes compared to previous version of SAP.
Version
Date
Changes


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Table of Contents
1
Statistical methods planned in the protocol and determination of sample size...................5
2
Statistical and analytical plans.............................................................................................5
2.1
Change in planned analyses from the protocol........................................................7
7
3
Subjects and treatments .......................................................................................................7
3.1
Analysis sets ............................................................................................................7
3.2
Subject disposition...................................................................................................8
3.3
Study Treatment and other concomitant medications .............................................9
4
Patient demographics and other baseline characteristics.....................................................9
5
Study treatment exposure and other medications..............................................................10
5.1
Study treatment......................................................................................................10
5.2
Prior and concomitant medications/non-drug therapies ........................................11
6
Efficacy and PRO evaluation ............................................................................................11
6.1
Clinical Benefit Rate (CBR)..................................................................................11
6.2
Overall Response Rate (ORR)...............................................................................12
6.3
Progression Free Survival (PFS) ...........................................................................12
6.4
Overall Survival (OS)............................................................................................13
6.5
Clinical Benefit Rate by Gene Mutations..............................................................13
7
Safety evaluation ...............................................................................................................13
7.1
Adverse events.......................................................................................................13
7.1.1
Specific safety event categories ............................................................14
7.2
Deaths ....................................................................................................................15
7.3
Vital signs..............................................................................................................15
7.4
Laboratory evaluations ..........................................................................................15
7.5
Other safety evaluations ........................................................................................16
8
Interim analyses.................................................................................................................16
9
Determination of sample size............................................................................................16
10 Bayesian Adaptive Design ................................................................................................18
10.1
Introduction............................................................................................................18
10.1.1
Primary Analysis...................................................................................18
10.1.2
Trial Logistics .......................................................................................19
10.2
Statistical Modeling...............................................................................................19
10.2.1
Hierarchical Model with Clustering......................................................20
10.3
Evaluation of Trial Success and Futility................................................................21
10.3.1
Early Futility .........................................................................................21


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10.3.2
Early Success ........................................................................................21
10.3.3
Final Analysis........................................................................................21
10.4
Simulation..............................................................................................................21
10.4.1
Assumptions..........................................................................................21
10.4.2
Results...................................................................................................22
10.5
Modeling Details ...................................................................................................23
11 References .........................................................................................................................25


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1
Statistical methods planned in the protocol and 
determination of sample size
The primary efficacy variable, clinical benefit rate, will be analyzed by a Novartis designated 
Contract Research Organization (CRO), 
. Analysis details are provided in 
Appendix R of the protocol, which is also included in Section Error! Reference source not 
found. of this Statistical Analysis Plan (SAP). 
Exploratory mutation profile analyses will be conducted by a Novartis computational 
biologist.
All other data will be analyzed by a different Novartis-designated CRO, 
 
according to Section 10 of the study protocol which will be available in 
Appendix 16.1.1 of the Clinical Study Report (CSR).  Important information is given in the 
following sections and details will be provided, as applicable, in Appendix 16.1.9 of the CSR.  
All statistical analyses will be performed using SAS® Version 9.3 (or higher).  
2
Statistical and analytical plans
Data from all centers that participate in this protocol will be used.  Per protocol, the analyses 
stated in this document will be based on all subjects’ data up to the time when all subjects 
have had the opportunity to complete at least 4 cycles (or 16 weeks) of study treatment or all 
subjects have discontinued study treatment, whichever is first. All subjects will be followed 
for survival status every 3 months for 2 years after the last subject has enrolled in the study
regardless of treatment discontinuation reason (except if consent is withdrawn or patient is 
lost to follow-up). However, as most subjects have been discontinued study treatment, the 
primary CSR analyses will be conducted after last patient discontinues study treatment.  
All statistical analyses presented in this document are related to subject background 
information, efficacy, and safety variables collected for the study.  All analyses are descriptive
and no hypothesis testing is planned (except for the primary efficacy variable, which is 
described in Section Error! Reference source not found.).  Data from all centers will be 
combined for any analysis.  In general, there is no stratification factor being considered for the 
analysis with the exception of tumor type in the primary efficacy variable analyses.  Missing 
data will not be imputed unless otherwise specified.  All data collected in the study will be 
presented in the listings.  In general, this document will detail the methods used in 
summaries/tabulations. 
A total of approximately 70-90 adults with a diagnosis of a solid tumor or hematological 
malignancy that have been pre-identified as having FGFR genetic alteration or FGF ligand 
amplification are planned to be enrolled. Subjects with history/current evidence of tumor-
induced osteomalacia (TIO) and FGF23-mediated hypophosphatemia with or without 
identification of an FGFR genetic alteration in the tumor are allowed.  Pre-identification of 
the mutation or activation in the pathway will be performed locally at a Clinical Laboratory
Improvement Amendments (CLIA) certified laboratory prior to participation in the study.  
Subject must have archival or fresh tissue available for submission to a central laboratory 
selected by Novartis to allow for molecular testing related to pathway regulation.
If the 


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tissue is not available or is insufficient, the subject must be willing to undergo a fresh tumor 
biopsy to allow for this analysis.  An archival or fresh tumor sample may not be required if 
the patient has had their genomic profiling performed at a laboratory selected by Novartis and 
the patient has agreed to allow Novartis to use baseline molecular analysis results.  Mutation 
types from both local and central laboratories will be analyzed.
To be eligible for enrollment to this study, subjects must have received at least one prior 
treatment for their recurrent, metastatic and/or locally advanced disease and have no 
remaining standard therapy options anticipated to result in a durable response. Subjects
must have progressive and measurable disease (per RECIST 1.1 or appropriate 
hematological response criteria) and are in need of treatment.  For patients with TIO 
diagnosis, the presence of measurable or evaluable disease is not required provided there is 
evidence of FGF23-mediated hypophosphatemia.
Subjects are administered with BGJ398 at 125 mg once daily, 3 weeks on 1 week off. A 
complete treatment cycle is defined as 28 days.  Subjects may continue on study treatment 
until disease progression, withdrawal of consent, unacceptable toxicity, death, or any other 
reasons (e.g., physician’s decision).
After discontinuation of study treatment, subjects, 
regardless of reason for study treatment discontinuation will be followed for safety for 30 
days after the last dose. Survival information will be collected every 3 months until 2 years 
after the last subject has enrolled in the study regardless of treatment discontinuation reason 
(except if consent is withdrawn). If the study’s primary efficacy endpoint is not met, 
Novartis may decide not to conduct survival follow up for the study. Additional survival 
assessments may be performed outside the 3 months follow-up schedules if a survival 
update is required for an interim assessment to meet safety or regulatory needs.
The primary efficacy objectives of the study, clinical benefit (definition details see Section 
6.1) associated with BGJ398 treatment based on local investigator assessment, will be 
summarized.  The clinical benefit rate will be analyzed using a Bayesian hierarchical model to 
evaluate trial success and futility, and the relationship between relevant pathway regulation 
and the response to treatment with BGJ398 (if applicable).  Analysis details are documented 
in Section Error! Reference source not found..
Duration of response (DOR) based on local investigator assessment will be analyzed.  In the 
event of a low response rate, DOR will be listed only without frequency summaries. Overall 
response (OR) will be summarized with the number and percentages of subjects for each 
response category (e.g., for solid tumor - CR, PR, SD, PD, Not evaluable).  Progression-free 
survival (PFS) and overall survival (OS) will be summarized using Kaplan-Meier (KM) 
methodology.
Subject demographics, disease characteristics (including mutation analyses), BGJ398
treatment, and safety variables will be summarized descriptively, by nominal visit (if 
applicable), and/or overall.
Data used for the analyses specified in this document will come from the Electronic Data 
Capture (EDC) system. In addition, the mutation data from the central laboratory will be 
collected in an Excel spreadsheet format and subsequently be uploaded to a secure FTP site
by Novartis.


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2.1
Change in planned analyses from the protocol
The protocol specifies that analyses are to be conducted by “patient group” which is formed 
by the types of cancer at study entry.  That is, subjects with the same tumor type will be 
considered as in the same “patient group”.  For efficacy analyses, with exception of the 
primary analysis of clinical benefit rate (i.e., summarized by ‘patient group’), other 
descriptive summaries in general will be produced overall for all BGJ-treated subjects.  
Separate summaries may be produced for those groups with at least 10 subjects.  All subjects 
will be combined for any safety analyses.
In the event of a low response rate, DOR will only be listed, and not tabulated. Subjects who 
had no disease progression/death will be censored at last adequate tumor assessment on or 
before the discontinuation/completion of the study or data cut-off.
For determination of PFS events, due to tumor assessments post study treatment are not 
collected, deaths occurred more than 30 days post treatment without prior progressive 
disease/relapse of disease will not be considered as an event.
For vital signs, values will be descriptively summarized by nominal visit. Separate summaries 
of significant abnormalities will not be provided, but will be reflected in adverse events (AEs).
3
Subjects and treatments 
3.1
Analysis sets
The following analysis data sets will be used in the analyses:
Full analysis set (FAS): The FAS will include all subjects who have received at least one 
dose of the study drug.  The FAS will be the primary set for efficacy analyses. 


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Safety set (SS): The SS will include all subjects who have received at least one dose of the
study treatment and had at least one post-baseline safety assessment. A subjects who has
received a dose of study treatment and who has no post-treatment safety data of any kind (i.e., 
no AE assessment, no vitals, no ECG, no cardiac imaging, no ECOG performance status, and
no laboratory assessment) will be excluded from the SS.  Note that the statement ‘no adverse 
event’ is considered as an assessment of AE.
3.2
Subject disposition
The number and percentage of subjects who completed study treatment or prematurely 
discontinued from the study treatment will be summarized with reasons for premature 
discontinuation.  The reasons for study treatment discontinuation are as follows:
1. Adverse events
2. Lost to follow-up
3. Death
4. Disease progression
a.
Radiological assessment
b. Clinical assessment
5. Protocol deviation
6. Non-compliance with study treatment
7. Pregnancy
8. Physician’s decision
9. Subject/guardian decision
10. Study terminated by sponsor
In addition, the number and percentage of subjects who consent to be followed for survival 
will be presented.
For subjects who were screened but did not take the study treatment, a listing with reasons for 
screen failure will be provided.  The reasons collected for screen failure are as follows:
1. Unacceptable past medical history/concomitant diagnosis
2. Intercurrent medical event
3. Unacceptable laboratory value(s)
4. Unacceptable test procedure result(s)
5. Did not meet diagnostic/severity criteria
6. Unacceptable use of excluded medications/therapies
7. Subject withdrew consent
8. Unknown
9. Other
In addition, a listing of subjects’ deviations/violations during the study will be provided.


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3.3
Study Treatment and other concomitant medications
Subjects receive BGJ398 at 125 mg once daily, 3 weeks on 1 week off.  A complete treatment 
cycle is 28 days.  There is no break between dosing cycles. For subjects who are unable to 
tolerate the protocol-specified dosing schedule, dose adjustments are permitted in order to 
allow these subjects to continue study treatment.  Protocol section 6.3 provides the details.  
In general, concomitant medications and therapies deemed necessary for the care of the
subject are permitted (see Protocol Section 6.4.1 and 6.4.2), except as specifically prohibited 
(see Protocol Section 6.4.3). All medications, procedures and significant non-drug therapies 
(including physical therapy and blood transfusions) administered within 30 days prior to the 
administration of BGJ398 and through 30 days after the last dose of study treatment will be 
recorded in the corresponding CRF page. 
Detailed summaries of study treatment and other concomitant medications are described in 
Section 5 below.
4
Patient demographics and other baseline characteristics
Demographic data, medical history, disease characteristics and other baseline characteristics 
are collected at the screening visit.
In general, the baseline value will be considered as the last measurement observed prior to the 
first dose of study treatment, and includes assessments taken on the date of the first dose of 
study treatment.
Unless specified otherwise, for continuous data, the mean, standard deviation, median, 25th
and 75th percentiles, minimum, and maximum will be presented.  For categorical data, 
frequencies and percentages will be presented. 
Demographic characteristics
Demographic variables include: 

Age (years), age group (<65, ≥65-<75, ≥75 years)

Sex (Male, Female – able to bear children, premenarche, post menopausal, sterile of 
child bearing age)

Race (Caucasian, Black, Asian, Native American, Pacific Islander, Other)
Medical history
Number and percentage of subjects with relevant and/or current medical history/conditions 
will be summarized by categories of conditions.  For ongoing conditions, grade of condition 
(i.e., 1-4) will also be summarized. Medical history/current medical conditions will be coded 
using Medical Dictionary for Regulatory Activities (MedDRA). The MedDRA version used 
for reporting the study will be specified as a footnote in the tables/listings.
Disease characteristics
Disease characteristics variables include:


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
Gene mutations as detected by local and central labs in pre-defined per-protocol 
mutation categories

Primary tumor type (Sponsor adjudicated)
Note: The tumor type adjudication is made based on the combination of the primary 
site of tumor with the tumor histology/cytology as collected in the CRFs.

Time (in months) from initial diagnosis to the first dose of BGJ398

Time (in months) from date of most recent recurrence/relapse to the first dose of 
BGJ398

Presence of B symptoms (for lymphoma subjects only)

Stage at initial diagnosis

Age of biopsy samples (in months) calculated from date of biopsy sample date to the 
first dose of BGJ398
Other baseline assessments

Vital signs (height, weight, body temperature, respiratory rate, sitting pulse, sitting 
systolic/diastolic blood pressures [SBP/DBP])

12 lead ECG (QTcF, heart rate, PR duration, QT duration, QRS duration)

Cardiac imaging (LVEF)

ECOG performance status

Prior lines of antineoplastic medication therapy

Prior antineoplastic radiotherapy (yes/no)

Prior antineoplastic surgery (yes/no)  
5
Study treatment exposure and other medications
5.1
Study treatment
Duration of BGJ398 treatment (in months) and actual total dose (sum of daily BGJ398
treatment) will be summarized with mean, standard deviation, median, 25th percentile, 75th
percentile, minimum and maximum.  Duration of the treatment is defined as the last dose date 
of BGJ398 minus the first dose date of BGJ398 + 1.  The number and percentage of subjects 
with BGJ exposure for the following categories will be presented as well: day 1 – day 61 (≤ 2
month), day 62 – day 122 (> 2 months - ≤ 4 months), day 123 – day 183 (> 4 months - ≤ 6
months), day 184 – day 244 (> 6 months - ≤ 8 months), day 245 – day 365 (> 8 months - ≤ 12 
months), and ≥ day 366 (> 12 months).
Actual dose intensity and relative dose intensity of BGJ398 will be summarized. Dose 
intensity is defined as the total dose of BGJ398 (mg) divided by duration of BGJ398 (in days).  
Relative dose intensity (in percent) is the actual dose intensity divided by planned dose 
intensity (i.e., 125 mg/day), and expressed in percent.


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In addition, the number and percentage of subjects who had a dose change will be 
summarized with reasons for the change (as per protocol: AE, dosing error, lab test 
abnormality, scheduling conflict, or dispensing error).  
5.2
Prior and concomitant medications/non-drug therapies
Prior and concomitant medications will be coded according to the World Health Organization-
Drug Dictionary (WHO-DD). The WHO-DD version will be specified as a footnote in the 
tables/listings. Prior and concomitant medications are mutually exclusive, as defined below: 

Prior medications are defined as any medications with an end date prior to the first 
dose of BGJ398;

Concomitant medications are defined as any medications taken during the treatment 
period (from the first dose date and on).  Prior medications that are ‘ongoing’ at the 
time of first study treatment or whose end date is after first study treatment will be 
considered concomitant medication.
The number and percentage of subjects with prior medications, concomitant medications that 
started prior to BGJ398 initiation, as well as concomitant medications that started after 
BGJ398 initiation, will be summarized by preferred term.  Non-drug therapies (surgical and 
medical procedures) will be listed for each subject. A standard imputation method will be 
used for partial start/stop date of medications.
6
Efficacy and PRO evaluation
6.1
Clinical Benefit Rate (CBR)
Clinical benefit is determined by investigator assessment for each tumor assessment and is 
defined as responses of CR or PR or SD ≥ 16 weeks.  For subjects with TIO diagnosis without 
measureable/evaluable disease, the following criteria will be used to determine the assessment 
at 16 weeks:

the tumor associated changes of metabolic parameters:  plasma level of FGF23 < or 
=180 RU/mL; and inorganic phosphorous, calcium, and 1-25-dihydroxy vitamin D 
greater than the lower limit of normal (LLN) (20%); and

without requirement of supplementation therapy for at least the preceding cycle of the 
16 week assessment.
Subjects with TIO diagnosis, but having known underlying tumor/disease type, their tumor 
response summaries will be treated same as for subjects with the same underlying tumor type.
In addition to tumor-specific measurements (e.g., radiological assessment of tumor response 
for solid tumors), progressive disease will also be considered when it was indicated either as a 
reason based on clinical assessment for the study treatment discontinuation or as a cause of 
on-treatment death. CR and PR (for solid tumors) require a confirmation that is at least a 
minimum of 4 weeks after the initial observation of response.  Subjects who had confirmed 
CR/PR or SD prior to 16 weeks, but discontinued prior to 16 weeks for reasons other than 


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progressive disease, will have their clinical benefit defined as non-evaluable; subjects who had 
confirmed CR/PR or SD prior to 16 weeks, but progressed prior to 16 weeks, will be
considered as not achieving clinical benefit; subjects who had CR/PR/SD occurred prior to 16 
weeks, but progressed at or after 16 weeks without evidence of CR/PR/SD at or after 16 
weeks, will also be considered as not achieving clinical benefit. CBR will be analyzed by 
comparing achieved CBR with a historical control rate of each tumor type, and if there is at 
least 90% probability that the response rate in a tumor type exceeds the historical rate, then the 
tumor type will be considered a success; it will be considered as promising if the probability is 
between 80% and 90%.  Details for the analyses of CBR are located in Section Error! 
Reference source not found..
6.2
Overall Response Rate (ORR)
Overall response is determined by investigator assessment for each tumor assessment in the 
study.  For subjects with solid tumors (other than lymphoma) the assessment criteria will be 
RECIST 1.1 and will include responses of CR and/or PR; for lymphoma, Cheson criteria will 
be used; for hematologic tumors, other appropriate hematological response criteria will apply.  
The number and percentage of subjects for different categories of overall response (e.g., for 
solid tumors – CR, PR, SD, PD, Not Evaluable) will be provided for solid tumors (non-
lymphoma), lymphoma (if applicable), and each hematological tumor type (if applicable).  
Ninety-five percent (95%) exact confidence intervals (CIs) will be provided for the response
rate(s) (e.g., for solid tumors – CR and/or PR) as well.  For cohorts with at least 10 subjects, 
overall responses will be summarized separately.  Components of tumor assessments (e.g., for 
solid tumors – target lesion response, non-target lesion response, new lesion [yes/no]) will 
also be listed.  In addition, Cancer Antigen-125 (CA-125) (if applicable) in the assessment of 
ovarian cancer response, Prostate-specific Antigen (PSA) (if applicable) in the assessment of 
prostate cancer will be listed.
The above analyses will be performed for the FAS.
6.3
Progression Free Survival (PFS)
PFS is defined as the time from the date of first dose of BGJ398 to the date of the first 
documented disease progression/relapse or death due to any cause within 30 days of the last 
dose, and is calculated as PFS = (date of progression/relapse or death – date of first study 
treatment + 1). Disease progression noted as the reason for discontinuation of treatment will 
be considered as a progression, thus will be considered as an event for PFS.
Subjects who discontinue or complete study treatment without disease progression will be 
censored at last adequate tumor assessment on or before the discontinuation/completion of the 
study. For subjects who are still on study treatment at the time of data cut-off date for the
primary analyses, PFS will be censored at the last adequate tumor assessment before the data 
cut-off date for the analysis of PFS on the primary CSR. For subjects who have no tumor 
assessment post baseline, PFS will be censored at Day 1. The final CSR (i.e., addendum to 
the primary CSR) will utilize additional PFS data obtained from these subjects after the 
primary CSR cut-off date. 


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PFS will be summarized and graphed using the Kaplan-Meier product-limit method1.   The 
estimated median survival time, the corresponding 95% CIs2, and 25th and 75th percentiles will 
be provided.  In addition, survival rate estimates at 1, 2, 3, 4, 5, 6, and 12 months with 95% 
CIs will also be provided.  For cohorts with at least 10 subjects, separate PFS analyses will be 
conducted for each cohort.
The above analyses will be performed for the FAS.
6.4
Overall Survival (OS)
Overall survival, defined as the time from the date of the first dose of BGJ398 to the date of 
death will be analyzed using methods similar to those stated above for PFS.  That is, 25th
percentile, median, and 75th percentile of survival time with corresponding 95% CIs will be 
provided; survival curve and survival rates at 3, 6, 12, 18, and 24 months will also be 
presented.  Subjects who are alive at the time of discontinuation/completion of the study will 
be censored at the last contact date or end of treatment visit date if the subject elected not to 
be followed post study treatment.  If the subject is still being followed in the study as of the 
data cut-off date for the primary CSR, the subject will be censored at the data cut-off date.
For groups with at least 10 subjects, separate OS analyses will be conducted for each group.  
The final CSR (i.e., addendum to the primary CSR) will utilize additional survival data
obtained from these subjects after the primary CSR cut-off date.
The above analyses will be performed for the FAS.
6.5
Clinical Benefit Rate by Gene Mutations
The concordance between gene mutations detected by local and central labs will be 
summarized on protocol pre-defined mutations. A frequency summary will be provided for 
summarizing clinical benefit rate per gene mutation using mutation data provided by the 
central lab (on protocol pre-defined mutations only) as well as by the local lab. The data will 
also be presented in a listing. This analysis will be performed for the FAS.
7
Safety evaluation
7.1
Adverse events
Adverse events data will be collected at each visit.  They will be assessed according to the 
most current version of the Common Toxicity Criteria for Adverse Events (CTCAE).  If 
CTCAE grading does not exist for an adverse event, the severity of mild, moderate, severe, 
and life-threatening, or grades 1-4 were used.  CTCAE grade 5 (death) was not used in this 
study; rather, this information was collected in the End of Treatment/Study or Survival 
Information CRF page.
All AEs will be coded by Preferred Term (PT) and associated primary System Organ Class 
(SOC) using MedDRA (Medical Dictionary for Regulatory Activities, version 16.1 or above).  
The CRF collects the verbatim term for MedDRA coding.


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Summaries of AE will be based on treatment emergent adverse events (TEAEs), which is 
defined as all new or worsening events collected from first study treatment date to last 
treatment date + 30.  Novartis standard partial date imputation methods will be used for 
imputation of partial AE onset/resolution dates.
Analysis of Adverse Events
In general, the subject incidence of TEAEs will be summarized for all tables, unless otherwise 
noted, by SOC and PT.  TEAEs will be shown in alphabetical order for SOCs and in 
decreasing frequencies for PTs within each SOC.  Subject frequencies and percentages will be 
presented.
All summaries will be based on subject counts (i.e., the number and percentage of subjects
who satisfy the criteria), and will depict all AEs and all grade 3/4 AEs at minimum.  Each 
subject will be counted at most once per category.  For subjects with multiple grades for the 
same event, only the worst grade will be counted.
The following summary tables will be provided for the SS:

Summary of TEAEs by SOC, PT, and maximum severity

Summary of serious TEAEs by SOC and PT

Summary of the most common TEAEs (10% or more of subjects) by PT and 
decreasing frequency

Summary of suspected TEAEs by SOC and PT

Summary of TEAEs associated with permanent discontinuation of study drug

Summary of TEAEs associated with dosage adjusted/temporarily interrupted of study 
drug

Summary of adverse events of special interest (see details below in Section 7.1.1)
Individual records of AEs will also be listed alphabetically by the SOC/PT and then in 
chronological order (i.e., by start date of the event as recorded in the CRF).  The listing will
include subject identifier, age, race, gender, and all related event status information (e.g., 
grade, relationship to study medication, etc.).  For the overall AE listing, AEs that are non-
treatment emergent will be included.  Separate AE listings that include only TEAEs (e.g., 
suspected AEs, serious TEAEs) will also be presented.
7.1.1
Specific safety event categories
Specific Safety Event Categories (SEC) consists of adverse events for which there is a 
specific clinical interest in connection with BGJ398 treatment (i.e. where BGJ398 may 
influence a common mechanism of action responsible for triggering them) or adverse events 
which are similar in nature (although not identical). 
Each of these SECs uses MedDRA categories (Standard MedDRA Query [SMQ], Novartis 
MedDRA Query [NMQ], High Level Group Term [HLGT], etc.) to group preferred terms for 
which there is a specific clinical interest. One SEC can be defined by one or several MedDRA 
categories. These SECs are defined in the current version of the BGJ398 Safety profiling 
plan/BGJ398 Case Retrieval Strategy (CRS) document.


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Standard data of analysis for all SECs will be conducted as follows:
- The number and percentage of subjects will be reported by SEC, by MedDRA 
category and by preferred term. 
- All AEs of subjects having at least one AE in that SEC will be listed.
7.2
Deaths
A subject listing of deaths with recorded principal cause of death (if available) will be 
provided.
7.3
Vital signs
Actual raw values and changes from baseline for vital sign results (sitting systolic and 
diastolic blood pressure, sitting pulse, body temperature, respiratory rate, and weight) 
obtained for each scheduled visit will be summarized using descriptive statistics (number of 
subjects, mean, standard deviation, median, 25th percentile, 75th percentile, minimum, and
maximum).  Baseline is defined as the last non-missing measurement prior to the first BGJ398
dose.  Vital signs will also be presented in a listing.  These analyses will be performed using 
the SS.
7.4
Laboratory evaluations
Laboratory assessment will be collected at screening and post baseline (at scheduled visits 
outlined in the protocol or as clinically indicated).  The collected laboratory values will be 
converted into standard units and the severity grade will be calculated using CTCAE v4.03.  
A severity grade of 0 will be assigned when the value is within normal limits. For laboratory
parameters where severity grades are determined both through normal limits and absolute cut-
offs, in the unlikely case that a local laboratory normal range overlaps into the higher (i.e.,
non-zero) CTCAE grade, the laboratory value will still be taken as within normal limits and 
assigned a CTCAE grade of zero.  Baseline is defined as the last non-missing measurement on 
or prior to the first BGJ398 treatment.  On-treatment laboratory evaluations are defined as 
laboratory values collected post baseline and no later than 30 days after the last study 
treatment.
Abnormal on-treatment laboratory values will be summarized using shift tables (from baseline 
to any abnormal laboratory value post baseline) by each laboratory parameter at its worst 
severity grade.  The number and percentage of subjects with abnormal laboratory values will 
be presented by CTCAE grade for each laboratory parameter that is CTCAE gradable.  For 
laboratory parameters 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
will be provided.  Listings
of all laboratory values
(Blood chemistry, 
Hematology/Coagulation parameters separately) in chronologic order will be provided for 
each laboratory parameter.  Laboratory values collected more than 30 days after study 
treatment discontinuation will be flagged in the listing. A separate listing will also be 
provided for notable laboratory abnormalities (i.e., grade 3 or 4 laboratory toxicities post start 
of study treatment).  In addition, other labs such as urinalysis and pregnancy tests will be 
listed separately.  These presentations will be performed for the SS.


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7.5
Other safety evaluations
ECOG performance status will be summarized by visit for SS.  The number and percentage of 
subjects in each score (0-5) will be displayed.  In addition, the shift table of ECOG value from 
baseline to the worst score post baseline will be presented. 
ECG values will be summarized descriptively by visit for the SS.  Change from baseline for 
each collected parameter will also be summarized.  The ECG parameters to be summarized 
include: QTcF, HR, PR, QT, and QRS.
Ophthalmic examinations will also be summarized for the SS. Abnormalities discovered via 
slit lamp, visual fields, fundoscopy examinations, optical coherence tomography, and 
flucorescein angiography will be summarized as a shift table for the worst cases and/or listed. 
In addition, visual acuity and intraocular pressure will be summarized descriptively by visit. 
Visual acuity will be presented using LogMAR (which is derived from Snellen equivalent 
using formula LogMAR = [-Log10 (decimal acuity, i.e., Snellen equivalent)]). These 
summaries will be presented for right and left eyes separately.
Cardiac imaging evaluations will be summarized by visit for the SS. Change from baseline for 
LVEF will also be summarized.  In addition, the incidence of cardiac abnormality will be 
provided. 
Baseline for the safety evaluation is defined as the last non-missing measurement on or prior 
to the first BGJ398 dose.
8
Interim analyses
Scheduled interim analysis is planned for the primary endpoint of clinical benefit rate only as 
required by the Bayesian Hierarchical design. The first interim analysis performs after the first 
30 patients have been dosed for at least 16 weeks or discontinued then every 13 weeks 
thereafter until study enrollment closure. After that, one CBR analysis will be done after 
database lock. Interim analyses may be performed more frequently dependent on enrollment 
rate to avoid over-enrollment in any of the disease groups. At each interim analysis, the 
groups will be evaluated for early futility and early success by comparing posterior quantities 
for the response rate to pre-specified early stopping criteria.
There is no plan for a formal interim analysis of safety or other secondary endpoints for this 
study. However, for publication or other purposes, interim data review of clean data will be 
performed as necessary. At these interim reviews, patient demographics/baseline 
characteristics, the primary and secondary endpoints as applicable, and all important safety 
endpoints will be summarized. No formal report will be issued for these interim data reviews.  
9
Determination of sample size
The sample size was chosen by the usual criteria of obtaining adequate power for the 
alternative hypothesis of interest as shown in the protocol Tables 4.2 of Appendix R (same as 
Table 2 as shown below in Section 10.4.2).  This hypothesis corresponds to a generally 
effective treatment across groups and incorporates variation in treatment effects to reflect the 
realistic expectation that treatment effects may differ by group. In this setting, analytical 


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power calculations are not possible, but the design was simulated to obtain the power of the 
study as shown in Section 10 below.  The sample size shown (minimum of 10 for futility 
stopping, minimum of 15 for early success and maximum of 30 as group cap) achieve 
adequate power for the alternative hypothesis.  The simulations included the expected variable 
accrual by simulating a Poisson process with expected accrual also shown in the protocol 
Appendix R (same as Section 10 below).
Given the exploratory nature of the study design, there is no power consideration for 
secondary objectives.


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10
Bayesian Adaptive Design
10.1
Introduction
This document outlines the adaptive design framework to be used for all trials within 
Novartis’s Modular phase II program designed to link targeted therapy to subjects with
pathway activated tumors.
Although the selected tumor types may vary by trial, this document outlines the design and 
analysis approach based on 8 example tumor cohorts:

Lung NSCL

Bladder

Breast

Colorectal

GIST

HNSCC

Ovarian

Sarcoma
Other tumor types may be considered for trials if 1) 4 or more subjects are enrolled in the 
cohort, and 2) a reasonable estimate of the clinical benefit rate is available.  
The primary endpoint is clinical benefit rate (CBR) in each cohort, with clinical benefit being 
assessed at 16 weeks.  All subjects will receive the experimental treatment for that particular 
trial.
10.1.1
Primary Analysis
We let Yi be the response indicator for the ith subject, and let Rg be the assumed probability of 
response within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability 
of response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
Thus, θg is the group specific logistic regression coefficient for group g. The primary analysis 
is a set of group specific tests that θg>0, meaning that the experimental treatment is better than 
the assumed control rate for that group. Thus, we wish to test the set of hypotheses
H0g : θg≤0
H1g : θg>0
We proceed in a Bayesian fashion, assigning a prior distribution (discussed below) and 
computing the posterior probability of H1g within each group g. If, at the final analysis,
Pr(θg>0 | data) > 0.90


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Then group g will be declared a success (thus, the final analysis produces a separate decision 
for each group). The trial also allows for early stopping of groups, described below.
10.1.2
Trial Logistics
Each trial will enroll all available subjects in all cohorts for 2 years unless a cohort cap is 
reached, or a cohort is stopped early, or the trial is stopped early by Novartis. Each trial will 
enroll no more than 30 evaluable subjects in each cohort. Interim monitoring will be 
conducted starting after the first 30 subjects are enrolled overall (across all cohorts), and 
continuing each 13 weeks thereafter till study enrollment closure. After that, one CBR 
analysis will be done after database lock. At each interim data review, response information 
for the various cohorts will be evaluated to determine the current Pr(θg>0 | data) within each 
cohort, with sufficiently high/low values used to stop the cohort for success/futility. A 
minimum of 10 subjects will be required in a cohort before it may discontinue enrollment for 
futility, and a minimum of 15 subjects are required before discontinuing a cohort for efficacy.
If a cohort stops enrolling early, the remaining cohorts will continue until the end of 2 years or 
until the other cohorts reach their own early stopping criteria. The final analysis will occur 
after the database lock for the primary CSR.
Each trial will enroll subjects in all listed cohorts. In addition, should other cohorts be 
identified throughout the trial, the following mechanism will be used. If another cohort is 
identified, it will not be placed into the statistical analysis unless 3 subjects enroll within the 
cohort (thus, the trial may enroll multiple additional cohorts, but a cohort will only be added 
to the list if at least 3 subjects enroll from that cohort). Thus, it is possible (but not viewed as 
likely) that multiple additional cohorts may be added to the trial if the trial has sufficient 
enrollment in multiple additional cohorts. In addition to sufficient enrollment, the sponsor 
must have a reasonable estimate of the control clinical benefit rate.
Subjects within any cohort which does not reach the minimum enrollment will be excluded 
from the interim and final analyses. As the study continues, early interim data reviews may be 
based on fewer cohorts than later interim data reviews, as the interim data reviews will 
include whatever cohorts have satisfied the criteria at the time of the data review.
10.2
Statistical Modeling
We let Yi be the response indicator for the ith subject, and let Rg be the probability of response 
within a control population and πg = Pr(Yi = 1 | gi = g) be the underlying probability of 
response for group g within the trial. We transform to the logit scale for modeling purposes. 
Let θg be the mean log odds treatment effect, i.e.:
The statistical design borrows information across groups with a hierarchical model. The 
hierarchical model allows dynamic borrowing of information between groups such that more 
borrowing occurs when the groups are consistent and less borrowing occurs when the groups 
differ.  In this way, the model is a compromise between the two alternate extremes of either a 
completely pooled analysis or a separate analysis in each group. We additionally incorporate a 


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clustering mechanism that allows borrowing within clusters but treats clusters separately. This 
minimizes borrowing across groups that are quite different in terms of CBR.
The purpose of such an analysis is to produce higher power or lower type I error in situations 
where we see some commonality (identical effects are not required) among the groups. The 
model will borrow more in situations where the groups appear similar than situations where 
the groups appear different.
10.2.1
Hierarchical Model with Clustering
Our hierarchical approach involves two stages. The goal of both stages is to allow the data to 
drive the amount of borrowing across groups. If the data indicate a large amount of borrowing 
is appropriate (due to similar results), the model will borrow more and thus increase the 
overall power of the trial within each group. In contrast, if the data indicate a small amount of 
borrowing is appropriate (due to dissimilar results) the model will adjust and each group will 
stand more on its own. This “dynamic” borrowing property is distinct from other approaches 
which use a fixed informative prior or apriori assume an amount of borrowing across groups. 
Here the approach includes two stages to identify the appropriate amount of borrowing based 
on the data.
The first stage of model places the groups into distinct clusters. The purpose of this stage is to 
minimize borrowing of information across groups that appear to be quite different. Thus, for 
example, should 2 of the groups appear similar while the others differ significantly, the model 
may place a large probability on two clusters, one containing the two similar groups with the 
other containing the remaining groups. The model incorporates the uncertainty of the data in 
this determination, producing a probability distribution over the possible clusterings. Thus, in 
our example, the model may consider it highly likely that the 2 similar groups are in one 
cluster with the remaining groups in another, but it would also retain lower probabilities on 
the possibility all groups are in one cluster (e.g. we are simply seeing differences in the two 
groups by chance) as well as other possibilities. The complete analysis averages over this 
uncertainty. This clustering approach is implemented through a Dirichlet Process Mixture 
(DPM) model, described in Section 10.5.
At the second stage, we place hierarchical models over the groups within each cluster (thus, 
conditional on the clustering, there is no borrowing of information across clusters, only within 
clusters). The hierarchical model assumes that the 
have an across groups distribution
θg ~ N(μ, τ2)
The across group mean µ and variance τ2 are unknown, and hence have a prior distribution 
which is combined with the data to produce estimates of µ and τ2.
The variance component τ controls the degree of borrowing among groups.  Small values of τ
result in a greater degree of borrowing while large values of τ correspond to less borrowing. 
The parameter τ is estimated using the data, so the observed between group variation is a key 
component of the model behavior. 
Combined, the two stages allow groups with similar results to borrow information between 
them (they will have a high probability of being in the same cluster) while groups with 


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different results with borrow far less information between them (they will have a low 
probability of being in the same cluster).
Details of the two stages may be found in Section 10.5.
10.3
Evaluation of Trial Success and Futility 
Interim monitoring will occur after the first 30 subjects are on the study for 16 weeks (112 
days), then every 13 weeks thereafter till study enrollment closure. At each interim data 
review, the groups will be evaluated for early futility and early success by comparing 
posterior quantities for the response rate to pre-specified early stopping criteria.
10.3.1
Early Futility 
If there is less than 10% probability that the response rate in a group exceeds the historical 
rate Rg, then the group will stop enrollment early for futility.  Formally, enrollment will stop 
early for futility if:
Pr(πg > Rg) < 0.10.
A group is only eligible for early stopping once a minimum of 10 subjects has been evaluated 
for response in that group.
10.3.2
Early Success
If there is at least 95% probability that the response rate in a group exceeds the historical rate, 
then the group will stop enrollment early for success.  Formally, enrollment will stop early for 
success if:
Pr(πg > Rg) > 0.95.
A minimum of 15 subjects will need to be evaluated prior to declaring a group to be 
efficacious.
10.3.3
Final Analysis
In addition, recall the final analysis will occur when both accrual and follow-up are complete 
in all groups, or after the database lock for the primary CSR. If, at the completion of the trial, 
there is at least 90% probability that the response rate in a group exceeds the historical rate, 
then the group will be considered a success. Formally:
Pr(πg > Rg) > 0.90.
10.4
Simulation
We evaluated type I error and power for each of the 8 possible groups under a variety of 
possible “truths” indicating various possible true underlying probabilities within each group.
10.4.1
Assumptions
Accrual – Two scenarios for the assumed two-year expected accrual are investigated: 1) 10 
subjects per group and 2) 5 subjects per group.  Note that these are averages, the actual 
number of available subjects is simulated as a Poisson distribution with the specified mean.  


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Also note that the group cap of 30 applies, and thus if the number of available subjects in a 
group exceeds 30, only the first 30 available subjects in that group will be enrolled in the 
study.
Dropouts – We assume no dropouts for the purpose of this simulation.
Control Rates –Table 1 shows the assumed control clinical benefit rates for each group.
Table 1 – Controlled CBR values used in the simulations
Tumor Type
Assumed Control Rate (Rg)
Lung LSCL
0.45
Bladder
0.47
Breast
0.50
Colorectal
0.38
GIST
0.50
HNSCC
0.45
Ovarian
0.47
Sarcoma
0.40
We consider four possible scenarios, or possible “truths” in the simulation. These consisted of 
a null scenario (where the treatment has no effect for any group), an alternative scenario 
(where the treatment is effective in all groups), a scenario where the treatment was effective in 
two of the groups, and a scenario where the treatment was effective in half of the groups. 
Treatment Rates - The treatment rates for each scenario are shown in the table below. Values 
identical to the control are shown in normal text, while values greater than the assumed 
control rate are shown in bold.
Null
Alternative
Two
Half
Lung LSCL
0.45
0.71
0.45
0.45
Bladder
0.47
0.73
0.47
0.47
Breast
0.50
0.75
0.50
0.50
Colorectal
0.38
0.65
0.38
0.38
GIST
0.50
0.75
0.50
0.75
HNSCC
0.45
0.71
0.45
0.71
Ovarian
0.47
0.73
0.73
0.73
Sarcoma
0.40
0.67
0.67
0.67
Simulation Details – For each scenario we simulated 1000 trials. For each interim within each 
trial, we ran 50,000 MCMC iterations after a 1,000 MCMC iteration burnin.
10.4.2
Results
A total of 8 scenarios were simulated (two accrual scenarios and four possible ‘truths’ for the 
clinical benefit rate).  The probability of group success for each group is provided for each 
scenario in the below two tables.
Table 2 provides the probability of group success for each of the cohort – assuming expected 
accrual of 10 subjects/cohort and 5 subjects/cohort separately


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Table 2 – Probability of Group Success
Two-year expected accrual: 10 subjects/cohort
Group
Null
Alternative
Two
Half
Lung LSCL
0.158
0.915
0.208
0.305
Bladder
0.131
0.918
0.232
0.322
Breast
0.147
0.909
0.233
0.312
Colorectal
0.138
0.921
0.200
0.276
GIST
0.162
0.921
0.233
0.826
HNSCC
0.139
0.906
0.217
0.834
Ovarian
0.145
0.929
0.786
0.829
Sarcoma
0.135
0.939
0.758
0.852
Two-year expected accrual: 5 subjects/cohort
Group
Null
Alternative
Two
Half
Lung LSCL
0.132
0.803
0.204
0.258
Bladder
0.140
0.830
0.196
0.265
Breast
0.160
0.807
0.232
0.261
Colorectal
0.135
0.794
0.194
0.278
GIST
0.155
0.826
0.212
0.688
HNSCC
0.140
0.820
0.190
0.657
Ovarian
0.151
0.819
0.587
0.652
Sarcoma
0.139
0.799
0.579
0.667
Entries in normal text represent groups where the treatment effect is 0 (e.g. the treatment is 
ineffective). Thus, entries in normal text are type I errors. Entries in bold appear where the 
treatment is effective, and thus indicate the power of the design.
Generally, type I error is controlled below 0.20 under the null scenario (the borrowing 
compensates for the multiple interim data reviews) and power is an increasing function of the 
expected sample size (power is higher in the higher accrual situation across treatment rate 
scenarios).  In the alternative scenario there remains decently high probability of success even 
in the lower accruing situations. When fewer groups are effective in truth, the scenarios “half” 
and “two” are harder to discern. Note in any particular trial there should be a mix of high and 
low enrolling groups, thus some groups may enroll closer to 10 subjects while others may 
only enroll five. This would produce a power value somewhere between the two tables.
Power is reduced and type I error is inflated when the truth is a mixture of effective and 
ineffective treatment effects across the groups. Generally power is a function of the sample 
size.
10.5
Modeling Details
Recall at the first stage the groups are clustered according to a Dirichlet Process Mixture 
Model.
The number of clusters is not assumed to be known in advance but will instead be inferred 
from the data using Dirichlet Process Mixtures (DPM). The DPM looks across all the possible 
clusterings of the groups and assigns a probability to each based on the data. The prior 
distribution in a DPM is governed by a parameter α. When α is small, the prior favors large 


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clusters. As α tends to zero, the prior tends to place all its mass on a single cluster containing 
all the groups. As α increases, the prior places more mass on clusterings with a large number 
of clusters. As α becomes very large, the prior places all of its mass on having a separate 
cluster for each group (that is, no borrowing across groups). Thus, by specifying extreme 
values of the prior one could force the groups into one cluster or force the groups to be 
analyzed in separate clusters. Here we choose a moderate version of α=2 (common values 
might be anywhere between 0.5 and 5) and allow the data more control over the clustering. 
The details of the prior are as follows. Let zg represent the cluster to which group g belongs.  
Then zg ~ Categorical(p), where p is the vector such that pk is the probability that a group 
belongs to cluster k and 
. We construct p using a stick-breaking process:
and
βk ~ Beta(1, α).
A large value of α thus removes a very small amount of probability for p, resulting in many 
clusters, while a small value of α tends to produce probabilities near 1 for the first cluster. 
Conditional on the clustering, we fit a hierarchical model which has an across groups 
distribution 
θg ~ N(μ, τ2)
As discussed above, this across group distribution states that within a cluster we expect to see 
some variation in the parameters, with that variation governed by τ. When τ is small, there is 
minimal variation across groups within a cluster, and thus within the cluster the model would 
approach pooling. In contrast, when τ is large we expect large amount of across group 
variation, and thus even though the groups are in the same cluster the θg values may be quite 
different. Apriori we have no way of knowing τ, so we estimate it using the data combined 
with the prior distributions
μ ~ N(0, 1.82)
and
τ2 ~ IG(3,0.5),
where IG(α, β) is the inverse gamma distribution defined by:
When the entire model is implemented (via Markov Chain Monte Carlo) we consider the full 
joint distribution of the clustering combined with the hierarchical model parameters. We 
average over the entire range of the uncertainty in the parameters to produce the posterior 
distribution for each group parameter θg, which is then used to drive the decisions in the 
model.


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11
References
                                                
1 Kaplan EL, Meier P.  Nonparametric Estimation from Incomplete Observations.  J Am Stat 
Assoc. 1958; 53: 457-81.
2 Brookmeyer R., Crowley, J.  A Confidence Interval for the Median Survival Time.  
Biometrics, 1982; 38: 29-41